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The phase transition from supercooled water to ice is closely related to the electrochemical performance and lifetime of an energy device at sub-zero temperatures. In particular, fuel cells for passenger cars face this issue because they are frequently started and stopped under sub-zero conditions during the winter season. However, there is a lack of visual information regarding the processes that occur within the fuel cell stack, and insight into how to improve the safety and performance during cold starts is lacking. In this study, we developed an operando neutron imaging system to visualise the water distribution inside an automotive single cell simulating a fuel cell stack during cold starts. This was achieved using a rapid heating unit. In addition, we showcased cold-start tests at three different sub-zero temperatures, and the obtained results suggest that pre-conditioning residual water and post-cold-start meltwater have an impact on the rapid cold-start performance.

Introduction: Lignin is a promising resource for obtaining aromatic materials, however, its heterogeneous structure poses a challenge for effective utilization. One approach to produce homogeneous aromatic materials from lignin involves the application of microbial catabolism, which is gaining attention. This current study focused on constructing a catabolic pathway in Pseudomonas sp. NGC7 to produce vanillate (VA) from aromatic compounds derived from the chemical depolymerization of sulfite lignin., Results: Alkaline oxidation of sulfite lignin was performed using a hydroxide nanorod copper foam [Cu(OH) 2 /CF]-equipped flow reactor. The flow reactor operated continuously for 50 h without clogging and it yielded a sulfite lignin stream containing acetovanillone (AV), vanillin (VN), and VA as the major aromatic monomers. The catabolic pathway of Pseudomonas sp. NGC7 was optimized to maximize VA production from aromatic monomers in the sulfite lignin stream derived from this oxidation process. Pseudomonas sp. NGC7 possesses four gene sets for vanillate O-demethylase, comprising the oxygenase component (vanA) and its oxidoreductase component (vanB). Among these, the vanA4B4 gene set was identified as the key contributor to VA catabolism. To facilitate the conversion of AV to VA, AV-converting enzyme genes from Sphingobium lignivorans SYK-6 were introduced. The ΔvanA4B4 strain, harboring these AV-converting genes, produced VA from the sulfite lignin stream with 91 mol%. Further disruption of vanA1B1, vanA2B2, vanA3B3, and a vanillin reductase gene, in addition to vanA4B4, and introduction of a 5-carboxyvanillate decarboxylase gene from S. lignivorans SYK-6 to utilize 5-carboxyvanillin and 5-carboxyvanillate from the sulfite lignin stream for VA production achieved a VA yield of 103 mol%., Conclusion: Developing methods to overcome lignin heterogeneity is essential for its use as a raw material. Consolidating continuous alkaline oxidation of lignin in a Cu(OH) 2 /CF-packed flow reactor and biological funneling using an engineered catabolic pathway of Pseudomonas sp. NGC7 is a promising approach to produce VA for aromatic materials synthesis. NGC7 possesses a higher adaptability to various aromatic compounds generated from the alkaline oxidation of lignin and its natural ability to grow on p-hydroxyphenyl, guaiacyl, and syringyl compounds underscores its potential as a bacterial chassis for VA production from a wide range of lignin-derived aromatic compounds., Competing Interests: Declarations Competing interests Y.H, A.Y, N.K, E.M, and T.S. are the inventors on the patent related to this work (PCT/JP2022/13826). The authors declare no competing financial interest., (© 2024. The Author(s).)

Purpose: To evaluate the impact of intravascular ultrasound (IVUS)-evaluated tissue morphology on recurrence following drug-coated balloon (DCB) angioplasty for the treatment of femoropopliteal in-stent restenosis (FP-ISR)., Methods: This study was a single-center, retrospective, observational study. Study subjects were 65 FP-ISR lesions (mean lesion length: 165 ± 88 mm, occlusive restenosis: 25%) in 53 patients (age: 76 ± 8, diabetes mellitus: 66%) who underwent DCB angioplasty and whose IVUS data of tissue morphology were available. The morphology of ISR was determined by dominant tissue and classified into two group with and without fibrous tissue. Fibrous tissue was defined as the absence of calcification, equal to or more advanced than the echo luminance of the outer membrane, but without acoustic shadow. The outcome measure was recurrence-ISR, and cox proportional hazards models were used to explore factors associated with recurrence-ISR., Results: During mean follow-up period of 16 ± 12 months, recurrence-ISR was found in 32% (n = 21). The tissue morphology of FP-ISR before DCB angioplasty was distributed with 68% (n = 44) in fibrous tissue group and with 33% (n = 21) in non-fibrous tissue group. Factors associated with recurrence-ISR were drug-eluting stent (DES)-ISR (hazard ratio [HR]: 4.329; 95% confidence interval [CI]: 1.572-11.918, P = 0.005) and non-fibrous tissue (HR: 4.595; 95% CI: 1.484-14.228, P = 0.008)., Conclusion: The current study revealed IVUS-evaluated tissue morphology and DES-ISR lesions were significantly associated with recurrence FP-ISR after DCB angioplasty., Competing Interests: Declarations Conflict of interest O. Iida has received remuneration from Boston Scientific Japan. T. Mano has received a research grant from Abbott Medical Japan. The remaining authors have no disclosures to report. The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: OI received honoraria from Medtronic Japan. Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

Background: Although the optimal extent of lymph node dissection in esophagogastric junction cancer (EGJC) has been reported, the efficacy of mediastinal lymph node dissection remains unclear. We aimed to identify risk factors for mediastinal lymph node metastasis and its prognostic impact in patients with EGJC., Methods: A total of 100 consecutive patients who underwent curative surgery for EGJC were eligible. We examined the rates of metastasis, prognosis, and therapeutic value index at each mediastinal lymph node station. In addition, multivariate analyses were performed to identify risk factors for mediastinal lymph node metastasis., Results: The rates of upper, middle, and lower mediastinal lymph node metastases were 12.0%, 20.7%, and 13.2%, respectively. The 5-year overall survival rate was lower in patients with mediastinal lymph node metastasis than in those without mediastinal lymph node metastasis (11.1% vs. 59.2%, p < 0.01). The therapeutic value index was 0 in patients with upper/middle mediastinal lymph node metastasis, and mediastinal lymph node metastasis was an independent prognostic factor (hazard ratio 6.59, 95% confidence interval [CI] 2.48-17.9, p < 0.01). Additionally, the length of esophageal invasion and the presence of hiatal hernia were independent predictors of mediastinal lymph node metastasis (odds ratio 8.21, 95%CI 1.44-46.8, p = 0.02 and odds ratio 7.13, 95%CI 1.22-41.8, p = 0.03)., Conclusion: No survival benefit of mediastinal lymph node dissection was observed. Intensive multidisciplinary treatment could be considered in patients with predicted mediastinal lymph node metastasis, such as those with longer esophageal invasion and those with hiatal hernia., Competing Interests: Declarations Competing interests The authors declare no competing interests. Informed consent All study participants provided informed written consent prior to their study enrollment. This study was approved by the institutional review board and performed under the ethical standards of the Declaration of Helsinki and its later amendments., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Intestinal bacteria play a crucial role in human health, for example, by maintaining immune and metabolic homeostasis and protecting against pathogens. Survival in the human intestine depends on the bacterium's ability to utilize complex carbohydrates. Some species are known to use host-derived glycans; for example, Bifidobacteria can utilize O-glycan of mucin. However, there are few studies on intestinal bacteria utilizing host-derived N-glycan. Here, we identified the mechanism underlying the breakdown and utilization of complex-type N-glycan by the human intestinal bacterium Barnesiella intestinihominis. A growth assay showed that B. intestinihominis can utilize complex-type N-glycan as a carbon source, while RNA-seq analysis identified enzymes and transporters involved in the mechanism of N-glycan breakdown. In particular, the expression of three genes encoding glycoside hydrolase 85 endo-β-N-acetylglucosaminidase (endo-BIN1, endo-BIN2, and endo-BIN3) rose markedly in bacterial cells cultured in complex-type N-glycoprotein medium. We also found that the susC and susD genes, encoding the SusC/SusD membrane complex, form a gene cluster with endo-BIN genes, suggesting that SusC/SusD is involved in transportation of the glycan into the cell. Other genes encoding exo-type glycoside hydrolase enzymes showed elevated expression in cells grown in complex-type N-glycoprotein medium, suggesting that these enzymes function in further degradation of glycan for metabolism by the bacterium. Collectively, these findings suggest the survival strategy of an intestinal bacterium that has a unique metabolic pathway to use host-derived complex-type N-glycan as a nutrient., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Objectives: Northern Japanese children tend to have larger physiques; however, the underlying cause remains unknown. Previous geographical correlation analyses revealed an unusual trend; effective day length was negatively correlated with height and positively correlated with weight (adjusted for height). This paradoxical relationship suggests a thyroid hormone-like effect and possible photoperiodic response. This study aimed to determine whether this phenomenon remains consistent over time and across different regions of Japan., Methods: We used geographically and temporally weighted regression (GTWR) to examine whether the relationship between height and effective day length, which differs from the relationship between weight and effective day length, varies by location and time. GTWR models each observation point separately, allowing for spatial and temporal variations. The analysis included the average height and weight data of children and adolescents by prefecture from 1989 to 2019, along with effective day length considering illuminance above 5000 lx derived from the agrometeorological grid square data., Results: Height was used as the dependent variable, whereas weight and effective day length were used as independent variables. For height estimation, the coefficients of weight and effective day length were consistently positive and negative, respectively, although the regression coefficients showed minor geographical and temporal variations., Conclusion: The opposite correlation between height and effective day length and that between weight and effective day length were consistent. This suggests that the phenomenon is more likely driven by environmental factors than by economic or genetic influences., (© 2024 Wiley Periodicals LLC.)

