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Enterocutaneous fistulas (ECFs) occurring in the setting of Crohn's disease (CD) are difficult to cure with medical treatment alone and affects a patient's quality of life. A 39-year-old man was diagnosed with an ileocolitis-type CD in 2007. His inflammation was insufficiently controlled despite the administration of an anti-tumor necrosis factor-alpha antibody. Therefore, he underwent subtotal colectomy, terminal ileal resection, and ileostomy for multiple colon and anal stenoses in Dec 2015. The patient subsequently received ustekinumab; however, purulent discharge was observed from a postoperative scar around the umbilicus in July 2019. In July 2021, enteroscopy and magnetic resonance imaging (MRI) showed an ECF extending from the small intestine to the umbilicus. Upon referral to our hospital, laboratory data showed elevated C-reactive protein (CRP) and serum amyloid A (SAA). After receiving colchicine, his purulent discharge disappeared, and his CRP and SAA levels rapidly decreased. Enteroscopy and MRI performed 1 year and 5 months after the administration of colchicine revealed ECF closure. Genetic analysis revealed that the patient harbored an MEFV exon 1 (E84K) mutation., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest. Informed consent: The patient presented in this study provided informed consent. Human rights: All procedures were performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its amendments., (© 2024. Japanese Society of Gastroenterology.)

Background and Purpose: High-density surface electromyography (HD-sEMG) allows non-invasive analysis of motor unit (MU) activity and recruitment. This study examines MU recruitment features as well as action potential using HD-sEMG in the suprahyoid muscles of patients with Parkinson's disease (PD) and assesses alterations caused by cervical percutaneous interferential current stimulation., Methods: Electrical activity of the suprahyoid muscles during tongue elevation was measured using HD-sEMG. Maximum voluntary contraction (MVC) was measured, then the modified entropy, coefficient of variation, correlation coefficient, and root mean square (RMS) were examined. For comparison, HD-sEMG was also conducted on healthy controls. In addition, this study assessed the impact of cervical percutaneous interferential current stimulation on HD-sEMG in patients with PD (Hoehn-Yahr stages 2-4) over 8 weeks., Results: Twenty-two patients with PD (mean age 71.7 ± 6.0, 7 females) and 14 healthy controls (mean age 74.9 ± 6.1, 7 females) were included. The RMS at 60 % MVC was significantly lower in patients with PD than in healthy controls (p = 0.007). After cervical percutaneous interferential current stimulation, the correlation coefficients at 40 % and 60 % MVC significantly decreased (p = 0.040 and p = 0.048, respectively), and the RMS at 60 % MVC significantly increased (p = 0.035)., Conclusion: HD-sEMG of the suprahyoid muscles showed characteristic findings in patients with PD and was able to detect subtle changes due to electrical stimulation intervention. Thus, HD-sEMG could be a promising tool for evaluating swallowing-related muscle conditions and interventions., Competing Interests: Declaration of competing interest HM received honoraria from Eisai, Shionogi, Otsuka Pharmaceutical, and Sumitomo Pharma. The other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Fusicoccin-A (FC-A) is a diterpene glucoside produced by a pathogenic fungus. Since its discovery, FC-A has been widely recognized as a phytotoxin that induces stomatal opening and leaf wilting, eventually leading to plant death. In this study, we present the first evidence that FC-A enhances plant growth by stabilizing the protein-protein interaction between plasma membrane (PM) H + -ATPase and 14-3-3 in guard cells. Long-term treatment of Arabidopsis plants with FC-A resulted in ~ 30% growth enhancement. Structurally similar fusicoccin-J (FC-J) showed a similar degree of growth-promotion activity as FC-A, whereas the more hydrophilic fusicoccin-H (FC-H) exhibited no effect on plant growth, indicating that the enhancement of plant growth observed with FC-A and FC-J involves upregulation of the protein-protein interaction between PM H + -ATPase and 14-3-3 in guard cells, which promotes stomatal opening and photosynthesis., (© 2024. The Author(s).)

The individualization of chromosomes during early mitosis and their clustering upon exit from cell division are two key transitions that ensure efficient segregation of eukaryotic chromosomes. Both processes are regulated by the surfactant-like protein Ki-67, but how Ki-67 achieves these diametric functions has remained unknown. Here, we report that Ki-67 radically switches from a chromosome repellent to a chromosome attractant during anaphase in human cells. We show that Ki-67 dephosphorylation during mitotic exit and the simultaneous exposure of a conserved basic patch induce the RNA-dependent formation of a liquid-like condensed phase on the chromosome surface. Experiments and coarse-grained simulations support a model in which the coalescence of chromosome surfaces, driven by co-condensation of Ki-67 and RNA, promotes clustering of chromosomes. Our study reveals how the switch of Ki-67 from a surfactant to a liquid-like condensed phase can generate mechanical forces during genome segregation that are required for re-establishing nuclear-cytoplasmic compartmentalization after mitosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Proteostasis of the endoplasmic reticulum (ER) is maintained by coordinated action of two major catabolic pathways: proteasome-dependent ER-associated degradation (ERAD) and less characterized lysosomal pathways. Recent studies on ER-specific autophagy (termed "reticulophagy") have highlighted the importance of lysosomes for ER proteostasis. Key to this process are proteins termed reticulophagy receptors that connect ER fragments and Atg8-family proteins, facilitating the lysosomal degradation of both native and aberrant ER proteins in a relatively nonselective manner. In contrast, our recent work identified TOLLIP as a novel type of cargo receptor specifically dedicated to the lysosomal degradation of aberrant ER membrane proteins. The clients of TOLLIP include an engineered model substrate, which mimics an ER-retained aberrant membrane protein, and motor neuron disease-linked misfolded mutants of VAPB and BSCL2/Seipin. TOLLIP acts as a receptor to connect these aberrant ER membrane proteins and phosphatidylinositol-3-phosphate (PtdIns3P) by recognizing the former through its misfolding-sensing intrinsically disordered region (IDR) and ubiquitin-binding CUE domain, and the latter through its C2 domain. These interactions enable PtdIns3P-dependent vesicular trafficking of aberrant membrane proteins to lysosomes without promoting reticulophagic turnover of bulk ER.

A structural alteration in copper/zinc superoxide dismutase (SOD1) is one of the common features caused by amyotrophic lateral sclerosis (ALS)-linked mutations. Although a large number of SOD1 variants have been reported in ALS patients, the detailed structural properties of each variant are not well summarized. We present SoDCoD, a database of superoxide dismutase conformational diversity, collecting our comprehensive biochemical analyses of the structural changes in SOD1 caused by ALS-linked gene mutations and other perturbations. SoDCoD version 1.0 contains information about the properties of 188 types of SOD1 mutants, including structural changes and their binding to Derlin-1, as well as a set of genes contributing to the proteostasis of mutant-like wild-type SOD1. This database provides valuable insights into the diagnosis and treatment of ALS, particularly by targeting conformational alterations in SOD1. Database URL: https://fujisawagroup.github.io/SoDCoDweb/., (© The Author(s) 2024. Published by Oxford University Press.)

