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The biliary tract is a ductal network comprising the intrahepatic (IHBDs) and extrahepatic bile duct (EHBDs). Biliary duct disorders include cholangitis, neoplasms, and injury. However, the underlying mechanisms are not fully understood. With advancements in 3D culture technology, cholangiocyte organoids (COs) derived from primary tissues or induced pluripotent stem cells (iPSCs) can accurately replicate the structural and functional properties of biliary tissues. These organoids have become powerful tools for studying the pathogenesis of biliary diseases, such as cystic fibrosis and primary sclerosing cholangitis, and for developing new therapeutic strategies for cholangiocarcinoma. Additionally, COs have the potential to repair bile duct injuries and facilitate transplantation therapies. This review also discusses the use of organoids in genetically engineered mouse models to provide mechanistic insights into tumorigenesis and cancer progression. Continued innovation and standardization of organoid technology are crucial for advancing precision medicine for biliary diseases and cancer., 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 © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Diffuse alveolar damage (DAD) is a pathological hallmark of severe interstitial lung diseases, such as acute respiratory distress syndrome (ARDS), and is linked to poor prognosis. Previously, we identified 14-3-3σ/stratifin (SFN) as a serum biomarker candidate for diagnosing DAD. To clarify the time-dependent relationship between SFN expression and DAD, we here investigated pathological and molecular changes in serum, bronchoalveolar lavage fluid (BALF), and lung tissue in an oleic acid (OA)-induced ARDS rat model. Acute alveolar edema was observed after OA administration, followed by alveolar epithelial cell proliferation and increased BALF and serum SFN levels. Proteomic analysis of lung tissue extracts revealed that proteins related to "inflammatory response" and "HIF-1 signaling," including plasminogen activator inhibitor-1, were markedly increased 3 h after acute lung injury, followed by a gradual decrease. Conversely, proteins associated with "cell cycle" and "p53 pathway," including SFN, showed a persistent increase starting at 3 h and peaking at 48 h. Western blotting and immunohistochemistry confirmed that SFN was expressed in a part of proliferated alveolar type-II cells, accompanied by p53 activation, an important event for differentiation into type-I cells. SFN may be a biomarker closely related to alveolar remodeling during the repair process after lung injury.

We herein report two extremely rare cases of gastric adenocarcinoma with enteroblastic differentiation (GAED) that underscore the aggressive nature of GAED. Case 1: endoscopic submucosal dissection (ESD) was scheduled for early-stage gastric cancer, however, the tumor increased in size drastically and the morphology changed to type "0-I + IIc" in one month. Surgery was performed and the patient was diagnosed with GAED. Case 2: ESD was performed for early-stage gastric cancer, and the pathological findings revealed GAED. The horizontal margin was positive for clear cells in the muscularis mucosa. Additional surgery was performed; however, recurrence occurred one year later. Therefore, the treatment strategies should be carefully considered for GAED.

Objective: Hot environments negatively affect cattle productivity, and global warming also causes heat stress, thereby adversely impacting cattle production. Improving cattle management under such conditions is an urgent issue. Trehalose can ameliorate volatile fatty acid production and the diversity of ruminal microbiota in dairy cattle. However, no studies have evaluated on Japanese beef heifers. In this study, we investigated the effects of trehalose supplementation on the ruminal microbiota and productivity of Japanese Black heifers under heat-stressed conditions., Methods: Six cyclic Japanese Black heifers were divided into two groups: control and trehalose supplemented. The ruminal microbiota, pH, and volatile fatty acid production of these heifers were analyzed over 10 weeks in the summer in central Japan., Results: During the experimental period, the heifers in the control group showed significantly higher concentrations of ruminal acetic and propionic acids than those in the trehalose-supplemented group (p<0.05, two-way repeated measures ANOVA). The acetic/propionic acid ratio showed no significant difference between the two groups. The alpha diversity in the ruminal bacterial biota in the trehalose supplemented group was higher than that in the control group (p<0.05, two-way repeated measures ANOVA) along with a change in the beta diversity of the ruminal fungal biota (p<0.05, PERMANOVA). LEfSe analysis in ruminal microbiota identified specific microorganisms in the control and the trehalose-supplemented samples: 4 and 13 in bacteria; each one fungus; 5 and 4 protozoan families, respectively., Conclusion: Trehalose supplementation in the summer improved ruminal microbiota, especially the types of ruminal bacteria and fungi related to carbohydrate digestion, and maintained the balance of ruminal VFA production in Japanese Black heifers. Therefore, trehalose supplementation in feed could improve cattle production under heat-stressed conditions and in global-warming scenarios.

OX40, a member of the tumor necrosis factor (TNF) receptor superfamily, is expressed on the surface of activated T cells. Upon interaction with its cognate ligand, OX40L, OX40 transmits costimulatory signals to antigen-primed T cells, promoting their activation, differentiation, and survival - processes essential for the establishment of adaptive immunity. Although the OX40-OX40L interaction has been extensively studied in the context of disease treatment, developing a substitute for the naturally expressed membrane-bound OX40L, particularly a multimerized OX40L trimers, that effectively regulates OX40-driven T cell responses remains a significant challenge. In this study, we successfully engineered soluble OX40L-fusion proteins capable of robustly activating OX40 on T cells. This was achieved by incorporating functional multimerization domains into the TNF homology domain of OX40L. These OX40L proteins bound to OX40, subsequently activated NF-κB signaling, and induced cytokine production by T cells in vitro . In vivo , mice treated with one of the OX40L-fusion proteins - comprising a single-chain OX40L trimer linked to the C-terminus of the human IgG1 Fc domain, forming a dimer of trimers - exhibited significantly enhanced clonal expansion of antigen-specific CD4 + T cells during the primary phase of the immune response. A comparable antibody-fusion single-chain TNF protein incorporating 4-1BBL, CD70 (CD27L), or GITRL in place of OX40L elicited similar in vivo T cell responses. Thus, we propose that optimizing the multimerization of OX40L proteins through innovative design strategies may facilitate the development of more effective agonists for targeted immunotherapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be consulted as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2025 Sato, Nagai, Suzuki, Ito, Matsuyama, Shibui, Morita, Hikosaka-Kuniishi, Ishii and So.)

Background: Hybrid emergency rooms (ERs) allow computed tomography (CT) scanning, interventional radiology, and surgery all in the same suite. Severe trauma patients with blunt thoracic aortic injury (BTAI) require rapid diagnosis and treatment. Hybrid ERs allow the potential for clinicians to implement multiple therapeutic procedures, including thoracic endovascular aortic repair (TEVAR), for these types of conditions without the need to transport the patients., Case Presentation: A 35-year-old man sustained multiple injuries after a motor vehicle accident and was transferred to our hospital in shock status. CT revealed a grade IV BTAI rupturing into the thoracic cavity and pelvic fracture. Soon after preperitoneal pelvic packing and transcatheter arterial embolization for pelvic fracture, TEVAR was performed in the hybrid ER without transporting the patient. The patient was transferred to a rehabilitation hospital on postoperative day 41., Conclusion: Hybrid ERs enable clinicians to perform all life-saving procedures, including stent grafting for traumatic patients with aortic injuries, in the same place., Competing Interests: None., (© 2025 The Authors. Published by Elsevier Ltd.)

