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Soft sedimentary rocks, especially mudstones, disintegrated or crumbled when subjected to cyclic drying and wetting, known as slaking, which was the cause of severe slope failures and ground settlement. Drying/wetting and temperature variation are the influential factors of the slaking. In this study, a conventional oedometer was modified to make a drying/wetting cycle with temperature variation to examine the effects of slaking for four materials with different slaking ratios. Further, one of the four materials (Hamamatsu mudstone), showing higher vertical strains along the drying/wetting cycle, was experimented with under three loading conditions (100 kPa, 200kPa & 500 kPa) and drying/wetting cycles, in which the particle breakage was also measured along the drying/wetting cycles. In addition, a needle penetration test was conducted along the drying/wetting cycles. In the continuous drying/wetting cycles, the occurrence of particle breakage was higher in lower-stress conditions, where the void ratio became a governing factor for the breakage over vertical stress. The needle penetration resistance is dependent on two factors which are density and particle size, and there was a trade-off between them along the drying/wetting cycles. After a couple of drying/wetting cycles, the particle crushing resulted in a noticeable reduction in penetration resistance in lower stress conditions.

Adult neural stem cells (NSCs) in the hippocampal dentate gyrus continuously proliferate and generate new neurons throughout life. Although various functions of organelles are closely related to the regulation of adult neurogenesis, the role of endoplasmic reticulum (ER)-related molecules in this process remains largely unexplored. Here we show that Derlin-1, an ER-associated degradation component, spatiotemporally maintains adult hippocampal neurogenesis through a mechanism distinct from its established role as an ER quality controller. Derlin-1 deficiency in the mouse central nervous system leads to the ectopic localization of newborn neurons and impairs NSC transition from active to quiescent states, resulting in early depletion of hippocampal NSCs. As a result, Derlin-1-deficient mice exhibit phenotypes of increased seizure susceptibility and cognitive dysfunction. Reduced Stat5b expression is responsible for adult neurogenesis defects in Derlin-1-deficient NSCs. Inhibition of histone deacetylase activity effectively induces Stat5b expression and restores abnormal adult neurogenesis, resulting in improved seizure susceptibility and cognitive dysfunction in Derlin-1-deficient mice. Our findings indicate that the Derlin-1-Stat5b axis is indispensable for the homeostasis of adult hippocampal neurogenesis., (© 2024. The Author(s).)

During follow-up of a 60-year-old patient with dilated cardiomyopathy, a Holter electrocardiogram revealed monomorphic premature ventricular complexes (PVCs) accounting for 21-30% of total beats. Oral beta-blockers led to no improvement in PVC burden. The first radiofrequency catheter ablation attempt identified the PVC arising from the left ventricle summit communicating vein (CV) but failed to eliminate the PVC's origin. The second ablation attempt with selective infusions of 100% ethanol into the summit CV resulted in immediate termination of PVCs. The post-ablation course was uneventful. Echocardiography showed an improved ejection fraction, and a repeated Holter electrocardiogram showed no recurrence of PVCs during follow-up. Ethics The RCVEA procedures were approved by the Takagi Hospital Ethical Committee and were performed under an institutional review board-approved protocol. (Kouhou-kai Ethical Committee, ID: KR168) Fundings This work was supported by the Takagi Hospital Cardiology Research Grant. The authors declare no competing interests. Acknowledgements: We thank the patient, the patient's family, and the medical staff of Takagi Hospital for their valuable cooperation and kind support. Consent Written informed consent was obtained from the patient for the publication of this case report and accompanying images.

Heifer growth and milk production in lactating cows may diminish the nutrient supply to the fetus. This study aimed to analyze the characteristics of the nutrient supply to the fetus in primiparous and multiparous cows. We investigated maternal, umbilical cord, and calf blood glucose and amino acid levels, as well as placental development in 28 primiparous (PP) and 30 multiparous (MP) Holstein cows. Although the total cotyledonary weight and surface area showed no significant differences, the MP group exhibited larger individual cotyledons (P < 0.01) and fewer medium-sized cotyledons (P < 0.05). Within the PP group, total cotyledonary weight and surface area positively correlated with blood glucose (r = 0.71-0.77; P < 0.01) and total essential amino acid (r = 0.55; P < 0.05) concentrations in the umbilical veins. However, no significant correlation was observed in the MP group. Blood glucose and amino acid concentrations in the umbilical vein, umbilical artery, and calf were significantly lower in the MP group (P < 0.05), although no difference was observed in the dams between the groups. In conclusion, the nutrient status of primiparous cows can alter fetal nutrient supply. Moreover, multiparous cows have larger individual cotyledons as an adaptive response to increased milk production during pregnancy. However, this adaptive response in multiparous cows did not completely restore nutrient supply to the fetus to the same extent as that in primiparous cows. Therefore, the nutritional management of multiparous cows during pregnancy must be reconsidered.

Knowledge on the distribution and dynamics of glycosylation enzymes in the Golgi is essential for better understanding this modification. Here, using a combination of CRISPR/Cas9 knockin technology and super-resolution microscopy, we show that the Golgi complex is assembled by a number of small 'Golgi units' that have 1-3 μm in diameter. Each Golgi unit contains small domains of glycosylation enzymes which we call 'zones'. The zones of N- and O-glycosylation enzymes are colocalised. However, they are less colocalised with the zones of a glycosaminoglycan synthesizing enzyme. Golgi units change shapes dynamically and the zones of glycosylation enzymes rapidly move near the rim of the unit. Photobleaching analysis indicates that a glycosaminoglycan synthesizing enzyme moves between units. Depletion of giantin dissociates units and prevents the movement of glycosaminoglycan synthesizing enzymes, which leads to insufficient glycosaminoglycan synthesis. Thus, we show the structure-function relationship of the Golgi and its implications in human pathogenesis., (© 2024. The Author(s).)