Aims: Specific cavins and caveolins, known as caveola-related proteins, have been implicated in cardiac hypertrophy and myocardial injury. Cavin-2 forms complexes with other caveola-related proteins, but the role of Cavin-2 in cardiomyocytes (CMs) is poorly understood. Here, we investigated an unknown function of Cavin-2 in CMs., Methods and Results: Under cardiac stress-free conditions, systemic Cavin-2 knockout (KO) induced mild and significant CM hypertrophy. Cavin-2 KO suppressed phosphatase and tensin homologue (PTEN) associated with Akt signalling, whereas there was no difference in Akt activity between the hearts of the wild-type and the Cavin-2 KO mice under cardiac stress-free conditions. However, after swim training, CM hypertrophy was more facilitated with enhanced phosphoinositide 3-kinase (PI3K)-Akt activity in the hearts of Cavin-2 KO mice. Cavin-2 knockdown neonatal rat CMs (NRCMs) using adenovirus expressing Cavin-2 short hairpin RNA were hypertrophied and resistant to hypoxia and H2O2-induced apoptosis. Cavin-2 knockdown increased Akt phosphorylation in NRCMs, and an Akt inhibitor inhibited Cavin-2 knockdown-induced anti-apoptotic responses in a dose-dependent manner. Cavin-2 knockdown increased phosphatidylinositol-3,4,5-triphosphate production and attenuated PTEN at the membrane fraction of NRCMs. Immunostaining and immunoprecipitation showed that Cavin-2 was associated with PTEN at the plasma membrane of NRCMs. A protein stability assay showed that Cavin-2 knockdown promoted PTEN destabilization in NRCMs. In an Angiotensin II (2-week continuous infusion)-induced pathological cardiac hypertrophy model, CM hypertrophy and CM apoptosis were suppressed in CM-specific Cavin-2 conditional KO (Cavin-2 cKO) mice. Because Cavin-2 cKO mouse hearts showed increased Akt activity but not decreased extracellular signal-regulated kinase activity, suppression of pathological hypertrophy by Cavin-2 loss may be due to increased survival of healthy CMs., Conclusion: Cavin-2 plays a negative regulator in the PI3K-Akt signalling in CMs through interaction with PTEN. Loss of Cavin-2 enhances Akt activity by promoting PTEN destabilization, which promotes physiological CM hypertrophy and may enhance Akt-mediated cardioprotective effects against pathological CM hypertrophy., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objective: This study aimed to determine the impact of infrapopliteal (IP) revascularisation establishing in line flow to the wound (IFW) on wound healing in chronic limb threatening ischaemia (CLTI), using a core laboratory assessment for wounds and in line flow., Methods: The Wound directed Angiosome RevasculaRIsation apprOach to patients with cRitical limb iSchaemia (WARRIORS) multicentre observational study enrolled patients with CLTI with tissue loss undergoing IP revascularisation in Japan, with scheduled two year follow up. The primary outcome measure was complete wound healing, defined as achievement of complete epithelialisation of all wounds without major amputation. IP revascularisation establishing IFW was defined as revascularisation after which a tibiopedal artery that actually fed an injured pedal unit was patent. The incidence of wound healing was compared between the IFW and non-IFW groups using inverse probability of treatment weighting based on the propensity score., Results: A total of 440 patients with CLTI (median age, 75 years; male, 64.1%; diabetes mellitus, 72.0%; dialysis, 57.7%) with tissue loss (Wound, Ischaemia, and foot Infection stage 4, 66.4%) who underwent IP revascularisation (endovascular procedure, n = 304; bypass grafting, n = 136) between October 2017 and June 2020 were registered. During a median follow up of 23.6 months, 51.1% achieved wound healing. Successful IP revascularisation with IFW was achieved in 68.2%. After analysis, the IFW group had a higher rate of wound healing than the non-IFW group (34.5 vs. 16.1 per 100 person years; p = .030). The association between IFW and wound healing was not statistically different between patients undergoing bypass grafting and those undergoing an endovascular procedure (p for interaction = .38). There was no statistically significant interaction effect between IFW and direct revascularisation for wound healing (p for interaction = .51)., Conclusion: IP revascularisation establishing IFW was statistically significantly associated with a higher wound healing rate in patients with CLTI., (Copyright © 2024 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.)

For the direct alkaline oxidation of rice husk lignin, we developed a copper foam-based heterogeneous catalyst that offers advantages in its recovery after the reaction mixture. The depolymerized products were utilized for muconate production by an engineered Pseudomonas sp. NGC7-based strain. A hydroxide nanorod-modified copper foam was prepared by the surface oxidation of copper foam, followed by alkaline oxidation of rice husk lignin over the catalyst. The catalyst was easily separated from the cellulosic residues in the reaction mixture, and the residues were then recovered by filtration. The resulting lignin stream was composed of a variety of aromatic monomers containing p-hydroxyphenyl, guaiacyl, and syringyl compounds. The catabolic activity of Pseudomonas sp. NGC7 was demonstrated to be more suitable for muconate production from a mixture comprising 4-hydroxybenzoate (a typical p-hydroxyphenyl compound), vanillate (a guaiacyl compound), and syringate (a syringyl compound), owing to its natural ability to grow on syringate. Thus, it was applied to produce muconate from a rice husk lignin stream prepared through hydroxide nanorod-modified copper foam-catalyzed alkaline oxidation by conferring the genes responsible for converting the acetophenone derivatives to their corresponding aromatic acids and protocatechuate decarboxylase to an NGC7-based strain deficient in protocatechuate 3,4-dioxygenase and muconate cycloisomerase. As a result, the engineered NGC7-based muconate-producing strain produced muconate selectively from the rice husk lignin stream at 93.7 mol% yield., (Copyright © 2024 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Protein trafficking to vacuoles in plants and fungi, and to lysosomes in animals, is essential for the maintenance of cellular homeostasis. In Saccharomyces cerevisiae, the vacuolar protein sorting (VPS) pathway has been well studied by using vacuolar carboxypeptidase Y (CPY) as a model, and many VPS genes have been identified. By contrast, the vacuolar protein trafficking pathway in Schizosaccharomyces pombe remains poorly understood. In this study, we identified a novel VPS gene (SPBC1709.03) in S. pombe that is broadly conserved in fungi, but not in S. cerevisiae. Owing to its DUF3844 domain of unknown function, the gene was named vps3844. Disruption mutants of vps3844 had defects in both CPY sorting and incorporation of FM4-64 dye into the vacuolar membrane. Partial deletion analysis of the Vps3844 protein revealed that, within the DUF3844 domain, the region comprising amino acids 354 to 380 is important for protein trafficking to the vacuole. Our findings represent the first report of a VPS gene involved in vacuolar transport that is conserved in fungi, particularly S. pombe, but lacks representation in S. cerevisiae.