We herein describe a case of severe post-biopsy bleeding and perforation in gastric amyloidosis. A 70-year-old man who had been on dialysis underwent esophagogastroduodenoscopy and biopsy was performed. Post-biopsy bleeding occurred, and three times of coagulation hemostasis and once clip hemostasis were performed. After the hemostasis, he eventually had a gastric perforation and omental patch surgery was performed, however, he passed away after the surgery. From the pathological finding of biopsy specimen, he was diagnosed with gastric amyloidosis caused by dialysis-related amyloidosis. In patients of amyloidosis, the risk of bleeding and perforation is elevated due to vascular and tissue fragility. Therefore, when performing hemostasis in patients with gastrointestinal amyloidosis, clip hemostasis which minimizes tissue damage is considered preferable to coagulation hemostasis., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Solid Co nanorod fillers were pushed out of multi-walled carbon nanotubes via electromigration and their behaviors were observed in situ by transmission electron microscopy. When a solid Co nanorod was pushed out, the portion outside the nanotube increased in diameter. The behavior of the plastic deformation depended on the crystal orientation of the Co nanorod filler. When the direction of the electron flow was reversed, the Co nanorod was pulled into the host nanotube. In one trial, the Co nanorod was split into two portions inside the nanotube near one of the electrodes., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The nuptial flight of ants usually occurs during certain periods of the year. Alate females and males fly out of their nests to mate simultaneously. In the genus Camponotus, sex-specific chemicals are deposited in the male head; however, their roles in nuptial flight have not yet been clarified. This study aimed to elucidate the functions of male-specific chemicals in the Japanese carpenter ant Camponotus japonicus. First, we identified three chemicals characteristic to the male - methyl salicylate (MS), methyl 6-methylsalicylate (MMS), and methyl anthranilate (MA) - all of which triggered electroantennogram (EAG) responses in both alate males and females. As the relative content of MS was insufficient for GC comparison, we investigated the quantitative changes of MMS and MA in the male head capsules before and after flight under laboratory conditions. The amounts of both compounds were significantly reduced after flight, which suggested that males secrete them during flight. Thereafter, a field trap experiment was conducted in three fields of the Kyoto Prefecture, Japan, during the nuptial flight season in 2021 using MMS and MA as baits. The number of captured alate males was significantly higher than that of the females, suggesting that these compounds primarily attracted males rather than females. Considering the field conditions, if the local concentration of these chemicals is increased by male aggregation, females may be attracted as they also showed EAG responses. Our findings represent a first step toward understanding chemically mediated male lek formation during the process of male aggregation syndrome in this species., Competing Interests: Declarations. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We propose a multi-frame blind deconvolution method using an in-plane rotating sample optimized for X-ray microscopy, where the application of existing deconvolution methods is technically difficult. Untrained neural networks are employed as the reconstruction algorithm to enable robust reconstruction against stage motion errors caused by the in-plane rotation of samples. From demonstration experiments using full-field X-ray microscopy with advanced Kirkpatrick-Baez mirror optics at SPring-8, a spatial resolution of 34 nm (half period) was successfully achieved by removing the wavefront aberration and improving the apparent numerical aperture. This method can contribute to the cost-effective improvement of X-ray microscopes with imperfect lenses as well as the reconstruction of the phase information of samples and lenses., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

During a coronavirus infection, the spike protein undergoes sequential structural transitions triggered by its receptor and the host protease at the interface between the virus and cell membranes, thereby mediating membrane fusion. After receptor binding, the heptad repeat motif (HR1/HR2) within the viral spike protein bridges the viral and cellular membranes; however, the intermediate conformation adopted by the spike protein when drawing the viral and cellular membranes into close proximity remains unclear due to its transient and unstable nature. Here, we experimentally induced conformational changes in the spike protein of a murine coronavirus by incubating the virus with its receptor, followed by exposure to trypsin. We then treated the virus/receptor complex with proteinase K to probe the tightly packed core structure of the spike protein. The conformations of the spike protein were predicted from the sizes of the protease digestion products detected by western blot analysis. Upon receptor binding, two bands (each showing different reactivity with a fusion-inhibiting HR2-peptide) were detected; we propose that these bands correspond to the packed and unpacked HR1/HR2 motifs. After trypsin-mediated triggering, measurement of temperature and time dependency revealed that packing of the remaining unpacked HR1/HR2 motifs and assembly of three HR1 motifs in a trimer occur almost simultaneously. Thus, the trimeric spike protein adopts an asymmetric-unassembled conformation after receptor binding, followed by direct assembly into the post-fusion form triggered by the host protease. This biochemical study provides mechanistic insight into the previously unknown intermediate structure of the viral fusion protein.IMPORTANCEDuring infection by an enveloped virus, receptor binding triggers fusion between the cellular membrane and the virus envelope, enabling delivery of the viral genome to the cytoplasm. The viral spike protein mediates membrane fusion; however the molecular mechanism underlying this process is unclear. This is because using structural biology methods to track the transient conformational changes induced in the unstable spike trimer is challenging. Here, we harnessed the ability of protease enzymes to recognize subtle differences on protein surfaces, allowing us to detect structural differences in the spike protein before and after conformational changes. Differences in the size of the degradation products were analyzed by western blot analysis. The proposed model explaining the conformational changes presented herein is a plausible candidate that provides valuable insight into unanswered questions in the field of virology., Competing Interests: The authors declare no conflict of interest.

We herein report a rare case of duodenal adenocarcinoma with a rapidly progressive course. Esophagogastroduodenoscopy revealed Brunner's gland hyperplasia in the bulbs of the duodenum three years prior to this presentation. Two years earlier, gastric foveolar metaplasia had been observed in the bulbs. One year earlier, the lesion had increased slightly in size. At this time, the lesion had markedly increased in size, and the duodenum was circumferentially stenotic due to the mass. Pathologically, he was diagnosed with duodenal adenocarcinoma with a gastric-dominant immunophenotype and he died two months later. Although extremely rare, we should keep in mind that duodenal tumors with a gastric phenotype may sometimes progress rapidly within a short period of time.

