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Introduction Ecological studies have suggested the protective effect of micro-dose lithium in drinking water against suicide, however, the association between body lithium level and suicide is unknown. Objectives We aimed to compare body lithium levels between suicide and non-suicide fatalities. Methods This cross-sectional study included 12 suicides and 16 non-suicides who were examined or dissected at the Tokyo Medical Examiner’s Office from March 2018 to June 2021. The aqueous humor lithium concentration was measured twice using inductively coupled plasma mass spectrometry. Analysis of covariance (ANCOVA) was used to compare the lithium concentration between suicides and non-suicides. Mixed-effects model was conducted to account for all lithium concentration data. Results The aqueous humor lithium concentration did not change after death (t(7)=-0.70, SE=0.03, 95% CI=[-0.09, 0.05], P=0.51, Cohen’s d=0.01). The aqueous humor lithium concentration was lower in suicides (mean 0.50 μg/L (variance s2 0.04)) than in non-suicides (mean 0.92 μg/L (s2 0.07)) (t(26)=4.47, SE=0.09, 95% CI=[0.22 to 0.61], P

An ideal Weyl semimetal is characterized by a dispersion in which only Weyl cones intersect the Fermi level, with low-energy behavior being governed by Weyl fermions. Although ideal Weyl semimetals have long been anticipated, only a few are realized in nonmagnetic materials. In this study, we confirm the presence of Weyl-fermion excitations in the ideal Weyl semimetal CuTlSe_{2} via a combination of magnetoresistance, Hall-effect, magnetic-susceptibility, nuclear magnetic resonance (NMR), and muon-spin relaxation (µSR) experiments. Magnetoresistance measurements reveal a negative longitudinal magnetoresistance (LMR), which scales as B^{2}, while Hall-effect results indicate a predominant contribution from Weyl fermions with a hole-type charge. Magnetic susceptibility and µSR measurements indicate the lack of any intrinsic spontaneous magnetic moments down to base temperature. Finally, the NMR results can be modeled by a two-component effective Hamiltonian, which reproduces well the temperature-dependent ^{63}Cu NMR (T_{1}T)^{−1} factor, shown to scale as T^{2} below 100 K and as T^{1} above 100 K. Overall, we find that the extremely low concentration (10^{17}cm^{−3}) of carriers in CuTlSe_{2} originates from an ideal nonmagnetic Weyl semimetallic state, persisting up to a thermal excitation energy of 9 meV (100 K), above which trivial electronic bands close to E_{F} take over. Our findings highlight CuTlSe_{2} as a new member of the intriguing class of Weyl semimetals.

Muonium (Mu), a pseudoisotope of hydrogen with a positively charged muon in place of the proton, takes the form Mu^{+,0,−} (like isolated hydrogen, i.e., H^{+,0,−}) in semiconductors. The specifics of the charge state depend on the local electronic environment of the host. After initial muon implantation, generated Mu centers interact with free charge carriers and electronic spins, transition between sites, and form a dynamic network of state exchange. We identified the model of Mu dynamics in n-type GaAs using the density matrix simulation method and photoexcited muon spin spectroscopy technique. Fitting to the dark and illuminated μSR data provided transition rates between Mu states, revealing the underlying mechanisms at play between the Mu centers (cf. isolated H) and the host. Deduced capture/scattering cross sections of the Mu states reflected the microscopic dynamics of Mu. Illumination studies enabled us to measure interactions between Mu and minority carriers, which would be unavailable in dark measurements without heating. The methodology developed in this study may be applied to other semiconductor systems for a deeper understanding of the Mu state exchange dynamics.

The rotary ATPases use a rotary catalytic mechanism to drive transmembrane proton movement powered by ATP hydrolysis. Here, the authors report a collection of V/A-ATPase V1 domain structures, providing insights into rotary mechanism of the enzyme and potentially other rotary motor proteins driven by ATP hydrolysis.

Introduction In Japan, the effectiveness of health checkups for children aged 5 years has attracted attention as the basis for a support system for early detection and support of children with developmental disabilities. However, these have not yet become statutory health checkups, and their assessment has not been standardized. This study employed the Strength and Difficulties Questionnaire (SDQ) in examining the health of a 5-year-old child. This study aims to demonstrate the scores’ distribution and obtain the standard land and cutoff values of the SDQ. Objectives From 2010 to 2012, children reaching 5 years of age in Kanie-cho, Aichi Prefecture, Japan, underwent a health checkup. Of the 888 children for whom parental consent was obtained, 884 responses without missing values (453 boys: 51.2%, 430 girls: 48.6%) were included in the analysis. Methods SDQ and medical questionnaires for 5-year-old children were sent to the parents with a formal request for approval for the child to participate in the study. Further, the parents were asked to respond to the questionnaire. The Ethics Committee of the Graduate School of Education and Developmental Sciences, Nagoya University approved this study (No.298). Results A confirmatory factor analysis using the maximum likelihood method revealed a factor structure almost identical to that of Goodman (JCPP 1997; 38 581-586). Nonetheless, items 3, 10, 11, 13, 14, and 22 showed high loadings on factors different from those in the original version. Similar to the original version, we set our criteria so that Some and High Needs would be approximately 10% each. Furthermore, we calculated the percentage of children who fell into these categories and found that the scores that fell into the Need category differed from those in the previous study(Table 1). Image: Conclusions Although the five-factor structure of the SDQ was generally accepted, as pointed out in previous studies (Matsuishi et al. Brain Dev 2008;30 410-415 : Iida et al. 2014; 33-41), differences in expression between English and Japanese and cultural differences may have influenced the results. Therefore, it is necessary to be careful in interpreting the results. Additionally, the differences in the Need classification indicated that the difficulty level tends to be slightly lower in the 5-year-old children’s health checkups and that boys may be more likely to recognize the “Hyperactivity/inattention” problem. Based on these results, it is necessary to consider more effective ways of using the SDQ in 5-year-old children’s health checkups, such as evaluating the SDQ scores in combination with the actual condition of the children at the time of the checkup. Disclosure of Interest None Declared

