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Abstract The genome is constantly exposed to DNA damage from endogenous and exogenous sources. Fine modulation of DNA repair, chromatin remodeling, and transcription factors is necessary for protecting genome integrity, but the precise mechanisms are still largely unclear. We found that after ionizing radiation (IR), global trimethylation of histone H3 at lysine 4 (H3K4me3) was decreased at an early (5 min) post-IR phase but increased at an intermediate (180 min) post-IR phase in both human and mouse hematopoietic cells. We demonstrated that PTIP, a component of the MLL histone methyltransferase complex, is required for H3K4me3 upregulation in the intermediate post-IR phase and promotes cell cycle arrest by epigenetically inducing a cell cycle inhibitor, PRDM1. In addition, we found that PTIP expression is specifically downregulated in acute myeloid leukemia patients. These findings collectively suggest that the PTIP-PRDM1 axis plays an essential role in proper DNA damage response and its deregulation contributes to leukemogenesis.

Abstract Odours used by insects for foraging and mating are carried by the air. Insects induce airflows around them by flapping their wings, and the distribution of these airflows may strongly influence odour source localisation. The flightless silkworm moth, Bombyx mori, has been a prominent insect model for olfactory research. However, although there have been numerous studies on antenna morphology and its fluid dynamics, neurophysiology, and localisation algorithms, the airflow manipulation of the B. mori by fanning has not been thoroughly investigated. In this study, we performed computational fluid dynamics (CFD) analyses of flapping B. mori to analyse this mechanism in depth. A three-dimensional simulation using reconstructed wing kinematics was used to investigate the effects of B. mori fanning on locomotion and pheromone capture. The fanning of the B. mori was found to generate an aerodynamic force on the scale of its weight through an aerodynamic mechanism similar to that of flying insects. Our simulations further indicate that the B. mori guides particles from its anterior direction within the ~ 60° horizontally by wing fanning. Hence, if it detects pheromones during fanning, the pheromone can be concluded to originate from the direction the head is pointing. The anisotropy in the sampling volume enables the B. mori to orient to the pheromone plume direction. These results provide new insights into insect behaviour and offer design guidelines for robots for odour source localisation.

Abstract We conducted a large-scale online survey in February 2023 to investigate the public’s perceptions of COVID-19 infection and fatality risks in Japan. We identified two key findings. First, univariate analysis comparing perceived and actual risk suggested overestimation and nonnegligible underestimation of COVID-19 risk. Second, multivariate logistic regression analyses revealed that age, income, education levels, health status, information sources, and experiences related to COVID-19 were associated with risk perceptions. Given that risk perceptions are closely correlated with daily socioeconomic activities and well-being, it is important for policy-makers and public health experts to understand how to communicate COVID-19 risk to the public effectively.

Abstract During the 3 years of the COVID-19 pandemic, Japanese children had to live with strict mitigation measures at school, such as eating school lunches silently and wearing masks during physical exercise classes, even after those mitigation measures have been relaxed worldwide. Excursions and other school events were frequently cancelled, especially in 2020 and 2021. This study conducts a retrospective survey on school experiences to understand how the strict mitigation measures were related to children's mental health and well-being. Results revealed school excursion cancellation to be associated with a higher risk of developing depressive symptoms {odds ratio [OR] 1.543 [95% confidence interval (CI) 1.109–2.148]}, and high cancellation rate of other school events to be associated with dissatisfaction in school experience [OR 1.650 (95% CI 1.222–2.228)]. In the subsample analysis, we found that girls and children with no extracurricular activities tended to exhibit depressive symptoms due to the cancellation of school excursions. Overall, the study demonstrated that persistent strict mitigation measures at schools might be a key factor in understanding children’s mental health and psychological well-being during a long-lasting pandemic.