The sarcomere is the contractile unit of striated muscle and is composed of actin and myosin filaments. There is increasing evidence to support that actin assembly mediated by Fhod3, a member of the formin family of proteins, is critical for sarcomere formation and maintenance in cardiac muscle. Fhod3, which is abundantly expressed in the heart, localizes to the center of sarcomeres and contributes to the regulation of the cardiac function, as evidenced by the fact that mutations in Fhod3 cause cardiomyopathy. However, the role of Fhod3 in skeletal muscle, another type of striated muscle, is unclear. We herein show that Fhod3 is expressed in the tongue at both mRNA and protein levels, although in smaller amounts than in the heart. To determine the physiological role of Fhod3 expressed in the tongue, we generated embryos lacking Fhod3 in the tongue. The tongue tissue of the Fhod3-depleted embryos did not show any significant structural defects, suggesting that Fhod3 is dispensable for normal development of the mouse tongue. Unexpectedly, the immunostaining analysis revealed the absence of specific sarcomeric signals for Fhod3 in the wild-type tongue when compared to the Fhod3-depleted tongue as a negative control, despite the use of antibodies that had previously been validated by immunostaining of heart tissues. Taken together, although Fhod3 protein is expressed at a significant level in the tongue, Fhod3 in the tongue does not appear to exhibit the same sarcomeric pattern as observed in the heart, suggesting a different role for Fhod3 in the tongue muscles.Key words: actin, formin, sarcomere, striated muscle.

Embryo survival and pre-implantation development depend on uterine luminal fluid, which is believed to play a role in early embryonic death and infertility in cows. Extracellular vesicles (EVs) in the uterine luminal fluid contain microRNAs (miRNAs), crucial mediators of intercellular communication. miRNAs regulate conceptus-maternal interactions and participate in embryonic development by suppressing gene expression. Therefore, we hypothesized that miRNAs in the intrauterine EVs of low-fertility cows would hinder embryonic survival and development. EVs were collected from the bovine uterine luminal fluid of both normal- and low-fertility cows 7 days post-estrus. Small RNA-sequencing analysis of miRNAs isolated from these EVs identified eight miRNAs that were highly expressed in normal-fertility cows (normal-fertility miRNAs) and eight with elevated expression in low-fertility cows (low-fertility miRNAs). These two sets of miRNAs were transfected into hatched blastocysts via lipofection. RNA-seq following lipofection with low-fertility miRNAs identified 424 differentially expressed genes (DEGs) relative to the control; in contrast, following lipofection with normal-fertility miRNAs, seven DEGs were identified. Pathway analysis of the DEGs identified following lipofection with low-fertility miRNAs revealed substantial enrichment of mitogen-activated protein kinase (MAPK) signaling. Expression of activator protein 1 (AP1) and interferon-tau (IFNT) mRNA was significantly lower in the low-fertility miRNA transfection group than in the control. IFNT is essential for maternal pregnancy recognition. Therefore, miRNAs in intrauterine EVs from low-fertility cows at 7 days post-estrus may inhibit embryo development and suppress IFNT expression by altering MAPK signaling., (© 2024 The Author(s). The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Background: Higher education level is associated with longer disability-free life expectancy (DFLE). However, evidence is scarce regarding factors that can contribute to eliminating inequality in DFLE according to education level. This study aimed to clarify the association between education and DFLE and estimate whether DFLE in people with lower education may increase to the same level as that in people with higher education through social participation., Methods: We analyzed data from 13,849 Japanese people aged 65 years and older who participated in a 13-year prospective study. At baseline, we collected information on education levels (low, middle, or high) and social participation. DFLE was defined as the average duration people expect to live without disability. To calculate DFLE for each education level group, the multistate life table method was employed using a Markov model., Results: At the age of 65 years, DFLE (95 % confidence interval [CI]) in women with low education was 21.3 years (20.8-21.8) without social participation and 24.3 (23.8-24.9) with social participation. In the middle education group, DFLE was 22.1 (21.6-22.6) without social participation and 25.0 (24.6-25.5) with social participation. In the high education group, DFLE was 22.1 (21.5-22.8) without social participation and 25.5 (25.0-26.0) with social participation. Similar results were found for men., Conclusions: DFLE in people with low or middle education with social participation was almost the same as that in those with high education with social participation, suggesting the possibility that disparities in DFLE by education level could be offset by promoting social participation in older adults., 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 © 2024. Published by Elsevier B.V.)

Cryopreservation adversely affects embryo quality and viability in vitro. We investigated the effects of cryopreservation solutions supplemented with the antioxidant carnosine on frozen-thawed bovine embryo viability. Bovine blastocysts were produced in vitro and cryopreserved using slow freezing. The rates of re-expanded and hatched blastocysts in the 50 μg/ml carnosine-supplemented group at 4, 24, and 48 h after thawing were higher than those in the control (P < 0.05) group. In frozen-thawed embryos, cryopreservation solution supplemented with carnosine (50 μg/ml) significantly reduced reactive oxygen species (ROS) production (P < 0.05), decreased TUNEL-positive apoptotic cells (P < 0.05), and increased the mRNA expression of BCL2 (P < 0.05), an apoptosis suppressor gene. The expression of translocase of outer mitochondrial membrane 20 (TOMM20), which is involved in protein mitochondrial transport, in the carnosine (50 μg/ml)-treated embryos was significantly higher than that in the control group (P < 0.05). ATP production in frozen-thawed embryos in the 50 μg/ml carnosine-supplemented group was significantly higher than that in the control group (P < 0.05), however no significant difference in the total number of cells per embryo among the groups was observed. These results suggest that supplementing the cryopreservation solution with carnosine can improve the viability of frozen-thawed bovine embryos by reducing oxidative damage.

(1) Background: HASPIN kinase is involved in regulating spindle function and chromosome segregation, as well as phosphorylating histone H3 at Thr3 in mitotic cells. Several HASPIN inhibitors suppress cancer cell proliferation. It was recently reported that coumestrol from bean sprouts inhibits HASPIN, and a cultivation method for bean sprouts containing large amounts of coumestrol has been established. Here, we showed the effects of bean sprout ingestion on intestinal polyp development, cachexia, and hypogonadism in a mouse model of familial adenomatous polyposis ( Apc Min/+ ). (2) Methods: Apc Min/+ mice were randomized into control and treatment groups. Mice in the control group were given the standard diet, while those in the treatment group were given the same standard diet with the addition of 15% bean sprouts. Treatments were commenced at 7 weeks old and analyses were performed at 12 weeks old. (3) Results: ingesting bean sprouts suppressed the development of intestinal polyps, cachexia, and hypogonadism, and also increased serum levels of testosterone in male wild-type and Apc Min/+ mice. (4) Conclusions: ingesting bean sprouts helps prevent cancer and increases serum levels of testosterone in a mouse model. These results are expected to be applicable to humans.

