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In Japan, Lyme disease and tick-borne encephalitis (TBE) are primarily in the northernmost prefecture Hokkaido, where their primary vectors Ixodes ovatus and Ixodes persulcatus are most abundant. Recently, tick surveillance activities have collected both species across Japan, indicating potential expansion of their tick-borne pathogens (TBPs). We built a machine-learning (ML) model using available tick surveillance and environmental data to predict suitable habitat areas for I. ovatus and I. persulcatus and identify potential higher-risk areas of Lyme disease and TBE across Japan. Data on the occurrence and abundance of 11 vector tick species between 1990 and 2023 were extracted from studies identified via systematic literature search in two online databases or provided by local experts for ML development. After multiple iterations and permutations, separate Random Forest ML algorithms for I. ovatus and I. persulcatus were trained via 26 abiotic variables of climate and topography based on the occurrence and abundance respective to each species. Data on 93,289 ticks from 57 sources were extracted, and the ML algorithms' area under the curves were high (> 0.89). Climate-related variables were the strongest predictors (> 90% cumulative model importance) for both I. ovatus and I. persulcatus. High suitability for both species was identified in Hokkaido and cooler, wetter regions in central Honshu, while I. ovatus had a broader ecological niche than I. persulcatus, with moderate suitability in mountainous regions of central Kyushu and surrounding the Tokyo Bay area. Our ML models suggest high suitability areas for Ixodes vectors may be widespread in Japan, indicating expanding potential risks of TBPs.

RNAemia, defined as the presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in blood, is correlated with the severity of coronavirus disease 2019 (COVID-19). Although serum or plasma is commonly used for viral RNA extraction in clinical studies, separating serum in forensic postmortem specimens is often difficult because of postmortem changes. This study aimed to establish an efficient method for extracting SARS-CoV-2 RNA from postmortem whole blood and assess its forensic applicability using actual case specimens. Three extraction methods-acid guanidinium thiocyanate-phenol-chloroform (AGPC), spin column (SC), and magnetic bead method-were compared to identify an efficient approach for SARS-CoV-2 RNA extraction from whole blood. The AGPC method yielded the highest viral RNA recovery, although reproducibility was limited. We therefore evaluated a modified AGPC-SC method, in which whole blood was homogenized, subjected to AGPC phase separation, and purified using the SC method. This procedure maintained the yield of viral RNA while improving reproducibility. The optimized method showed a positive percent agreement of 85.3% and a negative percent agreement of 92.5% for postmortem whole blood samples from COVID-19 cases compared with serum. Whole blood and serum viral RNA loads were strongly correlated (Spearman's ρ = 0.9014), with a small mean difference on Bland-Altman analysis (-0.053 log10 copies/µL). Thus, postmortem whole blood may serve as an alternative to serum, and the AGPC-SC method involving homogenization provides a practical approach for SARS-CoV-2 RNA extraction in forensic practice.

The alkaline hydrogen evolution reaction (HER) remains limited by sluggish water dissociation and slow release of adsorbed hydrogen intermediates. Despite the growing interest in alloy catalysts, the fundamental origin of the alloy-induced HER enhancement remains unclear because of the lack of in situ evidence linking the role of metal species to catalytic dynamics. Here, we synthesize ultrathin Rh-based binary alloy nanosheets (RhM-NS, M = Fe, Co, Cu), whose atomic-layer thickness and homogeneous solid-solution structures provide an ideal platform for mechanistic investigation. Electrochemical measurements reveal that RhFe-NS exhibits substantially higher alkaline HER activity than Rh-NS. In situ XAFS measurements show that both Rh and Fe remain metallic under operating conditions and that Fe does not primarily serve as an oxygen adsorption site, indicating that the enhanced activity does not derive from facilitated OH bond cleavage. In situ Raman spectroscopy reveals an attenuated RhH vibrational feature in RhFe-NS compared with the pronounced RhH band observed in Rh-NS, indicating a substantially lower surface coverage of the adsorbed hydrogen intermediate (Had) and consequently accelerated desorption of Had toward H₂ formation. These results indicate that alloying enhances the alkaline HER by promoting Had desorption rather than accelerating water dissociation. This study provides a clear mechanistic picture of the alloy-induced enhancement of the alkaline HER and establishes a foundation for the rational design of next-generation alloy electrocatalysts.