Introduction Screening for early detection of health issues and support are provided to children needing developmental support. In Japan, a significant percentage of infants requiring support are identified during health checkups. Sometimes, however, problems are first observed when children are of school age. It is, therefore, important to identify the age at which children need early support. Objectives Of the children born in 2005 in Kanie-cho, in Japan, 106 participated in the survey at all time points: age 5, first grade, fifth grade, and eighth grade. Methods The medical checkup results of the participants at age 5 were used to determine who among them needed support After entering school, the participants who scored less than 70 points on the Children’s Global Assessment Scale, where their adjustment was assessed based on the interview with the homeroom teacher, were considered maladjusted. Results The results are presented in Table 1. Thirty participants needed supports at age 5; of these, 20 (66.7%) were maladjusted at any point in their school years—19 (95%) in the first grade, 14 (70%) till the fifth grade, and five (25%) till the eighth grade. Of the 76 participants who did not need support in early childhood, 24 (31.6%) were maladjusted at some point in their school years—nine (37.5%) experienced maladjustment in the first grade, but none of them continued to be maladjusted till the fifth grade, and 14 (58.3%) who were not maladjusted in the first grade experienced it in the fifth or eighth grade (adolescents). Thus, the participants maladjusted in their school years were categorized as follows: 1. The developmental disorders group (experiencing maladjustment throughout since early childhood): 19 2. The “first grade problem” group (experiencing transient problems only in the first grade): 9 3. The adolescent group (experiencing problems during adolescence): 14 Image: Conclusions Since maladjusted children with developmental disabilities are identified in early childhood, support can be provided before they reach school age. Many children with developmental disabilities improve their adjustment as they grow up. It is thus advisable to take a long-term perspective in dealing with problematic behaviors. From late school age to adolescence, problems unrelated to developmental disabilities emerge. By listening to the child’s upbringing, it may be possible to ascertain whether or not the problem stems from a developmental disability. Disclosure of Interest None Declared

Control of oxidation/antioxidation homeostasis is important for cellular protective functions, and disruption of the antioxidation balance by exogenous and endogenous ligands can lead to profound pathological consequences of cancerous commitment within cells. Although cancers are sensitive to antioxidation drugs, these drugs are sometimes associated with problems including tumor resistance or dose-limiting toxicity in host animals and patients. These problems are often caused by the imbalance between the levels of oxidative stress-induced reactive oxygen species (ROS) and the redox efficacy of antioxidants. Increased ROS levels, because of abnormal function, including metabolic abnormality and signaling aberrations, can promote tumorigenesis and the progression of malignancy, which are generated by genome mutations and activation of proto-oncogene signaling. This hypothesis is supported by various experiments showing that the balance of oxidative stress and redox control is important for cancer therapy. Although many antioxidant drugs exhibit therapeutic potential, there is a heterogeneity of antioxidation functions, including cell growth, cell survival, invasion abilities, and tumor formation, as well as the expression of marker genes including tumor suppressor proteins, cell cycle regulators, nuclear factor erythroid 2-related factor 2, and Jun dimerization protein 2; their effectiveness in cancer remains unproven. Here, we summarize the rationale for the use of antioxidative drugs in preclinical and clinical antioxidant therapy of cancer, and recent advances in this area using cancer cells and their organoids, including the targeting of ROS homeostasis.