Background and Aim: Recently, noninvasive fecal markers have been used as indicators of intestinal inflammation in patients with inflammatory bowel disease (IBD). We conducted a clinical validation study to measure fecal calprotectin (Cp), lactoferrin (Lf), and hemoglobin (Hb) levels using an all-in-one kit in patients with IBD and colorectal tumors and aimed to clarify the utility of these fecal markers., Methods: In this study, 104 patients were analyzed, including 25 patients with ulcerative colitis (UC), 20 with Crohn's disease (CD), 48 with colorectal tumors, and 13 healthy controls (HC). Of the 48 patients with colorectal tumors, 14 had invasive cancer. We validated the utility of fecal Cp, Lf, and Hb levels by simultaneously measuring fecal markers in patients with IBD and colorectal tumors., Results: Fecal Cp and Lf had almost equivalent abilities in detecting clinical remission in patients with UC; however, fecal Cp was slightly superior to Lf. Regarding colorectal tumors, fecal Cp and Lf levels tended to be higher in patients with adenomas and colorectal cancer than in HCs. Although fecal Hb alone had the best sensitivity and specificity for detecting colorectal cancer, it had relatively low sensitivity for detecting advanced neoplasms and colorectal cancer., Conclusion: Fecal Cp and Lf can be used as almost equivalent biomarkers to assess the clinical activity in patients with UC. Fecal Hb is the most useful marker for screening colorectal cancer; however, adding fecal Cp and Lf may compensate for the low sensitivity of detecting for advanced colorectal tumors based on Hb alone., (© 2024 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Aspiration pneumonia is the leading cause of death in patients with Parkinson's disease. The incidence of silent aspiration is high in such patients owing to decreased pharyngeal and laryngeal sensation; thus, interventions for this condition may help prevent pneumonia. In this single-arm, open-label study, we used a cervical percutaneous interferential current stimulation device to activate pharyngeal and laryngeal sensory nerves. We evaluated its effectiveness in patients with Hoehn-Yahr stages 2-4 Parkinson's disease. The primary endpoint was the proportion of patients with a normal cough reflex after consuming 1% citric acid at the end of the intervention compared with baseline measurements. In total, 25 patients received neck percutaneous interferential current stimulation for 20 min twice weekly for 8 weeks. Afterward, the proportion of patients with a normal cough reflex after 1% citric acid consumption increased significantly (p = 0.001), whereas other indicators, such as tongue pressure, peak expiratory flow, and penetration or aspiration during videofluoroscopic examination, remained unchanged. A longer duration of illness, higher Unified Parkinson's Disease Rating Scale total scores, and higher levodopa equivalent daily doses were significantly associated with improved cough test outcomes. Hence, cervical percutaneous interferential current stimulation significantly improved cough reflexes and may improve silent aspiration. Trial Registration: Japan Registry of Clinical Trials, jRCTs062220013, first registered 09/05/2022., (© 2024. The Author(s).)

Background: Parkinson's disease (PD) presents with motor symptoms that hinder physical activity. This study aimed to thoroughly investigate swallowing dysfunction in patients with PD using videofluoroscopy (VF) and the Movement Disorder Society (MDS)-Unified PD Rating Scale (UPDRS) sub-scores., Methods: This study was part of an intervention project to evaluate the effectiveness of cervical percutaneous interferential current stimulation in patients with Hoehn and Yahr stages 2-4 PD. Baseline data, including swallowing-related indicators such as VF, were obtained and compared to the MDS-UPDRS sub-scores including rigidity, tremor, postural instability/gait difficulty, and limb scores., Results: Twenty-seven patients were included in this study. In the VF analysis, laryngeal penetration/aspiration, oral cavity residue, epiglottic vallecular residue, and pharyngeal residue were observed with remarkable frequency. The multivariate analysis revealed that the mean rigidity score of UPDRS was an independent and significantly correlated factor with laryngeal penetration/aspiration during the ingestion of 10 mL of water (odds ratio 1.294, 95% confidence interval 1.035-1.617; p = 0.024)., Conclusion: This study revealed a correlation between muscle rigidity and laryngeal penetration or aspiration risk. The detailed comparative analysis of various individual PD symptoms and swallowing disorders was substantial, which enabled early detection of the risk of swallowing disorder and the implementation of appropriate measures., Trial Registration Number: jRCTs062220013., (© 2023. The Author(s).)

Cytokine-targeted therapies have shown efficacy in treating patients with ulcerative colitis (UC), but responses to these advanced therapies can vary. This variability may be due to differences in cytokine profiles among patients with UC. While the etiology of UC is not fully understood, abnormalities of the cytokine profiles are deeply involved in its pathophysiology. Therefore, an approach focused on the cytokine profile of individual patients with UC is ideal. Recent studies have demonstrated that molecular analysis of cytokine profiles in UC can predict response to each advanced therapy. This narrative review summarizes the molecules involved in the efficacy of various advanced therapies for UC. Understanding these associations may be helpful in selecting optimal therapeutic agents.

Purpose: The microenvironment is required for tissues to maintain their properties in vivo . This microenvironment encompasses the types and three-dimensional arrangement of cells forming the tissues, and their interactions with neighboring cells and extracellular matrices, as represented by the stem cell niche. Tissue regeneration depends not on the original tissue source of the transplanted cells, but on the microenvironment in which they are transplanted. We have previously reported pulp regeneration in a heterotopic root graft model by transplantation of conditioned medium alone, which suggests that host-derived cells expressing receptors for migration factors in conditioned medium migrate into the root canal and cause pulp regeneration. Regenerative medicine is needed to restore the original function of complex tissues. To achieve this, it is necessary to reproduce the changes in the microenvironment of the host tissue that accompany the regenerative response. Therefore, it is important to reproduce the microenvironment in vivo for further development of tissue regeneration therapy. Periostin is also found in the epithelial-mesenchymal junction, with expression sites that differ depending on the mineralized matrix stage, and is involved in regulation of calcification., Methods: We investigate whether periostin contributes to microenvironmental changes in regenerated pulp tissue. Dental pulp stem cells were induced into dentin, and gene expression of DSPP, nestin, DMP1, Runx2, and periostin was analyzed by qPCR and protein expression by IHC. Similarly, gene expression was analyzed using qPCR and protein expression using IHC in regenerated dental pulp obtained by ectopic transplantation., Results: Since these regenerated tissues were observable on the same slice, it was possible to understand changes in the microenvironment within the tissues., Conclusions: Periostin promoted proliferation of pulp stem cells, migration in type I collagen, and calcification in regenerated pulp, which strongly suggests that periostin is a promising candidate as a factor that contributes to the microenvironment of regenerated pulp., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2024 Shintarou Sakatoku et al.)

Plasma membrane (PM) H + -ATPase is crucial for light-induced stomatal opening and phosphorylation of a penultimate residue, Thr948 (pen-Thr, numbering according to Arabidopsis AHA1) is required for enzyme activation. In this study, a comprehensive phosphoproteomic analysis using guard cell protoplasts from Vicia faba shows that both red and blue light increase the phosphorylation of Thr881, of PM H + -ATPase. Light-induced stomatal opening and the blue light-induced increase in stomatal conductance are reduced in transgenic Arabidopsis plants expressing mutant AHA1-T881A in aha1-9, whereas the blue light-induced phosphorylation of pen-Thr is unaffected. Auxin and photosynthetically active radiation induce the phosphorylation of both Thr881 and pen-Thr in etiolated seedlings and leaves, respectively. The dephosphorylation of phosphorylated Thr881 and pen-Thr are mediated by type 2 C protein phosphatase clade D isoforms. Taken together, Thr881 phosphorylation, in addition of the pen-Thr phosphorylation, are important for PM H + -ATPase function during physiological responses, such as light-induced stomatal opening in Arabidopsis thaliana., (© 2024. The Author(s).)

Oral tolerance has been defined as the specific suppression of immune responses to an antigen by prior oral administration of the antigen. It has been thought to serve to suppress food allergy. Previous studies have shown that dendritic cells (DCs) and regulatory T cells (Tregs) are involved in the induction of oral tolerance. However, the detailed mechanisms of Treg induction in oral tolerance remain largely unknown. Eosinophils have been recognized as effector cells in allergic diseases, but in recent years, the diverse functions of tissue-resident eosinophils have been reported. Eosinophils in the intestine have been reported to induce Tregs by releasing TGF-β, but the role of eosinophils in oral tolerance is still controversial. In this study, we analyzed the roles of eosinophils in oral tolerance using eosinophil-deficient ΔdblGATA mice (mice lacking a high-affinity GATA-binding site in the GATA1 promoter). ΔdblGATA mice showed impaired antigen-induced oral tolerance compared to wild-type mice. The induction of RORγt + Tregs in mesenteric lymph nodes (MLNs) by oral tolerance induction was impaired in ΔdblGATA mice compared to wild-type mice. An increase in RORγt + antigen-presenting cells (APCs), which are involved in RORγt + Treg differentiation, in the intestine and MLNs was not seen in ΔdblGATA mice. Notably, the expansion of group 3 innate lymphoid cells (ILC3s), a subset of RORγt + APCs, by oral tolerance induction was seen in wild-type mice but not ΔdblGATA mice. These results suggest that eosinophils are crucial in the induction of oral tolerance, possibly via the induction of RORγt + APCs and RORγt + Tregs.