The sensor response of pressure-sensitive conductive elastomers using polymeric materials can be adjusted by altering the type and quantity of fillers used during manufacturing. Another method involves modifying the surface shape of the elastomer. This study investigates the sensor response by altering the surface shape of an electrode using a readily available pressure-sensitive conductive elastomer. By employing an oxygen-free copper electrode with a flat surface (with surface roughness parameters Ra = 0.064 μm and Rz = 0.564 μm) as a baseline, we examined the sensor system's characteristics. Electrodes were fabricated with triangular wave concavo-convex surfaces, featuring tip angles of 60, 90, and 120°. Improved sensor responses were observed with electrodes having tip angles of 60 and 90°. Additionally, even with varying conductive properties of elastomers, the conductance of the elastomer sensor increased similarly when using an electrode with a 90° tip angle. This study demonstrates the potential for expanding the applications of conductive elastomer sensors, highlighting the noteworthy improvement in sensor response and performance achieved by altering the surface shape of electrodes used with commercially available conductive elastomers.

Introduction: The peptide-based cancer vaccine targeting Wilms' tumor 1 (WT1) is a promising immunotherapeutic strategy for hematological malignancies. It remains unclear how long and to what extent the WT1-specific CD8 + cytotoxic T cell (CTL) persist after WT1 peptide vaccination., Methods: The WT1 peptide vaccine was administered with written consent to a patient with CML in the chronic phase who did not respond well to imatinib, and the patient was followed for 12 years after vaccination. Immune monitoring was performed by specific amplification of WT1-specific CTLs using a mixed lymphocyte peptide culture. T-cell receptors (TCRs) of amplified WT1-specific CTLs were analyzed using next-generation sequencing. This study was approved by the Institutional Review Board of our institution., Result: WT1-specific CTLs, which were initially detected during WT1 peptide vaccination, persisted at a frequency of less than 5 cells per 1,000,000 CD8 + T cells for more than 10 years. TCR repertoire analysis confirmed the diversity of WT1-specific CTLs 11 years after vaccination. CTLs exhibited WT1 peptide-specific cytotoxicity in vitro., Conclusion: The WT1 peptide vaccine induced an immune response that persists for more than 10 years, even after cessation of vaccination in the CML patient., (© 2024. Japanese Society of Hematology.)

Diabetic neuropathy (DN) is a major complication of diabetes mellitus . Chondroitin sulfate (CS) is one of the most important extracellular matrix components and is known to interact with various diffusible factors; however, its role in DN pathology has not been examined. Therefore, we generated CSGalNAc-T1 knockout (T1KO) mice, in which CS levels were reduced. We demonstrated that diabetic T1KO mice were much more resistant to DN than diabetic wild-type (WT) mice. We also found that interactions between pericytes and vascular endothelial cells were more stable in T1KO mice. Among the RNA-seq results, we focused on the transforming growth factor β signaling pathway and found that the phosphorylation of Smad2/3 was less upregulated in T1KO mice than in WT mice under hyperglycemic conditions. Taken together, a reduction in CS level attenuates DN progression, indicating that CS is an important factor in DN pathogenesis., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Dry gene powder is a novel non-viral gene-delivery system, which is inhalable with high gene expression. Previously, we showed that the transfection of p16 INK4a or TP53 by dry gene powder resulted in growth inhibitions of lung cancer and malignant pleural mesothelioma (MPM) in vitro and in vivo. Here, we report that dry gene powder containing p53- expression-plasmid DNA enhanced the therapeutic effects of cisplatin (CDDP) against MPM even in the presence of endogenous p53. Furthermore, our results indicated that the safe transfection with a higher plasmid DNA (pDNA) concentration suppressed MPM growth independently of chemotherapeutic agents. To develop a new therapeutic alternative for MPM patients without safety concerns over "vector doses", our in vitro data provide basic understandings for dry gene powder., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

In patients with immune-mediated acquired aplastic anemia (AA), HLA class I alleles often disappear from the surface of hematopoietic progenitor cells, potentially enabling evasion from cytotoxic T lymphocyte-mediated pathogenesis. Although HLA class I allele loss has been studied in AA patients treated with immunosuppressive therapy (IST), its impact on allogeneic bone marrow transplantation (BMT) has not been thoroughly investigated. The purpose of this study was to evaluate the clinical implications of HLA class I allele loss in patients with acquired AA undergoing allogeneic BMT. The study enrolled acquired AA patients who underwent initial BMT from unrelated donors through the Japan Marrow Donor Program between 1993 and 2011. The presence of HLA class I allele loss due to loss of heterozygosity (HLA-LOH) was assessed using pretransplantation blood DNA and correlated with clinical data obtained from the Japanese Transplant Registry Unified Management Program. A total of 432 patients with acquired AA were included in the study, and HLA-LOH was detected in 20 of the 178 patients (11%) available for analysis. Patients with HLA-LOH typically presented with more severe AA at diagnosis (P = .017) and underwent BMT earlier (P < .0001) compared to those without HLA-LOH. They also showed a slight but significant recovery in platelet count from the time of diagnosis to BMT (P = .00085). However, HLA-LOH status had no significant effect on survival, engraftment, graft failure, chimerism status, graft-versus-host disease, or other complications following BMT, even when the 20 HLA-LOH + patients were compared with the 40 propensity score-matched HLA-LOH - patients. Nevertheless, patients lacking HLA-A*02:06 or HLA-B*40:02, the alleles most frequently lost and associated with a better IST response, showed higher survival rates compared to those lacking other alleles, with estimated 5-year overall survival (OS) rates of 100% and 44%, respectively (P = .0042). In addition, in a specific subset of HLA-LOH - patients showing clinical features similar to HLA-LOH + patients, the HLA-A*02:06 and HLA-B*40:02 allele genotypes correlated with better survival rates compared with other allele genotypes, with estimated 5-year OS rates of 100% and 43%, respectively (P = .0096). However, this genotype correlation did not extend to all patients, suggesting that immunopathogenic mechanisms linked to the loss of certain HLA alleles, rather than the HLA genotypes themselves, influence survival outcomes. The survival benefit associated with the loss of these two alleles was confirmed in a multivariable Cox regression model. The observed correlations between HLA loss and the pretransplantation clinical manifestations and between loss of specific HLA class I alleles and survival outcomes in AA patients may improve patient selection for unrelated BMT and facilitate further investigations into the immune pathophysiology of the disease., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