Abstract Background Crosstalk between the aryl hydrocarbon receptor (AhR) and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling is called the “AhR–Nrf2 gene battery”, which works synergistically in detoxification to support cell survival. Nrf2-dependent phase II gene promoters are controlled by coordinated recruitment of the AhR to adjacent dioxin responsive element (DRE) and Nrf2 recruitment to the antioxidative response element (ARE). The molecular interaction between AhR and Nrf2 members, and the regulation of each target, including phase I and II gene complexes, and their mediators are poorly understood. Methods Knockdown and forced expression of AhR–Nrf2 battery members were used to examine the molecular interactions between the AhR–Nrf2 axis and AhR promoter activation. Sequential immunoprecipitation, chromatin immunoprecipitation, and histology were used to identify each protein complex recruited to their respective cis-elements in the AhR promoter. Actin fiber distribution, cell spreading, and invasion were examined to identify functional differences in the AhR–Jdp2 axis between wild-type and Jdp2 knockout cells. The possible tumorigenic role of Jdp2 in the AhR–Nrf2 axis was examined in mutant Kras-Trp53-driven pancreatic tumors. Results Crosstalk between AhR and Nrf2 was evident at the transcriptional level. The AhR promoter was activated by phase I ligands such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the AhR–Jdp2–Nrf2 axis in a time- and spatial transcription-dependent manner. Jdp2 was a bifunctional activator of DRE- and ARE-mediated transcription in response to TCDD. After TCDD exposure, Jdp2 activated the AhR promoter at the DRE and then moved to the ARE where it activated the promoter to increase reactive oxygen species (ROS)-mediated functions such as cell spreading and invasion in normal cells, and cancer regression in mutant Kras-Trp53-driven pancreatic tumor cells. Conclusions Jdp2 plays a critical role in AhR promoter activation through the AhR–Jdp2–Nrf2 axis in a spatiotemporal manner. The AhR functions to maintain ROS balance and cell spreading, invasion, and cancer regression in a mouse model of mutant Kras–Trp53 pancreatic cancer. These findings provide new insights into the roles of Jdp2 in the homeostatic regulation of oxidative stress and in the antioxidation response in detoxification, inflammation, and cancer progression.

We retrospectively investigated the impact of CTLA-4 polymorphism on outcomes for adult patients who received single-unit cord blood transplantation (CBT) at our institution. CTLA-4 genotyping was performed using real-time polymerase chain reaction with the TaqMan ® SNP genotyping assay for rs231775. This study included 143 recipient-donor pairs. The multivariate analysis showed that recipient rs231775 AA was associated with worse overall survival (OS) (hazard ratio [HR], 2.92; p  = 0.008) and a higher relapse rate (HR, 4.79; p  = 0.002), but donor rs231775 was not. The rs231775 polymorphism in recipients and donors did not affect non-relapse mortality, hematopoietic recovery, or acute and chronic graft-versus-host disease. The beneficial effects of rs231775 GG+GA recipients on OS and relapse were notable in subgroups of patients with high-risk disease status and those with myeloid diseases. The polymorphism of CTLA-4 rs231775in recipients might be associated with the clinical outcomes of single-unit CBT.

Although it has been established that patients with chronic kidney disease and iron deficiency, as indicated by a transferrin saturation of < 20%, are at increased risk of all-cause mortality and cardiovascular events, the optimal management of such patients has not yet been determined. In this post hoc subgroup analysis, we aimed to clarify the effect of ferric citrate hydrate on transferrin saturation in patients with chronic kidney disease and low transferrin saturation (< 20%) undergoing hemodialysis. To accomplish this, we extracted the relevant data on a subset of patients drawn from two previous studies: the ASTRIO study (A Study examining the contribution to Renal anemia treatment with ferric citrate hydrate, Iron-based Oral phosphate binder, UMIN000019176) and a post-marketing surveillance study. The subset of patients used for the present study were those with baseline transferrin saturation < 20%. We found that administration of ferric citrate hydrate increased transferrin saturation and maintained transferrin saturation at approximately 30%. However, because we did not have access to data on all-cause mortality or cardiovascular events, we could not ascertain whether the frequency of these outcomes was reduced in parallel with improvements in transferrin saturation. Further large studies are required.

Objectives: To investigate the relationship between the size and location of osteochondral defects in capitellar osteochondritis dissecans (OCD) measured on coronal and sagittal reconstructed computed tomography (CT) images and the clinical outcomes of arthroscopic debridement in adolescent baseball players., Methods: This retrospective study investigated the clinical outcomes of arthroscopic debridement for capitellar OCD in adolescent baseball players with ≥24 months of follow-up after surgery between 2008 and 2020. On preoperative coronal CT images, medial and lateral distance (%) were used to evaluate the location of the defect. Defect size (%) was also evaluated. On preoperative sagittal CT images, superior and inferior angles (deg) were used to evaluate the location of the defect. The size of the defect was evaluated using the defect angle (deg). Outcome measures were determined using the Timmerman-Andrews score at the latest follow-up. Spearman's rank correlation coefficient was used to examine relationships between these parameters and the Timmerman-Andrews score. Statistical significance was set at p ​< ​0.05., Results: Thirty players [mean age, 14 (range, 11-16) years] underwent arthroscopic debridement: 5 were pitchers, 7 were catchers, 13 were infielders, and 5 were outfielders. Mean follow-up duration was 26 (range, 24-66) months. The median Timmerman-Andrews score at the latest follow-up was 193 [interquartile range (IQR), 181-200] points. Inferior angle showed statistically significant positive correlations with Timmerman-Andrews score (r s  ​= ​0.520, p ​< ​0.01), pain (r s  ​= ​0.478, p ​< ​0.01), and sagittal arc of motion (r s  ​= ​0.409, p ​= ​0.025). Defect angle showed statistically significant negative correlations with Timmerman-Andrews score (r s  ​= ​-0.462, p ​= ​0.010) and flexion contracture (r s  ​= ​-0.424, p ​= ​0.020). Medial distance, lateral distance, defect size, and superior angle were not correlated with the Timmerman-Andrews score or any of its subscores., Conclusion: Posterior or large osteochondral defects of the humeral capitellum on preoperative sagittal CT images affected the outcomes of arthroscopic debridement for capitellar OCD in adolescent baseball players., Level of Evidence: Level V, case series., 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 Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: The authors declare that they have no conflict of interest.