Ferronickel slag is a by-product generated during the production of raw materials for stainless steel. In recent years, it has attracted attention as a potential alternative to natural resources for use in infrastructure in marine environments; however, concerns remain regarding nickel release and its potential ecological implications. This study evaluated nickel leaching from ferronickel slag-containing concrete by combining species sensitivity distribution (SSD) analysis for marine organisms with leaching experiments. The SSD analysis, based on EC10 values, yielded a hazardous concentration for 5% of species (HC5) of 6.09 µg/L for nickel. Concrete blocks (cylindrical shape; diameter, 10 cm; height, 20 cm; surface area, 0.0785 m2) were prepared with ferronickel slag replacing natural fine aggregate at proportions ranging from 0 to 60%, and leaching tests were conducted using artificial seawater (35 PSU). Nickel concentrations appeared to reach a plateau at higher replacement ratios (45% and 60%). Using the SSD-derived HC5 under a conservative closed-system assumption, which represents a worst-case scenario for screening purposes, the maximum allowable surface area of slag-containing concrete was estimated to range from 0.186 to 1.473 m2/L, suggesting that the potential for adverse ecological effects in marine environments is expected to be limited under conditions where dilution and dispersion occur. This integrated approach provides screening-level insight into the environmentally responsible utilization of ferronickel slag in marine applications.

Realistically simulating natural walking is essential to create an immersive virtual reality experience. However, differences between the virtual reality environment (VRE) and real environment (RE) can alter gait characteristics. Therefore, this study aimed to investigate differences in lower limb spatiotemporal parameters, joint kinematics, and muscle activity between overground walking in a VRE and RE. A total of 13 participants walked at 3 cadences (60 steps per minute [SPM], 80 SPM, and 100 SPM) in the VRE and RE. Motion capture and electromyography were employed to collect the spatiotemporal gait parameters, muscle activities of the right tibialis anterior and medial gastrocnemius muscles, and right lower limb joint angles of the participants. Our results showed that overground walking in the VRE altered several spatiotemporal gait parameters. In addition, the mean electromyography activity of the tibialis anterior and medial gastrocnemius muscles was reduced in the VRE during the initial double- and single-support phases. Most measured biomechanical parameters showed no significant interaction between the walking cadence and environment. This study clarifies biomechanical differences underlying the more cautious gait observed in a VRE, offering practical implications to enhance usability and optimize virtual reality locomotion design.

Preoperative biliary drainage (PBD) is frequently required in patients with pancreatic ductal adenocarcinoma (PDAC) undergoing curative intent surgery presenting with obstructive jaundice. With the increasing use of neoadjuvant therapy (NAT), optimal stent selection-plastic stents (PS) versus metal stents (MS)-remains controversial, particularly regarding long-term outcomes. Here, using the National Clinical Database (NCD), we compared overall survival (OS) and recurrence-free survival (RFS) between MS and PS in patients undergoing ERCP before pancreaticoduodenectomy (PD) for PDAC. We performed a nationwide propensity score-matched cohort study of patients with PDAC who underwent PD after PBD between 2012 and 2017. Patients who underwent ERCP were categorized into two groups: PS and MS. The primary endpoint was OS; secondary endpoints included RFS and surgical outcomes. Secondary analyses included a NAT subgroup and comparison of ERCP with PTBD. Among 6,429 eligible patients, 5,621 underwent ERCP (PS: n=3225; MS: n=451; endoscopic nasobiliary drainage: n=1823; excluded cases: n=122) and 808 underwent PTBD. After matching, with a median follow-up period of 63.1 months (IQR, 38.9-77.6), OS and RFS demonstrated no significant differences between PS and MS, both in the overall ERCP cohort and the NAT subgroup. Postoperative adverse events did not differ significantly between the groups. Secondary analysis showed no survival differences between ERCP and PTBD. In this nationwide real-world propensity score-matched study, no significant differences were observed between PS and MS in long-term oncologic and surgical outcomes after PD for PDAC, including among patients who received NAT. Stent choice should be individualized based on drainage duration and treatment strategy, rather than expectations of long-term prognosis.

