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Abstract Background Depression and anxiety are the most common mental health issues experienced by workers. Although organizational intervention has been extensively evaluated as a primary prevention of depression and anxiety, the corresponding scientific evidence remains limited because of the lack of cluster randomized controlled trials (cRCT) and failure to detect organizational-level effects. Therefore, the present study aims to assess the preventive effects of four types of interventions on depression and anxiety among workers in an open, five-arm, parallel-group cRCT. Methods Overall, 140 worksites and 18,200 nested employees will be recruited from September 2023. The eligible worksites will be randomly assigned to each of the five arms, and programs will be offered for 6–12 months. The five arms are 1) psychoeducation for workers, 2) psychoeducation for supervisors, 3) work environment improvement, 4) physical activity promotion, and 5) active control. The primary outcomes of interest are depression and anxiety. We will also assess psychosocial factors at work, work engagement, health-related quality of life, well-being, economic outcomes, physiological outcomes of health checkups, cortisol levels extracted from fingernails, and indices representing the process and implementation outcomes, including program completion rates. Follow-up surveys will be conducted at 6, 12, and 18 months from baseline, and the primary endpoint is set at the 6-month follow-up. Repeated-measures multi-level mixed modeling will be used to evaluate the effect of each intervention compared with the control. Ethics and dissemination The study protocol was approved by the Research Ethics Committee of the Kitasato University Medical Ethics Organization (C22-082). The results and findings of this study will be published in a scientific journal and disseminated to companies that participate in the study. Trial registration number UMIN000050949.

BackgroundThe diversity of the antigenic T cell receptor (TCR) repertoire clonally expressed on T lymphocytes is a key element of the adaptive immune system protective functions. A decline in diversity in the older adults is associated with health deterioration. This diversity is generated by the rearrangement of TRB genes coding for TCR chains during lymphocyte differentiation in the thymus, but is essentially maintained by peripheral T lymphocytes proliferation for most of life. Deep sequencing of rearranged TRB genes from blood cells allows the monitoring of peripheral T cell repertoire dynamics. We analysed two aspects of rearranged TRB diversity, related to T lymphocyte proliferation and to the distribution of the T cell clone size, in a collection of repertoires obtained from 1 to 74 years-old donors.ResultsOur results show that peripheral T lymphocytes expansion differs according to the recombination status of their TRB loci. Their proliferation rate changes with age, with different patterns in men and women. T cell clone size becomes more heterogeneous with time, and, in adults, is always more even in women. Importantly, a longitudinal analysis of TRB repertoires obtained at ten years intervals from individual men and women confirms the findings of this cross-sectional study.ConclusionsPeripheral T lymphocyte proliferation partially depends on their thymic developmental history. The rate of proliferation of T cells differing in their TRB rearrangement status is different in men and women before the age of 18 years old, but similar thereafter.

Abstract Clonal hematopoiesis (CH) is prevalent in the elderly and associates with hematologic malignancy and cardiovascular disease. Although the risk of developing these diseases increases with radiation doses in atomic-bomb survivors, the causal relationship between radiation exposure and CH is unclear. This study investigated whether radiation exposure induces CH in mice 12–18 months after 3-Gy whole-body irradiation. We found radiation-associated increases in peripheral blood myeloid cells and red blood cell distribution width (RDW). Deep sequencing of bone marrow and non-hematopoietic tissue cells revealed recurrent somatic mutations specifically in the hematopoietic system in 11 of 12 irradiated mice but none in 6 non-irradiated mice. The irradiated mice possessed mutations with variant allele frequencies (VAFs) of > 0.02 on an average of 5.8 per mouse; mutations with VAFs of > 0.1 and/or deletion were prevalent. Examining hematopoietic stem/progenitor cells in two irradiated mice revealed several mutations co-existing in the same clones and multiple independent clones that deliver 60–80% of bone marrow nuclear cells. Our results indicate development of massive CH due to radiation exposure. Moreover, we have characterized mutations in radiation-induced CH.

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.

The influence of the heat treatment on the plastic anisotropy of an Al–Mg–Si sheet was investigated by experiments and crystal plasticity simulations. Uniaxial tension tests were conducted for the naturally aged (T4 temper) and annealed (O temper) Al–Mg–Si sheets. Solute atoms Mg and Si form clusters in the T4 temper sheet, while they bind to form precipitates in the O temper sheet. It is found that the in-plane variation of the R value, texture, and grain size are almost identical for both sheets. By contrast, the anisotropy of the flow stress is clearly dissimilar; the flow stress is the highest in the diagonal direction for the O temper sheet, whereas the flow stress in that direction is nearly lowest for the T4 temper sheet. Thus, the heat treatment alters the anisotropy of the flow stress. The plastic behaviors of the specimens were simulated using the dislocation density-based crystal plasticity model. The influence of the dislocation interaction matrix on the plastic anisotropy was examined. The orientation dependence of the flow stress is found to be sensitive to the interaction matrix. The flow stresses predicted by the interaction matrix determined based on the dislocation dynamic simulation agree with the experimental results for the O temper sheet. Whereas this interaction matrix does not reproduce the flow stress anisotropy for the T4 temper sheet. When the interactions among the dislocations are set to equivalent—i.e., the interaction matrix is filled with unity—the crystal plasticity simulation results in the flow stress anisotropy that is similar to the experimental trend of the T4 temper sheet. In contrast to the flow stress, the R value is insensitive to the interaction matrix, and the predicted R values agree with the experimental results for both specimens.