Abstract This study aimed to confirm urinary protein fragments in relation to the presence of pancreatic ductal adenocarcinoma (PDAC) via a C-terminal proteomics strategy using exploratory and validation cohorts. Urinary fragments were examined by iTRAQ-labelling of tryptic peptides and concentrations of C-terminal fragments were evaluated. Only the urinary CD276 fragment showed a fold change (FC) of > 1.5 with a significant difference of P

Abstract HIV-1 drug resistance genotypic tests have primarily been performed by Sanger sequencing of gene segments encoding different drug target proteins. Since the number of targets has increased with the addition of a new class of antiretroviral drugs, a simple high-throughput system for assessing nucleotide sequences throughout the HIV-1 genome is required. Here, we developed a new solution using nanopore sequencing of viral pangenomes amplified by PCR. Benchmark tests using HIV-1 molecular clones demonstrated an accuracy of up to 99.9%. In addition, validation tests of our protocol in 106 clinical samples demonstrated high concordance of drug resistance and tropism genotypes (92.5% and 98.1%, respectively) between the nanopore sequencing-based results and archived clinical determinations made based on Sanger sequencing data. These results suggest that our new approach will be a powerful solution for the comprehensive survey of HIV-1 drug resistance mutations in clinical settings.

Abstract Menkes disease is an X-linked disorder of copper metabolism caused by mutations in the ATP7A gene, and female carriers are usually asymptomatic. We describe a 7-month-old female patient with severe intellectual disability, epilepsy, and low levels of serum copper and ceruloplasmin. While heterozygous deletion of exons 16 and 17 of the ATP7A gene was detected in the proband, her mother, and her grandmother, only the proband suffered from Menkes disease clinically. Intriguingly, X chromosome inactivation (XCI) analysis demonstrated that the grandmother and the mother showed skewing of XCI toward the allele with the ATP7A deletion and that the proband had extremely skewed XCI toward the normal allele, resulting in exclusive expression of the pathogenic ATP7A mRNA transcripts. Expression bias analysis and recombination mapping of the X chromosome by the combination of whole genome and RNA sequencing demonstrated that meiotic recombination occurred at Xp21-p22 and Xq26-q28. Assuming that a genetic factor on the X chromosome enhanced or suppressed XCI of its allele, the factor must be on either of the two distal regions derived from her grandfather. Although we were unable to fully uncover the molecular mechanism, we concluded that unfavorable switching of skewed XCI caused Menkes disease in the proband.

Abstract Tennis is a popular leisure sport, and studies have indicated that playing tennis regularly provides many health benefits. We aimed to clarify the characteristics of physical activity during beginner-level group tennis lessons and daily physical activity of the participants. Physical activity was measured using an accelerometer sensor device for four weeks, including the 80-min duration tennis lessons held twice a week. Valid data were categorized for tennis and non-tennis days. The mean physical activity intensity during the tennis lesson was 3.37 METs. The mean ratio of short-bout rest periods to the tennis lesson time in 90 and 120 s was 7% and 4%, respectively. The mean physical activity intensity was significantly higher (p

Abstract In patients undergoing hemodialysis, the impact of atrial fibrillation (AF) through cardiac thromboembolism on the development of ischemic stroke may be influenced by the severity of atherosclerosis present. However, there are no large-scale reports confirming whether the severity of atherosclerosis influences the relationship between AF and stroke development in patients requiring hemodialysis. We aimed to investigate the effects of atherosclerotic disease on the relationship between AF and new-onset ischemic stroke. This nationwide longitudinal study based on dialysis facilities across Japan used data collected from the Japanese Renal Data Registry at the end of 2019 and 2020. The exposure was AF at the end of 2019, identified using a resting 12-lead electrocardiography. The primary outcome was the incidence of cerebral infarction (CI) after 1 year. To examine whether the number of atherosclerotic diseases modified the association between AF and the outcome, we estimated the odds ratios (ORs) using a logistic regression model and then assessed the presence of global interaction using Wald test. Following the study criteria, data from 151,350 patients (mean age, 69 years; men, 65.2%; diabetic patients, 48.7%) were included in the final analysis. A total of 9841 patients had AF (prevalence, 6.5%). Between 2019 and 2020, 4967 patients (3.2%) developed ischemic stroke. The adjusted OR of AF for new-onset CI was 1.5, which showed a decreasing trend with an increasing number of atherosclerotic diseases; the interaction was not significant (P = 0.34). While age, diabetes mellitus, smoking, systolic blood pressure, and serum C-reactive protein concentration were positively associated with CI, intradialytic weight gain, body mass index, and serum albumin level were negatively associated. While we demonstrated the association between AF and new-onset CI among Japanese patients on hemodialysis, we failed to demonstrate the evidence that the association was attenuated with an increasing numbers of atherosclerotic complications.