The 16th edition of the Japanese Classification of Gastric Carcinoma newly distinguishes pTis from pT1a to improve international translatability with the WHO classification and UICC TNM system. However, the histologic boundary between intraepithelial neoplasia and lamina propria invasion remains difficult in routine practice. We retrospectively evaluated interobserver agreement in 50 gastric endoscopic submucosal dissection lesions randomly selected from 238 lesions previously diagnosed as intramucosal carcinoma under the 15th edition criteria. For each lesion, two representative histologic images were independently reviewed by 10 pathologists, who classified each lesion as pTis or pT1a according to predefined architectural criteria. Complete agreement was obtained in 21 lesions, including 10 unanimously diagnosed as pTis and 11 as pT1a, whereas 29 showed disagreement. Overall agreement was moderate, with a Fleiss' kappa value of 0.483. Discordant lesions involved fused or anastomosing glands, cribriform-like structures, crawling or lateral expansion-like patterns, and invasion mimics related to erosion, artifact, or mucosal remodeling. These findings indicate that distinguishing true invasive architecture from morphologic mimics is central to reproducible implementation of the revised classification.

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Aberrant epigenetic modification is one of the characteristics of the cancer genome. DNA hypermethylation of cytosine-phospho-guanine (CpG) islands, a hallmark of cancer cells, is well-studied and contributes to cancer development by silencing tumor suppressor genes. However, the mechanisms and biological significance of global DNA hypomethylation in cancer are still unclear. Here, using the v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) V600E knock-in mouse models, we demonstrate that endogenous expression of oncogenic BRAFV600E in non-transformed cells promotes global DNA hypomethylation by increasing the levels of ten-eleven translocation 3 (TET3), which converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC). Furthermore, TET3 is targeted for proteasomal degradation by F-box and WD repeat domain containing 7 (FBXW7). BRAFV600E increases TET3 levels by inhibiting glycogen synthase kinase 3β (GSK3β), which phosphorylates TET3 and leads to its ubiquitination and proteasomal degradation. We further found elevated levels of TET3 and 5-hmC in BRAFV600E-induced mouse lung tumors and show that TET3 enhances the ability of BRAFV600E to induce the formation of lung tumors. Notably, endogenous expression of oncogenic Kirsten rat sarcoma virus (KRAS) G12D also promotes global DNA hypomethylation and induces lung tumors through a similar TET3-mediated mechanism. Our findings elucidate one of the unknown mechanisms of global DNA hypomethylation promoted by oncogenic BRAF and KRAS and establish a role for TET3 to promote transformation in cooperation with BRAF and KRAS at an early stage of tumorigenesis.

Copper resistance in the budding yeast Saccharomyces cerevisiae is primarily mediated by the tandemly arrayed metallothionein gene CUP1 . We analyzed eight isogenic strains harboring CUP1 arrays of varying lengths, including those artificially expanded beyond their natural ranges. CUP1 mRNA levels and copper resistance increased with copy number before reaching a plateau. Increased dosage of the transcriptional activator Cup2 partially mitigated the plateaued resistance in strains with intermediate, but not high, copy numbers. These findings indicate that CUP1 confers resistance dose-dependently until transcriptional capacity becomes limiting, suggesting a possible strategy for engineering extreme copper resistance.