Objectives: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study., Methods: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma., Results: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n  = 8; essential thrombocythemia, n  = 14; and primary myelofibrosis, n  = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed ( n  = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy., Conclusion: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Hyalinized clear cell carcinoma (HCCC) is a rare tumor of the minor salivary gland, characterized by pale cytoplasm and EWSR1::ATF1 fusion. Recently, new fusions such as EWSR1::LARP4 and SMARCA2::CREM have also been identified. Histologically, HCCC closely resembles other salivary gland tumors like mucoepidermoid carcinoma and myoepithelial carcinoma, and there are no specific immunohistological markers for its identification. In this study, we investigated potential markers for HCCC based on the characteristics of minor salivary gland acini, from which these tumors may originate. SOX10 is a known marker for serous gland clusters and NKX3.1 for mucus gland clusters. Fluorescence intensity analysis of double staining, objectively evaluated by AI, revealed variations in the positive intensity of cells single positive for NKX3.1 and SOX10, as well as cells positive for both markers, which are commonly observed in normal minor salivary glands. We evaluated NKX3.1 expression by immunohistochemistry in 12 HCCC cases (including 9 EWSR1::ATF1, one EWSR1::LARP4, and one SMARCA2::CREM), 12 myoepithelial carcinoma cases and Tissue micro array (TMA) containing 88 cases of multiple salivary gland tumors using immunohistochemistry. NKX3.1 was expressed in all 12 HCCC cases (100%), with NKX3.1-positive cells ≧90% in four 3 cases, ≧60% one case, ≧30% five 4 cases, and <30% two 4 cases, respectively. SOX10 was negative in 10 cases and weakly positive in 2 cases. This finding mimics the pattern of expression in minor salivary glands and may explain the occurrence of weak NKX3.1 staining and SOX10 positive cases in HCCC. Additionally, in the TMA analysis, NKX3.1 staining was observed in only one HCCC case. These findings indicate that NKX3.1 is a useful marker for distinguishing HCCC from other clear cell salivary gland neoplasms. This study suggests that NKX3.1, along with SOX10 and CK7, can be utilized to improve the accuracy of HCCC diagnosis., (Copyright © 2024. Published by Elsevier Inc.)