Abstract Optogenetics enables precise regulation of intracellular signaling in target cells. However, the application of optogenetics to induce the differentiation of precursor cells and generate mature cells with specific functions has not yet been fully explored. Here, we focused on osteoclasts, which play an important role in bone remodeling, to develop a novel optogenetics tool, Opto-RANK, which can manipulate intracellular signals involved in osteoclast differentiation and maturation using blue light. We engineered Opto-RANK variants, Opto-RANKc and Opto-RANKm, and generated stable cell lines through retroviral transduction. Differentiation was induced by blue light, and various assays were conducted for functional analysis. Osteoclast precursor cells expressing Opto-RANK differentiated into multinucleated giant cells on light exposure and displayed upregulation of genes normally induced in differentiated osteoclasts. Furthermore, the differentiated cells exhibited bone-resorbing activities, with the possibility of spatial control of the resorption by targeted light illumination. These results suggested that Opto-RANK cells differentiated by light possess the features of osteoclasts, both morphological and functional. Thus, Opto-RANK should be useful for detailed spatiotemporal analysis of intracellular signaling during osteoclast differentiation and the development of new therapies for various bone diseases.

Abstract It has been argued that teaching promotes the accurate transmission of cultural traits and eventually leads to cumulative cultural evolution (CCE). However, previous studies have questioned this argument. In this study, we modified the action sequences model into a network exploring model with reinforcement learning to examine the conditions under which teaching promotes CCE. Our model incorporates a time trade-off between innovation and teaching. Simulations revealed that the positive influence of teaching on CCE depends on task difficulty. When the task was too difficult and advanced, such that it could not be accomplished through individual learning within a limited time, spending more time on teaching—even at the expense of time for innovation—contributed to CCE. On the contrary, the easier the task, the more time was spent on innovation than on teaching, which contributed to the improvement of performance. These findings suggest that teaching becomes more valuable as cultures become more complex. Therefore, humanity must have co-evolved a complex cumulative culture and teaching that supports cultural fidelity.

Abstract In Japan an original pathological classification of IgA nephropathy was used, while Oxford classification of IgA nephropathy was used globally. The Oxford classification requires ≥ 8 glomeruli while the Japanese classification requires ≥ 10. Ninety-nine patients diagnosed with IgA nephropathy were included. To determine the accuracy of histological staging, we calculated the posterior probability using Bayes' theorem and adopted three model of prior distribution. First, the actual staging distribution was reclassified using the beta distribution (reclassified distribution). Second a model with the same distribution (actual distribution) as the actual staging was used. Third, a model assuming that all cases are equally distributed (equal distribution) was used. The median number of collected glomeruli was 12 (8–19). There were 33 cases (33%) wherein the glomerular count was ≤ 9. When only cases with ≥ 10 glomeruli were included, the median posterior probability was 91% (74–99) (actual distribution, 90% [74–98]; equal distribution, 85% [73–96]). Even among the 33 cases with ≤ 9 glomeruli, there were approximately 7 cases in which the posterior probability was ≥ 90% for each model. Using Bayesian probabilistic analysis, it was possible to evaluate the histologic classification of IgA nephropathy, even when the number of obtained glomeruli was ≤ 9.

Abstract This randomized controlled trial aimed to investigate the effects of eight weeks of lactotripeptide (LTP) ingestion, physical activity (PA) intervention, and combined intervention on the fatigue status of middle-aged and older adults. A total of 78 middle-aged and older adults (63 ± 8 years of age) were randomly assigned to four groups: placebo, LTP, placebo with PA intervention (placebo + PA), and LTP with PA intervention (LTP + PA). All participants ingested the placebo or LTP tablets daily (three tablets/day). The placebo + PA and LTP + PA groups participated in a weekly supervised exercise class and were instructed to increase their moderate- to vigorous-intensity PA at home. The visual analog scale, Brief Fatigue Inventory, Profile of Mood States second edition (POMS2), and Beck Depression Inventory second edition (BDI-II) were administered before and after the intervention. No significant interactions or main effects were observed between LTP ingestion and PA intervention on any of the fatigue scales. The main-effect analyses revealed that the PA intervention improved the total mood disturbance score of the POMS2 (F = 5.22, P = 0.03) and BDI-II score (F = 4.81, P = 0.03). After the post hoc paired comparisons, the total mood disturbance and BDI-II scores improved more with the combined intervention than with the PA intervention alone (percentage difference between the effect of combined intervention and PA intervention alone was 3.7% for total mood disturbance score and 13.7% for BDI-II score). The present study suggests that eight weeks of LTP ingestion and PA intervention did not have a significant effect on fatigue status. However, the PA intervention improved mood status and depressive symptoms, and these effects were enhanced by LTP ingestion.