Background: Many studies have defined sarcopenia based on psoas muscle mass using abdominal computed tomography (CT). We hypothesized that sarcopenia can be assessed by measuring pectoralis muscle mass on chest CT and aimed to examine its relationship with the postoperative prognosis of cardiac surgery., Methods: This retrospective study included 189 patients who underwent cardiac surgery via median sternotomy between July 2020 and June 2022. We excluded patients <70 years old, urgent/emergent cases, no chest CT within 90 days before surgery, and cases in which evaluation of the pectoralis muscle was impossible with CT. The pectoralis muscle area (PMA) was measured using a preoperative chest CT. The sarcopenia cut-off value was defined as the lowest sex-specific tertile in PMA at the level of the 4th thoracic vertebrae., Results: Eighty patients were included. The lower tertile were classified as the sarcopenia group (SG) (n = 26) and the rest as the non-sarcopenia group (NSG) (n = 54). In the SG, 1-year survival was significantly worse than that in NSG (NSG: 92.7% vs. SG: 54.9%, p < 0.0001). In the multivariate model, sarcopenia was an independent risk factor for mid-term all-cause death (hazard ratio, 4.89; 95% confidence interval: 1.14-21.0, p = 0.033)., Conclusion: Preoperative sarcopenia defined using PMA was associated with poor mid-term survival after elective cardiac surgery via median sternotomy. The pectoralis muscle mass observed through a chest CT could be used for preoperative risk scoring in older patients undergoing cardiac surgery.

Facial asymmetry is often seen in patients with skeletal mandibular prognathism and is associated with deformities in the maxillofacial and head regions. The maxillofacial deviation is three-dimensional and affects not only the lateral deviation of the mandible and midface, but also the cranium. This study conducted a three-dimensional morphological evaluation of the cranial base morphology of patients with skeletal mandibular prognathism (ANB < 0°, Wits < 0 mm) with the aim of examining the relationship between deformities of the head region and facial asymmetry. Data obtained from computed tomography conducted during the initial examination of patients with and without skeletal mandibular prognathism with facial asymmetry were used. Differences in the position of structures present in the cranial base were measured, and the association between cranial deformities and mandibular deviation was assessed. The middle cranial base area and the lateral deviation of the mandibular fossa were significantly larger in patients with facial asymmetry compared to those without facial asymmetry. In addition, a correlation between the amount of mandibular deviation and the area of the anterior cranial base was identified in patients with significant cranial deformity ( p = 0.012). Given the identified association between the structure of the head region and facial asymmetry, further studies are needed to determine the factors implicated in the growth process.

Background: The efficacy of intermittent cerebrospinal fluid (CSF) drainage compared with that of continuous CSF drainage in patients with subarachnoid hemorrhage (SAH) remains undetermined to date. Therefore, we investigated whether intermittent CSF drainage is effective in reducing secondary chronic hydrocephalus (sCH) after aneurysmal SAH., Methods: Overall, 204 patients (69 men and 135 women) treated for aneurysmal SAH between 2007 and 2022 were included in this study. Following SAH onset, 136 patients were managed with continuous CSF drainage, whereas 68 were managed with intermittent CSF drainage. Logistic regression analyses were used to calculate the age-adjusted and multivariate odds ratios for the development of sCH. The Cox proportional hazards regression model were used to compare the effects of intermittent and continuous CSF drainage on sCH development., Results: Overall, 96 patients developed sCH among the 204 patients with SAH. In total, 74 (54.4%) of the 136 patients managed with continuous CSF drainage developed sCH, whereas 22 (32.4%) of the 68 patients managed with intermittent CSF drainage developed sCH. This demonstrated that the rate of sCH development was significantly lower among patients managed with intermittent CSF drainage. Compared with continuous CSF drainage, intermittent CSF drainage exhibited a multivariate odds ratio (95% confidential interval) of 0.25 (0.11-0.57) for sCH development. Intermittent CSF drainage was more effective (0.20, 0.04-0.95) in patients with severe-grade SAH than in those with mild-grade SAH (0.33, 0.12-0.95). Intermittent CSF drainage was ineffective in patients with acute hydrocephalus (8.37, 0.56-125.2), but it was effective in patients without acute hydrocephalus (0.11, 0.04-0.31)., Conclusions: Compared with continuous CSF drainage, intermittent drainage is more effective in reducing sCH after aneurysmal SAH. Although intermittent drainage was ineffective in cases of co-occurrence of acute hydrocephalus, it was effective in reducing sCH development regardless of the severity of initial symptoms at SAH onset., (© 2023. The Author(s).)

The quantification of stomatal pore size has long been a fundamental approach to understand the physiological response of plants in the context of environmental adaptation. Automation of such methodologies not only alleviates human labor and bias but also realizes new experimental research methods through massive analysis. Here, we present an image analysis pipeline that automatically quantifies stomatal aperture of Arabidopsis thaliana leaves from bright-field microscopy images containing mesophyll tissue as noisy backgrounds. By combining a You Only Look Once X-based stomatal detection submodule and a U-Net-based pore segmentation submodule, we achieved a mean average precision with an intersection of union (IoU) threshold of 50% value of 0.875 (stomata detection performance) and an IoU of 0.745 (pore segmentation performance) against images of leaf discs taken with a bright-field microscope. Moreover, we designed a portable imaging device that allows easy acquisition of stomatal images from detached/undetached intact leaves on-site. We demonstrated that this device in combination with fine-tuned models of the pipeline we generated here provides robust measurements that can substitute for manual measurement of stomatal responses against pathogen inoculation. Utilization of our hardware and pipeline for automated stomatal aperture measurements is expected to accelerate research on stomatal biology of model dicots., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Left ventricular pseudoaneurysm with a left-to-right shunt is extremely rare, requiring surgery if symptomatic; however, surgery has a high risk. Here, the case of a 77-year-old man with heart failure symptoms is reported, in which he develops a giant left ventricular pseudoaneurysm 16 months after ventricular septal perforation repair as a result of acute myocardial infarction, with mild shunt blood flow from the pseudoaneurysm to the right ventricle. Intraoperative findings showed a free wall rupture along the area where the patch was secured during the initial surgery. The patient was discharged on postoperative day 13, and postoperative examination revealed no abnormalities., (© 2023 The Author(s). Published by The Texas Heart Institute®.)

Cryo-electron tomography (cryo-ET) allows for label-free high-resolution imaging of macromolecular assemblies in their native cellular context. However, the localization of macromolecules of interest in tomographic volumes can be challenging. Here we present a ligand-inducible labeling strategy for intracellular proteins based on fluorescent, 25-nm-sized, genetically encoded multimeric particles (GEMs). The particles exhibit recognizable structural signatures, enabling their automated detection in cryo-ET data by convolutional neural networks. The coupling of GEMs to green fluorescent protein-tagged macromolecules of interest is triggered by addition of a small-molecule ligand, allowing for time-controlled labeling to minimize disturbance to native protein function. We demonstrate the applicability of GEMs for subcellular-level localization of endogenous and overexpressed proteins across different organelles in human cells using cryo-correlative fluorescence and cryo-ET imaging. We describe means for quantifying labeling specificity and efficiency, and for systematic optimization for rare and abundant protein targets, with emphasis on assessing the potential effects of labeling on protein function., (© 2023. The Author(s).)