A man in his 70s suffered cardiac arrest, and his family initiated cardiopulmonary resuscitation after placing an emergency call. The initial waveform of the automated external defibrillator performed by emergency medical technicians revealed ventricular fibrillation. The patient received cardiovascular life support, including direct current countershock, and was transported to the hospital. Upon arrival, he underwent extracorporeal cardiopulmonary resuscitation using an automated chest compression device. Additionally, an intra-aortic balloon pumping was introduced after coronary angiography and percutaneous coronary intervention. Plain computed tomography images revealed leakage of the contrast medium used during coronary angiography in the bilateral renal pelvis and perirenal area as well as bladder retention. Furthermore, a urine test revealed gross hematuria. There were no findings of prostatic hypertrophy or urinary tract disease. Based on the patient's clinical course, injury caused by chest compression was the most likely etiology of urinary tract injury, which must be considered in such patients. The patient was discharged with cerebral performance category 1, without any complication except urinary tract., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Tada et al.)

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.

The coordinated interspecific variation in leaf traits and leaf lifespan is known as the leaf economic spectrum (LES). The limitation of CO 2 diffusion to chloroplasts within the lamina is significant in C 3 photosynthesis, resulting in a shortage of CO 2 for Rubisco. Although Rubisco CO 2 /O 2 specificity (S C/O ) should be adaptively adjusted in response to the interspecific variation in CO 2 concentrations [CO 2 ] associated with Rubisco, S C/O variations across species along the LES remain unknown. We investigated the coordination among leaf traits, including S C/O , CO 2 conductance, leaf protein content, and leaf mass area, across 23 woody C 3 species coexisting on an oceanic island through phylogenetic correlation analyses. A high S C/O indicates a high CO 2 specificity of Rubisco. S C/O was negatively correlated with [CO 2 ] at Rubisco and total CO 2 conductance within lamina, while it was positively correlated with leaf protein across species, regardless of phylogenetic constraint. A simulation analysis shows that the optimal S C/O for maximizing photosynthesis depends on both [CO 2 ] at Rubisco sites and leaf protein per unit leaf area. S C/O is a key parameter along the LES axis and is crucial for maximizing photosynthesis across species and the adaptation of woody plants., (© 2024 The Authors. New Phytologist © 2024 New Phytologist Foundation.)

Background: Serum levels of stratifin (SFN), a member of the 14-3-3 protein family, increase in patients with drug-induced lung injury associated with diffuse alveolar damage. Therefore, we hypothesised that SFN levels would be higher in those experiencing acute exacerbation of interstitial lung disease (AE-ILD). A secondary analysis was also planned to determine whether SFN levels could discriminate survival in those with AE., Methods: Thirty-two patients with clinically stable ILD (CS-ILD) and 22 patients with AE-ILD were examined to assess whether high serum SFN levels were associated with AE-ILD and whether SFN levels reflected disease severity or prognosis in patients with AE-ILD., Results: Serum SFN levels were higher in the AE-ILD group than in the CS-ILD group (8.4 ± 7.6 vs. 1.3 ± 1.2 ng/mL, p < 0.001). The cut-off value of the serum SFN concentration for predicting 90-day and 1-year survival was 6.6 ng/mL. SFN levels were higher in patients who died within 90 days and 1 year than in patients who survived beyond these time points (13.5 ± 8.7 vs. 5.6 ± 5.3 ng/mL; p = 0.011 and 13.1 ± 7.5 vs. 3.1 ± 1.9 ng/mL; p < 0.001, respectively) in the AE-ILD group. When this cut-off value was used, the 90-day and 1-year survival rates were significantly better in the population below the cut-off value than in those above the cut-off value (p = 0.0017 vs. p < 0.0001)., Conclusions: High serum SFN levels are associated with AE-ILD and can discriminate survival in patients with AE-ILD., (© 2024. The Author(s).)

Boron neutron capture therapy (BNCT) is a unique radiotherapy of selectively eradicating tumor cells using boron compounds (e.g., 4-borono-L-phenylalanine [BPA]) that are heterogeneously taken up at the cellular level. Such heterogenicity potentially reduces the curative efficiency. However, the effects of temporospatial heterogenicity on cell killing remain unclear. With the technical combination of radiation track detector and biophysical simulations, this study revealed the cell cycle-dependent heterogenicity of BPA uptake and subsequent biological effects of BNCT on HeLa cells expressing fluorescent ubiquitination-based cell cycle indicators, as well as the modification effects of polyvinyl alcohol (PVA). The results showed that the BPA concentration in the S/G 2 /M phase was higher than that in the G 1 /S phase and that PVA enhances the biological effects both by improving the uptake and by canceling the heterogenicity. These findings might contribute to a maximization of therapeutic efficacy when BNCT is combined with PVA and/or cell cycle-specific anticancer agents., (© 2024. The Author(s).)

Early B-cell factor 3 (EBF3)-related syndrome, also known as hypotonia, ataxia, and delayed development syndrome (HADDS), is a recently recognized neurodevelopmental disorder frequently associated with bladder dysfunction. Despite bladder dysfunction possibly caused by detrusor sphincter dyssynergia, previous studies reported relatively accepted bladder compliance in patients with HADDS. We present the first case of bladder augmentation, in the English literature, in a girl with EBF3-related syndrome due to poor bladder compliance with clean intermittent catheterization and anticholinergic medication., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Kiyama et al.)

Purpose: Generalized anxiety disorder (GAD) is among the most prevalent and highly disabling mental health conditions that negatively impacts patient's quality of life (QOL) and disrupts activities of daily living. However, the recognition of GAD is difficult due to substantial overlap with other mental disorders. The purpose of this study was to estimate the prevalence of GAD, assess QOL of probable GAD patients in Japan, and gain insights on the status of visiting medical institutions as well as their recognition/awareness of the disorder., Patients and Methods: We conducted a web-based cross-sectional survey of 20,009 participants using a questionnaire with approximately 30 single/multiple choice or open-ended questions in Japanese., Results: Overall prevalence of GAD based on Generalized Anxiety Disorder 7-item (GAD-7) cutoff score of ≥10 and questionnaires developed with reference to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria was 7.6% (n=1530) and 6.0% (n=1197), respectively. The degree of coincidence between GAD diagnosis by DSM-5 criteria and GAD-7 scores was moderate (Cohen's Kappa=0.47, p <0.01). Younger people reported a substantially higher prevalence of GAD compared to older. QOL scores assessed using EuroQol 5 dimensions 5-level and EuroQol Visual Analog Scale were substantially lower in probable GAD patients than those with GAD-7<10. Anxiety/depression and pain/discomfort were the most prevalent issues and depression was the most reported comorbidity for the probable GAD patients. Probable GAD patients "currently visiting medical institutions" for anxiety or other mental issues were 27.6% (422/1530); a majority had seen specialists. Most of the probable GAD patients had never heard of the disease., Conclusion: We found higher prevalence of GAD and lower QOL of probable GAD patients in Japan. There is a need for creating awareness about GAD among the general population and developing clinical guidelines on GAD in Japan so that physicians can educate their patients., Competing Interests: Satoshi Matsuyama, Keisuke Nomoto, and Shingo Higa are full-time employees of Viatris Pharmaceuticals Japan Inc. Tempei Otsubo has received lecture fees from Viatris Pharmaceuticals Japan Inc.; Takeda Pharmaceutical Co., Ltd.; Otsuka Pharmaceutical; Sumitomo Pharma Co., Ltd.; YoshitomiYakuhin; Mochida; Meiji Seika Pharma Co., Ltd.; Kyowa Pharmaceutical; Lundbeck Japan; and IQVIA. Osamu Takashio reported honoraria for lectures from Viatris Pharmaceuticals Japan Inc.; Meiji Seika Pharma Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Sumitomo Pharma Co., Ltd.; and Otsuka Pharmaceutical. The authors report no other conflicts of interest in this work., (© 2024 Matsuyama et al.)