Background: A serum biomarker for diagnosing ulcerative colitis (UC) remains to be established. Although we recently reported an anti-integrin αvβ6 antibody (V6 Ab) for diagnosing UC with high sensitivity and specificity, no large-scale validation study exists. This study aimed to validate the diagnostic value of V6 Ab for UC using a nationwide multicenter cohort study., Methods: We measured V6 Ab titers in patients definitively diagnosed with UC, Crohn's disease (CD), or other gastrointestinal disorders (OGDs). The primary outcome was the diagnostic value of V6 Ab. Secondary outcomes were factors associated with false-negative results in patients with UC and false-positive results in patients without UC and the heterogeneity of the diagnostic value of V6 Ab among the participating facilities., Results: We enrolled 1241, 796, and 206 patients with UC, CD, and OGD, respectively, from 28 Japanese high-volume referral centers. The diagnostic sensitivity of V6 Ab for UC was 87.7%, and its specificities for CD and OGDs were 82.0% and 87.4%, respectively. Multivariable logistic regression analysis showed that false-negative results were associated with older age at the time of sample collection, current smokers, lower partial Mayo score, and not receiving advanced therapies in patients with UC, and false-positive results were associated with colonic CD in patients with CD. No factor was associated with false-positive results in patients with OGDs. There were no significant differences in the diagnostic value of V6 Ab among the centers., Conclusions: The diagnostic value of V6 Ab for UC was validated in the large-scale nationwide multicenter study., Competing Interests: Declarations. Conflict of interest: Masahiro Shiokawa received patent royalties and research grants from Medical and Biological Laboratories Co., Ltd. Tadakazu Hisamatsu received consulting fees from Mitsubishi Tanabe Pharma Co., EA Pharma Co., Abbvie GK., Janssen Pharmaceutical K.K, Nichi-Iko Pharmaceutical Co., Ltd., Eli Lilly, and Gilead Sciences Inc., honorariums from Mitsubishi Tanabe Pharma Co., Abbvie GK., EA Pharma Co., Kyorin Pharmaceutical Co., Ltd., JIMRO Co., Ltd., Janssen Pharmaceutical K.K, Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., and Kissei Pharmaceutical Co., Ltd., and research grants from EA Pharma Co., Abbvie GK., Pfizer Inc., Mitsubishi Tanabe Pharma Co., Kyorin Pharmaceutical Co., Ltd., JIMRO Co., Ltd., Mochida Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Zeria Pharmaceutical Co., Ltd., Nippon Kayaku Co. Ltd., and Boston Scientific Corporation. Hajime Yamazaki received research grants from Takeda Pharmaceutical Co., Ltd. Aki Sakatani received endowed chair from Toukeikai Kyoritsu Hospital. Toshimitsu Fujii received honorariums from Abbvie GK., Janssen Pharmaceutical K.K, Mitsubishi Tanabe Pharma Co. and Takeda Pharmaceutical Co., Ltd., and research grants from Abbvie GK., Alfresa Pharma Co., Boehringer Ingelheim co., Bristol-Myers Squibb, Celgene Inc., Celltrion Inc., EA Pharma Co., Eli Lilly Japan K.K., Gilead Sciences Inc., Janssen Pharmaceutical KK., Kissei Pharmaceutical Co., Ltd., Mebix Inc., Sanofi Ltd., and Takeda Pharmaceutical Co., Ltd. Minoru Matsuura received honorariums from Janssen Pharmaceutical K.K., and Abbvie GK. Reiko Kunisaki received honorariums from Abbvie GK., Janssen Pharmaceutical K.K, Mitsubishi Tanabe Pharma Co., and Takeda Pharmaceutical Co., Ltd., and research grants from Eli Lilly Japan K.K., Janssen Pharmaceutical K.K, and Takeda Pharmaceutical Co., Ltd. Tomohisa Takagi received honorariums from Janssen Pharmaceutical K.K, Mitsubishi Tanabe Pharma Co., Towa Pharmaceutical Co., Mochida Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Abbvie GK., EA Pharma Co., Ltd., and Pfizer Japan Inc., research grants from PreMedia Inc., and scholarship grants from Mitsubishi Tanabe Pharma Co. Tetsuo Takehara received honorariums from Abbvie GK., Gilead Sciences Inc., research grants from Gilead Sciences Inc., Janssen Pharmaceutical K.K, and scholarship grants from Abbvie GK., EA Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Daiichi-Sankyo Co., Ltd., and Nippon Kayaku Co., Ltd. Fumihito Hirai received honorariums from Abbvie GK., EA Pharma Co., Ltd., Janssen Pharmaceutical K.K, Mochida Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., and Takeda Pharmaceutical Co., Ltd., research grants from Eli Lilly Japan K.K., Janssen Pharmaceutical K.K, and Abbvie GK., and scholarship grants from Abbvie GK., EA Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Mitsubishi Tanabe Pharma Co. Motohiro Esaki received honorariums from Abbvie GK., Mitsubishi Chemical Group Co., EA Pharma Co., Ltd., Janssen Pharmaceutical K.K, Takeda Pharmaceutical Co., Ltd., and Pfizer Japan Inc. Hiroshi Nakase received honorariums from Abbvie GK., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Janssen Pharmaceutical K.K, Gilead Sciences Inc., Pfizer Inc., EA Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., VIATRIS Inc, and JIMRO Co., Ltd., research grants from Abbvie GK. and Hoya group Pentax Medical, scholarship grants from Nippon Kayaku Co., Mochida Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Zeria Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co. and EA Pharma Co., Ltd., and endowed chair from Miyarisan Pharmaceutical Co., Ltd., JIMRO Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Kyorin Pharmaceutical Co., Ltd. Katsuyoshi Matsuoka received honorariums from Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Abbvie GK, EA Pharma Co., Ltd., Pfizer Inc., Mochida Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Gilead Sciences, and Eli Lilly Japan K.K., research grants from Janssen Pharmaceutical K.K., and scholarship grants from Mochida Pharmaceutical Co., Ltd. and EA Pharma Co., Ltd. Kaoru Yokoyama received honorariums from Abbvie GK, EA Pharma Co., Ltd., Gilead Sciences Inc., and Takeda Pharmaceutical Co., Ltd. Makoto Naganuma received honorariums from EA Pharma Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical KK., Abbvie GK., JIMRO Co., Ltd., Pfizer Inc., Gilead Sciences Inc., and Takeda Pharmaceutical Co., Ltd., research grants from Kyorin Pharmaceutical Co., Ltd. Mitsubishi Tanabe Pharma Co., Abbvie GK., and Miyarisan Pharmaceutical Co., Ltd., and fees paid for writing a pamphlet from Alfresa Pharma Co. Ltd., Masayuki Saruta received honorariums from Abbvie GK., Takeda Pharmaceutical Co., Ltd., EA Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Gilead Sciences Inc., Janssen Pharmaceutical K.K, Kissei Pharmaceutical Co., Ltd., Viatris Pharmaceutical Co., Ltd., and Nobel Pharma Co. Ltd., research grants from Abbvie GK. CMO Co. Ltd. and PPD-SNBL KK., and scholarship grants from Abbvie GK., Zeria Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Kissei Pharmaceutical Co., Ltd. Hiroshi Seno received honorariums from Eisai Co., Ltd., and scholarship grants from Mitsubishi Tanabe Pharma Co. All other authors have no conflicts of interest., (© 2024. The Author(s).)