Endoplasmic reticulum (ER) proteostasis is maintained by various catabolic pathways. Lysosomes clear entire ER portions by ER-phagy, while proteasomes selectively clear misfolded or surplus aberrant proteins by ER-associated degradation (ERAD). Recently, lysosomes have also been implicated in the selective clearance of aberrant ER proteins, but the molecular basis remains unclear. Here, we show that the phosphatidylinositol-3-phosphate (PI3P)-binding protein TOLLIP promotes selective lysosomal degradation of aberrant membrane proteins, including an artificial substrate and motoneuron disease-causing mutants of VAPB and Seipin. These cargos are recognized by TOLLIP through its misfolding-sensing intrinsically disordered region (IDR) and ubiquitin-binding CUE domain. In contrast to ER-phagy receptors, which clear both native and aberrant proteins by ER-phagy, TOLLIP selectively clears aberrant cargos by coupling them with the PI3P-dependent lysosomal trafficking without promoting bulk ER turnover. Moreover, TOLLIP depletion augments ER stress after ERAD inhibition, indicating that TOLLIP and ERAD cooperatively safeguard ER proteostasis. Our study identifies TOLLIP as a unique type of cargo-specific adaptor dedicated to the clearance of aberrant ER cargos and provides insights into molecular mechanisms underlying lysosome-mediated quality control of membrane proteins., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Background and Purpose: Several noninvasive tools assess swallowing disorders, including electronic stethoscope artificial intelligence (AI) analysis for remote diagnosis, with the potential for telemedicine. This study investigated the swallowing sound index in patients with Parkinson's disease (PD)., Methods: This single-arm, open-label trial assessed the impact of cervical percutaneous interferential current stimulation on swallowing in patients with PD classified as Hoehn-Yahr stages 2-4. Stimulation was conducted for 8 weeks. Baseline data were used to examine the link between the swallowing sound index and indicators such as videofluoroscopy (VF). Furthermore, we examined changes in the swallowing sound index after the intervention., Results: Twenty-five patients were included. The swallowing sound index in patients with PD was higher than that in those with amyotrophic lateral sclerosis but considerably lower than that in healthy controls. The number of patients with normal EAT-10 scores positively correlated with the swallowing sound index, whereas elevated C-reactive protein levels were negatively correlated with the swallowing sound index. However, the index displayed no correlation with other indicators, including the VF results. Despite the intervention, the index remained unchanged throughout the study., Conclusion: In patients with PD, a decrease in the swallowing sound index suggests a potential association between swallowing disorders and the risk of aspiration pneumonia., Trial Registration Number: jRCTs062220013., Competing Interests: Declaration of Competing Interest HM received honoraria from Eisai, Shionogi, Otsuka Pharmaceutical, Sumitomo Pharma, Country. All other authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Parkinson's disease (PD) leads to various types of swallowing disorders. We investigated the effect of cervical percutaneous interferential current stimulation on dysphagia. By conducting detailed qualitative and quantitative analysis of videofluoroscopic examination, we aimed to understand dysphagia in patients with PD and investigate its effects on swallowing function., Methods: Patients received cervical percutaneous interferential current stimulation for 20 min twice a week for 8 weeks. In this exploratory study, we evaluated aspiration/laryngeal penetration, oral cavity residue, vallecular residue, and pharyngeal residue. In addition, we performed temporal analysis., Results: Twenty-five patients were completely evaluated. At baseline, the proportions of laryngeal penetration/aspiration, oral cavity residue, epiglottic vallecula residue, and pharyngeal residue were 40.0, 88.0, 72.0, 60.0, and 16.0%, respectively. Conversely, pharyngeal transit time, laryngeal elevation delay time, pharyngeal delay time, and swallowing reflex delay were nearly within the normal ranges. Cervical percutaneous interferential current sensory stimulation improved only oral cavity residue at the end of the intervention, from 88.0 to 56.0%., Discussion: Patients with PD demonstrated remarkably high frequencies of residues in the oral and pharyngeal regions. The usefulness of cervical interferential current stimulation was partially demonstrated for oral cavity residue. Considering that PD exhibits diverse symptoms, further accumulation of cases and knowledge is warranted., Trial Registration: jRCTs062220013., Competing Interests: HM received honoraria from Eisai, Shionogi, Otsuka Pharmaceutical, Sumitomo Pharma. 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 © 2023 Nakamori, Toko, Yamada, Hayashi, Haruta, Hiraoka, Yoshikawa, Nagasaki, Ushio, Yoshikawa, Shimizu, Mikami and Maruyama.)

Background and Purpose: Various prophylactic drugs for cerebral vasospasm and delayed cerebral infarction (DCI) after subarachnoid hemorrhage (SAH) have been used in Japan. To investigate the treatment trends for cerebral vasospasm and frequency of DCI after SAH throughout Japan in 2021., Methods: In 2021 we conducted an anonymous questionnaire survey on management for preventing cerebral vasospasm after aneurysmal SAH, and the frequency of DCI. The questionnaire was emailed to 955 certified neurosurgeons at 553 hospitals in Japan. Of them, 162 hospitals (29% response rate) responded to the questionnaire. Of these, 158 were included in this study, while four hospitals that responded insufficiently were excluded. The efficacy of treatments for reducing DCI were examined through a logistic regression analysis., Results: Among 3,093 patients treated with aneurysmal SAH, 281 patients (9.1%) were diagnosed with DCI related to cerebral vasospasm. Coil embolization had significantly lower DCI frequency (6.9%), compared to microsurgical clipping (11.8%, odds ratio, 0.90; 95% confidential intervals, 0.84-0.96; P , 0.007). In addition, cilostazol administration was associated with significantly lower DCI frequency (0.48; 0.27-0.82; 0.026). The efficacy of cilostazol in reducing DCI remained unchanged after adjustment for covariates. The most effective combination of multiple prophylactic drugs in reducing DCI related to cerebral vasospasm was cilostazol, fasudil, and statin (0.38; 0.22-0.67; 0.005)., Conclusions: This study elucidated the trends in prophylactic drugs to prevent cerebral vasospasm and frequency of DCI after aneurysmal SAH in Japan. Coil embolization and cilostazol administration showed effectiveness in reducing DCI related to cerebral vasospasm in 2021., 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 © 2023 Nishikawa, Yamada, Uchida, Yamanaka, Hayashi, Katano, Tanikawa, Iwama, Iihara, Morioka and Mase.)

Introduction: At our institute, we usually perform robot-assisted surgery for rectal cancer as minimally invasive surgery. It is necessary to recognize the tumor edge accurately when deciding where to place the distal cutting line of the rectum. In this article, with video presentation, we demonstrate the usefulness of intraoperative sonography (IOUS) for detecting the rectal tumor site in robotic surgery. This is the first report to discuss the IOUS image of rectal cancer., Materials and Surgical Technique: After mobilization of the rectum in robotic procedure, the rectum should be straightened. Drop the laparoscopic ultrasonography probe through the 12-mm assistant port and place it at the anterior wall of the rectum. By presenting operative and ultrasound findings simultaneously on a single monitor, the operator can recognize the tumor location accurately and decide on the cutting line. We report three cases in the supporting video presentation., Discussion: Rectal tumors can be detected by IOUS, and this modality is effective for determining the cutting line of the rectum. Real-time navigation by IOUS can be performed noninvasively and easily, so it is expected to be helpful in cases of robotic rectal cancer resection., (© 2023 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Murine IL-17-producing γδT (γδT17) cells are divided into two subsets: natural γδT17 (nγδT17) cells, whose development is restricted to the fetal thymus, and inducible γδT17 cells, which require antigen exposure for their IL-17 production and are presumed to develop from Rorc + Il17a - CCR9 + immature γδT17 cells in the adult thymus and whose T cell receptor (TCR) is biased toward Vγ4. Although IL-23 is known to be involved in developing γδT17 cells, the roles of other cytokines, such as IL-21, which is involved in developing Th17 cells like IL-23, in the development, maintenance, and pathophysiology of γδT17 cells remain unknown. Here, we show that IL-21 is dispensable for the fetal thymic development of nγδT17 cells but is required for the peripheral maintenance of Vγ4 + nγδT17 cells. Upon stimulation with γδTCR, IL-1 plus IL-21 induces the proliferation of Vγ4 + nγδT17 cells via STAT3 as effectively as IL-1 plus IL-23. Using bone marrow chimeric mice, we demonstrated that immature γδT17 cells are produced de novo in the adult mice from donor adult bone marrow cells and that IL-21 is dispensable for their development. Instead, IL-21 is required to expand newly induced Vγ4 + γδT17 cells in the periphery upon immunization. Finally, using adoptive transfer experiments of γδT17 cells, we found that IL-21 receptors on γδT17 cells are involved in maintaining Vγ4 + γδT17 cells, subsequent infiltration of Th17 cells into the spinal cord, and exacerbation of experimental autoimmune encephalomyelitis. Collectively, IL-21 plays a vital role in the maintenance and pathogenesis of Vγ4 + γδT17 cells., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ishikawa, Suto, Abe, Hayashi, Suga, Tanaka, Kageyama, Iwata, Suzuki, Suzuki and Nakajima.)