Abstract This study aimed to clarify the relationship between maternal mortality and advanced maternal age in Japan and to provide useful information for future perinatal management. Maternal death rates by age group were investigated for all maternal deaths in Japan for an 11-year period, from 2010 to 2021. Maternal deaths among those aged ≥ 40 years were examined in detail to determine the cause, and the number of deaths by cause was calculated. The causes of onset of the most common causes of death were also investigated. The maternal mortality rates were 0.8 (95% confidence interval [CI] 0.3–4.7) for 40 years of age. More than half of hemorrhagic strokes are associated with hypertension disorder of pregnancy. These facts should be considered by women who become pregnant at an advanced age and by healthcare providers involved in their perinatal care.

Abstract γ-Glutamylcyclotransferase (GGCT) is highly expressed in multiple types of cancer tissues and its knockdown suppresses the growth of cancer cells in vitro and in vivo. Although GGCT is a promising target for cancer therapy, the mechanisms underlying the antitumor effects remain unclear. The knockdown of GGCT inhibited the MEK-ERK pathway, and activated the tumor suppressor retinoblastoma gene (RB) at the protein level in cancer cell lines. c-Met was down-regulated by the knockdown of GGCT in cancer cells and its overexpression attenuated the dephosphorylation of RB and cell cycle arrest induced by the knockdown of GGCT in lung cancer A549 cells. STAT3 is a transcription factor that induces c-Met expression. STAT3 phosphorylation and its nuclear expression level were decreased in GGCT-depleted A549 and prostate cancer PC3 cells. The simultaneous knockdown of AMPK and GGCT restored the down-regulated expression of c-Met, and attenuated the dephosphorylation of STAT3 and MEK-ERK-RB induced by the knockdown of GGCT in PC3 cells. An intraperitoneal injection of a GGCT inhibitor decreased c-Met protein expression in a mouse xenograft model of PC3 cells. These results suggest that the knockdown of GGCT activates the RB protein by inhibiting the STAT3-c-Met-MEK-ERK pathway via AMPK activation.

Abstract Huge coastal boulders are useful to reconstruct the size of past extreme waves such as those associated with tsunamis and storms using inverse-type or forward-type boulder transport models. These models fundamentally require the precise shape of boulders. Traditionally, they have often been assumed to be rectangular or ellipsoidal with three axes measured in the field. However, if the boulder’s shape is complex, this method is unable to represent the actual shape accurately. Therefore, it prevents estimation of the tsunami or storm size reasonably using models. For this reason, boulders have recently been surveyed using 3D scanning techniques such as LiDAR. However, coastal boulders now on land in tropical and subtropical areas such as Japan and Tonga are often covered by deep vegetation, which makes 3D surveys difficult. This report presents new methods to ascertain boulder shapes when they are obscured by vegetation. First, using UAV-type and mobile-type LiDAR, we scanned well-known tsunami boulders in southwestern Japan that had been covered with deep vegetation. Then, we developed a new method to extract only boulders and filter out vegetation from a point cloud. Thereby, we created 3D models of the boulders. We improved the boulder transport model further to assume the 3D boulder model accurately. In addition to coastal boulders, this filtering method is expected to be useful for unveiling any object, such as an archaeological structure, that is hidden in deep vegetation.