Background: Three Janus kinase (JAK) inhibitors are approved for ulcerative colitis (UC) in Japan., Aim: To compare the real-world efficacy and safety of these three JAK inhibitors in UC., Methods: This was a multicentre, retrospective study of patients with UC started on JAK inhibitors. The primary outcome was clinical remission at 10, 26 and 58 weeks, and at the most recent follow-up. To compare the efficacy and safety among the JAK inhibitors, we created three matched cohorts (upadacitinib vs. filgotinib, tofacitinib vs. filgotinib and upadacitinib vs. tofacitinib) using propensity score matching., Results: We identified 228 upadacitinib-treated patients (median follow-up 49 weeks; IQR 25-72), 215 filgotinib-treated patients (follow-up 56 weeks; IQR 17-82) and 159 tofacitinib-treated patients (follow-up 112 weeks; IQR 10-258). Clinical remission rates for upadacitinib, filgotinib and tofacitinib at the most recent follow-up were 72.8%, 50.6% and 45.8%, respectively. Over 70% of the patients previously treated with other biologics or JAK inhibitors achieved clinical remission with upadacitinib. On multivariate analysis, the number of previous advanced therapies was inversely associated with the efficacy of filgotinib and tofacitinib. Comparative analysis showed that upadacitinib-treated patients had higher efficacy and lower risk of discontinuation than patients treated with other JAK inhibitors. However, upadacitinib had a significant risk of acne., Conclusions: Considering the particularly high efficacy of upadacitinib, even in patients with refractory UC, filgotinib or tofacitinib may be considered as an upfront JAK inhibitor before using upadacitinib., (© 2024 John Wiley & Sons Ltd.)

Campylobacter jejuni is one of the major bacterial strains that cause diarrhea in humans. It has been associated with many cases of food poisoning in Japan caused by eating raw, undercooked, and/or improperly prepared chicken meat, liver, and grilled chicken (Yakitori). Campylobacter jejuni is also known to be a preceding infectious pathogen of Guillain-Barré syndrome (GBS), which has a considerably negative health impact on humans. In a case of C. jejuni food poisoning that occurred at a restaurant in Tokyo (Japan) in January 2022, 1 of 4 patients with diarrhea developed GBS, which was presumed to have been caused by undercooked chicken, which has emerged as one of the most common causes of food poisoning in Japan. Moreover, C. jejuni isolates from 3 patients, including those with GBS, had the same genotypes (ST22, HS19, and LOS A). This genotype was frequently detected in patients with GBS in the authors' previous study. Findings confirmed that the patient developed GBS due to food poisoning after consuming undercooked chicken.

ATP synthases play a crucial role in energy production by utilizing the proton motive force (pmf) across the membrane to rotate their membrane-embedded rotor c-ring, and thus driving ATP synthesis in the hydrophilic catalytic hexamer. However, the mechanism of how pmf converts into c-ring rotation remains unclear. This study presents a 2.8 Å cryo-EM structure of the V o domain of V/A-ATPase from Thermus thermophilus, revealing precise orientations of glutamate (Glu) residues in the c 12 -ring. Three Glu residues face a water channel, with one forming a salt bridge with the Arginine in the stator (a/Arg). Molecular dynamics (MD) simulations show that protonation of specific Glu residues triggers unidirectional Brownian motion of the c 12 -ring towards ATP synthesis. When the key Glu remains unprotonated, the salt bridge persists, blocking rotation. These findings suggest that asymmetry in the protonation of c/Glu residues biases c 12 -ring movement, facilitating rotation and ATP synthesis., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Dynobactins are recently discovered ribosomally synthesized and post-translationally modified peptide (RiPP) antibiotics that selectively kill Gram-negative pathogens by inhibiting the β-barrel assembly machinery (Bam) located on their outer membranes. Such activity of dynobactins derives from their unique cross-links between Trp1-Asn4 and His6-Tyr8. In particular, the His6-Tyr8 cross-link is formed between N τ of His6 and C β of Tyr8, an unprecedented type of cross-link in RiPP natural products. The mechanism of the C-N cross-link formation remains elusive. In this work, using in vitro characterizations, we demonstrate that both cross-links in dynobactins are biosynthesized by the radical S -adenosylmethionine (SAM) enzyme DynA. Subsequent mechanistic studies using deuterium-labeled DynB precursor peptides suggested that the C-N cross-linking proceeds through the Tyr8-H β atom abstraction by 5'-deoxyadenosyl radical. The absence of solvent exchange of Tyr8-H α suggested that the mechanism unlikely involves α,β-desaturation of Tyr8. Furthermore, DynA catalyzed covalent modification of Tyr8 of H6A-DynB with small-molecule nucleophiles, suggesting the presence of a highly electrophilic Tyr-derived intermediate. Based on all these observations, we propose that DynA catalyzes Tyr8-H β atom abstraction to generate Tyr8-C β radical followed by its oxidation to a p -quinone methide intermediate, to which His6-N τ attacks to form the C-N cross-link. This quinone methide-dependent mechanism of RiPPs cross-linking is distinct from the previously reported RiPPs cross-linking mechanisms and represents a novel mechanism in RiPPs biosynthesis. We will also discuss the functional, mechanistic, and evolutional relationships of DynA with other peptide-modifying radical SAM enzymes.