The mechanisms underlying hepatitis-associated aplastic anaemia (HAAA) that occurs several weeks after the development of acute hepatitis are unknown. A 20-year-old male developed HAAA following living-donor liver transplantation for fulminant hepatitis. The patient's leucocytes lacked HLA-class I due to loss of heterozygosity in the short arm of chromosome 6p (6pLOH). Interestingly, the patient's liver cells resected during the transplantation also exhibited 6pLOH that affected the same HLA haplotype as the leucocytes, suggesting that CD8 + T cells recognizing antigens presented by specific HLA molecules on liver cells may have attacked the haematopoietic stem cells of the patient, leading to the HAAA development., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Lung cancer, primarily non-small-cell lung cancer (NSCLC), is a significant cause of cancer-related mortality worldwide. Cisplatin-based chemotherapy is a standard treatment for NSCLC; however, its effectiveness is often limited due to the development of resistance, leading to NSCLC recurrence. Thus, the identification of effective chemosensitizers for cisplatin is of paramount importance. The integrated stress response (ISR), activated by various cellular stresses and mediated by eIF2α kinases, has been implicated in drug sensitivity. ISR activation globally suppresses protein synthesis while selectively promoting the translation of ATF4 mRNA, which can induce pro-apoptotic proteins such as CHOP, ATF3, and TRIB3. To expedite and economize the development of chemosensitizers for cisplatin treatment in NSCLC, we employed a strategy to screen an FDA-approved drug library for ISR activators. In this study, we identified mifepristone as a potent ISR activator. Mifepristone activated the HRI/eIF2α/ATF4 axis, leading to the induction of pro-apoptotic factors, independent of its known role as a synthetic steroid. Our in vitro and in vivo models demonstrated mifepristone's potential to inhibit NSCLC re-proliferation following cisplatin treatment and tumor growth, respectively, via the ISR-mediated cell death pathway. These findings suggest that mifepristone, as an ISR activator, could enhance the efficacy of cisplatin-based therapy for NSCLC, highlighting the potential of drug repositioning in the search for effective chemosensitizers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Edwardsiella tarda (E. tarda), an intracellular pathogen, has caused severe economic losses in aquaculture. Effective vaccine development for E. tarda prevention is urgently needed. A previous study indicates that cell-mediated immunity (CMI) might play an important role in E. tarda infection. We believe that the involvement of allograft rejection and CMI has now been well documented in mammals and some fishes. However, there is still little research on the application of blood allograft rejection in vaccine development. In the current study, we investigate the immune response and vaccine effect in fish vaccinated with allogeneic blood + formalin-killed cells vaccine (FKC), allogeneic blood + phosphate-buffered saline (PBS), PBS + FKC and PBS + PBS. In the challenge test, the relative percentage survival (RPS) of the allogeneic + FKC, the allogeneic blood + PBS and the PBS + FKC group was 61.46, 35.41, and 30.63 % respectively. The up-regulated expression of Th1-related genes IFN-γ 1, IFN-γ 1rel2, IL-12p35 and T-bet suggests the protection is via CMI induction. Only in the allogeneic + FKC group, gene expression of IFN-γ 1, IL-12p35 and T-bet is significantly higher, indicating synergy between the two substances. Furthermore, among the fish injected with the allogeneic blood cells, syngeneic blood cells and PBS group, only in the fish of the allogenic blood cells injection group, did expression of IFN-γ 1, IFN-γ 2 and IFN-γ rel2 gene expression significantly increased. The results indicate that the rejection was induced by allogeneic components. Thus, our findings might provide essential information and insights into vaccine development in aquaculture., Competing Interests: Declaration of competing interest Takayuki Katagiri reports financial support was provided by Japan Society for the Promotion of Science., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

To select the most suitable chelate for 225 Ac radiolabeling of the anti-FZD10 antibody OTSA101, we directly compared three chelates: S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 2,2',2″-(10-(1-carboxy-4-((4-isothiocyanatobenzyl)amino)-4-oxobutyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetic acid (p-SCN-Bn-DOTAGA), and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid mono-N-hydroxysuccinimide ester (DO3A-NHS-ester). We evaluated the binding affinity of the chelate-conjugated OTSA101 antibodies, as well as the labeling efficiency and stability in murine serum of 225 Ac-labeled OTSA101 as in vitro properties. The biodistribution, intratumoral distribution, absorbed doses, and therapeutic effects of the chelate-conjugated OTSA101 antibodies were assessed in the synovial sarcoma mouse model SYO-1. Of the three conjugates, DOTAGA conjugation had the smallest impact on the binding affinity (p < 0.01). The labeling efficiencies of DOTAGA-OTSA101 and DO3A-OTSA101 were 1.8-fold higher than that of DOTA-OTSA101 (p < 0.01). The stabilities were similar between 225 Ac-labeled DOTA-OTSA101, DOTAGA-OTSA101, and DO3A-OTSA101in serum at 37 and 4°C. The dosimetric analysis based on the biodistribution revealed significantly higher tumor-absorbed doses by 225 Ac-labeled DOTA-OTSA101 and DOTAGA-OTSA101 compared with 225 Ac-DO3A-OTSA101 (p < 0.05). 225 Ac-DOTAGA-OTSA101 exhibited the highest tumor-to-bone marrow ratio, with bone marrow being the dose-limiting tissue. The therapeutic and adverse effects were not significantly different between the three conjugates. Our findings indicate that among the three evaluated chelates, DOTAGA appears to be the most promising chelate to produce 225 Ac-labeled OTSA101 with high binding affinity and high radiochemical yields while providing high absorbed doses to tumors and limited absorbed doses to bone marrow., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Interstitial lung disease/pneumonitis (ILD/pneumonitis) has been identified as a drug-related adverse event of special interest of trastuzumab deruxtecan (T-DXd), but there were a few reports of T-DXd-related ILD/pneumonitis in clinical practice., Methods: Between May 25, 2020 (the launch of T-DXd in Japan) and February 24, 2022, there were 287 physician-reported potential ILD/pneumonitis cases from the Japanese post-marketing all-case surveillance. By February 27, 2022, an independent adjudication committee assessed 138 cases and adjudicated 130 cases as T-DXd-related ILD/pneumonitis. The clinical features and imaging characteristics of these cases were evaluated., Results: The majority of adjudicated T-DXd-related ILD/pneumonitis cases were grade 1 or 2 (100/130, 76.9%). The most common radiological pattern types observed were organizing pneumonia patterns (63.1%), hypersensitivity pneumonitis patterns (16.9%), and diffuse alveolar damage (DAD) patterns (14.6%). Eleven cases (8.5%) from 130 resulted in death; the majority of these (8/11, 72.7%) had DAD patterns. The overall proportion of recovery (including the outcomes of recovered, recovered with sequelae, and recovering) was 76.9%, and the median time to recovery was 83.5 days (interquartile range: 42.25-143.75 days). Most cases (59/71, 83.1%) that were treated with corticosteroids were considered responsive to treatment., Conclusions: This is the first report to evaluate T-DXd-related ILD/pneumonitis cases in clinical practice. Our findings are consistent with previous reports and suggest that patients with DAD patterns have poor outcomes. Evaluation of a larger real-world dataset may further identify predictors of clinical outcome., (© 2023. The Author(s).)