Using the GISAID EpiCoV database, we identified 256 COVID-19 patients in Japan during March 31-December 31, 2023, who had mutations in the SARS-CoV-2 nonstructural protein 5 conferring ensitrelvir resistance. Ongoing genomic surveillance is required to monitor emergence of SARS-CoV-2 mutations that are resistant to anticoronaviral drugs.

BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis. M109S was administered starting 5 h after ONC for 7 days. M109S was orally administered in two groups (5 mg/kg twice a day or 7.5 mg/kg once a day). The retina was stained with anti-BRN3A and cleaved Caspase-3 (active Caspase-3) that are the markers of RGC and apoptotic cells, respectively. ONC decreased the number of BRN3A-positive RGC and increased the number of active Caspase-3-expressing apoptotic cells. In ONC-treated retina, there were cells that were double stained with anti-BRN3A and ant-cleaved Caspase-3, indicating that apoptosis in BRN3A-positive RGCs occurred. M109S inhibited the decrease of BRN3A-positive cells whereas it inhibited the increase of active Caspase-3-positive cells in the retina of ONC-treated mice, suggesting that M109S inhibited apoptosis in RGCs. M109S did not induce detectable histological damage to the lungs or kidneys in mice, suggesting that M109S did not show toxicities in the lung or kidneys when the therapeutic dose was used. The present study suggests that M109S is effective in rescuing damaged RGCs. Since M109S is an orally bioactive small compound, M109S may become the basis for a portable patient-friendly medicine that can be used to prevent blindness by rescuing damaged optic nerve cells from death.

Purpose: Generalized anxiety disorder (GAD) is a suboptimally managed chronic recurring psychiatric condition with a lifetime prevalence of 2.6% in Japan. We assessed the current status of GAD management in Japan., Patients and Methods: This was an observational, cross-sectional study conducted through an anonymous web-based survey in Japan from December 12-16, 2022. Psychiatrists and psychosomatic medicine physicians who agreed to participate and saw ≥10 outpatients in the previous month were eligible. Survey questionnaire comprised 37 single/multiple choice, numerical entry, or open-ended questions in Japanese., Results: Among 509 participants (493 psychiatrists and 16 psychosomatic medicine physicians), 96.9% were aware of GAD. On average, 12.4 outpatients and 1.0 inpatient were diagnosed with GAD per physician per month. Of 433 physicians having patients diagnosed with GAD, 46.9% used operational diagnostic tools; among these, DSM-5 diagnostic criteria were used by 81.5% physicians. The majority (54.7%) of participants did not use a self-administered rating scale; depression scales were used more than anxiety scales. Among these 433 physicians, 96.8% used selective serotonin reuptake inhibitors for GAD management, and 79.2% used it as the first choice; of 431 physicians who prescribed drug therapy, 54.3% gave antidepressant monotherapy as first choice. The most frequent symptom in patients diagnosed with GAD was excessive anxiety/worry (96.5%); depression was the most commonly reported comorbidity (84.3%) as per physicians aware of GAD (N=508)., Conclusion: This study illustrates that although GAD awareness is high among Japanese psychiatric specialists, GAD is not frequently diagnosed using operational diagnostic approaches. Due to a lack of Japanese guidelines for GAD diagnosis and treatment, diverse international guidelines are followed, with similar treatment paradigms as that of depression. This may not be an optimal approach given cultural/geographical differences. These findings highlight the need for uniform diagnosis and treatment recommendations for GAD management in Japan., Clinical Trial Registration: UMIN-CTR: UMIN000049572., Competing Interests: Keisuke Nomoto, Satoshi Matsuyama, and Shingo Higa are full-time employees of Viatris Pharmaceuticals Japan Inc. Osamu Takashio reported honoraria from lectures from Viatris Pharmaceuticals Japan Inc., Meiji Seika Pharma, Takeda Pharmaceutical, Sumitomo Pharma, and Otsuka Pharmaceutical. Tempei Otsubo has received lecture fees from Viatris Pharmaceuticals Japan Inc., Takeda Pharmaceutical, Otsuka Pharmaceutical, Sumitomo Pharma, Yoshitomi Yakuhin, Mochida, Meiji Seika Pharma, Kyowa Pharmaceutical, Lundbeck Japan, and IQVIA., (© 2024 Nomoto et al.)

Allogenic hematopoietic stem cell transplantation is a therapeutic procedure performed over a wide range of donor and recipient age combinations, representing natural experiments of how the age of the recipient affects aging in transplanted donor cells in vivo. We measured DNA methylation and epigenetic aging in donors and recipients and found that biological epigenetic clocks are accelerated in cells transplanted into an older body and decelerated in a younger body. This is the first evidence that the age of the circulating environment influences human epigenetic aging in vivo., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: The DNA-dependent protein kinase (DNA-PK) complex comprises a catalytic (PRKDC) and two requisite DNA-binding (Ku70/Ku80) subunits. The role of the complex in repairing double-stranded DNA breaks (DSBs) is established, but its role in inflammation, as a complex or individual subunits, remains elusive. While only ~ 1% of PRKDC is necessary for DNA repair, we reported that partial inhibition blocks asthma in mice without causing SCID., Methods: We investigated the central role of PRKDC in inflammation and its potential association with DNA repair. We also elucidated the relationship between inflammatory cytokines (e.g., TNF-α) and PRKDC by analyzing its connections to inflammatory kinases. Human cell lines, primary human endothelial cells, and mouse fibroblasts were used to conduct the in vitro studies. For animal studies, LPS- and oxazolone-induced mouse models of acute lung injury (ALI) and delayed-type hypersensitivity (DHT) were used. Wild-type, PRKDC +/- , or Ku70 +/- mice used in this study., Results: A ~ 50% reduction in PRKDC markedly blocked TNF-α-induced expression of inflammatory factors (e.g., ICAM-1/VCAM-1). PRKDC regulates Th1-mediated inflammation, such as DHT and ALI, and its role is highly sensitive to inhibition achieved by gene heterozygosity or pharmacologically. In endothelial or epithelial cells, TNF-α promoted rapid PRKDC phosphorylation in a fashion resembling that induced by, but independent of, DSBs. Ku70 heterozygosity exerted little to no effect on ALI in mice, and whatever effect it had was associated with a specific increase in MCP-1 in the lungs and systemically. While Ku70 knockout blocked VP-16-induced PRKDC phosphorylation, it did not prevent TNF-α - induced phosphorylation of the kinase, suggesting Ku70 dispensability. Immunoprecipitation studies revealed that PRKDC transiently interacts with p38MAPK. Inhibition of p38MAPK blocked TNF-α-induced PRKDC phosphorylation. Direct phosphorylation of PRKDC by p38MAPK was demonstrated using a cell-free system., Conclusions: This study presents compelling evidence that PRKDC functions independently of the DNA-PK complex, emphasizing its central role in Th1-mediated inflammation. The distinct functionality of PRKDC as an individual enzyme, its remarkable sensitivity to inhibition, and its phosphorylation by p38MAPK offer promising therapeutic opportunities to mitigate inflammation while sparing DNA repair processes. These findings expand our understanding of PRKDC biology and open new avenues for targeted anti-inflammatory interventions., (© 2024. The Author(s).)