Introduction: Trends regarding the locations of hypertensive cerebral hemorrhages are unclear. To clarify hypertensive hemorrhage trends, we investigated intracerebral hemorrhages (ICHs) over an 18-year period, focusing on thalamic hemorrhages compared with other sites of hemorrhages., Methods: We reviewed the cases of patients hospitalized for hypertensive ICH in 2004-2021 at our hospital; 1,320 eligible patients were registered with a primary ICH/intraventricular hemorrhage. After exclusion criteria were applied, we retrospectively analyzed 1,026 hypertensive ICH cases., Results: The proportions of thalamic and subcortical hemorrhages increased over the 18-year period, whereas putaminal hemorrhage decreased. Multivariate logistic regression analyses revealed that for thalamic hemorrhage, ≥200 mmHg systolic blood pressure ( p  = 0.031), bleeding <15 mL ( p  = 0.001), and higher modified Rankin scale (mRS) score ≥ 4 at discharge ( p  = 0.006) were significant variables in the late period (2013-2021) versus the early period (2004-2012), whereas for putaminal hemorrhage, significant factors in the late period were triglyceride <150 mg/dL ( p  = 0.006) and mRS score ≥ 4 at discharge ( p  = 0.002). Among the features of the thalamic hemorrhages in the late period revealed by our group comparison with the putaminal and subcortical hemorrhages, the total and subcortical microbleeds were more notable in the thalamic hemorrhages than in the other two types of hemorrhage, whereas cerebellar microbleeds were more prominent when compared only with subcortical hemorrhages., Discussion: Our findings revealed an increasing trend for thalamic hypertensive hemorrhage and a decreasing trend for putaminal hemorrhage. The thalamic hemorrhage increase was observed in both young and older patients, regardless of gender. The main features of thalamic hemorrhage in the late period versus the early period were decrease in larger hemorrhage (≥15 mL) and an increase in cases with higher systolic blood pressure (at least partially involved a small number of untreated hypertensive patients who developed major bleeding). The total and subcortical microbleeds were more notable in the thalamic hemorrhages of the late period than in the putaminal and subcortical hemorrhages. These results may contribute to a better understanding of the recent trends of hypertensive ICHs and may help guide their appropriate treatments for this condition., 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher., (Copyright © 2023 Katano, Nishikawa, Uchida, Yamanaka, Hayashi, Yamada, Tanikawa, Yamada and Mase.)

Background and Aims: Japan has experienced 8 waves of the coronavirus disease 2019 (COVID-19) outbreak over the past 3 years, resulting in an increasing number of deaths and incidence of severe infections. This study aimed to analyze the data from the Japanese inflammatory bowel disease (IBD) patients with COVID-19 registry (J-COSMOS) up to the eighth wave to investigate the clinical course of IBD patients with COVID-19 and factors contributing to disease severity., Methods: In this multicenter, observational, cohort study, we analyzed a cohort of 1308 IBD patients diagnosed with COVID-19, enrolled across 77 participating facilities in the J-COSMOS registry from June 2020 to December 2022. Data on age, sex, IBD (classification, treatment, and activity), and COVID-19 (symptoms, severity, and treatment) were analyzed., Results: The majority of patients (76%) were in clinical remission. According to the World Health Organization classification of COVID-19 severity, 98.4% of IBD patients had nonsevere disease, while 1.6% of patients had severe or critical disease. COVID-19 did not affect disease activity in most IBD patients. Stepwise logistic regression analysis revealed that high body mass index, and cerebrovascular disease were risk factors for severe COVID-19. Corticosteroids could affect COVID-19 severity, whereas anti-tumor necrosis factor α antibodies and thiopurines were associated with a reduced risk of severe COVID-19. No deaths were observed among IBD patients with COVID-19 registered in this cohort., Conclusion: The impact of COVID-19 on IBD disease activity and factors associated with COVID-19 severity were consistent with findings of previous reports. No deaths in Japanese patients with IBD were observed., (© 2023 The Authors.)

Appendiceal mucinous neoplasm is a relatively rare disease. It is classified as mucinous adenocarcinoma(MACA)and low- grade appendiceal mucinous neoplasm(LAMN). We retrospectively evaluated 16 cases of appendiceal mucinous neoplasm (LAMN: 13 cases, MACA: 3 cases)that were surgically resected in our hospital between January 2010 and July 2021. There were 7 men and 9 women, with a median age of 61 years(27-85 years). The most common chief complaint was abdominal pain(12 patients), while 3 cases were incidental findings following medical checkups for other diseases and without a chief complaint. Colonoscopy was performed for 9 cases. Of these, 5 revealed abnormal findings. The preoperative diagnosis was appendicitis in 7 patients and appendiceal tumor in 8 patients. The surgical procedures were planned for 8 cases and performed as emergencies in 8 cases. The procedures included laparoscopic surgery(n=6)and laparotomy(n=10). The resection range included appendectomy(n=9), partial cecal resection(n=4), and ileocecal resection(n=3). Surgical margins were negative in all cases. Metastases were not observed in patients who underwent lymph node dissections (2 patients with MACA and 1 patient with LAMN). The median follow-up was 17 months(1-43 months). Recurrence including peritoneal pseudomyxoma was not detected in any of the patients.