Background: The prognosis remains poor for stage III gastric cancer, and neoadjuvant chemotherapy is increasingly used to improve outcomes. Accurate diagnosis prior to treatment is essential to develop appropriate treatment strategies for poor prognosis subgroups. This study aims to enhance the accuracy of pre-treatment gastric cancer diagnosis using a biological approach centered on circulating circular RNA (circRNA)., Materials and Methods: We conducted a comprehensive analysis of circRNA expression profiles using two Gene Expression Omnibus datasets to identify circRNA candidates associated with stage III gastric cancer. Subsequently, we validated these circRNA biomarkers in two independent clinical cohorts comprising a total of 174 patients with gastric cancer and non-disease controls through real-time polymerase chain reaction (PCR)., Results: Genome-wide circRNA analysis identified a panel of four biomarkers capable of diagnosing pathologically confirmed stage III (pStage III) gastric cancer. In a training cohort (n = 83), a clinically applicable panel of four circRNAs was developed (AUC 0.81), which was successfully validated in an independent clinical cohort (n = 82; AUC 0.76). To assess clinical utility, we combined clinical imaging (cStage) with the circRNA panel. Among those initially diagnosed as cStage III but later confirmed as pStage I/II, 86% were accurately diagnosed using the molecular biological approach with circRNAs., Conclusions: We have developed a circRNA-based non-invasive liquid biopsy that can improve the diagnostic performance of pStage III gastric cancer before treatment. Our circRNA model could provide a sophisticated and personalized approach to assist in treatment planning for patients with advanced gastric cancer., (© 2024. Society of Surgical Oncology.)

[NiFe] hydrogenases catalyze the reversible cleavage of molecular hydrogen into protons and electrons. Here, we have studied the impact of temperature and illumination on an oxygen-tolerant and thermostable [NiFe] hydrogenase by IR and EPR spectroscopy. Equilibrium mixtures of two catalytic [NiFe] states, Ni a -C and Ni a -SR'', were found to drastically change with temperature, indicating a thermal exchange of electrons between the [NiFe] active site and iron-sulfur clusters of the enzyme. In addition, IR and EPR experiments performed under illumination revealed an unusual photochemical response of the enzyme. Ni a -SR'', a fully reduced hydride intermediate of the catalytic cycle, was found to be reversibly photoconverted into another catalytic state, Ni a -L. In contrast to the well-known photolysis of the more oxidized hydride intermediate Ni a -C, photoconversion of Ni a -SR'' into Ni a -L is an active-site redox reaction that involves light-driven electron transfer towards the enzyme's iron-sulfur clusters. Omitting the ground-state intermediate Ni a -C, this direct interconversion of these two states represents a potential photochemical shortcut of the catalytic cycle that integrates multiple redox sites of the enzyme. In total, our findings reveal the non-local redistribution of electrons via thermal and photochemical reaction channels and the potential of accelerating or controlling [NiFe] hydrogenases by light., (© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

We encountered a 67-year-old Japanese man with GNE myopathy and homozygous variants (c.1807G>C, p.V603L) of the GNE gene. The patient developed weakness in the left foot at 24 years old and could only move his wrist joints and hands 43 years after the onset. This genotype is the most common variant and causes severe muscle involvement; however, the distal upper extremities are preserved until the end-stage of the disease. Although severe heart failure is rare in GNE myopathy, mild cardiac dysfunction (ejection fraction 46.1%) was observed. Furthermore, respiratory dysfunction was noted with a preserved diaphragm.

Objectives: According to the conventional postoperative procedure after total ankle arthroplasty (TAA), mobilization and weight-bearing is currently started after completion of wound healing. Recently, early mobilization for dorsiflexion after TAA with modified antero-lateral approach was reported to be feasible and safe. To investigate the further possibility of expediting rehabilitation, this study evaluated the feasibility and safety of early full weight-bearing and gait exercise after cemented TAA., Materials and Methods: This retrospective, observational study investigated 23 consecutive ankles (OA: 14 ankles, RA: 9 ankles) that had received cemented TAA with a modified antero-lateral approach. These ankles were divided into three groups 1. conventional postoperative protocol, 2. early dorsiflexion protocol, 3. early dorsiflexion+full weight-bearing protocol. Postoperative wound complications were observed and recorded. Number of days for hospitalization was also evaluated., Results: No postoperative complications related to wound healing were observed even after early full weight-bearing and gait exercise. Days for hospitalization was significantly shortened in early full weight-bearing and gait exercise group (group 3) from 35-38 days to 24 days., Conclusions: Within this small number of cases, early full weight-bearing and gait exercise from 7 days after cemented TAA was feasible and safe with the modified antero-lateral approach. Combination of early dorsiflexion mobilization and weight-bearing/gait exercise contributed to shortening the hospitalization day. Innovations in postoperative procedures for rehabilitation after TAA can be expected., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Background: Despite recent reports, the effectiveness of postoperative oral nutritional supplementation (ONS) on body weight loss and malnutrition after gastrectomy remains controversial. We aimed to elucidate the effectiveness of ONS especially in octogenarian patients undergoing oncological gastrectomy., Methods: A total of 286 consecutive patients who underwent gastrectomy for gastric cancer were eligible. Postoperative body weight loss, malnutrition, and sarcopenia were compared between patients with and without postoperative ONS among octogenarian patients aged ≥ 80 years and non-octogenarian patients aged < 80 years., Results: In this study, 36 (62.1%) octogenarian and 121 (53.1%) non-octogenarian patients continued postoperative ONS for three months. The clinicopathologic characteristics were not different between the ONS (-) and ONS (+) groups among the octogenarian and non-octogenarian patients. The changes in body weight and serum albumin levels at postoperative 1 year were different between the ONS (-) and ONS (+) groups (P = 0.03 and P = 0.04, respectively) among the octogenarian patients, but not between the two groups among the non-octogenarian patients (P = 0.99 and P = 0.29, respectively). Also, the decline in psoas muscle mass index at postoperative 6 months and 1 year was significantly lower in the ONS (+) group than in the ONS (-) group (P < 0.01 and P < 0.01, respectively). In addition, similar results were found in octogenarian patients who underwent distal gastrectomy., Conclusions: Postoperative ONS could prevent body weight loss, malnutrition, and sarcopenia especially in octogenarian patients who underwent gastrectomy for gastric cancer., (© 2024. The Author(s).)