Background: The involvement of Mediterranean fever (MEFV) gene mutations in patients with inflammatory bowel disease unclassified (IBDU) remains unclear. This study aimed to determine the clinical characteristics and responsiveness to colchicine in Japanese patients with IBDU carrying MEFV mutations., Methods: In this retrospective cohort study, we examined MEFV mutations using gene analysis, clinical information, and colchicine responsiveness. Furthermore, we examined cytokine production in exon 2-mutated THP-1 cells (a monocytic cell line) and microbiome analysis., Findings: Of the 396 patients diagnosed with IBDU, 60.1% had MEFV mutations. Exon 2 mutations were the most common (83.7%). Among patients with available clinical information, 43.3% of patients with IBDU had typical Familial Mediterranean fever (FMF). The efficacy of colchicine in patients with IBDU carrying MEFV mutations was 84.6%. Significant differences were noted in the production of inflammatory; cytokines between THP-1 cells with and without MEFV mutations. Microbial compositions differed between patients with IBDU carrying MEFV mutations and patients with IBD and healthy controls., Interpretation: Patients with IBDU carrying MEFV mutations responded well to colchicine treatment. A notable subset of patients met the criteria for typical FMF. Alterations in intestinal microbiota may contribute to disease pathogenesis., Funding: This work was supported by the Japan Agency for Medical Research and Development (21ek0410057h0003), a grant from the Uehara Memorial Foundation, and the Health and Labour Sciences Research Grants for research on intractable diseases from the Ministry of Health, Labour and Welfare (MHLW) of Japan (Investigation and Research for Intractable Inflammatory Bowel Disease; Grant Number 20316729)., Competing Interests: Declaration of interests Dr Hiroshi Nakase (HN) reports receiving personal fees from Abbvie Inc., Kissei Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K, Takeda Pharmaceutical Co., Ltd., Pfizer Japan Inc., EA Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Gilead Sciences Inc., VIATRIS Inc., JIMRO Co., Ltd., and grants for commissioned/joint research from Hoya Group Pentax Medical, Mitsubishi Tanabe Pharma Corporation, Mochida Pharmaceutical Co., Ltd., and Abbvie Inc. He has endowed chair by Miyarisan Pharmaceutical Co., Mochida Pharmaceutical Co., Ltd. JIMRO Co., Ltd., and KYORIN Pharmaceutical Co., Ltd. Dr Taku Kobayashi (TK) served as an advisory board member, consultant, or speaker for AbbVie, Activaid, Alfresa Pharma, Alimentiv, Bristol Myers Squibb, Celltrion, Covidien, EA Pharma, Eli Lilly, Ferring Pharmaceuticals, Galapagos, Gilead Sciences, Janssen Pharmaceuticals, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical, and has received research funding from AbbVie, Alfresa Pharma, Bristol Myers Squibb, EA Pharma, Gilead Sciences, Kyorin Pharmaceutical, Mochida Pharmaceutical, Nippon Kayaku, Otsuka Holdings, Pfizer, Sekisui Medical, Takeda, and Zeria Pharmaceutical. Dr Takayuki Matsumoto (TM) reports receiving personal fees from Abbvie Inc., Kissei Pharmaceutical Co., Ltd., KYORIN Pharmaceutical Co., Ltd, Mitsubishi Tanabe Pharma Corporation, Janssen Pharmaceutical K.K, Takeda Pharmaceutical Co., Ltd., Pfizer Japan Inc., EA Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Gilead Sciences Inc., VIATRIS Inc., JIMRO Co., Ltd. Dr Motohiro Esaki (ME) reports receiving personal lecture fees from AbbVie GK, Mitsubishi Tanabe Pharma, EA Pharma Co., Ltd., Janssen Pharmaceutical; Takeda Pharmaceuticals, Pfizer Japan Inc., Gilead Sciences Inc., research grants from Alfresa Pharma Corporation, and scholarship donation from Pfizer Japan Inc. and KYORIN Pharmaceutical Co., Ltd. Dr Kenji Watanabe (KW) reports receiving research support or contract of clinical trial from EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., and AbbVie Japan Co., Ltd., and JIMRO Co., Ltd. He reports receiving payment for consulting, lectures, presentations, educational events, or expert testimony from EA Pharma Co., Ltd., AbbVie Japan Co., Ltd., Takeda Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., and Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Kyorin Pharmaceutical Co., Ltd., JIMRO Co., Ltd., Mochida Pharmaceutical Co., Ltd., Pfizer Japan Inc., Zeria Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd, and support for attending meetings from EA Pharma Co., Ltd., AbbVie Japan Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., JIMRO