Abstract In this paper, we develop a cell tracking method based on persistent homological figure detection technology. We apply our tracking method to 9 different time-series cell images and extract several kinds of cell movements. Being able to analyze various images with a single method allows researchers to systematically understand and compare different tracking data. Persistent homological cell tracking technology’s 9 parameters all have clear meanings. Thus, researchers can decide the parameters not by black box trial-and-error but by the purpose of their analysis. We use model data with ground truth to see our method’s performance. We compare persistent homological figure detection and cell tracking technology with Image-Pro, sure-foreground in watershed method, and cell detection methods in previous studies. We see that there are some cases where Image-Pro’s tracking stops and requires manual plots, while our method does not require manual plots. We show that our technology includes sure-foreground and has more information, and can be applied to different types of data that previously needed different methods. We also show that our technology is powerful as a detection technology by applying the technology to 5 different types of cell images.

Abstract Streptozotocin (STZ), an anti-cancer drug that is primarily used to treat neuroendocrine tumors (NETs) in clinical settings, is incorporated into pancreatic β-cells or proximal tubular epithelial cells through the glucose transporter, GLUT2. However, its cytotoxic effects on kidney cells have been underestimated and the underlying mechanisms remain unclear. We herein demonstrated that DNA damage and subsequent p53 signaling were responsible for the development of STZ-induced tubular epithelial injury. We detected tubular epithelial DNA damage in NET patients treated with STZ. Unbiased transcriptomics of STZ-treated tubular epithelial cells in vitro showed the activation of the p53 signaling pathway. STZ induced DNA damage and activated p53 signaling in vivo in a dose-dependent manner, resulting in reduced membrane transporters. The pharmacological inhibition of p53 and sodium-glucose transporter 2 (SGLT2) mitigated STZ-induced epithelial injury. However, the cytotoxic effects of STZ on pancreatic β-cells were preserved in SGLT2 inhibitor-treated mice. The present results demonstrate the proximal tubular-specific cytotoxicity of STZ and the underlying mechanisms in vivo. Since the cytotoxic effects of STZ against β-cells were not impaired by dapagliflozin, pretreatment with an SGLT2 inhibitor has potential as a preventative remedy for kidney injury in NET patients treated with STZ.

Abstract The Japanese rhinoceros beetle Trypoxylus dichotomus is a giant beetle with distinctive exaggerated horns present on the head and prothoracic regions of the male. T. dichotomus has been used as a research model in various fields such as evolutionary developmental biology, ecology, ethology, biomimetics, and drug discovery. In this study, de novo assembly of 615 Mb, representing 80% of the genome estimated by flow cytometry, was obtained using the 10 × Chromium platform. The scaffold N50 length of the genome assembly was 8.02 Mb, with repetitive elements predicted to comprise 49.5% of the assembly. In total, 23,987 protein-coding genes were predicted in the genome. In addition, de novo assembly of the mitochondrial genome yielded a contig of 20,217 bp. We also analyzed the transcriptome by generating 16 RNA-seq libraries from a variety of tissues of both sexes and developmental stages, which allowed us to identify 13 co-expressed gene modules. We focused on the genes related to horn formation and obtained new insights into the evolution of the gene repertoire and sexual dimorphism as exemplified by the sex-specific splicing pattern of the doublesex gene. This genomic information will be an excellent resource for further functional and evolutionary analyses, including the evolutionary origin and genetic regulation of beetle horns and the molecular mechanisms underlying sexual dimorphism.

Abstract Grapheme-color synesthesia is a consistent and automatic perception of non-physical color when presented with a grapheme. Many previous studies focused on the synesthetic visual system, but other cognitive functions in grapheme-color synesthetes have remained unclear. Therefore, the objective of the present study was to investigate the characteristics of cognitive processing for motor execution and inhibition during Go/No-go paradigms in grapheme-color synesthesia using event-related potentials (ERPs). Six grapheme-color synesthetes and 24 non-synesthetes performed visual, auditory, and somatosensory Go/No-go paradigms. Omission errors were higher in grapheme-color synesthetes than non-synesthetes. Group-trial interactions (i.e., synesthetes–non-synesthetes × Go–No-go) were observed for the latency of the visual N2 component and amplitude of the somatosensory N2 component. Latencies of auditory and somatosensory P3 components were shorter in grapheme-color synesthetes than non-synesthetes. These findings suggest that grapheme-color synesthetes have specific cognitive processing in motor execution and inhibition as well as synesthetic color perception. Our data advance understanding of cognitive processing in grapheme-color synesthesia.

