Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction

In autoimmune arthritis, traditionally classified as a T helper (Th) type 1 disease, the activation of T cells results in bone destruction mediated by osteoclasts, but how T cells enhance osteoclastogenesis despite the anti-osteoclastogenic effect of interferon (IFN)-γ remains to be elucidated. Here, we examine the effect of various Th cell subsets on osteoclastogenesis and identify Th17, a specialized inflammatory subset, as an osteoclastogenic Th cell subset that links T cell activation and bone resorption. The interleukin (IL)-23–IL-17 axis, rather than the IL-12–IFN-γ axis, is critical not only for the onset phase, but also for the bone destruction phase of autoimmune arthritis. Thus, Th17 is a powerful therapeutic target for the bone destruction associated with T cell activation

Co-activation of macrophages and T cells contribute to chronic GVHD in human IL-6 transgenic humanised mouse model.

BACKGROUND: Graft-versus host disease (GVHD) is a complication of stem cell transplantation associated with significant morbidity and mortality. Non-specific immune-suppression, the mainstay of treatment, may result in immune-surveillance dysfunction and disease recurrence. METHODS: We created humanised mice model for chronic GVHD (cGVHD) by injecting cord blood (CB)-derived human CD34 FINDINGS: In cGVHD humanised mice, we found activation of T cells in the spleen, lung, liver, and skin, activation of macrophages in lung and liver, and loss of appendages in skin, obstruction of bronchioles in lung and portal fibrosis in liver recapitulating cGVHD. Acute GVHD humanised mice showed activation of T cells with skewed TCR repertoire without significant macrophage activation. INTERPRETATION: Using humanised mouse models, we demonstrated distinct immune mechanisms contributing acute and chronic GVHD. In cGVHD model, co-activation of human HSPC-derived macrophages and T cells educated in the recipient thymus contributed to delayed onset, multi-organ disease. In acute GVHD model, mature human T cells contained in the graft resulted in rapid disease progression. These humanised mouse models may facilitate future development of new molecular medicine targeting GVHD

Design and baseline characteristics of a prospective cohort study for determinants of osteoporotic fracture in community-dwelling elderly Japanese men: the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study

<p>Abstract</p> <p>Background</p> <p>Osteoporosis and osteoporotic fracture in men are significant public health problems in an aging society. However, information on male osteoporosis remains impressively lacking, especially for Asians. We designed the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study as an ancillary study of a cohort study, the Fujiwara-kyo study, to determine risk factors for osteoporotic fractures in Japanese men.</p> <p>Methods/Design</p> <p><it><b>Design</b></it>: A community-based single-centre prospective cohort study with at least a 5-year follow-up</p> <p><it><b>Subjects</b></it>: All the male participants of the Fujiwara-kyo study who were living in the four cities studied, aged 65 years and older, and able to walk without aid from others.</p> <p><it><b>Primary outcome</b></it>: Incidence of osteoporotic fractures including vertebral and clinical non-vertebral fractures.</p> <p><it><b>Additional outcomes</b></it>: Change in bone mineral density (BMD), change in hip geometry, onset of receiving benefits from Long-term Care Insurance (LCI), health-related quality of life, and mortality.</p> <p><it><b>Baseline measurements</b></it>: BMD at the lumbar spine (LS) and hip (TH), hip geometry, vertebral deformity assessment, bone turnover markers, physical and cognitive performance, various medical and lifestyle factors, and geriatric psychosocial measures confirmed by interviews based on self-administrated questionnaires.</p> <p><it><b>Outcome surveillance</b></it>: Annual mail surveys and a follow-up survey at the fifth year comprising similar items to the baseline study will be used to determine the outcomes. Receipt of benefits from LCI and mortality will be obtained from the city governments.</p> <p><it><b>Current status</b></it>: The baseline study was conducted for 2174 eligible men, and 2012 completed the study and were eligible for follow-up. Prevalence rates of osteoporosis (BMD 2.5 SD or more below the young adult mean (YAM)) and low BMD (BMD 1 SD or more below YAM) in at least one of LS and TH were calculated to be 4.4% and 41.8%, respectively. The proportion of men with low BMD only at TH showed a significant increasing trend with aging (p < 0.0001) while that only at LS showed a decreasing trend (p = 0.0386). The prevalence rate of osteoporosis was underestimated when diagnosed using only BMD at LS. Other baseline measurements were successfully obtained.</p> <p>Discussion</p> <p>FORMEN baseline study was performed as designed and the FORMEN cohort study was successfully launched.</p

Use of anthropometric indicators in screening for undiagnosed vertebral fractures: A cross-sectional analysis of the Fukui Osteoporosis Cohort (FOC) study