Craniopharyngiomas, including adamantinomatous (ACP) and squamous papillary (PCP) types, are challenging to treat because of their proximity to crucial pituitary structures. This study aimed to characterize the cellular composition, tumor tissue diversity, and cell-cell interactions in ACPs and PCPs using single-cell RNA sequencing. Single-cell clustering revealed diverse cell types, further classified into developing epithelial, calcification, and immune response for ACP and developing epithelial, cell cycle, and immune response for PCP, based on gene expression patterns. Subclustering revealed the enrichment of classical M1 and M2 macrophages in ACP and PCP, respectively, with high expression of pro-inflammatory markers in classical M1 macrophages. The classical M1 and M2 macrophage ratio significantly correlated with the occurrence of diabetes insipidus and panhypopituitarism. Cell-cell interactions, particularly involving CD44-SPP, were identified between tumor cells. Thus, we developed a comprehensive cell atlas that elucidated the molecular characteristics and immune cell inter-networking in ACP and PCP tumor microenvironments., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Triazole pesticides are widely used fungicides, to which humans are rather highly exposed. They are known to activate drug-sensing receptors regulating expression of hepatic drug metabolizing enzymes and drug transporters, thus suggesting that the hepatic drug detoxification system is modified by these agrochemicals. To investigate this hypothesis, the effects of 9 triazole fungicides towards expression of drug metabolizing enzymes and transporters were characterized in cultured human HepaSH cells, that are human hepatocytes deriving from chimeric humanized liver TK-NOG mice. Most of triazoles used at 10 μM were found to act as inducers of cytochrome P-450 (CYP) 1A1, CYP1A2, CYP2B6, CYP3A4 and UDP-glucuronosyltransferase 1A1 mRNA levels and of CYP3A4 protein; some triazoles also enhanced mRNA expression of the canalicular transporters P-glycoprotein/MDR1, multidrug resistance-associated protein 2 and breast cancer resistance protein. Triazoles however concomitantly inhibited CYP2B6 and CYP3A4 activities and thus appeared as dual regulators of these CYPs, being both inducers of their expression and inhibitors of their activity. The inducing effect however predominated, at least for bromuconazole, propiconazole and tebuconazole. Bromuconazole was moreover predicted to enhance CYP2B6 and CYP3A4 expression in humans exposed to this fungicide in a chronic, acute or occupational context. These data demonstrate that key-actors of the human hepatic detoxification system are impacted by triazole pesticides, which may have to be considered for the risk assessment of these agrochemicals. They additionally highlight that the use of human HepaSH cells as surrogates to primary human hepatocytes represents an attractive and promising way for studying hepatic effects of environmental chemicals., 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 Ltd.. All rights reserved.)

The alpha rhythm in human electroencephalography (EEG) is known to decrease in frequency with age. Previous study has shown that elderly individuals with dementia exhibit higher S values (spatial variability) and SD values (temporal variability) in the triple correlation of the occipital region (P3, P4, Oz) compared to healthy elderly individuals. The objective of this research is to examine changes in S and SD values of the alpha band with aging in healthy individuals using triple correlation values from the frontal region. The subjects were 50 healthy elderly subjects (mean age 73.0 ± 5.1 years), 34 healthy younger subjects (mean age 28.1 ± 4.6 years), and 21 dementia patients (mean age 70.1 ± 9.1 years). The methodology involved recording EEG for 5 min during rest with closed eyes, and then calculating S and SD values of the alpha band (8-13 Hz) using three electrodes in the frontal region (F3, F4, Fpz). The findings indicated that the S values of young individuals were significantly higher than those of elderly individuals ( p  < 0.01), whereas the SD values of young individuals tended to be lower than those of elderly individuals. The elevated S values in young individuals imply greater spatial variability akin to individuals with dementia, whereas the reduced SD values in young individuals suggest lower temporal variability unlike individuals with dementia. The discrepancy between the S value and SD value in healthy young individuals suggests that the normal cortical dipole in the frontal regions might be more abundant in them compared to healthy elderly individuals., Competing Interests: YW, MT, YoK and YuK were employed by Brain Functions Laboratory, Inc. The remaining 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 Watanabe, Shibata, Tanaka, Ishii, Higuchi, Kobayashi and Kosugi.)

Skyrmion structures play critical roles in solid-state systems involving electric, magnetic and optical fields. Previous approaches to the study of skyrmions have involved specific structures in magnetic materials, liquid crystals and polymers in addition to two-dimensional arrays used for electrical control. These methods have encountered limitations and constraints on both the microscopic and macroscopic scales related to the physical properties of materials. The present work demonstrates an origami-based skyrmion engineering strategy that suggests a new approach to topological control. This technique utilizes the unique properties of orientational origami, combining polarization techniques with rotationally symmetric, periodically folded designs. This strategy enables the transformation of flat sheets into three-dimensional structures with associated changes in optical topology, similar to the characteristics of proteins. Topological defects such as misalignments and dislocations in folded molecularly oriented sheets lead to the creation of skyrmion clusters at boundaries having different orientational orders. The strategy reported herein involves the construction of unique metamaterial platforms that could provide new applications for twistronics in graphene and photonic crystals., (© 2024. The Author(s).)

Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the SLC25A48 gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Aims: Neoatherosclerosis is a leading cause of late (>1 year) stent failure following drug-eluting stent implantation. The role of biodegradable (BP) versus durable polymer (DP) drug-eluting stents on long-term occurrence of neoatherosclerosis remains unclear. Superiority of biodegradable against durable polymer current generation thin-strut everolimus-eluting stent (EES) was tested by assessing the frequency of neoatherosclerosis 3 years after primary percutaneous coronary intervention (pPCI) among patients with ST-segment elevation myocardial infarction (STEMI)., Methods: The randomized controlled, multicentre (Japan and Switzerland) CONNECT trial (NCT03440801) randomly (1:1) assigned 239 STEMI patients to pPCI with BP-EES or DP-EES. The primary endpoint was the frequency of neoatherosclerosis assessed by optical coherence tomography (OCT) at 3 years. Neoatherosclerosis was defined as fibroatheroma or fibrocalcific plaque or macrophage accumulation within the neointima., Results: Among 239 STEMI patients randomized, 236 received pPCI with stent implantation (119 BP-EES; 117 DP-EES). A total of 178 patients (75%; 88 in the BP-EES group and 90 in the DP-EES group) underwent OCT assessment at 3 years. Neoatherosclerosis did not differ between the BP-EES (11.4%) and DP-EES (13.3%; odds ratio 0.83, 95% confidence interval 0.33-2.04, p=0.69). There were no differences in the frequency of fibroatheroma (BP-EES 9.1% vs DP-EES 11.1%, p=0.66) or macrophage accumulation (BP-EES 4.5% vs DP-EES 3.3%, p=0.68), and no fibrocalcific neoatherosclerosis was observed. Rates of target lesion failure did not differ between groups (BP-EES 5.9% vs DP-EES 6.0%, p=0.97)., Conclusions: Use of BP-EES for primary PCI in patients presenting with STEMI was not superior to DP-EES regarding frequency of neoatherosclerosis at 3 years., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Despite the large body of work on local field potentials (LFPs), a measure of oscillatory activity in patients with Parkinson's disease (PD), the longitudinal evolution of LFPs is less explored., Objective: To determine LFP fluctuations collected in clinical settings in patients with PD and STN deep brain stimulation (DBS)., Methods: Twenty-two STN-DBS patients (age: 67.6 ± 8.3 years; 9 females; disease duration: 10.3 ± 4.5 years) completed bilateral LFP recordings over three visits in the OFF-stimulation setting. Peak and band power measures were calculated from each recording., Results: After bilateral LFP recordings, at least one peak was detected in 18 (81.8%), 20 (90.9%), and 22 (100%) patients at visit 1, 2, and 3, respectively. No significant differences were seen in primary peak amplitude (F = 2.91, p = 0.060) over time. Amplitude of the second largest peak (F = 5.49, p = 0.006) and low-beta (F = 6.89, p = 0.002), high-beta (F = 13.23, p < 0.001), and gamma (F = 12.71, p < 0.001) band power demonstrated a significant effect of time. Post hoc comparisons determined low-beta power (Visit 1-Visit 2: t = 3.59, p = 0.002; Visit 1-Visit 3: t = 2.61, p = 0.031), high-beta (Visit 1-Visit 2: t = 4.64, p < 0.001; Visit 1-Visit 3: t = 4.23, p < 0.001) and gamma band power (Visit 1-Visit 2: t = 4.65, p < 0.001; Visit 1-Visit 3: t = 4.00, p < 0.001) were significantly increased from visit 1 recordings to both follow-up visits., Conclusion: Our results provide substantial evidence that LFP can reliably be detected across multiple real-world clinical visits in patients with STN-DBS for PD. Moreover, it provides insights on the evolution of these LFPs., Competing Interests: Declaration of competing interest AF: Owns stock in Inbrain Pharma; consultancies from Abbvie, Abbott, Boston Scientific, Ceregate, Inbrain, Ipsen, Medtronic, Iota, and Syneos Health; advisory boards for Abbvie, Boston Scientific, Ceregate, Inbrain, Ipsen; honoraria from Abbvie, Abbott, American Academy of Neurology, Boston Scientific, Brainlab, Ipsen, Medtronic, Merz, Movement Disorders Society, Sunovion, Paladin Labs, UCB, Sunovion; royalties from Springer; grants from Abbvie, Boston Scientific, Dystonia Medical Research Foundation, University of Toronto, Michael J Fox Foundation, Medtronic, MSA coalition, Praxis, ES. HM: No conflicts to declare. GO: Honoraria from Medtronic, Boston Scientific, Abbott Japan LLC Otsuka Pharmaceutical, Co. Ltd., Sumitomo Pharma Co. Ltd., Eisai Co., Ltd., FP pharma, Takeda Pharmaceutical Company LTD., Kyowa Hakko Kirin Co. Ltd., and AbbVie, Inc.; grants from Grant from the Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C) (#21K12711s). NM: No conflicts to declare. TW: No conflicts to declare. YH: No conflicts to declare. AS: Employed by Medtronic. CS: Owns stock in Medtronic; employed by Medtronic. NM: Owns stock in Medtronic; employed by Medtronic., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: In recent years, clinicians have focused on the importance of preventing hypoglycemia. We evaluated the impact of different reconstruction procedures after proximal gastrectomy on glycemic variability in non-diabetic patients with gastric cancer., Methods: This prospective observational study was conducted between April 2020 and March 2023. Flash continuous glucose-monitoring, a novel method for assessing glycemic control, was used to evaluate the glycemic profiles after gastrectomy. A flash continuous glucose-monitoring sensor was placed subcutaneously at the time of discharge, and glucose trends were evaluated for 2 weeks., Results: The anastomotic methods for proximal gastrectomy were esophagogastrostomy in 10 patients and double-tract reconstruction in 10 patients. The time below this range (glucose levels < 70 mg/dL) was significantly higher in the double-tract reconstruction group than in the esophagogastrostomy group (p = 0.049). A higher nocturnal time below this range was significantly correlated with an older age and double-tract reconstruction (p = 0.025 and p = 0.025, respectively)., Conclusion: These findings provide new insights into reconstruction methods after proximal gastrectomy by assessing postoperative hypoglycemia in non-diabetic patients with gastric cancer., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Microtubules (MTs) are dynamic cytoskeletal polymers that play a critical role in determining cell polarity and shape. In plant cells, acentrosomal MTs are localized on the cell surface and are referred to as cortical MTs. Cortical MTs nucleate in the cell cortex and detach from nucleation sites. The released MT filaments perform treadmilling, with the plus-ends of MTs polymerizing and the minus-ends depolymerizing. Minus-end targeting proteins, -TIPs, include Spiral2, which regulates the minus-end dynamics of acentrosomal MTs. Spiral2 accumulates autonomously at MT minus-ends and inhibits filament shrinkage, but the mechanism by which Spiral2 specifically recognizes minus-ends of MTs remains unknown. Here we describe the crystal structure of Spiral2's N-terminal MT-binding domain. The structural properties of this domain resemble those of the HEAT repeat structure of the tumor overexpressed gene (TOG) domain, but the number of HEAT repeats is different and the conformation is highly arched. Gel filtration and co-sedimentation analyses demonstrate that the domain binds preferentially to MT filaments rather than the tubulin dimer, and that the tubulin-binding mode of Spiral2 via the basic surface is similar to that of the TOG domain. We constructed an in silico model of the Spiral2-tubulin complex to identify residues that potentially recognize tubulin. Mutational analysis revealed that the key residues inferred in the model are involved in microtubule recognition, and provide insight into the mechanism by which end-targeting proteins stabilize MT ends., 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 Elsevier B.V. All rights reserved.)

Esophageal diverticula are relatively uncommon, especially supradiaphragmatic diverticula. Esophageal diverticula are normally managed by observation; however, surgical treatment is sometimes indicated for large diverticula or diverticula in highly symptomatic patients. Surgical approaches for esophageal diverticula include thoracoscopic or laparoscopic resection; however, consensus has not yet been reached on the optimal approach. Here, we report a case of safe laparoscopic transhiatal esophageal diverticulectomy in a patient with a giant esophageal diverticulum with severe coexisting disease. The patient was a 63-year-old woman with a 17-year history of systemic lupus erythematosus (SLE) who was managed by outpatient therapy with steroids and immunosuppressive drugs. She had a history of SLE-associated renal dysfunction and SLE-associated pulmonary artery thromboembolism, and she was receiving anticoagulation therapy. During an outpatient visit, the patient experienced pericardial discomfort, and upper gastrointestinal endoscopy and computed tomography revealed the presence of a diaphragmatic diverticulum with a diameter of 3 cm. She subsequently developed aspiration pneumonia, which was thought to be caused in part by food stagnation in the diverticulum. However, due to the risks associated with systemic complications, she was initially managed by observation. One year later, the diverticulum had expanded to 6 cm in diameter, and it was determined that the risk of esophageal perforation and aspiration pneumonia was high. Surgery was performed under a laparoscope, and the diverticulum was resected with surgical staplers under an extremely good visual field by dissecting the area around the esophageal hiatus. Postoperative pathology confirmed that the diverticulum was a pseudodiverticulum. The patient's postoperative course was initially good, and she was discharged 10 days after surgery. However, the day after discharge, a hematoma infection occurred near the suture site, requiring re-hospitalization and drainage surgery. After reoperation, she recovered without complications and was discharged 14 days later. Subsequent follow-up showed no diverticulum or pneumonia recurrence. The laparoscopic approach is a minimally invasive approach for patients with diverticula who are at high surgical risk. With an adequate view from the abdominal cavity, even a patient with a fairly large diverticulum can be safely resected., 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, Ozawa et al.)

Background: A comprehensive cardiac rehabilitation (CR) program is recommended for coronary artery disease (CAD). However, many facilities do not have established programs for dietary guidance and patient education, resulting in an exercise-based CR program and limited efficacy for secondary prevention., Methods and Results: A pilot study will be conducted to develop an online Japanese-style intensive cardiac rehabilitation (J-ICR) program for Japanese patients with CAD and will examine adherence, safety, and efficacy. Twenty-four patients diagnosed with stable CAD will be randomly assigned in a 1 : 1 ratio to either an early or late-phase group. The program will comprise the following four parts: exercise sessions; dietary education centered on "the Japan diet"; mindfulness; and group support, with a frequency of 3 h per session, once a week for 12 weeks (a total of 36 h). The primary endpoint will be program feasibility, determined by examining its adherence. Physical examination and function, stress-coping skills, risk of classic CAD (e.g., lipid profile, glucose tolerance, and blood pressure), and dietary changes will be assessed as secondary endpoints., Conclusions: The online J-ICR program is designed as a comprehensive CR program for Japanese patients with CAD. If this program shows high adherence and an improvement in CAD risk factors, its secondary prevention effect should be verified with appropriately powered randomized trials at multiple centers., Competing Interests: K.O. is a member of Circulation Reports’ Editorial Team. The authors declare that there are no conflicts of interest. Conflicts of interest were reviewed by the Kyoto University Clinical Research Conflict of Interest Review Committee in accordance with the Kyoto University Conflict of Interest Policy and Kyoto University Conflict of Interest Management Regulations., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

Competing Interests: Conflict of interest: None declared.