Donor T cell activation, proliferation, differentiation, and migration are the major steps involved in graft-versus-host disease (GVHD) development following bone marrow transplantation. Chondroitin sulfate (CS) proteoglycan is a major component of the extracellular matrix and causes immune modulation by interacting with cell growth factors and inducing cell adhesion. However, its precise effects on immune function are unclear than those of other proteoglycan families. Thus, we investigated the significance of CS within donor cells in acute GVHD development utilizing CSGalNAc T1-knockout (T1KO) mice. To determine the effects of T1KO, the mice underwent allogenic bone marrow transplantation from major histocompatibility complex-mismatched donors. While transplantation resulted in hepatic GVHD with inflammatory cell infiltration of both CD4 + and CD8 + effector memory T cells, transplantation in T1KO-donors showed milder cell infiltration and improved survival with fewer splenic effector T cells. In vitro T-cell analyses showed that the ratio of effector memory T cells was significantly lower via phorbol myristate acetate/ionomycin stimulation. Moreover, quantitative PCR analyses showed significantly less production of inflammatory cytokines, such as IFN-γ and CCL-2, in splenocytes of T1KO mice. These results suggest that reduction of CS in donor blood cells may suppress the severity of acute GVHD after hematopoietic stem cell transplantation., (© 2023. Springer Nature Limited.)

Endochondral ossification contributes to longitudinal skeletal growth. Osteoblasts, which are bone-forming cells, appear close to terminally differentiated hypertrophic chondrocytes during endochondral ossification. We established mice with conditional knockout (cKO) of Smad4, an essential co-activator for transforming growth factor β family signaling. The mice showed a marked increase in bone volume in the metaphysis as a result of increased bone formation by osteoblasts, in which β-catenin, an effector of canonical Wnt signaling, accumulated. We identified Wnt7b as a factor with increased expression in growth plate cartilage in Smad4 cKO mice. Wnt7b mRNA was expressed in differentiated chondrocytes and suppressed by BMP4 stimulation. Ablation of Wnt7b blunted the increase in bone in adult Smad4 cKO mice and reduced skeletal growth in juvenile mice. Overall, we conclude that Wnt7b is a crucial factor secreted from hypertrophic chondrocytes to initiate endochondral ossification. These results suggest that Smad4-dependent BMP signaling regulates the Wnt7b-β-catenin axis during endochondral ossification., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2023. Published by The Company of Biologists Ltd.)

Background: This study aimed to provide an overview of ultrasonographic cartilage evaluation in patients with rheumatoid arthritis (RA) and identify research gaps in the utilization of cartilage evaluation., Methods: The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. A systematic literature search of the PubMed, Embase, and Cochrane Library databases was conducted for articles published up to July 2022 using the search term variations of "cartilage," "ultrasonography," and "rheumatoid arthritis." Studies that included patients with RA who underwent cartilage evaluation by ultrasonography were selected. Articles published in languages other than English and about juvenile idiopathic arthritis were excluded., Results: Twenty-nine articles were identified. Most were cross-sectional studies (86%), mainly involving the metacarpophalangeal (55%) and knee (34%) joints. Assessments were performed using quantitative, binary, and semi-quantitative methods in 15, 10, and 15 studies, respectively. Reliability assessments were conducted in 10 studies, which showed feasible reliability but were limited to the finger joints. The validity assessment was validated in one study each that compared cartilage thickness measurements with cadaveric specimens and histological and semi-quantitative methods with surgical specimens, respectively. Comparisons with conventional radiography were also performed in six studies, which showed significant correlations. However, there was heterogeneity in the examination and assessment methods, and no adequate longitudinal evaluation was conducted., Conclusion: This review highlights the need for further research and validation of ultrasonographic cartilage assessment in patients with RA., (© 2023. The Author(s).)

This study aimed to assess recurrence-free survival (RFS) rates and recurrence-related factors of patients who received adjuvant therapy (AT) with radioactive iodine (RAI) for differentiated thyroid cancer (DTC) following thyroidectomy. We evaluated 284 patients who underwent AT between January 2011 and July 2020 at our hospital. Recurrence was defined as visible recurrent lesions on image analysis or need for repeat surgery with pathologically confirmed recurrent lesions. RFS rate and prognostic factors were statistically evaluated. The median observation period was 30.2 months (range, 5.7-294 months). Overall, 192 patients were female and 92 were male, and the median age was 54 years (range, 9-85 years). Initial assessment revealed 39 recurrence cases. The 3-year RFS rate was 85.8% (95% confidence interval: 81.1-90.9%). Univariate analysis revealed that histology (except for papillary carcinoma), Tg level > 4 ng/dL before AT, and AT result significantly exacerbated the RFS rate. In multivariate analysis, histology and AT result were also important contributors to the worsening RFS rate. Results of AT can be determined relatively early and are important in predicting future recurrence in patients with DTC. Increasing the success rate of AT may lead to an improved prognosis., (© 2023. The Author(s).)