Photocaging has emerged as a robust and versatile strategy for achieving precise spatiotemporal control of complex biological processes through UV-induced photoactivation. Here, we sought to develop molecules that allow highly controlled modulation of polymerase function by employing sterically bulky photocaged compounds that are also synthetically accessible. Using the o-nitrobenzyl group, readily amenable to chemical modification, as a fundamental scaffold, we synthesized a series of derivatives with varying sizes and steric profiles, each conjugated at the C4 position of thymidine. These derivatives were incorporated into ODNs, and their duplex-forming abilities were evaluated. In all cases, a decrease in melting temperature was observed. Polymerase primer-extension assays further revealed that, although chain elongation was halted, derivatives bearing aromatic substituents, including the currently used NPOM group, underwent primer degradation due to exonuclease activity. Collectively, these results indicate that the newly synthesized derivatives featuring bulky substituents hold considerable promise for future applications.

Morphogenesis of complex body shapes is reproducible despite the noise inherent in the underlying morphogenetic processes. However, how these morphogenetic processes work together to achieve this reproducibility remains unclear. Here, we ask how this reproducibility is achieved by evolving complex morphologies in a multi-scale, computational model. Each morphology consists of a population of cells on a two-dimensional grid using the Cellular Potts Model framework. Each cell contains a genome that encodes a gene regulatory network, morphogens for cell-cell signalling, and proteins that determine cell behaviours. By repeatedly simulating our model with different initial conditions under selection for shape complexity, we obtained a "zoo" of evolved morphologies. We find that these evolved, complex morphologies are reproducible in a sizeable fraction of simulations, despite no direct selection for reproducibility. We show that high reproducibility is caused by spatially segregating moving cells that "shape" morphologies from stationary cells that "maintain" morphologies during morphogenesis. Strikingly, most highly reproducible morphologies also evolved cell differentiation, where proliferative, moving progenitor cells irreversibly differentiate into non-dividing, stationary differentiated cells at tissue boundaries. These results suggest that cell differentiation observed in natural development plays a fundamental role in morphogenesis in addition to the production of specialised cell types. This previously unrecognised role of cell differentiation has major implications for our understanding of how morphologies are generated and regenerated.

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A challenging working environment discourages younger generations from pursuing a surgical career, contributing to the decline in the number of surgeons in Japan. However, current surgeons' perceptions of their work environment remain poorly understood. To address this gap, an exploratory qualitative study was conducted. Two semi-structured interviews were conducted in person or via email: (i) focusing on surgeons' primary interests, career goals, and perceptions of daily workloads, and (ii) focusing on issues affecting work-family balance. A total of 24 interview transcripts were collected across two interviews (12 participants in Interview 1 and 12 in Interview 2, with partial overlap between them). Participants were recruited through purposive and snowball sampling. Data were analyzed using reflexive thematic analysis to identify patterns across datasets. In the first interview, participants showed diverse priorities: approximately one-quarter prioritized pursuing professional mastery, one-quarter prioritized family life, and a similar proportion reported aiming to balance both domains. Half of the participants accepted multitasking as part of their daily role, although many preferred to limit it to tasks directly related to surgery. More than half expressed frustration with workload disparities and indicated that salaries did not always correspond to actual duties. In the second interview, two-thirds of participants reported strong concern about night and weekend calls while raising children, and several described feelings of guilt regarding limited family time. Many participants described efforts to balance professional achievement with work-family considerations, while highlighting multitasking, workload disparities, and unpredictable after-hours calls as challenges. These findings provide insight into factors affecting surgeons' work experiences in Japan and may inform strategies to support work-life balance and surgical workforce sustainability in similar contexts.