Background: Inflammatory bowel disease (IBD) is a chronic intestinal disorder characterized by recurrent flare-ups and remission. Leucine-rich α2-glycoprotein (LRG) has been developed as a new serum biomarker of disease activity in patients with IBD. However, there have been no reports on whether plasma LRG can be used as an alternative to serum LRG. Therefore, in this retrospective study, we evaluated the usefulness of plasma LRG compared to serum LRG., Methods: We conducted a single-center retrospective observational study. A total of 108 IBD patients (ulcerative colitis [UC], 56; Crohn's disease [CD], 52) who received treatment at Sapporo Medical University Hospital between August 2020 and September 2021 were enrolled. Serum and plasma LRG levels were measured using the NANOPIA LRG kit. Disease activity was assessed using the Crohn's Disease Activity Index (CDAI) for CD and partial Mayo (pMayo) score for UC. Endoscopic activity was evaluated using the Mayo Endoscopic Subscore (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) in patients with UC and the Simple Endoscopic Score for Crohn's Disease (SES-CD) score in patients with CD., Results: Serum LRG levels significantly correlated with plasma LRG levels (r = 0.990, p<0.0001). Plasma LRG levels were significantly associated with SES-CD (r = 0.992, p<0.0001), indicating that plasma LRG levels may predict endoscopic activity in CD. In UC patients, the cutoff values of plasma LRG for remission were 12.7 μg/mL for MES ≤1 and 10.0 μg/mL for UCEIS of = 0., Conclusion: The present study showed that plasma LRG levels correlate well with serum LRG levels. Therefore, plasma LRG can be clinically applied as a biomarker for assessing endoscopic disease activity in patients with IBD., Competing Interests: Among the authors, H Nakase has received support from AbbVie, Celgene, Daiichi Sankyo, EA Pharma, Janssen, JIMRO, Kissei Pharmaceutical, Kyorin Pharmaceutical, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Nippon Kayaku, Pfizer, Takeda, and Zeria Pharmaceutical, as well as grants for commissioned/joint research from Boehringer Ingelheim, Bristol Myers Squibb, and Pentax Medical. There are no employment, consultancy, patents, products in development or marketed products to declare. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Ichimiya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Parkinson's disease (PD) can lead to swallowing dysfunction, resulting in aspiration pneumonia. Among the types of swallowing disorders, a characteristic and serious problem associated with PD is silent aspiration due to pharyngeal and laryngeal hypoesthesia., Methods: This single-arm, open-label study aims to evaluate the effectiveness of percutaneous neck interferential current sensory stimulation in enhancing swallowing function in patients with PD. The efficacy and safety of percutaneous neck interferential current sensory stimulation will be investigated for patients diagnosed with PD, based on the Movement Disorder Society criteria, of Hoehn-Yahr stages 2-4. The patients will receive neck percutaneous interferential current sensory stimulation for 20 min twice a week for 8 weeks using a Gentle Stim® (FoodCare Co., Ltd., Kanagawa, Japan) device. Once the intervention is initiated, evaluations will be performed every 4 weeks for a 16-week period. The primary endpoint to be assessed is the proportion of patients with normal cough with 1% citric acid at the end of the intervention (8 weeks after intervention initiation) compared with that at the beginning. This clinical trial will examine the usefulness of percutaneous neck interferential current sensory stimulation in patients with PD. In addition, this study will use novel instruments, such as multichannel surface electromyography and electronic stethoscope, to evaluate swallowing function., Discussion: This novel evaluation can provide insights into dysphagia in patients with PD and the usefulness of percutaneous neck interferential current stimulation. This exploratory study is limited by its single-arm, open-label design and small size., Trial Registration Number: jRCTs062220013; pre-results., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Objective: To elucidate the incidence and risk factors for paradoxical effects (i.e., increased seizure frequency, increased seizure severity, or onset of new seizure types) of levetiracetam (LEV) in people with epilepsy (PWE) and identify the usefulness of electroencephalography (EEG) in predicting these effects., Methods: We examined data for consecutive PWE treated with LEV. All PWE underwent EEG and magnetic resonance imaging (MRI) before LEV administration. We also evaluated the incidence of paradoxical LEV effects and conducted multivariate logistic regression analyses to identify the associated factors., Results: In total, 210 (66.2%) of 317 PWEs treated in our department had a history of LEV use. The incidence of paradoxical LEV effects was 5.2% (n = 11) and was significantly associated with a high LEV dose (p = 0.029), high seizure frequency (p = 0.005), temporal lobe epilepsy (p = 0.004), focal awareness seizure (p = 0.004), focal impaired awareness seizure (p = 0.007), spike (p = 0.015), rhythmic epileptiform discharges (REDs; p = 0.003), and MRI-identified focal cortical dysplasia (FCD; p < 0.0001). Multivariate analyses revealed that REDs (odds ratio [OR] = 5.35, p = 0.048, 95% confidence interval [CI]: 1.01-28.21) were independently associated with paradoxical LEV effects., Conclusions: Paradoxical LEV effects occurred in PWE, particularly in those with drug-resistant focal epilepsy. Furthermore, the occurrence of REDs in EEG was an independent factor associated with the paradoxical effects of LEV in PWE., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The prevalence of myopia has been steadily increasing for several decades, and this condition can cause extensive medical and economic issues in society. Exposure to violet light (VL), a short wavelength (360-400 nm) of visible light from sunlight, has been suggested as an effective preventive and suppressive treatments for the development and progression of myopia. However, the clinical application of VL remains unclear. In this study, we aimed to investigate the preventive and suppressive effects of VL on myopia progression. Various transmittances of VL (40%, 70%, and 100%) were tested in C57BL/6J mice with lens-induced myopia (LIM). Changes in the refractive error, axial length, and choroid thickness during the 3-week LIM were measured. The myopic shift in refractive error and difference in axial length between the 0 and -30 diopter lens was lessened in a transmission-dependent manner. Choroidal thinning, which was observed in myopic conditions, was suppressed by VL exposure and affected by its transmission. The results suggest that myopia progression can be managed using VL transmittance. Therefore, these factors should be considered for the prevention and treatment of myopia., Competing Interests: Declaration of competing interest H.T., T.K., and K.T. are in the process of applying for two international two patents for myopia-preventing devices based on VL illumination and transparency, (WO, 2015/186723 and WO, 2017/094886). The former has been registered in Japan, the United States, and China, while the latter has been registered in Japan, the United Kingdom, France, Germany, Italy, Hong Kong, and Singapore. There is a patent application for the design of the mouse eyeglass by Tsubota Laboratory, Inc. (patent application no. 2017–41349). K.T. reports his position as the CEO of Tsubota Laboratory, Inc., Tokyo, Japan, a company that produces myopia-related devices., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A series of six dications composed of pure hydrocarbons with one to six non-substituted 9,10-anthrylene units end-capped with two dibenzotropyliums were designed and synthesized to elucidate the electronic properties of huge oligo(9,10-anthrylene) backbones. Their structures were successfully determined by X-ray analyses even in the case of eight planar 14π-electron units, revealing that all dications adopt almost orthogonally twisted structures between neighboring units. Spectroscopic and voltammetric analyses show that neither the significant overlap of orbitals nor the delocalization of electrons between 14π-electron units occurs due to the orthogonally twisted geometry even in solution. As a result, sequential oxidation processes were observed with the reversible formation of multivalent cations with the release of the same number of electrons as the number of anthrylene units. Upon two-electron reduction, a closed-shell butterfly-shaped form was obtained from the dication containing one anthrylene unit, whereas open-shell twisted biradicals were isolated as stable entities in the cases of derivatives containing three to six anthrylene units. Notably, from the derivative with two anthrylene units, a metastable open-shell isomer was obtained quantitatively and underwent slow thermal conversion to the most stable closed-shell isomer ( E a = 23.1 kcal mol -1 ). There is a drastic change in oxidation potentials between two neutral species (Δ E = 1.32 V in CH 2 Cl 2 ). Since the present dications were regenerated upon oxidation of the isolated reduction products, these systems may contribute to the development of advanced response systems capable of switching color, magnetic properties, and oxidative properties by using a "cation-capped orthogonal geometry".