Fat embolism syndrome (FES) is a rare complication of long bone fractures, with fulminant FES developing within 12 h of injury and often proving fatal (Shaikh, 2009 [1]). Here, we present a case of fulminant FES in a patient who developed sudden right heart failure after undergoing external fixation of a lower leg fracture and required veno-arterial extracorporeal membrane oxygenation (VA-ECMO). A 79-year-old woman injured in a traffic accident was transferred to our emergency department. Upon arrival, her level of consciousness deteriorated, and she developed circulatory failure. We promptly performed transcatheter arterial embolization for the pelvic fracture and external fixation of the tibiofibular fracture. Within four hours of the injury, she was admitted to our intensive care unit (ICU). Two hours after ICU admission, her hemodynamic status worsened, necessitating the administration of maximum catecholamine dose. Echocardiography revealed petechial hemorrhage of the palpebral conjunctiva and enlargement of the right ventricle. Despite maximal supportive care, the patient remained cardiovascularly unstable. Therefore, VA-ECMO was initiated to stabilize her hemodynamic status. Thereafter, her hemodynamics stabilized, and ECMO support was weaned off and removed on day 3. Subsequent magnetic resonance imaging revealed evidence of cerebral fat embolism. On day 9, she underwent open reduction of the left lower leg with internal fixation and was transferred to another hospital on day 29. This report documents the successful management of fulminant FES during the acute phase of multiple traumas. Clinicians should consider VA-ECMO when suspecting uncontrolled circulatory failure due to fulminant FES, even in the acute phase of multiple trauma., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors.)

HIV-associated lipodystrophy has been reported in people taking anti-retroviral therapy (ART). Lipodystrophy can cause cardiovascular diseases, affecting the quality of life of HIV-infected individuals. In this study, we propose a pharmacological lipid index to estimate the risk of hyperlipidemia caused by anti-retroviral drugs. Lipid droplets were stained in cells treated with anti-retroviral drugs and cyclosporin A. Signal intensities of lipid droplets were plotted against the drug concentrations to obtain an isodose of 10 μM of cyclosporin A, which we call the Pharmacological Lipid Index (PLI). The PLI was then normalized by EC 50 . PLI/EC 50 values were low in early proteinase inhibitors and the nucleoside reverse transcriptase inhibitor, d4T, indicating high risk of hyperlipidemia, which is consistent with previous findings of hyperlipidemia. In contrast, there are few reports of hyperlipidemia for drugs with high PLI/EC 50 scores. Data suggests that PLI/EC 50 is a useful index for estimating the risk of hyperlipidemia., 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 © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Pre-ovulatory follicles are cooler than the neighboring reproductive organs in cows. Thus, measuring the temperature of reproductive organs could be a useful method for predicting estrus and ovulation in cows, and the establishment of a non-invasive technique is required. In this study, we used infrared thermography (IRT) to measure ocular surface temperature as a potential surrogate for reproductive organ temperature. Five Japanese Black cows with synchronized estrus were subjected to temperature measurements in five regions of the ocular surface, including the nasal conjunctiva, nasal limbus, center cornea, temporal limbus, and temporal conjunctiva, twice a day (0800 h and 1600 h) during the experimental period. The temperatures in the five regions significantly declined in cows from estrus to ovulation. To the best of our knowledge, this study is the first to use IRT to show a temperature decrease in the ocular surface along with estrus to ovulation in Japanese Black cows.

The movement of Co nanorods driven by electromigration inside multi-walled carbon nanotubes was observed using in situ transmission electron microscopy. This study provides a unique method of experimental determination of both the electromigration force strength and sliding friction. When the tip of a biased electrode was located within the portion of a Co nanorod filler and an electric current was applied to push a part of the Co filler along the flow of electrons, the Co filler showed a trigonometric motion. Both the electromigration force strength and sliding friction were determined by analysis of the trigonometric movements. When a reversed electric current was applied to pull a part of the Co nanorod filler, its motion was hyperbolic-cosine like, and the motion was not suitable to determine the strengths of the two forces. Our method and the results would be useful for the development of the methods to precisely control mass transfer at the nanoscale., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

A 50-year-old female was diagnosed with gastric hyperplastic polyps 7 years before and was followed up at another hospital. She was referred to our hospital because of the growth of gastric polyps and progression of anemia. She had no family history of polyposis. The polyps were observed only in the stomach, increased in size and number, and the erythematous edema got worse. Endoscopic mucosal resection (EMR) of the gastric polyp was performed. Pathologically, the gastric polyp was hamartomatous polyp, and the intervening mucosa between polyps showed no atypical structure without inflammation. Given that gastric juvenile polyposis (GJP) was clinically suspected, a genetic test using peripheral blood was performed. Target resequencing and Sanger sequencing analysis revealed a nonsense mutation in the SMAD4 gene at codon 169. The mutation was detected at a low frequency of 11%, and considered a mosaic mutation. Therefore, she was diagnosed with a sporadic GJP, and total gastrectomy was performed. Immunostaining of SMAD4 for the resected specimen showed a mixture of stained and unstained area in the epithelium of the polyp, indicating partial loss of SMAD4 expression. To our knowledge, this is the first reported case of GJP with a nonsense SMAD4 mutation at codon 169 in a mosaic pattern., (© 2023. Japanese Society of Gastroenterology.)