Plastic pollution and its effects on freshwater ecosystem function are increasingly recognized, with recent research demonstrating that even remote environments are impacted. Despite growing evidence, the relative importance of local versus large-scale transport processes in delivering microplastics (MPs) to remote mountain lakes remains poorly understood. Surface water samples were collected by net trawling in 15 remote mountain lakes, eleven in the Patagonia region of Argentina and four in Northern California, United States, and analyzed by stereomicroscopy and Raman spectroscopy for MP concentration, shape, size, color, and polymer composition. MPs (≥ 80 µm) were detected at all sites, with concentrations ranging from 0.23 to 2.79 particles m-3 (mean: 0.75 ± 0.62 particles m-3). No significant difference in MP concentration was observed between regions (U = 12; p = 0.215), despite contrasting socioeconomic contexts. Fibers were predominant (70%), followed by fragments (24%) and films (6%), with most particles measuring less than 1 mm and over half under 0.5 mm. Ten polymer types were identified, with polyester (PES) and polyethylene terephthalate (PET) most common, primarily as fibers. No significant relationships were found between MP concentration and watershed characteristics, proximity to urban areas, public access, or altitude. The consistent MP signature across these remote lakes, regardless of morphology, accessibility, or geographic region, suggests that diffuse, large-scale transport mechanisms such as atmospheric deposition and watershed connectivity are more influential than localized point sources in remote freshwater systems. However, certain lakes near urban infrastructure or camping areas exhibited higher MP concentrations, indicating that localized anthropogenic influences may still contribute in specific cases. These findings underscore the extensive impact of MP pollution and highlight the need for coordinated mitigation strategies at local, regional, and global scales.

While bleeding is an inherent risk of all anticoagulant therapies, individual susceptibility varies considerably. Rivaroxaban, a direct oral anticoagulant widely used for thromboembolic prevention, is associated with substantial interindividual variability in bleeding risk, posing an ongoing clinical challenge. To investigate associations between pharmacogenetic variants in five pharmacokinetic (PK) and nine pharmacodynamic (PD) genes, along with clinical factors, and bleeding outcomes in Thai patients receiving rivaroxaban. A retrospective case-control study was conducted among 91 patients with atrial fibrillation, including 27 who experienced bleeding events. Genetic variants in PK and PD genes were genotyped using the MassARRAY® system, and associations between pharmacogenetic variants, clinical factors, and bleeding risk were evaluated using logistic regression analysis. The CT genotype of ABCB1 rs10276036 (C>T) was associated with an increased risk of bleeding. Clinical factors, including prior bleeding history, were also significantly associated with increased bleeding risk. In addition, allele frequency patterns suggested population-specific genetic variation in this Thai cohort. These findings suggest that genetic and clinical factors may jointly contribute to bleeding susceptibility. Bleeding risk in Thai patients receiving rivaroxaban appeared to be influenced by both pharmacogenetic variants, particularly the ABCB1 rs10276036, and established clinical factors. These findings are exploratory and highlight the potential value of integrating genetic and clinical information for risk stratification, pending validation in larger cohorts. As a retrospective non-interventional study, this work was not registered in a clinical trial registry. Ethical approval was obtained (COA No. 1657/2022). Genetic differences and personal health factors related with the risk of bleeding in Thai patients who take rivaroxaban Why was the study done? Blood thinner agent (rivaroxaban) can increase the risk of bleeding side effects. However, different people have different risks. One possible reason is that people process medicines differently because of their genes. This study wanted to find out whether specific genetic differences, combined with clinical factors (such as kidney function or concurrent medicine use), could help identify which patients are more likely to bleed while taking rivaroxaban. What did the researchers do? The researchers reviewed medical records of 91 Thai patients with atrial fibrillation who were taking rivaroxaban. They compared the genetic profiles of patients who had bleeding events with those who did not. They tested several genes known to influence how the body handles rivaroxaban or responds to it. They applied statistical analyses to evaluate the association between genetic variants and clinical factors with bleeding events. What did the researchers find? They found that the variant in gene involved with drug transport, ABCB1 rs10276036 CT genotype showed the association with increased bleeding risk. Clinical factors also mattered: people with previous bleeding had a higher risk. These genetic associations should be interpreted in conjunction with clinical factors. What do the findings mean? These results suggest that doctors could better consider which patients are likely to bleed on rivaroxaban by looking at both genetic and clinical information. This could eventually help personalize care—choosing the safest dose or even a different medication for high-risk individuals.