Reduction of the naive T-cell population represents a deteriorating state in the immune system that occurs with advancing age. In animal model studies, obesity compromises the T-cell immune system as a result of enhanced adipogenesis in primary lymphoid organs and systemic inflammation. In this study, to test the hypothesis that obesity may contribute to the aging of human T-cell immunity, a thousand atomic-bomb survivors were examined for obesity status and ability to produce naive T cells, i.e., T-cell receptor excision circle (TREC) numbers in CD4 and CD8 T cells. The number of TRECs showed a strong positive correlation with naive T cell numbers, and lower TREC numbers were associated with higher age. We found that the TREC number was inversely associated with levels of obesity indicators (BMI, hemoglobin A1c) and serum CRP levels. Development of type-2 diabetes and fatty liver was also associated with lower TREC numbers. This population study suggests that obesity with enhanced inflammation is involved in aging of the human T-cell immune system. Given the fact that obesity increases the risk of numerous age-related diseases, attenuated immune competence is a possible mechanistic link between obesity and disease development among the elderly.

Background: The diversity of the antigenic T cell receptor (TCR) repertoire clonally expressed on T lymphocytes is a key element of the adaptive immune system protective functions. A decline in diversity in the older adults is associated with health deterioration. This diversity is generated by the rearrangement of TRB genes coding for TCR chains during lymphocyte differentiation in the thymus, but is essentially maintained by peripheral T lymphocytes proliferation for most of life. Deep sequencing of rearranged TRB genes from blood cells allows the monitoring of peripheral T cell repertoire dynamics. We analysed two aspects of rearranged TRB diversity, related to T lymphocyte proliferation and to the distribution of the T cell clone size, in a collection of repertoires obtained from 1 to 74 years-old donors. Results: Our results show that peripheral T lymphocytes expansion differs according to the recombination status of their TRB loci. Their proliferation rate changes with age, with different patterns in men and women. T cell clone size becomes more heterogeneous with time, and, in adults, is always more even in women. Importantly, a longitudinal analysis of TRB repertoires obtained at ten years intervals from individual men and women confirms the findings of this cross-sectional study. Conclusions: Peripheral T lymphocyte proliferation partially depends on their thymic developmental history. The rate of proliferation of T cells differing in their TRB rearrangement status is different in men and women before the age of 18 years old, but similar thereafter. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Gastric cancer (GC) is one of the cancers that reveal increased risk of mortality and incidence in atomic bomb survivors. The incidence of gastric cancer in the Life Span Study cohort of the Radiation Effects Research Foundation (RERF) increased with radiation dose (gender-averaged excess relative risk per Gy = 0.28) and remains high more than 65 years after exposure. To assess a possible role of gene-environment interaction, we examined the dose response for gastric cancer incidence based on immunosuppression-related IL-10 genotype, in a cohort study with 200 cancer cases (93 intestinal, 96 diffuse and 11 other types) among 4,690 atomic bomb survivors participating in an immunological substudy. Using a single haplotype block composed of four haplotype-tagging SNPs (comprising the major haplotype allele IL-10-ATTA and the minor haplotype allele IL-10-GGCG, which are categorized by IL-10 polymorphisms at -819A>G and 592T>G, + 1177T>C and +1589A>G), multiplicative and additive models for joint effects of radiation and this IL-10 haplotyping were examined. The IL-10 minor haplotype allele(s) was a risk factor for intestinal type gastric cancer but not for diffuse type gastric cancer. Radiation was not associated with intestinal type gastric cancer. In diffuse type gastric cancer, the haplotype-specific excess relative risk (ERR) for radiation was statistically significant only in the major homozygote category of IL-10 (ERR = 0.46/Gy, P = 0.037), whereas estimated ERR for radiation with the minor IL-10 homozygotes was close to 0 and nonsignificant. Thus, the minor IL-10 haplotype might act to reduce the radiation related risk of diffuse-type gastric cancer. The results suggest that this IL-10 haplotyping might be involved in development of radiation-associated gastric cancer of the diffuse type, and that IL-10 haplotypes may explain individual differences in the radiation-related risk of gastric cancer. [ABSTRACT FROM AUTHOR]

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-32c-Kitlow, a novel innate lymphocyte-committed HPC subpopulation. In contrast, Notch signaling induced CD45RA2Flt-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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]