Herbarium collections shape our understanding of Earth's flora and are crucial for addressing global change issues. Their formation, however, is not free from sociopolitical issues of immediate relevance. Despite increasing efforts addressing issues of representation and colonialism in natural history collections, herbaria have received comparatively less attention. While it has been noted that the majority of plant specimens are housed in the Global North, the extent and magnitude of this disparity have not been quantified. Here we examine the colonial legacy of botanical collections, analysing 85,621,930 specimen records and assessing survey responses from 92 herbarium collections across 39 countries. We find an inverse relationship between where plant diversity exists in nature and where it is housed in herbaria. Such disparities persist across physical and digital realms despite overt colonialism ending over half a century ago. We emphasize the need for acknowledging the colonial history of herbarium collections and implementing a more equitable global paradigm for their collection, curation and use., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

We studied the pathophysiology of aplastic anaemia (AA) in six different pairs of relatives without a family history of hematologic disorders or congenital AA. Five and four of the six pairs shared the HLA-DRB1*15:01 and B*40:02 alleles, respectively. Glycosylphosphatidylinositol-anchored protein-deficient blood cells were detected in eight of the 10 patients evaluated. In a mother-daughter pair from one family, flow cytometry detected leukocytes lacking HLA-A2 due to loss of heterogeneity in chromosome 6p. Whole-exome sequencing of the family pair revealed a missense mutation in MYSM1 . These results suggest that genetic inheritance of immune traits might underlie familial AA in some patients., Competing Interests: The authors declare no conflict of interest associated with this study. The funders had no role in the study design, data collection and analysis, decision to publish or manuscript preparation., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

CREB/ATF transcription factor OASIS/CREB3L1 is upregulated in long-term-cultured astrocytes undergoing cell-cycle arrest due to loss of DNA integrity by repeated replication. However, the roles of OASIS in the cell cycle remain unexplored. We find that OASIS arrests the cell cycle at G 2 /M phase after DNA damage via direct induction of p21. Cell-cycle arrest by OASIS is dominant in astrocytes and osteoblasts, but not in fibroblasts, which are dependent on p53. In a brain injury model, Oasis -/- reactive astrocytes surrounding the lesion core show sustained growth and inhibition of cell-cycle arrest, resulting in prolonged gliosis. We find that some glioma patients exhibit low expression of OASIS due to high methylation of its promoter. Specific removal of this hypermethylation in glioblastomas transplanted into nude mice by epigenomic engineering suppresses the tumorigenesis. These findings suggest OASIS as a critical cell-cycle inhibitor with potential to act as a tumor suppressor., Competing Interests: Declaration of interests All authors declare no competing financial interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mutations in activin receptor-like kinase 2 (ALK2) can cause the pathological osteogenic signaling seen in some patients with fibrodysplasia ossificans progressiva and other conditions such as diffuse intrinsic pontine glioma. Here, we report that intracellular domain of wild-type ALK2 readily dimerizes in response to BMP7 binding to drive osteogenic signaling. This osteogenic signaling is pathologically triggered by heterotetramers of type II receptor kinases and ALK2 mutant forms, which form intracellular domain dimers in response to activin A binding. We develop a blocking monoclonal antibody, Rm0443, that can suppress ALK2 signaling. We solve the crystal structure of the ALK2 extracellular domain complex with a Fab fragment of Rm0443 and show that Rm0443 induces dimerization of ALK2 extracellular domains in a back-to-back orientation on the cell membrane by binding the residues H64 and F63 on opposite faces of the ligand-binding site. Rm0443 could prevent heterotopic ossification in a mouse model of fibrodysplasia ossificans progressiva that carries the human R206H pathogenic mutant., (© 2023. The Author(s).)

Background: Synovial sarcoma (SS) has limited treatment options and there is an urgent need to develop a novel therapeutic strategy to treat SS. Blue light (BL) has been shown to inhibit the growth of several cancer cells. However, the efficacy of BL in soft tissue sarcomas such as SS has not been demonstrated, and the detailed mechanism underlying the antitumor activity of BL is not fully understood. In this study, we investigated the antitumor effect of BL on SS., Methods: Human SS cell lines were continuously irradiated with BL using light-emitting diodes (LEDs) in an incubator for in vitro analysis. The chicken chorioallantoic membrane (CAM) tumors and xenograft tumors in mice were subjected to daily BL irradiation with LEDs., Results: BL caused growth inhibition of SS cells and histological changes in CAM tumors. BL also suppressed the migration and invasion abilities of SS cells. The type of cell death in SS cells was revealed to be apoptosis. Furthermore, BL induced excessive production of reactive oxygen species (ROS) in mitochondria, resulting in oxidative stress and malfunctioned mitochondria. Reducing the production of ROS using N-acetylcysteine (NAC), a ROS scavenger, attenuated the inhibitory effect of BL on SS cells and mitochondrial dysfunction. In addition, BL induced autophagy, which was suppressed by the administration of NAC. The autophagy inhibitor of 3-methyladenine and small interfering RNA against the autophagy marker light chain 3B facilitated apoptotic cell death. Moreover, BL suppressed tumor growth in a mouse xenograft model., Conclusion: Taken together, our results revealed that BL induced apoptosis via the ROS-mitochondrial signaling pathway, and autophagy was activated in response to the production of ROS, which protected SS cells from apoptosis. Therefore, BL is a promising candidate for the development of an antitumor therapeutic strategy targeting SS., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The present retrospective study aimed to examine the real-world data regarding time-dependent changes in the age distribution of patients with coronavirus disease 2019 (COVID-19) as well as the severity and infectivity in a regional core hospital in Japan. Patients with COVID-19 who visited the fever outpatient branch in Takagi Hospital during phase I (May 1 to December 31, 2021), and during phase II (January 1 to April 30, 2022) were evaluated. The age distribution of outpatients and the characteristics of inpatients aged > 75 years were compared between phases I and II. The age distribution of outpatients shifted from the older generation in phase I to the younger generation in phase II (p < 0.01). Disease severity might be reduced in a time-dependent manner with a decrease in the hospitalization rate (phase I: 145/368 (39.4%); phase II: 104/1496 (7.0%); p < 0.01) and mortality rate (phase I: 10/368 (2.7%); phase II: 7/1496 (0.5%); p < 0.01). The number of patients increased in phase II (374.0/month) compared to that in phase I (36.8/month). Regarding the older inpatients, the disease severity of COVID-19 and hospitalization days were reduced in phase II compared to those in phase I (p < 0.01, each). In conclusion, the present study suggests a change in the age distribution of patients with COVID-19, a decrease in toxicity, and an increase in infectivity of severe acute respiratory syndrome coronavirus 2 in a time-dependent manner.