<p>Abstract</p> <p>Background</p> <p>Vertebral fractures are the most common type of osteoporotic fracture. Although often asymptomatic, each vertebral fracture increases the risk of additional fractures. Development of a safe and simple screening method is necessary to identify individuals with asymptomatic vertebral fractures.</p> <p>Methods</p> <p>Lateral imaging of the spine by single energy X-ray absorptiometry and vertebral morphometry were conducted in 116 Japanese women (mean age: 69.9 ± 9.3 yr). Vertebral deformities were diagnosed by the McCloskey-Kanis criteria and were used as a proxy for vertebral fractures. We evaluated whether anthropometric parameters including arm span-height difference (AHD), wall-occiput distance (WOD), and rib-pelvis distance (RPD) were related to vertebral deformities. Positive findings were defined for AHD as ≥ 4.0 cm, for WOD as ≥ 5 mm, and for RPD as ≤ two fingerbreadths. Receiver operating characteristics curves analysis was performed, and cut-off values were determined to give maximum difference between sensitivity and false-positive rate. Expected probabilities for vertebral deformities were calculated using logistic regression analysis.</p> <p>Results</p> <p>The mean AHD for those participants with and without vertebral deformities were 7.0 ± 4.1 cm and 4.2 ± 4.2 cm (p < 0.01), respectively. Sensitivity and specificity for use of AHD-positive, WOD-positive and RPD-positive values in predicting vertebral deformities were 0.85 (95% CI: 0.69, 1.01) and 0.52 (95% CI: 0.42, 0.62); 0.70 (95% CI: 0.50, 0.90) and 0.67 (95% CI: 0.57, 0.76); and 0.67 (95% CI: 0.47, 0.87) and 0.59 (95% CI: 0.50, 0.69), respectively. The sensitivity, specificity, and likelihood ratio for a positive result (LR) for use of combined AHD-positive and WOD-positive values were 0.65 (95% CI: 0.44, 0.86), 0.81 (95% CI: 0.73, 0.89), and 3.47 (95% CI: 3.01, 3.99), respectively. The expected probability of vertebral deformities (P) was obtained by the equation; P = 1-(exp [-1.327-0.040 × body weight +1.332 × WOD-positive + 1.623 × AHD-positive])^-1. The sensitivity, specificity and LR for use of a 0.306 cut-off value for probability of vertebral fractures were 0.65 (95% CI: 0.44, 0.86), 0.87 (95% CI: 0.80, 0.93), and 4.82 (95% CI: 4.00, 5.77), respectively.</p> <p>Conclusion</p> <p>Both WOD and AHD effectively predicted vertebral deformities. This screening method could be used in a strategy to prevent additional vertebral fractures, even when X-ray technology is not available.</p

Ferromagnetic Resonance Spectroscopy and Rock Magnetic Characterization of Fossil Coral Skeletons in Ishigaki Islands, Japan

Skeletons of hermatypic corals (e.g., Porites) might have enormous potential as a high-resolution paleomagnetic recorder owing to their rapid and continuous growth over hundreds of years at a rate of up to 2 cm/year, although typical corals show an extremely weak intensity of remanence and low stability. We found that coral tsunami boulders with negligible amounts of calcite on Ishigaki Island show a measurable intensity of remanence; thus, we attempted to characterize the magnetic assemblages in this coral skeleton to determine whether it is of biogenic or detrital magnetite using first-order reversal curve (FORC) measurements, ferromagnetic resonance (FMR) spectroscopy, and petrological observations through field-emission type scanning electron microscope (FE-SEM) with an acid treatment. The FMR derivative spectra of coral skeleton samples represent multiple derivative maxima and extended low-field absorption, indicating the presence of intact biogenic magnetite chains. FORC diagrams represent a &#8220;central ridge&#8222; signature with a vertical spread. These FMR and FORC features indicate the magnetization of these coral skeletons that are mainly created using intact biogenic magnetites and mixtures of grains from collapsed biogenic magnetites, pseudo-single domain grains, and multi-domain grains such as detrital magnetite. FE-SEM observations confirm the presence of a chain-like structure of iron oxides corresponding to the features of biogenic magnetite. Therefore, the magnetic mineral assemblage in coralline boulders from Ishigaki Island consists of dominant biogenic-origin single-domain magnetite and a trace amount of detrital component, indicating that fossil coral skeletons in Ishigaki Island have potential for utilization in paleomagnetic studies

Dating of tsunami boulders from Ishigaki Island, Japan, with a modified viscous remanent magnetization approach