Intracranial electroencephalography (iEEG) monitoring presents additional challenges in pediatric patients compared to adults due to factors such as smaller body size, increased surgical invasiveness, difficulty maintaining rest, higher sensitivity to pain, and a greater risk of electrode self-removal. However, long-term outcomes and complications following resective surgery after iEEG evaluation in children remain underreported. This study aimed to evaluate the long-term outcomes and safety of surgical treatment following iEEG monitoring in pediatric patients. We retrospectively analyzed 24 pediatric patients (aged ≤15 years) who underwent surgical treatment after iEEG implantation between 1994 and 2024, with a minimum follow-up period of 5 years. Clinical characteristics, neuroimaging findings, details of iEEG monitoring, surgical procedures, epilepsy etiology, and seizure outcomes were reviewed. The mean age at epilepsy onset was 4.5 years (range, 0.0-12.0), and the mean age at surgery was 10.4 years (range, 1.8-14.0). The average interval from seizure onset to surgery was 6.0 years (range, 0.9-14.8). The iEEG modalities included subdural grid electrodes alone (15 patients), a combination of subdural and depth electrodes (eight patients), and depth electrodes alone (one patient). The mean duration of iEEG monitoring was 9.1 days (range, 2-14). Surgical procedures included focal cortical resection and/or lesionectomy in 18 patients (75.0%), anterior temporal lobectomy in five (20.8%), and multiple subpial transections (MST) alone in one (4.2%). MST, in addition to resection, was performed in six patients (25.0%). Thirteen patients (54.2%) achieved Engel class I or II outcomes. No perioperative complications related to iEEG implantation occurred, and no patients experienced permanent neurological deterioration. Blood transfusion was not required in any case. MEG-MRI (magnetoencephalography-magnetic resonance imaging) concordance was significantly associated with favorable seizure outcomes. This study demonstrated a good seizure outcome rate of 54.2% in pediatric patients who underwent surgical treatment following iEEG monitoring. No major perioperative complications related to iEEG implantation were observed, and no patients experienced permanent neurological deterioration in this cohort. These findings suggest that with careful electrode selection, precise placement and fixation, and vigilant perioperative management, iEEG can be safely performed even in very young children. Furthermore, the presence of MEG clusters concordant with MRI lesions tended to be associated with better seizure outcomes after resection, suggesting a possible role of multimodal imaging data in individualized treatment planning.

Donation after circulatory death (DCD) heart transplantation is associated with higher rates of primary graft dysfunction (PGD) compared to donation after brain death (DBD), yet overall survival appears comparable. Contemporary data suggest comparable survival between groups, yet whether PGD associated with DCD confers a similar degree of mortality risk remains unclear. We performed a propensity score-matched analysis of adult heart transplant recipients in the OPTN registry (September 2023-July 2025). Severe PGD was classified by recovery trajectory: Non-PGD, Transient PGD (no support at 72 hours), and Persistent PGD (support at 72 hours). Multivariate Cox regression, adjusted for PSM covariates and ischemic time, compared 6-month survival and tested whether PGD trajectory effects differed between donor types. After 1:3 matching, 4,633 recipients (DCD 1,262; DBD 3,371) were analyzed. Six-month survival was comparable between DCD and DBD recipients (94.3% vs 93.9%; HR 0.73; 95% CI 0.51-1.05; p&#x202f;=&#x202f;0.09), despite a higher incidence of severe PGD in DCD recipients (11% vs 5.4%; p < 0.001). When stratified by donor type, persistent PGD was associated with increased mortality in both groups, but the point estimate was numerically lower in DCD (HR 7.29; 95% CI 3.91-13.59, p<0.001) than DBD (HR 9.04; 95% CI 6.26-13.08, p<0.001). The interaction test was not statistically significant (p&#x202f;=&#x202f;0.375), though the study had limited statistical power. DCD and DBD heart transplant recipients achieved comparable 6-month survival. PGD recovery trajectory, rather than donor type, was associated with outcomes.