The aldehyde degrading function of the ALDH2 enzyme is impaired by Glu504Lys polymorphisms (rs671, termed A allele), which causes alcohol flushing in east Asians, and elevates the risk of esophageal cancer among habitual drinkers. Recent studies suggested that the ALDH2 variant may lead to higher levels of DNA damage caused by endogenously generated aldehydes. This can be a threat to genome stability and/or cell viability in a synthetic manner in DNA repair-defective settings such as Fanconi anemia (FA). FA is an inherited bone marrow failure syndrome caused by defects in any one of so far identified 22 FANC genes including hereditary breast and ovarian cancer (HBOC) genes BRCA1 and BRCA2. We have previously reported that the progression of FA phenotypes is accelerated with the ALDH2 rs671 genotype. Individuals with HBOC are heterozygously mutated in either BRCA1 or BRCA2, and the cancer-initiating cells in these patients usually undergo loss of the wild-type BRCA1/2 allele, leading to homologous recombination defects. Therefore, we hypothesized that the ALDH2 genotypes may impact breast cancer development in BRCA1/2 mutant carriers. We genotyped ALDH2 in 103 HBOC patients recruited from multiple cancer centers in Japan. However, we were not able to detect any significant differences in clinical stages, histopathological classification, or age at clinical diagnosis across the ALDH2 genotypes. Unlike the effects in hematopoietic cells of FA, our current data suggest that there is no impact of the loss of ALDH2 function in cancer initiation and development in breast epithelium of HBOC patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

We demonstrate a newly designed, to the best of our knowledge, hollow optical fiber coupler for a mid-infrared (IR) laser heterodyne spectrometer that mixes a targeted light source with local oscillator (LO) light. The hollow fiber achieves a high transmission efficiency ∼80-90 % / m , not only for a coherent laser source but also for an incoherent blackbody source. The branching characteristics of the hollow optical fiber coupler are found to be strongly dependent on the curvature and length of the input port fiber, indicating that the branching ratio could be designed independently for each input port. Our laboratory measurements demonstrate that the branching ratio and transmittance of the coupler can be varied by coupling a flexible fiber to the input side owing to the excitation of higher-order modes. Using the hollow optical fiber coupler, a high-resolution emission spectrum of the quantum cascade laser at 10.3 µm for our C O 2 laser-based heterodyne spectrometer is successfully achieved. Using a C O 2 laser with a hollow fiber and a blackbody as a direct input signal in free space, we obtain the sensitivity performance of IR laser heterodyne spectrometer as 2000-3000 K of the system noise temperature. This suggests that the transmission of a coherent LO laser through a hollow optical fiber has almost the same sensitivity for the IR heterodyne detection as that without a fiber.

DNA methyltransferases (DNMTs) catalyze methylation at the C5 position of cytosine with S-adenosyl-L-methionine. Methylation regulates gene expression, serving a variety of physiological and pathophysiological roles. The chemical mechanisms regulating DNMT enzymatic activity, however, are not fully elucidated. Here, we show that protein S-nitrosylation of a cysteine residue in DNMT3B attenuates DNMT3B enzymatic activity and consequent aberrant upregulation of gene expression. These genes include Cyclin D2 (Ccnd2), which is required for neoplastic cell proliferation in some tumor types. In cell-based and in vivo cancer models, only DNMT3B enzymatic activity, and not DNMT1 or DNMT3A, affects Ccnd2 expression. Using structure-based virtual screening, we discovered chemical compounds that specifically inhibit S-nitrosylation without directly affecting DNMT3B enzymatic activity. The lead compound, designated DBIC, inhibits S-nitrosylation of DNMT3B at low concentrations (IC 50  ≤ 100 nM). Treatment with DBIC prevents nitric oxide (NO)-induced conversion of human colonic adenoma to adenocarcinoma in vitro. Additionally, in vivo treatment with DBIC strongly attenuates tumor development in a mouse model of carcinogenesis triggered by inflammation-induced generation of NO. Our results demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by NO, and DBIC protects against tumor formation by preventing aberrant S-nitrosylation of DNMT3B., (© 2023. The Author(s).)