Abstract The importance of a shared decision-making (SDM) approach is widely recognized worldwide. In Japan, hospital accreditation involves the promotion of SDM for patients with end-stage renal disease (ESRD) when considering renal replacement therapy (RRT). This study aimed to clarify the effectiveness and long-term medical benefits of SDM in RRT. Patients with ESRD who underwent dialysis therapy were retrospectively divided into those who visited outpatient clinics specific for ESRD (ESRD clinic) supporting RRT selection with an SDM approach (visited group) and those who did not visit the ESRD clinic (non-visited group). Data of 250 patients (129 in the non-visited group and 121 in the visited group) were analyzed. Mortality was significantly higher in the non-visited group than in the visited group. Not seeing an ESRD specialist was associated with emergent initiation of dialysis and subsequent 1 year mortality. The number of patients who chose peritoneal dialysis as a modality of RRT was significantly larger in the visited group. These findings demonstrate the association between the ESRD clinic, 1 year survival in patients with ESRD after initiating dialysis, and the different RRT modalities. This specific approach in the ESRD clinic may improve the management of patients with ESRD.

Abstract This sentinel node (SN) biopsy trial aimed to assess its effectiveness in identifying predictive factors of micrometastases and to determine whether elective neck dissection is necessary in oral squamous cell carcinoma. This retrospective study included 55 patients from three previous trials, with positive SNs. The relationship between the sizes of the metastatic focus and metastasis in non-sentinel node (NSN) was investigated. Four of the 55 largest metastatic focus were isolated tumor cells, and the remaining 51 were ranged from 0.2 to 15 mm, with a median of 2.6 mm. The difference of prevalence between 46 negative- and 9 positive-NSN was statistically significant with regard to age, long diameter of primary site and number of cases with regional recurrence. In comparing the size of largest metastatic focus dividing the number of positive SN, with metastaic focus range of

Abstract A simplified model to estimate nonlinear turbulent transport only by linear calculations is proposed, where the turbulent heat diffusivity in tokamak ion temperature gradient(ITG) driven turbulence is reproduced for a wide parameter range including near- and far-marginal ITG stability. The optimal nonlinear functional relation(NFR) between the turbulent diffusivity, the turbulence intensity $$\mathcal{T}$$ T , and the zonal-flow intensity $$\mathcal{Z}$$ Z is determined by means of mathematical optimization methods. Then, an extended modeling for $$\mathcal{T}$$ T and $$\mathcal{Z}$$ Z to incorporate the turbulence suppression effects and the temperature gradient dependence is carried out. The simplified transport model is expressed as a modified nonlinear function composed of the linear growth rate and the linear zonal-flow decay time. Good accuracy and wide applicability of the model are demonstrated, where the regression error of $$\sigma _{\textrm{model}} = 0.157$$ σ model = 0.157 indicates improvement by a factor of about 1/4 in comparison to that in the previous works.

Abstract Clinical trials on cancer treatments frequently exclude patients with prior cancer, but more evidence is needed to understand their possible effects on outcomes. This study analyzed the prognostic impact of prior cancer in newly diagnosed non-small cell lung cancer (NSCLC) patients while accounting for various patient and cancer characteristics. Using population-based cancer registry data linked with administrative claims data, this retrospective cohort study examined patients aged 15–84 years diagnosed with NSCLC between 2010 and 2015 in Japan. Cox proportional hazards models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of all-cause mortality in patients with versus without prior cancer. The analysis was stratified according to NSCLC stage and diagnostic time intervals between prior cancers and the index NSCLC. We analyzed 9103 patients (prior cancer: 1416 [15.6%]; no prior cancer: 7687 [84.4%]). Overall, prior cancer had a non-significant mortality HR of 1.07 (95% CI: 0.97–1.17). Furthermore, prior cancer had a significantly higher mortality hazard for diagnostic time intervals of 3 years (HR: 1.23, 95% CI: 1.06–1.43) and 5 years (1.18, 1.04–1.33), but not for longer intervals. However, prior cancer in patients with more advanced NSCLC did not show a higher mortality risk for any diagnostic time interval. Smoking-related prior cancers and prior cancers with poorer prognosis were associated with poorer survival. NSCLC patients with prior cancer do not have an invariably higher risk of mortality, and should be considered for inclusion in clinical trials depending on their cancer stage.