Background and Objectives: Several studies have reported on the resting-state electroencephalogram (EEG) power in patients with schizophrenia, with a decrease in α (especially α2) and an increase in δ and β1 power compared with healthy control; however, reports on at-risk mental states (ARMS) are few. In this study, we measured the resting-state EEG power in ARMS, and investigated its features and the relationship between the power of the frequency bands and their diagnostic outcomes., Methods: Patients with ARMS who were not on any psychotropic medication and met the Comprehensive Assessment of At-Risk Mental State criteria were included. Patients who developed psychotic disorders were labeled as the ARMS-P group, while patients with ARMS who were followed up prospectively for more than 2 years and did not develop psychotic disorders were classified as the ARMS-NP group. EEGs were measured in the resting state, and frequencies were analyzed using standardized low-resolution brain electromagnetic tomography (sLORETA). Seven bands (δ, θ, α1, α2, β1-3) underwent analysis. The sLORETA values (current source density [CSD]) were compared between the ARMS-P and ARMS-NP groups. Clinical symptoms were assessed at the time of EEG measurements using the Positive and Negative Syndrome Scale (PANSS)., Results: Of the 39 patients included (25 males, 14 females, 18.8 ± 4.5 years old), eight developed psychotic disorders (ARMS-P). The ARMS-P group exhibited significantly higher CSD in the β1 power within areas of the left middle frontal gyrus (MFG) compared with the ARMS-NP group (best match: X = -35, Y = 25, Z = 50 [MNI coordinates], Area 8, CSD = 2.33, p < 0.05). There was a significant positive correlation between the β1/α ratio of the CSD at left MFG and the Somatic concern score measured by the PANSS., Discussion: Increased β1 power was observed in the resting EEG before the onset of psychosis and correlated with a symptom. This suggests that resting EEG power may be a useful marker for predicting future conversion to psychosis and clinical symptoms in patients with ARMS., 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 Higuchi, Odagiri, Tateno, Suzuki and Takahashi.)

Background: The introduction of radial-specific equipment has made transradial (TR) aortoiliac (AI) endovascular therapy (EVT) more convenient., Objectives: The authors aimed to investigate the perioperative outcomes of the TR approach in patients undergoing AI EVT for symptomatic peripheral artery disease., Methods: The COMFORT (Contemporary Strategy for Aortoiliac Intervention) registry was a prospective, multicenter, observational study enrolling patients with symptomatic peripheral artery disease undergoing AI EVT between January 2021 and June 2023. The primary outcome was perioperative complications, whereas the secondary outcomes included core laboratory-evaluated residual stenosis >30%, time to hemostasis, time to ambulation, 30-day patency, and 30-day limb symptoms. These outcomes were compared between TR and non-TR AI EVT after propensity score matching., Results: The TR approach was selected for 231 of the 947 patients (24.3%). The TR approach was chosen more in patients with a higher ankle-brachial index, chronic total occlusion, aortic lesion, bare nitinol stent implantation, and plain angioplasty, whereas it was chosen less in patients with dialysis, a history of AI EVT, chronic limb-threatening ischemia, bilateral calcification, and simultaneous infrainguinal EVT (all P < 0.05). After propensity score matching, the incidence of perioperative complications did not differ significantly between the groups (TR group: 6.0% vs non-TR group: 5.1%; P = 0.69). The proportions of residual stenosis, 30-day patency, and 30-day limb symptoms were not significantly different (all P > 0.05); however, the time to hemostasis and the time to ambulation were shorter in the TR group (both P < 0.05)., Conclusions: Non-TR AI EVT and TR AI EVT using radial-specific equipment were associated with a similar risk of perioperative complications. The TR approach helps shorten the time required for hemostasis and ambulation., Competing Interests: Funding Support and Author Disclosures This study was supported by the Japan Endovascular Treatment Conference. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Primary familial brain calcification (PFBC) is a genetic neurological disorder characterized by symmetric brain calcifications that manifest with variable neurological symptoms. This study aimed to explore the genetic basis of PFBC and elucidate the underlying pathophysiological mechanisms. Six patients from four pedigrees with brain calcification were enrolled. Whole-exome sequencing identified two novel homozygous variants, c.488G > T (p.W163L) and c.2135G > A (p.W712*), within the myogenesis regulating glycosidase (MYORG) gene. Cerebellar ataxia (n = 5) and pyramidal signs (n = 4) were predominant symptoms, with significant clinical heterogeneity noted even within the same family. An autopsy of one patient revealed extensive brainstem calcifications, sparing the cerebral cortex, and marked by calcifications predominantly in capillaries and arterioles. The pathological study suggested morphological alterations characterized by shortened foot processes within astrocytes in regions with pronounced calcification and decreased immunoreactivity of AQP4. The morphology of astrocytes in regions without calcification remains preserved. Neuronal loss and gliosis were observed in the basal ganglia, thalamus, brainstem, cerebellum, and dentate nucleus. Notably, olivary hypertrophy, a previously undescribed feature in MYORG-PFBC, was discovered. Neuroimaging showed reduced blood flow in the cerebellum, highlighting the extent of cerebellar involvement. Among perivascular cells constituting the blood-brain barrier (BBB) and neurovascular unit, MYORG is most highly expressed in astrocytes. Astrocytes are integral components of the BBB, and their dysfunction can precipitate BBB disruption, potentially leading to brain calcification and subsequent neuronal loss. This study presents two novel homozygous variants in the MYORG gene and highlights the pivotal role of astrocytes in the development of brain calcifications, providing insights into the pathophysiological mechanisms underlying PFBC associated with MYORG variants., (© 2024. The Author(s).)

Platelets (PLTs) facilitate tumor progression and the spread of metastasis. They also interact with cancer cells in various cancer types. Furthermore, PLTs form complexes with gastric cancer (GC) cells via direct contact and promote their malignant behaviors. The objective of the present study was to explore the molecular mechanisms driving these interactions and to evaluate the potential for preventing peritoneal dissemination by inhibiting PLT activation in GC cells. The present study examined the roles of PLT activation pathways in the increased malignancy of GC cells facilitated by PLT-cancer cells. Transforming growth factor-β receptor kinase inhibitor (TRKI), Src family kinase inhibitor (PP2) and Syk inhibitor (R406) were used to identify the molecules influencing these interactions. Their therapeutic effects were verified via cell experiments and validated using a mouse GC peritoneal dissemination model. Notably, only the PLT activation pathway-related inhibitors TRKI and PP2, but not R406, inhibited the PLT-enhanced migration and invasion of GC cells. In vivo analyses revealed that PLT-enhanced peritoneal dissemination was suppressed by PP2. Overall, the present study revealed the important role of the Srk family in the interactions between PLTs and GC cells, suggesting kinase inhibitors as promising therapeutic agents to mitigate the progression of peritoneal metastasis in patients with GC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Nakayama et al.)

Although the efficacy of mechanical thrombectomy (MT) for acute basilar artery occlusion (ABAO) has been established in two randomized controlled studies, many patients have miserable clinical outcomes after MT for ABAO. Predicting severe disability prior to the procedure might be useful in determining the appropriateness of treatment interventions. Among the ABAO cases treated at 10 hospitals between July 2014 and December 2021, 144 were included in the study, all of whom underwent MRI before treatment. A miserable outcome was defined as a modified Rankin Scale (mRS) of 5-6 at 3 months. The associations between clinical, imaging, and procedural factors and miserable outcomes were evaluated. A miserable outcome was observed in 54 cases (37.5%). Multivariate analysis identified the National Institutes of Health Stroke Scale (NIHSS), transverse diameter of brainstem infarction, and symptomatic intracerebral hemorrhage as independent factors associated with miserable outcomes, with cutoff values of NIHSS 22 and transverse diameter of brainstem infarction 15 mm. Cases with a higher preoperative severity may result in miserable postoperative outcomes. Particularly, the transverse diameter of a brainstem infarction can be easily measured and serves as a useful criterion for determining treatment indications., (© 2024. The Author(s).)