Chemoradiotherapy followed by consolidation durvalumab (CCRT+D) improves survival in patients with stage III non-small-cell lung cancer (NSCLC). We compared recurrence patterns and survival in the CCRT+D and CCRT cohorts. We conducted a multicenter, retrospective study in Japan. Patients who received CCRT for stage III NSCLC were included in this study. Of 178 eligible patients, 136 were in the CCRT+D and 42 were in the CCRT cohorts. Locoregional recurrence (LR), LR plus distant metastases (DM), and DM were observed in 20.6%, 8.8%, 27.9% of the CCRT+D, and 26.2%, 16.7% and 33.3% of the CCRT cohorts, respectively. In-field recurrence was the most common LR pattern in both cohorts. Squamous cell carcinoma and PD-L1 expression < 1%, and female sex and EGFR mutations were significantly associated with an increased risk of LR and DM. In patients with any risk factors for LR, the incidence of LR was similar in the CCRT+D and CCRT (39.5% vs 45.5%). The 24 month progression-free survival (PFS) and overall survival (OS) were 40.3% and 69.4% in the CCRT+D and 24.7% and 61.0% in the CCRT cohorts, respectively. Poor performance status and no consolidation durvalumab were significantly associated with shorter PFS. There was a significant difference in PFS between the CCRT+D and CCRT in the propensity score-matched cohort (HR = 0.51, P = 0.005). In conclusion, consolidation durvalumab decreased both LR and DM, and significantly improved PFS. However, in-field recurrence was still a major problem, as well as DM., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Percutaneous coronary intervention (PCI) requires multiple staff members, including interventional cardiologists, with the physical burden of heavy protective measures to minimize radiation exposure. Here, we aimed to investigate the safety of task sharing with clinical engineers (CEs) working as 1st assistant during ad hoc PCI. We retrospectively included 286 patients who underwent ad hoc PCI following diagnostic catheterization for coronary artery disease between April 2019 and March 2021. Procedural complications including coronary perforation or rupture, myocardial infarction, cerebral embolism, cardiovascular death, decreased kidney function, and radiation parameters were compared between the two clinical settings [CE group, CEs as the 1st assistant from the beginning of diagnostic coronary angiography to the end of PCI vs. doctor (DR) group, others]. There was no increase in the ratio of procedural complications in the CE group (1.7%) versus the DR group (1.2%). Fluorescence time and radiation exposure dose were significantly reduced in the CE group {25 min [interquartile range (IQR), 19-35 min] vs. 28 min (IQR, 20-39 min), P = 0.036; 908 mGy (IQR, 654-1326 mGy) vs. 1062 mGy (IQR, 732-1594 mGy), P = 0.049}. The median amount of contrast medium was significantly reduced in the CE group [100 mL (IQR, 80-119 mL) vs. 110 mL (IQR 90-140 mL), P < 0.001]. After propensity matching, fluorescence time, radiation exposure dose, and contrast medium amount were similar between groups. Task sharing with CEs as the 1st assistant during ad hoc PCI could contribute to clinical safety in patients with coronary artery disease., (© 2022. The Author(s).)

We aimed to investigate the impact of post-discharge scheduled hospital visits on readmission due to heart failure (HF). In this retrospective study, a total of 245 patients (N = 101 in the scheduled hospital visit group, N = 144 in the non-scheduled hospital visit group) who were alive with free from readmission due to HF for 90 days after discharge were enrolled. The patients had been hospitalized with acute decompensated HF between August 2018 and July 2019. Scheduled hospital visits were recommended 90 days after the patients had been discharged. After checking their self-care adherence, nurse-led self-care maintenance and monitoring were provided. To determine the effectiveness of the scheduled hospital visits, we conducted landmark analyses divided into two periods: Scheduled visits within 180 days, and after 180 days. The readmission rate due to HF within 180 days was lower in the scheduled visit group. In the landmark analysis, the 1-year incidence rate of readmission was significantly lower in patients with a scheduled hospital visit than in those without, in the period within 180 days (2.0% vs 9.0%, P = 0.029) but not after 180 days. After adjusting for age and estimated glomerular filtration rate as confounders, scheduled hospital visits tended to reduce readmission due to HF ( P = 0.060); however, readmission was significantly reduced in the period within 180 days ( P = 0.007). In conclusion, scheduled hospital visits at 90 days after discharge may be beneficial in delaying readmission due to HF by reducing risk of readmission during the early post-visit period., Competing Interests: This study received no grants from any funding agency within the public, commercial, or non-profit sectors.

Significance: Raman spectroscopy is a well-established analytical method in the fields of chemistry, industry, biology, pharmaceutics, and medicine. Previous studies have investigated optical imaging and Raman spectroscopy for osteoarthritis (OA) diagnosis in weight-bearing joints such as hip and knee joints. However, to realize early diagnosis or a curable treatment, it is still challenging to understand the correlations with intrinsic factors or patients’ background., Aim: To elucidate the correlation between the Raman spectral features and pathological variations of human shoulder joint cartilage., Approach: Osteoarthritic cartilage specimens excised from the humeral heads of 14 patients who underwent shoulder arthroplasty were assessed by a confocal Raman microscope and histological staining. The Raman spectroscopic dataset of degenerative cartilage was further analyzed by principal component analysis and hierarchical cluster analysis., Results: Multivariate association of the Raman spectral data generated three major clusters. The first cluster of patients shows a relatively high Raman intensity of collagen. The second cluster displays relatively low Raman intensities of proteoglycans (PGs) and glycosaminoglycans (GAGs), whereas the third cluster shows relatively high Raman intensities of PGs and GAGs. The reduced PGs and GAGs are typical changes in OA cartilage, which have been confirmed by safranin–O staining. In contrast, the increased Raman intensities of collagen, PGs, and GAGs may reflect the instability of the cartilage matrix structure in OA patients., Conclusions: The results obtained confirm the correlation between the Raman spectral features and pathological variations of human shoulder joint cartilage. Unsupervised machine learning methods successfully yielded a clinically meaningful classification between the shoulder OA patients. This approach not only has potential to confirm severity of cartilage defects but also to determine the origin of an individual’s OA by evaluating the cartilage quality.

An increase in nicotinamide adenine dinucleotide (NAD + ) levels alleviates age-related disease progression and promotes healthy life expectancy. Several studies have demonstrated that NAD + levels can be efficiently replenished via nicotinamide mononucleotide (NMN) intake; additionally, the safety of its oral ingestion has been confirmed in recent clinical trials. However, the efficacy and safety of intravenous NMN administration in humans remain unclear. Therefore, we verified its safety in 10 healthy volunteers. Intravenous administration of NMN did not affect electrocardiograms, pulse, and blood pressure, nor did it affect metabolic markers in the liver, heart, pancreas, and kidneys. These results indicate that intravenous NMN administration is safe and beneficial in humans. Furthermore, NMN administration significantly increased blood NAD + levels without damaging blood cells and significantly reduced blood triglyceride (TG) levels. These findings imply that intravenous administration of NMN may lead to the prevention and treatment of diseases associated with increased TG levels, such as fatty liver and diabetes., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2022, Kimura et al.)