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine disorder in women of reproductive age, affecting 5-15% globally with a large proportion undiagnosed. This review explores the multifaceted nature of PCOS and its impact on pregnancy, including challenges in fertility due to hormonal imbalances and insulin resistance. Despite restoring ovulation pharmacologically, women with PCOS face lower pregnancy rates and higher risks of implantation failure and miscarriage. Our review focuses on the complexities of hormonal and metabolic imbalances that impair endometrial receptivity and decidualization in PCOS. Disrupted estrogen signaling, reduced integrity of endometrial epithelial tight junctions, and insulin resistance impair the window of endometrial receptivity. Furthermore, progesterone resistance adversely affects decidualization. Our review also examines the roles of various immune cells and inflammatory processes in the endometrium, contributing to the condition's reproductive challenges. Lastly, we discuss the use of rodent models in understanding PCOS, particularly those induced by hormonal interventions, offering insights into the syndrome's impact on pregnancy and potential treatments. This comprehensive review underscores the need for advanced understanding and treatment strategies to address the reproductive complications associated with PCOS, emphasizing its intricate interplay of hormonal, metabolic, and immune factors.

Despite the development of various in vitro differentiation protocols for the efficient derivation of specific cell types, human induced pluripotent stem cell (hiPSC) lines have varing ability to differentiate into specific lineages. Therefore, surrogate markers for accurately predicting the differentiation propensity of hiPSC lines may facilitate cell-based therapeutic product development and manufacture. We attempted to identify marker genes that could predict the differentiation propensity of hiPSCs into neural stem/progenitor cells (NS/PCs). Using Spearman's rank correlation coefficients, we investigated genes in the undifferentiated state, the expression levels of which were significantly correlated with the neuronal differentiation propensity of several hiPSC lines. Among genes significantly correlated with NS/PC differentiation (P < 0.01), we identified ROR2 as a novel predictive marker. ROR2 expression in hiPSCs was negatively correlated with NS/PC differentiation tendency, regardless of the differentiation method, whereas its knockdown enhanced differentiation. ROR2 regulates NS/PC differentiation, suggesting that ROR2 is functionally essential for NS/PC differentiation. Selecting cell lines with relatively low ROR2 expression facilitated identification of hiPSCs that can differentiate into NS/PCs. Cells with ROR2 knockdown showed increased efficiency of differentiation into forebrain GABAergic neurons compared to controls. These findings suggest that ROR2 is a surrogate marker for selecting hiPSC lines appropriate for NS/PC and GABAergic neuronal differentiations., (© 2024. The Author(s).)

Embryonic development and adult physiology are dependent on the action of steroid hormones. In particular, the reproductive system is reliant on hormonal signaling to promote gonadal function and to ensure fertility. Here we will describe hormone receptor functions and their impacts on testicular function, focusing on a specific group of essential hormones: androgens, estrogens, progesterone, cortisol, and aldosterone. In addition to focusing on hormone receptor function and localization within the testis, we will highlight the effects of altered receptor signaling, including the consequences of reduced and excess signaling activity. These hormones act through various cellular pathways and receptor types, emphasizing the need for a multifaceted research approach to understand their critical roles in testicular function. Hormones exhibit intricate interactions with each other, as evidenced, for example, by the antagonistic effects of progesterone on mineralocorticoid receptors and cortisol's impact on androgens. In light of research findings in the field demonstrating an intricate interplay between hormones, a systems biology approach is crucial for a nuanced understanding of this complex hormonal network. This review can serve as a resource for further investigation into hormonal support of male reproductive health., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Matsuyama and DeFalco.)

Purpose: The 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors uses an integrated approach involving histopathology and molecular profiling. Because majority of adult malignant brain tumors are gliomas and primary CNS lymphomas (PCNSL), rapid differentiation of these diseases is required for therapeutic decisions. In addition, diffuse gliomas require molecular information on single-nucleotide variants (SNV), such as IDH1/2. Here, we report an intraoperative integrated diagnostic (i-ID) system to classify CNS malignant tumors, which updates legacy frozen-section (FS) diagnosis through incorporation of a qPCR-based genotyping assay., Experimental Design: FS evaluation, including GFAP and CD20 rapid IHC, was performed on adult malignant CNS tumors. PCNSL was diagnosed through positive CD20 and negative GFAP immunostaining. For suspected glioma, genotyping for IDH1/2, TERT SNV, and CDKN2A copy-number alteration was routinely performed, whereas H3F3A and BRAF SNV were assessed for selected cases. i-ID was determined on the basis of the 2021 WHO classification and compared with the permanent integrated diagnosis (p-ID) to assess its reliability., Results: After retrospectively analyzing 153 cases, 101 cases were prospectively examined using the i-ID system. Assessment of IDH1/2, TERT, H3F3AK27M, BRAFV600E, and CDKN2A alterations with i-ID and permanent genomic analysis was concordant in 100%, 100%, 100%, 100%, and 96.4%, respectively. Combination with FS and intraoperative genotyping assay improved diagnostic accuracy in gliomas. Overall, i-ID matched with p-ID in 80/82 (97.6%) patients with glioma and 18/19 (94.7%) with PCNSL., Conclusions: The i-ID system provides reliable integrated diagnosis of adult malignant CNS tumors., (©2023 American Association for Cancer Research.)

A polystyrene (PS) certified reference material (CRM) for the analysis of decabromodiphenyl ether (BDE 209) was issued. PS disk was prepared by injection molding of the mixture of versine PS and BDE 209. The certification of the PS CRM was conducted by two analytical methods with different sample preparation methods using isotope dilution mass spectrometry (IDMS). The certified value, w CRM , was 978 mg/kg, and this value coincided with the regulation value of BDE 209 in the Restriction of Hazardous Substances directive (1000 mg/kg). The uncertainties related to certification, u wmean , inhomogeneity, u hom , and long- and short-term instability, u sts and u lts , respectively, were evaluated based on the mass fraction of BDE 209. The u wmean , u hom , u sts , and u lts were 0.0265, 0.0046, 0.0061, and 0.0099 (relative), respectively, and the expanded uncertainty for this CRM was determined as 57 mg/kg (coverage factor is 2). Additionally, the quantitative capability of the thermal desorption-gas chromatography/mass spectrometry (TD-GC/MS) method was evaluated. In TD-GC/MS, the analytical values of the developed CRM obtained by the external and internal standard methods with matrix-free calibrants were out of the range of the w CRM (almost 10% larger or smaller), whereas those with matrix-matched calibrants agreed with the w CRM . In contrast to these results, the analytical values obtained by TD-GC/MS using IDMS were consistent with the w CRM no matter if matrix-free or matrix-matched calibrants were used. These results indicated that, for quantification of BDE 209 in PS, the trueness and precision of TD-GC/MS can be enhanced by applying IDMS without matrix-matched calibrants., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Vitamin D (VD) deficiency can lead to health-related consequences. This study determined the effects of VD administration in VD-deficient children with severe motor and intellectual disabilities (SMID). Twenty-eight subjects were included. Among them, 25 subjects with parental consent for VD administration were given 10 µg/day (400 IU/day) of VD in April 2021. Serum 25-hydroxyvitamin D [25(OH)D] levels were measured at least 30 days after the start of VD administration. The total VD intake, serum 25(OH)D levels, and ultraviolet (UV) exposure before the blood tests were investigated. The results showed that the median serum 25(OH)D levels were 8.7 ng/mL (4.3-17.2) and 24.0 ng/mL (7.8-39 ng/mL) from March to May in 2020 and 2021, respectively. Among the 25 subjects, 22 with UV exposure had >20 ng/mL serum 25(OH)D level, and 2 without UV exposure had <20 ng/mL serum 25(OH)D level. Three subjects who did not receive VD supplementation had <20 ng/mL serum 25(OH)D level. Taken together, VD supplementation (10 µg/day) is effective in children with SMID in institutional care. Moreover, it may be sufficient for children with UV exposure, but not for those without.