Renal function significantly influences the appropriate warfarin dosage. However, studies investigating the impact of genetic factors on warfarin dosage, considering renal function, are limited. This study aimed to assess the role of genetic polymorphisms in VKORC1 , CYP2C9 , CYP2C19 , CYP4F2 , GGCX , and APOE in warfarin dosage adjustment considering renal function. A total of 108 outpatients receiving warfarin treatment with controlled prothrombin time-targeted international normalized ratio (1.5-3.0) were included. Patient data, warfarin dosage, and laboratory results were collected from electronic medical records. Each SNP [ VKORC1 rs9923231, CYP2C9 rs1057910, CYP4F2 rs2108622, CYP2C19 * 2 (rs4244285) and * 3 (rs4986893), GGCX rs699664 and rs12714145, and APOE rs7421] was analyzed. Multiple regression analysis revealed estimated glomerular filtration rate as the most significant factor influencing warfarin dose (p <0.001) ( β = -0.445). VKORC1 rs9923231 AA, CYP4F2 rs2108622 CT/TT, GGCX rs12714145 CT/TT, and CYP2C9 rs1057910 AC carriers were associated with warfarin dose (p <0.001, 0.015, 0.020, 0.038 and β = -0.317, 0.191, -0.188, -0.162, respectively); however, other genes showed no significant association. In conclusion, after adjusting for renal function, genetic factors of VKORC1 rs9923231, CYP4F2 rs2108622, GGCX rs12714145, and CYP2C9 rs1057910 were found to contribute to warfarin dosage, having impact in that order. In contrast, the contribution of other genes to warfarin dosage was absent or negligible.

Spinocerebellar ataxia type 14 (SCA14) is a rare form of autosomal dominant cerebellar ataxia caused by mutations in PRKCG. We herein report a case of SCA14 presenting with writer's cramp that predated the onset of progressive ataxia by four years. A 47-year-old Japanese woman had an 11-year history of writer's cramps, followed by unsteadiness. Whole-exome sequencing revealed a heterozygous mutation in PRKCG (p.C142S), leading to an SCA14 diagnosis. Therefore, writer's cramp might be a characteristic extracerebellar sign of SCA14 and can precede the onset of cerebellar ataxia.

Intricate signaling systems are required to maintain homeostasis and promote differentiation in the epidermis. Receptor tyrosine kinases are central in orchestrating these systems in epidermal keratinocytes. In particular, EPHA2 and EGFR transduce distinct signals to dictate keratinocyte fate, yet how these cell communication networks are integrated has not been investigated. Our work shows that loss of EPHA2 impairs keratinocyte stratification, differentiation, and barrier function. To determine the mechanism of this dysfunction, we drew from our proteomics data of potential EPHA2 interacting proteins. We identified EGFR as a high-ranking EPHA2 interactor and subsequently validated this interaction. We found that when EPHA2 is reduced, EGFR activation and downstream signaling are intensified and sustained. Evidence indicates that prolonged SRC association contributes to the increase in EGFR signaling. We show that hyperactive EGFR signaling underlies the differentiation defect caused by EPHA2 knockdown because EGFR inhibition restores differentiation in EPHA2-deficient 3-dimensional skin organoids. Our data implicate a mechanism whereby EPHA2 restrains EGFR signaling, allowing for fine tuning in the processes of terminal differentiation and barrier formation. Taken together, we purport that crosstalk between receptor tyrosine kinases EPHA2 and EGFR is critical for epidermal differentiation., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: We performed a validity test of a recently-reported, small cell lung cancer (SCLC) graded prognostic assessment (GPA) system for SCLC patients with brain metastases (BMs). Thereafter, we created a new prognostic index, the SCLC Grade, for such patients., Materials and Methods: We studied 508 SCLC patients selected from among nearly 7000 consecutive patients undergoing gamma knife SRS for BMs since 1998., Results: In the SCLC GPA, there were no median survival time (MST) differences among pairs of the neighboring subgroups. Therefore, the 508 patients were randomly divided into the two series, i.e., a test (340 patients) and a validity (168) series. In the test series, five factors were identified by univariable analyses as favoring longer survival (rounded lower 95 % CI of the HR was at least 1.3): Sex, Karnofsky Performance Status, tumor numbers, primary tumor status and extracerebral metastases. This new index is the sum of scores (0 and 1) of these five factors: SCLC-Grade 4-6 (score of 4, 5 or 6), 2-3 (2 or 3), and 0-1 (0 or 1). This new system showed highly statistically significant MST differences among subclasses. Next, this SCLC-Grade was applied to the verification series. Consistent results were obtained, i.e., there were highly statistically significant MST differences among subclasses., Conclusions: Our validity test results for the SCLC GPA demonstrated this system to not precisely reflect the outcomes of SCLC patients with BMs. Our results suggest the herein-proposed SCLC-Grade to have superior prognostic value., 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., (© 2024 The Author(s).)

The psychological impact of Internet-based rehabilitation information provision on family caregivers of inpatients has not yet been investigated. This study investigated the impact of the Internet-based rehabilitation information sharing program on anxiety and depression among family caregivers of inpatients. Participants were patients admitted to a rehabilitation hospital and their families. The Internet and Communication Technology (ICT) group received weekly reports with photos and videos showing rehabilitation progress and patients' activities of daily living, whereas the control group received only conventional care. The primary outcomes were the anxiety and depression scores of family caregivers, assessed at admission, discharge, and 1 month after discharge. Eighty-three participants were followed up (ICT group, n = 43; control group, n = 40). To minimize the impact of confounding factors, propensity-score matching was performed. Significant effects on anxiety (P = .03) and depression (P = .049) were found in the ICT group compared with the control group. The median difference in anxiety scores from discharge to 1 month post-discharge was -1.0 (interquartile range [IQR]: -2.0 to 0.8) in the ICT group versus 1.0 (IQR: -1.0 to 2.0) in the control group. The median difference in depression scores from admission to discharge was 0.5 (IQR: -1.0 to 2.8) in the ICT group and 2.0 (IQR: 1.0-3.8) in the control group. The Internet-based rehabilitation information sharing program may help reduce the family caregivers' psychological stress, enabling improved patient care., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The causative genes for over 60% of inherited peripheral neuropathy (IPN) remain unidentified. This study endeavours to enhance the genetic diagnostic rate in IPN cases by conducting screenings focused on non-coding repeat expansions., Methods: We gathered data from 2424 unrelated Japanese patients diagnosed with IPN, among whom 1555 cases with unidentified genetic causes, as determined through comprehensive prescreening analyses, were selected for the study. Screening for CGG non-coding repeat expansions in LRP12 , GIPC1 and RILPL1 genes was conducted using PCR and long-read sequencing technologies., Results: We identified CGG repeat expansions in LRP12 from 44 cases, establishing it as the fourth most common aetiology in Japanese IPN. Most cases (29/37) exhibited distal limb weakness, without ptosis, ophthalmoplegia, facial muscle weakness or bulbar palsy. Neurogenic changes were frequently observed in both needle electromyography (97%) and skeletal muscle tissue (100%). In nerve conduction studies, 28 cases primarily showed impairment in motor nerves without concurrent involvement of sensory nerves, consistent with the phenotype of hereditary motor neuropathy. In seven cases, both motor and sensory nerves were affected, resembling the Charcot-Marie-Tooth (CMT) phenotype. Importantly, the mean CGG repeat number detected in the present patients was significantly shorter than that of patients with LRP12 -oculopharyngodistal myopathy (p<0.0001). Additionally, GIPC1 and RILPL1 repeat expansions were absent in our IPN cases., Conclusion: We initially elucidate LRP12 repeat expansions as a prevalent cause of CMT, highlighting the necessity for an adapted screening strategy in clinical practice, particularly when addressing patients with IPN., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The placenta secretes a prolactin (PRL)-like hormone PRL3B1 (placental lactogen II), a luteotropic hormone essential for maintaining pregnancy until labor in mice. A report from 1984 examined the secretion pattern of PRL3B1 in prepartum mice. In the current study, we found contradictory findings in the secretion pattern that invalidate the previous report. By measuring maternal plasma PRL3B1 and PRL every 4 hrs from gestational day 17 (G17), we newly discovered that maternal plasma PRL3B1 levels decrease rapidly in prepartum C57BL/6 mice. Interestingly, the onset of this decline coincided with the PRL surge at G18, demonstrating a plasma prolactin axis shift from placental to pituitary origin. We also found that maternal plasma progesterone regression precedes the onset of the PRL shift. The level of Prl3b1 mRNA was determined by RT-qPCR in the placenta and remained stable until parturition, implying that PRL3B1 peptide production or secretion was suppressed. We hypothesized that production of the PRL family, the 25 paralogous PRL proteins exclusively expressed in mice placenta, would decrease alongside PRL3B1 during this period. To investigate this hypothesis and to seek proteomic changes, we performed a shotgun proteome analysis of the placental tissue using data-independent acquisition mass spectrometry (DIA-MS). Up to 5,891 proteins were identified, including 17 PRL family members. Relative quantitative analysis between embryonic day 17 (E17) and E18 placentas showed no significant difference in the expression of PRL3B1 and most PRL family members except PRL7C1. These results suggest that PRL3B1 secretion from the placenta is suppressed at G18 (E18).