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is frequently complicated with rapidly progressive-interstitial lung disease (RP-ILD). The prognosis of MDA5-DM with RP-ILD is mostly poor despite intensive treatment with a combination of high-dose glucocorticoids and single conventional immunosuppressants. It was reported that the triple therapy (high-dose glucocorticoids, cyclophosphamide and tacrolimus) was more effective than a combination of high-dose glucocorticoids and stepwise addition of immunosuppressants. In addition, the efficacy of tofacitinib 10 mg/day for MDA5-DM with RP-ILD refractory to the triple therapy was suggested. However, the effect of those therapies was evaluated only in comparison to the historical control. Moreover, more importantly, there are still refractory patients even if treated with those therapies. In this case series, we report six MDA5-DM cases with RP-ILD in which the dose of tofacitinib was increased from 10 mg to 20 mg/day due to poor response to the triple therapy, followed by tofacitinib 10 mg/day. Four of six patients improved after dose escalation of tofacitinib, while two non-responders died. All six patients developed at least one infection including five cases of cytomegalovirus reactivation, one pulmonary aspergillosis, one herpes zoster and one herpes simplex keratitis. These cases suggest that the dose escalation of tofacitinib can be an option for MDA5-DM patients refractory to 10 mg/day of tofacitinib and other immunosuppressants although the risk of infection is a concern. The risk-benefit balance of the dose escalation of tofacitinib should be carefully assessed in each case., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Stomata open in response to several environmental stimuli, such as light and low CO 2 . Plasma membrane (PM) H + -ATPase in guard cells plays a pivotal role for light-induced stomatal opening. In contrast, stomata close in response to the dark or plant hormone abscisic acid (ABA). However, molecular mechanisms of stomatal movements remain unclear. To elucidate the molecular mechanism of stomatal movements, we performed a genetic screen based on stomatal aperture-dependent weight decrease of detached leaves from EMS-treated Arabidopsis thaliana and isolated a rapid transpiration in detached leaves 2 ( rtl2 ). The rtl2 mutant showed constitutive open-stomata phenotype with lower leaf temperature. ABA had no effect on stomatal aperture in rtl2 . The rtl2 mutant also showed increased stomatal density, severe dwarf phenotype with pale green leaves and dark veins. Map-based analysis of the RTL2 locus revealed that the rtl2 mutant possesses a single nucleotide substitution, which induces amino acid substitution Gly162 to Glu in the tryptophan synthase ß subunit 1 (TSB1). The TSB1 encodes an enzyme in tryptophan (Trp) biosynthetic pathway. Amount of TSB1 protein was drastically reduced in rtl2 mutant. A different allele of tsb1 mutant ( tsb1-1 ) also showed constitutive open-stomata phenotype with reduced TSB1 protein as in rtl2 . Analyses of test-crossed plants of rtl2 and tsb1-1 showed open-stomata and dwarf phenotypes. These results indicate that a responsible gene for rtl2 is TSB1 . We further investigated stomatal phenotype in mutants from Trp biosynthetic pathway, such as wei2-1 wei7-1 , trp3-1 , and tsb2-1 . The trp3-1 mutant showed significant wider stomatal aperture as well as tsb1-1 . Trp biosynthetic pathway closely relates to auxin biosynthesis. Then, we investigated auxin responsible genes and found that an expression of AUR3 was up in rtl2 . In contrast, auxin had no effect on stomatal aperture in Arabidopsis and the phosphorylation status of PM H + -ATPase in guard cell protoplasts from Vicia faba . In addition, auxin antagonist had no effect on stomatal aperture. Interestingly, tsb1-1 grown under hydroponic culture system showed normal stomatal aperture by exogenously application of Trp. These results suggest that open stomata phenotype in tsb1-1 is due to Trp deficiency but not auxin., 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 © 2022 Soda, Hayashi, Takahashi and Kinoshita.)

To evaluate biological effects triggered by low levels of radiation, we established a uniquely sensitive experimental system to detect somatic mutations. By using the system, we found that mutant frequencies induced by X-rays were statistically significant at doses over 0.15 Gy, and a linear dose relationship with the mutant frequency was observed at doses over 0.15 Gy. The mutation spectra analysis revealed that mutation events generated by X-ray doses below 0.1 Gy were similar to those observed in unirradiated controls. In addition, a significant inflection point for both, the mutant frequency and the mutation spectra, was found at dose-rates around 11 mGy/day when cells were cultured in medium containing tritiated water. Because induced radiation-type events presented a clear dose/dose-rate dependency above the critical dose or the inflection point, these observations suggest that mutation events generated by radiation could change at a threshold dose-rate or a critical dose., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Endoscopic resection (ER) is a minimally invasive treatment for early gastric cancer (EGC); however, there is a high occurrence of bleeding. This study aimed to clarify the significance of red blood cell distribution width (RDW) as a predictive risk factor for bleeding after ER for EGC., Methods: We conducted a retrospective study based on data for patients who underwent ER for EGC from 2019 to 2021. This study included 79 lesions in 54 patients who underwent ER for EGC. The primary outcome was the association between RDW before ER and bleeding within 28 days of treatment. Receiver operating characteristic (ROC) curves were constructed, wherein areas under the curve (AUCs) and 95% confidence intervals were calculated to compare the discriminatory power of RDW for predicting bleeding., Results: Endoscopic submucosal dissection was used as the resection method for 73 lesions, whereas endoscopic mucosal resection was used for six lesions. En bloc resection was performed in all cases. There were no cases of perforation; however, bleeding after ER occurred in five cases (9.3%). ROC curve analysis of bleeding after ER showed that the AUC was 0.843 with a good diagnostic performance. When the cut-off value of RDW was set at 14.4%, sensitivity and specificity were 80% and 85.7%, respectively. There was a bleeding rate of 36.4% (4/11) at an RDW of ≥14.4%, which was significantly higher than that of 2.3% (1/43) at an RDW of <14.4%., Conclusion: RDW can be a predictor of bleeding risk after ER for EGC., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Purpose: To create and evaluate a machine-learning model for YOLOv3 that can simultaneously perform morphological evaluation and tracking in a short time, which can be adapted to video data under an inverted microscope., Methods: Japanese patients who underwent intracytoplasmic sperm injection at the Jikei University School of Medicine and Keiai Reproductive and Endosurgical Clinic from January 2019 to March 2020 were included. An AI model that simultaneously performs morphological assessment and tracking was created and its performance was evaluated., Results: For morphological assessment, the sensitivity and positive predictive value (PPV) of this model for abnormal sperm were 0.881 and 0.853, respectively. The sensitivity and PPV for normal sperm were 0.794 and 0.689, respectively. For tracking performance, among the 51 objects, 40 (78.4%) were mostly tracked, 11 (21.6%) were partially tracked, and 0 (0%) were mostly lost., Conclusions: This study showed that evaluating sperm morphology while tracking in a single model is possible by training YOLO v3. This model could acquire time-series data of one sperm, which will assist in acquiring and annotating sperm image data., Competing Interests: Aikou Okamoto funded the collaborative research expenses through Olympus Corporation. Toshiyuki Hattori is paid by Olympus. Shinji Nakazawa is paid by LPIXEL Inc. Olympus Corporation paid R&D commission to LPIXEL Inc. The other authors declare that they have no known competing financial interests or personal relationships that influenced the work reported in this paper., (© 2022 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine.)

Plasma membrane (PM) H+-ATPase in guard cells is activated by phosphorylation of the penultimate residue, threonine (Thr), in response to blue and red light, promoting stomatal opening. Previous in vitro biochemical investigation suggested that Mg2+- and Mn2+-dependent membrane-localized type 2C protein phosphatase (PP2C)-like activity mediates the dephosphorylation of PM H+-ATPase in guard cells. PP2C clade D (PP2C.D) was later demonstrated to be involved in PM H+-ATPase dephosphorylation during auxin-induced cell expansion in Arabidopsis (Arabidopsis thaliana). However, it is unclear whether PP2C.D phosphatases are involved in PM H+-ATPase dephosphorylation in guard cells. Transient expression experiments using Arabidopsis mesophyll cell protoplasts revealed that all PP2C.D isoforms dephosphorylate the endogenous PM H+-ATPase. We further analyzed PP2C.D6/8/9, which display higher expression levels than other isoforms in guard cells, observing that pp2c.d6, pp2c.d8, and pp2c.d9 single mutants showed similar light-induced stomatal opening and phosphorylation status of PM H+-ATPase in guard cells as Col-0. In contrast, the pp2c.d6/9 double mutant displayed wider stomatal apertures and greater PM H+-ATPase phosphorylation in response to blue light, but delayed dephosphorylation of PM H+-ATPase in guard cells; the pp2c.d6/8/9 triple mutant showed similar phenotypes to those of the pp2c.d6/9 double mutant. Taken together, these results indicate that PP2C.D6 and PP2C.D9 redundantly mediate PM H+-ATPase dephosphorylation in guard cells. Curiously, unlike auxin-induced cell expansion in seedlings, auxin had no effect on the phosphorylation status of PM H+-ATPase in guard cells., (© The Author(s) 2021. Published by Oxford University Press on behalf of American Society of Plant Biologists.)

Affective/cognitive engineering investigations typically require the quantitative assessment of object perception. Recent research has suggested that certain perceptions of object categorization can be derived from human eye fixation and that color images and line drawings induce similar neural activities. Line drawings contain less information than color images; therefore, line drawings are expected to simplify the investigations of object perception. The psychological potential field (PPF), which is a psychological feature, is an image feature of line drawings. On the basis of the PPF, the possibility that the general human perception of object categorization can be assessed from the similarity to fixation maps (FMs) generated from human eye fixations has been reported. However, this may be due to chance because image features other than the PPF have not been compared with FMs. This study examines the potential and effectiveness of the PPF by comparing its performance with that of other image features in terms of the similarity to FMs. The results show that the PPF shows the ideal performance for assessing the perception of object categorization. In particular, the PPF effectively distinguishes between animal and nonanimal targets; however, real-time assessment is difficult.