Reworked boulders are expected to acquire a viscous remanent magnetization (VRM) approximately parallel to Earth's modern magnetic field. The magnitude of such a VRM depends on several factors, including the time since reworking and ambient temperature, for which there are well-known theoretical relationships. VRM unblocking temperature can, therefore, be a powerful tool for determining the reworking age of boulders and can be used to assess the timing of geological hazards such as landslides and tsunami events. In this study, VRM unblocking temperatures for twenty-seven samples from four coral tsunami boulders on Ishigaki Island, Japan, are compared with three candidate time–temperature relationships for VRM acquisition. For the Pullaiah nomogram, which is applicable to single-domain magnetite particle assemblages, nineteen samples from four boulders agree well with the expected unblocking temperature derived from previously reported 14C ages. Two samples have low unblocking temperatures and six samples appear to have anomalously high VRM unblocking. The Walton nomogram, which is used for lognormal grain-size distributions, relates acquisition temperatures required to produce equal magnetic (paleo)intensities and cannot explain the high unblocking temperatures; it produces younger predicted ages than the youngest boulder 14C age. We find that an alternative time–temperature relationship, defined by a stretched exponential law, has the potential to yield reworking ages for the anomalous boulders that are consistent with the 14C ages. We suggest that future VRM dating can be undertaken using a combination of the Pullaiah nomogram and the stretched exponential law.This work was supported by the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Scientific Research (C) (No. 18K03755), Grant-in-Aid for Scientific Research (B) (No. 15H02986), Grant-in-Aid for Challenging Exploratory Research (25560173), Grant-in-Aid for Scientific Research (B) (No. 26302007), Grant-in-Aid for JSPS Fellows (No. 15J02522), JSPS Overseas Challenge Program for Young Researchers (20170821), and the Australian Research Council (grant DP160100805). This work was partially supported by the National Institute of Advanced Industrial Science and Technology, Japan

S-Adenosylmethionine Synthesis Is Regulated by Selective N6-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1

Summary: S-adenosylmethionine (SAM) is an important metabolite as a methyl-group donor in DNA and histone methylation, tuning regulation of gene expression. Appropriate intracellular SAM levels must be maintained, because methyltransferase reaction rates can be limited by SAM availability. In response to SAM depletion, MAT2A, which encodes a ubiquitous mammalian methionine adenosyltransferase isozyme, was upregulated through mRNA stabilization. SAM-depletion reduced N6-methyladenosine (m6A) in the 3′ UTR of MAT2A. In vitro reactions using recombinant METTL16 revealed multiple, conserved methylation targets in the 3′ UTR. Knockdown of METTL16 and the m6A reader YTHDC1 abolished SAM-responsive regulation of MAT2A. Mutations of the target adenine sites of METTL16 within the 3′ UTR revealed that these m6As were redundantly required for regulation. MAT2A mRNA methylation by METTL16 is read by YTHDC1, and we suggest that this allows cells to monitor and maintain intracellular SAM levels. : Shima et al. find that MAT2A mRNA is stabilized upon depletion of intracellular S-adenosylmethionine (SAM). This regulation involves m6A modification in the 3′ UTR, the m6A writer METTL16, and the reader YTHDC1. Additionally, the authors show that multiple specific sites in hairpin regions of the 3′ UTR are targeted by METTL16. Keywords: cycloleucine, MAT2A, methionine adenosyltransferase, METTL16, methyladenosine, RNA, RNA degradation, S-adenosylmethionine, untranslated region, YTHDC

Perceptions of older adults and generativity among older citizens in Japan: a descriptive cross-sectional study

Objectives As the population ages worldwide, including in Japan, there is a growing expectation for older adults to remain active participants in society. The act of sharing one’s experiences and knowledge with younger generations through social engagement not only enriches the lives of older individuals, but also holds significant value for our society. In this study, we examined both positive and negative perceptions of older adults and investigated the correlation between these perceptions and generativity among older citizens. Additionally, we evaluated the impact of life satisfaction on these factors. Methods We conducted a survey of 100 older adults in Japan (mean age, 71.68 years) and utilized multiple regression analyses, using positive and negative perceptions of older adults, life satisfaction, and demographic factors as independent variables. The sub-categories of generativity—namely, generative action, concern, and accomplishment—were used as dependent variables. Results Participants who held a more positive perception of older adults demonstrated a higher level of generative actions and concerns. Additionally, participants who reported higher levels of life satisfaction also exhibited more generative actions, concerns, and accomplishments. Conversely, those who held a more negative perception of older adults were found to have higher levels of generative actions. Conclusion Enhancing positive perceptions of older adults among them can boost the sub-categories of generativity. This study, which was conducted from an exploratory perspective, has several limitations, including a potential sampling bias. A more comprehensive examination of the relationship between perceptions of older adults and generativity is anticipated in future research