In the evolving field of drug discovery and development, multiorgans-on-a-chip and microphysiological systems are gaining popularity owing to their ability to emulate in vivo biological environments. Among the various gut-liver-on-a-chip systems for studying oral drug absorption, the chip developed in this study stands out with two distinct features: incorporation of perfluoropolyether (PFPE) to effectively mitigate drug sorption and a unique enterohepatic single-passage system, which simplifies the analysis of first-pass metabolism and oral bioavailability. By introducing a bolus drug injection into the liver compartment, hepatic extraction alone could be evaluated, further enhancing our estimation of intestinal availability. In a study on midazolam (MDZ), PFPE-based chips showed more than 20-times the appearance of intact MDZ in the liver compartment effluent compared to PDMS-based counterparts. Notably, saturation of hepatic metabolism at higher concentrations was confirmed by observations when the dose was reduced from 200 μM to 10 μM. This result was further emphasized when the metabolism was significantly inhibited by the coadministration of ketoconazole. Our chip, which is designed to minimize the dead volume between the gut and liver compartments, is adept at sensitively observing the saturation of metabolism and the effect of inhibitors. Using genome-edited CYP3A4/UGT1A1-expressing Caco-2 cells, the estimates for intestinal and hepatic availabilities were 0.96 and 0.82, respectively; these values are higher than the known human in vivo values. Although the metabolic activity in each compartment can be further improved, this gut-liver-on-a-chip can not only be used to evaluate oral bioavailability but also to carry out individual assessment of both intestinal and hepatic availability.

Objectives: This article aims to examine the ability of the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) risk score to predict the occurrence of serious infections in Japanese patients with rheumatoid arthritis (RA), after initiating their first biologic disease-modifying antirheumatic drug (bDMARD)., Methods: We used data from the Institute of Rheumatology, Rheumatoid Arthritis cohort from 2008 to 2020. Patients with RA who were started on their first bDMARDs were included. Those with missing data required to calculate the score were excluded. A receiver operating characteristic curve was used to evaluate the discriminatory ability of the RABBIT score., Results: A total of 1081 patients were enrolled. During the 1-year observational period, 23 (1.7%) patients had serious infections; the most frequent one was bacterial pneumonia (n = 11, 44%). The median RABBIT score in the serious infection group was significantly higher than that in the non-serious infection group [2.3 (1.5-5.4) vs 1.6 (1.2-2.5), P < .001]. The area under the receiver operating characteristic curve for the occurrence of serious infections was 0.67 (95% confidence interval 0.52-0.79), suggesting that the score had low accuracy., Conclusions: Our present study revealed that the RABBIT risk score did not have sufficient discriminatory ability for predicting the development of severe infections in Japanese patients with RA after initiating their first bDMARD., (© Japan College of Rheumatology 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Here, we describe two patients with juvenile xanthogranuloma (JXG) manifesting with Langerhans cell histiocytosis (LCH)-associated neurodegenerative disease (ND)-like radiological findings. One patient showed typical radiological abnormalities at onset, which worsened with progressing central nervous system symptoms 7 years after LCH-oriented chemotherapy. Another showed spontaneous regression of clinical symptoms, with a transient radiological change 1 year after salvage chemotherapy for recurrence of JXG. These data regarding JXG-associated ND will facilitate future investigation of the disease, as well as development of therapeutic interventions., (© 2024 Wiley Periodicals LLC.)

Background: Postoperative pneumonia in patients with esophageal cancer occurs due to swallowing dysfunction and aspiration. Recently, maximum phonation time (MPT) assessment and repetitive saliva swallowing test (RSST) have been focused on as swallowing function assessment methods that can identify patients as high risk for pneumonia. We aimed to evaluate the clinical utility of MPT assessment and RSST in patients undergoing oncological esophagectomy., Methods: In total, 47 consecutive patients who underwent esophagectomy for esophageal cancer between August 2020 and July 2023 were eligible. The perioperative changes in MPTs and RSST scores were examined. In addition, univariate and multivariate analyses were performed to identify the predictive factors of postoperative pneumonia., Results: The median MPTs before surgery and on postoperative days (PODs) 3, 6, and 10 were 18.4, 7.2, 10.6, and 12.4 s, respectively; postoperative MPTs were significantly lower than preoperative MPT. In addition, the MPT of POD 6 was significantly longer than that of POD 3 (P < 0.05). Meanwhile, there were no significant changes in perioperative RSST scores. Overall, 8 of 47 patients (17.0%) developed pneumonia postoperatively. A short MPT on POD 6 was one of the independent predictive factors for the incidence of postoperative pneumonia (odds ratio: 12.6, 95% confidence interval: 1.29-123, P = 0.03) in the multivariate analysis., Conclusions: The MPT significantly decreased after esophagectomy. However, the RSST score did not. The MPT on POD6 can be a predictor of postoperative pneumonia., (© 2024. The Author(s), under exclusive licence to The Author(s) under exclusive licence to The Japan Esophageal Society.)

It is ideal to ingest bioactive substances from daily foods to stay healthy. Rice is the staple food for almost half of the human population. We found that an orally administered enzymatic digest of rice endosperm protein exhibits antidepressant-like effects in the tail suspension test (TST) using mice. A comprehensive peptide analysis of the digest using liquid chromatography-tandem mass spectrometry was performed, and a tridecapeptide QQFLPEGQSQSQK, detected in the digest, was chemosynthesized. Oral administration of the tridecapeptide exhibited antidepressant-like effects at a low dose comparable to classical antidepressant in the TST. This also exhibited anti-depressant-like effect in the forced swim test. We named it rice endosperm-derived antidepressant-like peptide (REAP). Intriguingly, intraperitoneal administration had no effect. Orally administered REAP(8-13) but not REAP(1-7) exhibited antidepressant-like activity, suggesting that the C-terminal structure is important for the antidepressant-like effect. We confirmed the presence of REAP, corresponding to rice glutelin type B4(130-142) and B5(130-142), in the digest. The effects of REAP were blocked by both dopamine D 1 and D 2 antagonists. These results suggest that it exerts its antidepressant-like activity through activation of the dopamine system. Taken together, oral administration of a novel tridecapeptide exhibited antidepressant-like effects via the dopamine system. This is the first report of a rice-derived peptide that exhibits antidepressant-like effects., Competing Interests: Conflict of Interest A. Ito, Y. Higuchi, R. Nakayama, and H. Takahashi are the employees of Kameda Seika Co., Ltd. The other authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)