Perception of pathogen-derived ligands by corresponding host receptors is a pivotal strategy in eukaryotic innate immunity. In plants, this is complemented by circadian anticipation of infection timing, promoting basal resistance even in the absence of pathogen threat. Here, we report that trichomes, hair-like structures on the epidermis, directly sense external mechanical forces, including raindrops, to anticipate pathogen infections in Arabidopsis thaliana. Exposure of leaf surfaces to mechanical stimuli initiates the concentric propagation of intercellular calcium waves away from trichomes to induce defence-related genes. Propagating calcium waves enable effective immunity against pathogenic microbes through the CALMODULIN-BINDING TRANSCRIPTION ACTIVATOR 3 (CAMTA3) and mitogen-activated protein kinases. We propose an early layer of plant immunity in which trichomes function as mechanosensory cells that detect potential risks., (© 2022. The Author(s).)

Background: The spread of coronavirus disease 2019 (COVID-19) had a major impact on the health of people worldwide. The clinical background and clinical course of inflammatory bowel disease (IBD) among Japanese patients with COVID-19 remains unclear., Methods: This study is an observational cohort of Japanese IBD patients diagnosed with COVID-19. Data on age, sex, IBD (classification, treatment, and activity), COVID-19 symptoms and severity, and treatment of COVID-19 were analyzed., Results: From 72 participating facilities in Japan, 187 patients were registered from June 2020 to October 2021. The estimated incidence of COVID19 in Japanese IBD patients was 0.61%. The majority of IBD patients with COVID-19 (73%) were in clinical remission. According to the WHO classification regarding COVID-19 severity, 93% (172/184) of IBD patients had non-severe episodes, while 7% (12/184) were severe cases including serious conditions. 90.9% (165/187) of IBD patients with COVID-19 had no change in IBD disease activity. A logistic regression analysis stepwise method revealed that older age, higher body mass index (BMI), and steroid use were independent risk factors for COVID-19 severity. Six of nine patients who had COVID-19 after vaccination were receiving anti-tumor necrosis factor (TNF)-α antibodies., Conclusion: Age, BMI and steroid use were associated with COVID-19 severity in Japanese IBD patients., (© 2022. The Author(s).)

Crohn's disease (CD) is an inflammatory bowel disease (IBD) with repeated remissions and relapses. As the disease progresses, fibrosis and narrowing of the intestine occur, leading to severe complications such as intestinal obstruction. Endoscopic balloon dilatation, surgical stricture plasty, and bowel resection have been performed to treat intestinal stenosis. The clinical issue is that some patients with CD have a recurrence of intestinal stenosis even after the medical treatments. On the other hand, there exist no established medical therapies to prevent stenosis. With the progressive intestinal inflammation, cytokines and growth factors, including transforming growth factor (TGF-β), stimulate intestinal myofibroblasts, contributing to fibrosis of the intestine, smooth muscle hypertrophy, and mesenteric fat hypertrophy. Therefore, chronically sustained inflammation has long been considered a cause of intestinal fibrosis and stenosis. Still, even after the advent of biologics and tighter control of inflammation, intestinal fibrosis's surgical rate has not necessarily decreased. It is essential to elucidate the mechanisms involved in intestinal fibrosis in CD from a molecular biological level to overcome clinical issues. Recently, much attention has been paid to several key molecules of intestinal fibrosis: peroxisome proliferator-activating receptor gamma (PPARγ), toll-like receptor 4 (TLR4), adherent-invasive Escherichia coli (AIEC), Th17 immune response, and plasminogen activator inhibitor 1 (PAI-1). As a major problem in the treatment of CD, the pathophysiology of patients with CD is not the same and varies depending on each patient. It is necessary to integrate these key molecules for a better understanding of the mechanism of intestinal inflammation and fibrosis., 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 © 2022 Hayashi and Nakase.)

Atherosclerosis is an important risk factor for cognitive decline. This study aimed to investigate the relationship of ankle-brachial pressure index (ABI) and brachial-ankle pulse wave velocity (baPWV) with cognitive function in patients with lacunar infarction. We included records of consecutive patients with their first-ever acute stroke and a diagnosis of lacunar infarction through magnetic resonance imaging (MRI) from July 1, 2011 to December 31, 2018. We excluded patients diagnosed with dementia, including strategic single-infarct dementia, before or after stroke onset. Moreover, we excluded patients with one or more microbleeds, severe white matter lesions, or severe medial temporal atrophy on MRI. For ABI, we used the lower ankle side and divided the results into ABI < 1.0 and ABI ≥ 1.0. For baPWV, we used the higher ankle side and divided the results into two groups based on the median value of the participants. We analyzed 176 patients with stroke (age 72.5 ± 11.4 years, 67 females). The median score on the Mini-Mental State Examination (MMSE) was 27. The number of patients with ABI < 1.0 was 19 (10.8%). Univariate analysis revealed that the MMSE score was associated with age, body mass index, education, chronic kidney disease, periventricular hyperintensity, and ABI < 1.0 (p < 0.10), but not baPWV. Multivariate analysis revealed that body mass index (p = 0.039) and ABI < 1.0 (p = 0.015) were independently associated with the MMSE score. For patients with lacunar infarction, a lower ABI, but not a higher PWV, was associated with cognitive decline., Competing Interests: The authors have declared that no competing interests exist.

Splicing precursor messenger RNA (pre-mRNA) is a critical step to produce physiologically functional protein. Splicing failure not only gives rise to dysfunctional proteins but also generates abnormal protein function, which causes several diseases. Several pre-mRNA splicing factors are reported to regulate mitosis directly at mitotic structures and/or indirectly through controlling the pre-mRNA splicing for mitotic proteins. In this study, we described the mitotic functions of SF3B14, a component of the spliceosomal U2 small nuclear ribonucleoprotein (snRNP), which we identified as a candidate involved in mitosis based on the large-scale RNA interference (RNAi) screen of the nucleolar proteome database. We observed that SF3B14 depletion caused prolonged mitosis and several mitotic defects, such as monopolar spindle and chromosome misalignment during metaphase. Although SF3B14 was found in the nucleolar proteome database, our immunofluorescent stainings demonstrated that SF3B14 was predominantly localized in the nucleoplasm and excluded from the nucleolus during interphase. In addition, SF3B14 did not colocalize with specific mitotic structures during mitosis, which is not in line with its direct mitotic function. Notably, we found that the SF3B14 depletion reduced protein levels of TUBGCP6, required for centrosome regulation, and increased the unspliced/spliced ratio of its mRNA. Taken together, we propose that the pre-mRNA of TUBGCP6 is one of the targets for SF3B14 splicing through which SF3B14 controls mitotic chromosome behavior., Competing Interests: Declaration of competing interest The authors declare no conflict of the interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

One of the main sequelae of stroke is difficulty walking, which is characterised by decreased walking speed and asymmetrical walking patterns. Physical therapists often rely on explicit motor learning strategies, i.e., providing mainly verbal instructions for how movements should be performed. However, the voluntary movement induced by explicit instruction may lead to associated unintended muscle contractions or higher cognitive demand, which could be detrimental. We introduce a vibrotactile cueing device that implicitly improves walking speed. The stroke patient walks while alternating vibrational cues are given to the left and right sides of their waist. At each specified step, cueing frequency increases in the cueing group without the patient's awareness. The four patients in the cueing group did not notice the increase in walking speed during training; however, we observed an improvement in walking speed and cadence in patients using the proposed cueing system, which was maintained during the posttest phase. Additionally, patients using the cueing system were able to suppress excessive compensatory movements during training compared with patients who did not use the system. This case series study indicates that the proposed system for gait rehabilitation of stroke patients can enable an increase in walking speed without excessive effort.