Co., Ltd., Mochida Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Pfizer Japan Inc., Zeria Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd, Kissei Pharmaceutical Co., Ltd., and Olympus Corporation. He reports participating on data safety monitoring board or advisory board for EA Pharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., AbbVie Japan Co., Ltd., Janssen Pharmaceutical K.K., JIMRO Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Kissei Pharmaceutical Co., Ltd. and receiving medical writing from Takeda Pharmaceutical Co., Ltd., Pfizer Inc., and AbbVie Japan Co., Ltd., and trial use of endoscopic equipment from Olympus Corporation. Dr Reiko Kunisaki (RK) reports receiving personal fees from Abbvie Inc., EA Pharma Co., Ltd., Janssen Pharmaceutical K.K, JIMRO Co., Ltd, KYORIN Pharmaceutical Co., Ltd, Nippon Kayaku Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharma Co Ltd, and grants for commissioned/joint research from Abbvie Inc., EA Pharma Co., Ltd., Eli Lill Japan, Janssen Pharmaceutical K.K, JIMRO Co., Ltd, Takeda Pharma Co Ltd, Viatris Inc, VectivBio, outside the submitted work. Dr Katsuhiro Arai (KA) reports receiving grants support from Janssen Pharmaceutical K.K., Bristol-Myers Squibb Company, Eli Lilly Japan K.K., Takeda Pharmaceutical CO., Ltd., Pfizer Inc., and Zeria Pharmaceutical Co., Ltd., and consulting fees from EA Pharma Co., Ltd., AbbVie GK, Takeda Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., and Zeria Pharmaceutical Co., Ltd., and honoraria for lecture from AbbVie GK, EA Pharma Co., Ltd., Nobelpharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., and Chugai Pharmaceutical Co., Ltd. Dr Dai Ishikawa (DI) reports receiving personal lecture fees from AbbVie GK, EA Pharma Co., Ltd., Zeria Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Pfizer Japan Inc. Dr Yuichi Matsuno (YM) reports receiving personal lecture fees from Mitsubishi Tanabe Pharma, Mochida Pharmaceutical Co., Ltd. Dr Hirotake Sakuraba (HS) receiving personal fees from AbbVie Inc., Takeda Pharmaceutical Co., Ltd, Janssen Pharmaceutical K.K., Pfizer Japan Inc., Mitsubishi Tanabe Pharma Factory Ltd., Eisai Co., Ltd, Nippon Kayaku Co., Ltd, EA Pharma Co., Ltd., and research grants from Yakult Honsha Co., Ltd, LAVIEPRE Co., Ltd, Kao Corporation, Bristol-Myers Squibb Company, AbbVie Inc., AsahiKASEI Pharma Co., Ltd. Dr Nobuhiro Ueno (NU) reports receiving educational grant support from Pfizer Inc. Dr Kaoru Yokoyama (KY) reports receiving personal fees from Abbvie Inc., EA Pharma Co., Ltd., Gilead Sciences Inc. and Takeda Pharmaceutical Co., Ltd. Dr Masayuki Saruta (MS) received scholarship grants form Abbvie GK, EPS Corporation, Zeria Pharmaceutical Co., Ltd, Mochida Pharmaceutical Co., Ltd, EA Pharma Co., Ltd, Kissei Pharmaceutical Co., Ltd, CMIC CMO Co., Ltd., PPD-SNBL K.K. and lecture fees from Abbvie GK, Janssen Pharma K.K., Mitsubishi Tanabe Pharma, Takeda Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd, EA Pharma Co., Ltd, Gilead Sciences K.K., Mochida Pharmaceutical Co., Ltd, Viatris Pharmaceutical Co., Ltd., Nobelpharma Co., Ltd. Dr Masanori Nojima (MN) reports receiving consulting fees from Chugai Pharmaceutical Co., Ltd., JIMRO Co. Ltd., and Alfresa Pharma Corporation, and honoraria for lectures from EA pharma Co. Ltd., Eisai Co., Ltd., and JIMRO Co. Ltd. Dr Tadakazu Hisamatsu (TH) reports jointing research of EA pharma Co. Ltd., and Kissei Pharmaceutical Co. Ltd., and receiving grants support from Mitsubishi Tanabe Pharma Corporation, AbbVie GK, JIMRO Co. Ltd., Zeria Pharmaceutical Co. Ltd., Kyorin Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Takeda Pharmaceutical Co. Ltd., Pfizer Inc., Mochida Pharmaceutical Co. Ltd., and Boston Scientific Corporation, and consulting fees from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Nichi-Iko Pharmaceutical Co. Ltd., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, and Takeda Pharmaceutical Co. Ltd., and honoraria for lectures from Mitsubishi Tanabe Pharma Corporation, EA pharma Co. Ltd., AbbVie GK, Janssen Pharmaceutical K.K., Pfizer Inc., Nichi-Iko Pharmaceutical Co. Ltd., Eli Lilly, Gilead Sciences, Bristol Myers Squibb, Mochida Pharmaceutical Co., Ltd., JIMRO Co. Ltd., and Takeda Pharmaceutical Co. Ltd. Dr. Kohei Wagatsuma (KH), Teruyuki Takeda (TT), Takashi Ibuka (TI), Ryota Hokari (RH), Junji Yokoyama (JK), and Shu Tamano (ST) reports no relevant conflicts of interest for this article., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)