Unlike most mammalian cell lines, fish cell lines are immortal and resistant to cellular senescence. Elevated expression of H-Ras contributes to the induction of senescence in a fish cell line, EPC, but is not sufficient to induce full senescence. Here, we focused on the absence of a p16 INK4a /ARF locus in the fish genome, and investigated whether this might be a critical determinant of the resistance of EPC cells to full senescence. We found that transfected EPC cells constitutively overexpressing p16 INK4a exhibited large size and flat morphology characteristic of prematurely senescent cells; the cells also showed p53-independent senescence-like growth arrest and senescence-associated β-galactosidase (SA-β-gal) activity. Furthermore, the mRNA levels of proinflammatory senescence-associated secretory phenotype (SASP) factors increased in EPC cells constitutively overexpressing p16 INK4a . These results suggest that the lack of p16 INK4a in the fish genome may be a critical determinant of senescence resistance in fish cell lines., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The nuclear factor-κB (NF-κB) transcription factor family consists of five related proteins, RelA (p65), c-Rel, RelB, p50/p105 (NF-κB1), and p52/p100 (NF-κB2). These proteins are important not only for inflammation and the immune response but also for bone metabolism. Activation of NF-κB occurs via the classic and alternative pathways. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, activate the former, and cytokines involved in lymph node formation, such as receptor activator of NF-κB ligand (RANKL) and CD40L, activate the latter. p50 and p52 double-knockout mice revealed severe osteopetrosis due to the total lack of osteoclasts, which are specialized cells for bone resorption. This finding suggests that the activation of NF-κB is required for osteoclast differentiation. The NF-κB signaling pathway is controlled by various regulators, including NF-κB essential modulator (NEMO), which is encoded by the IKBKG gene. In recent years, mutant forms of the IKBKG gene have been reported as causative genes of osteopetrosis, lymphedema, hypohidrotic ectodermal dysplasia, and immunodeficiency (OL-EDA-ID). In addition, a mutation in the RELA gene, encoding RelA, has been reported for the first time in newborns with high neonatal bone mass. Osteopetrosis is characterized by a diffuse increase in bone mass, ranging from a lethal form observed in newborns to an asymptomatic form that appears in adulthood. This review describes the genetic mutations in NF-κB signaling molecules that have been identified in patients with osteopetrosis.

The phenotypic changes in hematopoietic stem progenitor cells (HSPCs) with somatic mutations of malignancy-related genes in patients with acquired aplastic anemia (AA) are poorly understood. As our initial study showed increased CXCR4 expression on HLA allele-lacking (HLA[-]) HSPCs that solely support hematopoiesis in comparison to redundant HLA(+) HSPCs in AA patients, we screened the HSPCs of patients with various types of bone marrow (BM) failure to investigate their CXCR4 expression. In comparison to healthy individuals ( n  = 15, 12.3%-49.9%, median 43.2%), the median CXCR4 + cell percentages in the HSPCs of patients without somatic mutations were low: 29.3% (14.3%-37.3%) in the eight patients without HLA(-) granulocytes, 8.8% (4.1%-9.8%) in the five patients with HLA(-) cells accounting for >90% of granulocytes, and 7.8 (2.1%-8.7%) in the six patients with paroxysmal nocturnal hemoglobinuria. In contrast, the median percentage was much higher (78% [61.4%-88.7%]) in the five AA patients without HLA(-) granulocytes possessing somatic mutations ( c-kit , t[8;21], monosomy 7 [one for each], ASXL1 [ n  = 2]), findings that were comparable to those (66.5%, 63.1%-88.9%) in the four patients with advanced myelodysplastic syndromes. The increased expression of CXCR4 may therefore reflect intrinsic abnormalities of HSPCs caused by somatic mutations that allow them to evade restriction by BM stromal cells., Competing Interests: All authors declare no conflicts of interest in association with the present study., (© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Control of gut microbes is crucial for not only local defense in the intestine but also proper systemic immune responses. Although intestinal epithelial cells (IECs) play important roles in cytokine-mediated control of enterobacteria, the underlying mechanisms are not fully understood. Here we show that deletion of IκBζ in IECs in mice leads to dysbiosis with marked expansion of segmented filamentous bacteria (SFB), thereby enhancing Th17 cell development and exacerbating inflammatory diseases. Mechanistically, the IκBζ deficiency results in decrease in the number of Paneth cells and impairment in expression of IL-17-inducible genes involved in IgA production. The decrease in Paneth cells is caused by aberrant activation of IFN-γ signaling and a failure of IL-17-dependent recovery from IFN-γ-induced damage. Thus, the IL-17R-IκBζ axis in IECs contributes to the maintenance of intestinal homeostasis by serving as a key component in a regulatory loop between the gut microbiota and immune cells., (© 2022. The Author(s).)

To determine whether antigen presentation by HLA-DR on hematopoietic stem progenitor cells (HSPCs) is involved in the development of acquired aplastic anemia (AA), we studied the HLA-DR expression on CD45 dim CD34 + CD38 + cells in the peripheral blood of 61 AA patients including 23 patients possessing HLA-class I allele-lacking (HLA-class I[-]) leukocytes. HLA-DR-lacking (DR[-]) cells accounted for 13.0-57.1% of the total HSPCs in seven (11.5%) patients with HLA-DR15 who did not possess HLA-class I(-) leukocytes. The incubation of sorted DR(-) HSPCs in the presence of IFN-γ for 72 h resulted in the full restoration of the DR expression. A comparison of the transcriptome profile between DR(-) and DR(+) HSPCs revealed the lower expression of immune response-related genes including co-stimulatory molecules (e.g., CD48, CD74, and CD86) in DR(-) cells, which was not evident in HLA-class I(-) HSPCs. DR(-) cells were exclusively detected in GPI(+) HSPCs in four patients whose HSPCs could be analyzed separately for GPI(+) and GPI(-) HSPCs. These findings suggest that CD4 + T cells specific to antigens presented by HLA-DR15 on HSPCs may contribute to the development of AA as well as the immune escape of GPI(-) HSPCs in a distinct way from CD8 + T cells recognizing HLA-class I-restricted antigens., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)