A 70-year-old woman was referred to our hospital because of slight elevation of soluble interleukin-2 receptor (sIL-2R) and accumulation of 18F-fluorodeoxyglucose (FDG) in S8 of the liver on positron emission tomography. The mass was strongly suspected to be malignant because of contrast enhancement and enlargement in size of the mass, and suspicion of portal vein invasion. Hepatic S8 subsegmentectomy was performed for diagnostic and therapeutic purposes. Hematoxylin and eosin staining of the resected specimen showed small lymphocytes with no atypia and no formation of lymphoid follicles. Immunostaining showed CD3-positive cells in the interfollicular region and CD20-positive cells in the lymphoid follicles. Both CD10 and BCL-2 were negative in the follicular germinal center. CD138-positive plasma cells were observed and there was no light chain restriction. Based on polyclonal growth pattern of lymphocytes in the lymphoid follicles and interfollicular region, she was diagnosed with hepatic reactive lymphoid hyperplasia (RLH).Review of the English literature of hepatic RLH which referred to imaging findings yielded 23 cases, including this case. As a result, we suggest that liver biopsy should be performed for definitive diagnosis, when hepatic RLH is suspected by imaging findings and backgrounds., (© 2023. Japanese Society of Gastroenterology.)

We report a case of a solitary kidney and a single-system ectopic ureter draining into the vestibule in an infant with a Müllerian duct defect. Due to the absence of the upper vagina and uterus, an extremely underdeveloped bladder masqueraded as the vagina, and bladder agenesis was suspected preoperatively. Urinary continence was achieved using staged bladder surgery without augmentation or urinary diversion., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

We report an exceedingly rare case of Klippel-Feil syndrome (KFS), compounded by ipsilateral absence of the vas deferens, renal agenesis, and diaphragmatic hernia. Unilateral absence of the vas deferens was found incidentally during orchidopexy. To the best of our knowledge, no case of unilateral absence of the kidney and vas deferens has been reported in children with KFS., Competing Interests: 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., (© 2023 The Authors.)

X-ray diffraction of silicon irradiated with tightly focused femtosecond x-ray pulses (photon energy, 11.5 keV; pulse duration, 6 fs) was measured at various x-ray intensities up to 4.6×10^{19}  W/cm^{2}. The measurement reveals that the diffraction intensity is highly suppressed when the x-ray intensity reaches of the order of 10^{19}  W/cm^{2}. With a dedicated simulation, we confirm that the observed reduction of the diffraction intensity can be attributed to the femtosecond change in individual atomic scattering factors due to the ultrafast creation of highly ionized atoms through photoionization, Auger decay, and subsequent collisional ionization. We anticipate that this ultrafast reduction of atomic scattering factor will be a basis for new x-ray nonlinear techniques, such as pulse shortening and contrast variation x-ray scattering.

We identified cytoprotective small molecules (CSMs) by a cell-based high-throughput screening of Bax inhibitors. Through a medicinal chemistry program, M109S was developed, which is orally bioactive and penetrates the blood-brain/retina barriers. M109S protected retinal cells in ocular disease mouse models. M109S directly interacted with Bax and inhibited the conformational change and mitochondrial translocation of Bax. M109S inhibited ABT-737-induced apoptosis both in Bax-only and Bak-only mouse embryonic fibroblasts. M109S also inhibited apoptosis induced by staurosporine, etoposide, and obatoclax. M109S decreased maximal mitochondrial oxygen consumption rate and reactive oxygen species production, whereas it increased glycolysis. These effects on cellular metabolism may contribute to the cytoprotective activity of M109S. M109S is a novel small molecule protecting cells from mitochondria-dependent apoptosis both in vitro and in vivo . M109S has the potential to become a research tool for studying cell death mechanisms and to develop therapeutics targeting mitochondria-dependent cell death pathway., Competing Interests: SM and WG filed a patent application for the development of CSMs including M109S.16 All other authors have no competing interest., (© 2023 The Authors.)

Background: Desired longevity represents how strongly people esteem possible extensions of their own lifetime. The association between desired longevity and mortality risk has been reported in only one prospective study, which examined a small sample of older participants. We aimed to examine the hypothesis that desired longevity at middle-age predicted long-term survival., Methods: In the prospective cohort study, residents aged 40-64 years were asked how long they would like to live and asked to choose one from three options: longer than, as long as, or shorter than the life expectancy. We used Cox proportional hazards model to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality according to the three groups for desired longevity, treating the "longer than" group as the reference. We conducted mediation analysis to investigate the mechanism for the association between desired longevity and mortality., Results: We recruited 39,902 residents to the study. Risk of all-cause mortality was significantly higher in the "shorter than" group (HR 1.12; 95% CI, 1.04-1.21). The association was independent of sex, age, marital status, education, medical history, and health status. Regarding cause of death, mortality risk of cancer (HR 1.14; 95% CI, 1.00-1.29) and suicide (HR 2.15; 95% CI, 1.37-3.38) were also higher in the "shorter than" group. The unhealthy lifestyle mediated this association with all-cause mortality by 30.4%., Conclusion: Shorter desired longevity was significantly associated with an increased risk of all-cause mortality, and mortality from cancer and suicide. Lifestyle behaviors particularly mediated this association.

We demonstrate a propagation-based phase-contrast imaging method for full-field X-ray microscopy based on advanced Kirkpatrick-Baez (AKB) mirrors to achieve high-contrast observations of weak phase objects and correct field curvature aberrations. Through a demonstration performed at SPring-8, the phase contrast of weak phase objects such as polystyrene spheres and chemically fixed cells was successfully observed with high sensitivity (∼0.03 rad). Furthermore, the field of view of the AKB mirrors was expanded to the full area of the obtained images (25 × 30 µm) by correcting the field curvature aberration using reconstructed complex wavefields.