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Abstract To advance the development of high-strength polycrystalline metallic materials towards achieving carbon neutrality, it is essential to design materials in which the atomic level control of general grain boundaries (GGBs), which govern the material properties, is achieved. However, owing to the complex and diverse structures of GGBs, there have been no reports on interatomic potentials capable of reproducing them. This accuracy is essential for conducting molecular dynamics analyses to derive material design guidelines. In this study, we constructed a machine learning interatomic potential (MLIP) with density functional theory (DFT) accuracy to model the energy, atomic structure, and dynamics of arbitrary grain boundaries (GBs), including GGBs, in α-Fe. Specifically, we employed a training dataset comprising diverse atomic structures generated based on crystal space groups. The GGB accuracy was evaluated by directly comparing with DFT calculations performed on cells cut near GBs from nano-polycrystals, and extrapolation grades of the local atomic environment based on active learning methods for the entire nano-polycrystal. Furthermore, we analyzed the GB energy and atomic structure in α-Fe polycrystals through large-scale molecular dynamics analysis using the constructed MLIP. The average GB energy of α-Fe polycrystals calculated by the constructed MLIP is 1.57 J/m2, exhibiting good agreement with experimental predictions. Our findings demonstrate the methodology for constructing an MLIP capable of representing GGBs with high accuracy, thereby paving the way for materials design based on computational materials science for polycrystalline materials.

Abstract Sweat is an essential protection system for the body, but its failure can result in pathologic conditions, including several skin diseases, such as palmoplantar pustulosis (PPP). As reduced intraepidermal E-cadherin expression in skin lesions was confirmed in PPP skin lesions, a role for interleukin (IL)-1-rich sweat in PPP has been proposed, and IL-1 has been implicated in the altered E-cadherin expression observed in both cultured keratinocytes and mice epidermis. For further investigation, live imaging of sweat perspiration on a mouse toe-pad under two-photon excitation microscopy was performed using a novel fluorescent dye cocktail (which we named JSAC). Finally, intraepidermal vesicle formation which is the main cause of PPP pathogenesis was successfully induced using our "LASER-snipe" technique with JSAC. "LASER-snipe" is a type of laser ablation technique that uses two-photon absorption of fluorescent material to destroy a few acrosyringium cells at a pinpoint location in three-dimensional space of living tissue to cause eccrine sweat leakage. These observatory techniques and this mouse model may be useful not only in live imaging for physiological phenomena in vivo such as PPP pathomechanism investigation, but also for the field of functional physiological morphology.

Background: Although several studies have investigated the accuracy of clinical diagnoses of skin tumors, specific ways to improve diagnostic accuracy have not been identified. This study investigated factors that influence the accuracy of clinical skin tumor diagnostic methods and discusses strategies to improve accuracy. Methods: Study 1 retrospectively analyzed 657 skin tumors excised at our hospital between March 2001 and March 2011. Data were extracted from surgical records to establish a diagnostic template for further research. Study 2 prospectively applied this template to aid clinical diagnosis at four facilities between April 2011 and March 2013. The clinical diagnoses were compared with the histological ones and the concordance was determined. Results: A total of 448 and 209 benign and malignant tumors, respectively, were included in Study 1. The overall diagnostic accuracy was 79.0%. In Study 2, 310 patients were clinically diagnosed using a standardized template, which did not affect the diagnostic accuracy. Age, sex, duration of disease, tumor size and location, skin tone, mobility, stiffness, and years of diagnostic experience did not significantly affect diagnostic accuracy. A high proportion of pathologically malignant tumors were clinically misdiagnosed as benign (16/22; 72%). Other clinical examinations were performed in only 35 cases. Conclusions: Auxiliary diagnostic tools such as dermoscopy and biopsies should be used to accurately diagnose malignant tumors.

Arteriovenous malformation or arteriovenous hemangioma of the maxillary sinus is relatively rare. The coexistence of the 2 lesions in the maxillary sinus is extremely rare. Such lesions may cause severe epistaxis due to arterial bleeding. A 73-year-old woman visited our department for recurrent and severe epistaxis, and a blood transfusion (400 mL) was required owing to the decrease in hemoglobin level (8.0 g/dL). On magnetic resonance imaging, the mass expanding in the right maxillary sinus had mixed high signal intensity on T1 magnetic resonance imaging with heterogeneous enhancement. The angiography showed no dilatation or meandering of the blood vessels of the relevant region and any apparent bleeding sites were not detected. An endoscopic nasal surgery could remove the maxillary sinus mass without preoperative embolization. Pathological examination clarified the coexistence of arteriovenous malformation and arteriovenous hemangioma in the mass. She has never complained of epistaxis for 6 months after the surgery.

Abstract Background Although previous studies have reported general inexperience with the Epley manoeuvre (EM) among general physicians, no report has evaluated the effect of EM on benign paroxysmal positional vertigo (BPPV) in primary care by using point estimates or certainty of evidence. We conducted this systematic review and meta-analysis and clarified the efficacy of EM for BPPV, regardless of primary-care and subspecialty settings. Methods Systematic review and meta-analysis of randomised sham-controlled trials of EM for the treatment of posterior canal BPPV in primary-care and subspecialty settings. A primary-care setting was defined as a practice setting by general practitioners, primary-care doctors, or family doctors. A systematic search was conducted in January 2022 across databases, including Cochrane Central Resister of Controlled Trial, MEDLINE, Embase, Cumulative Index of Nursing and Allied Health Literature, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. Primary outcomes were the disappearance of subjective symptoms (vertigo), negative findings (Dix–Hallpike test), and all adverse events. We evaluated the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluation approach. Results Twenty-seven randomised controlled trials were identified. In primary-care settings, EM reduced the subjective symptoms [risk ratio (RR), 3.14; 95% confidence interval (CI), 1.96–5.02]; however, there was no applicable article for all adverse events. In the subspeciality setting, EM reduced the subjective symptoms (RR, 2.42; 95% CI, 1.64–3.56), resulting in an increase in negative findings (RR, 1.81; 95% CI, 1.40–2.34). The evidence exhibited uncertainty about the effect of EM on negative findings in primary-care settings and all adverse events in subspecialty settings. Conclusions Regardless of primary-care and subspecialty settings, EM for BPPV was effective. This study has shown the significance of performing EM for BPPV in primary-care settings. EM for BPPV in a primary-care setting may aid in preventing referrals to higher tertiary care facilities and hospitalisation for follow-up. Trial registration The study was registered in protocols.io (PROTOCOL INTEGER ID: 51,464) on July 11, 2021.

Several factors related to liana abundance have been shown at broad scales, however, the information on factors affecting liana distribution in temperate zones is limited. Climbing types of lianas appear to be associated with interspecific variations of lianas and may be related to the broad-scale distribution and functions of lianas. We aimed to assess the environmental factors related to the abundance of all lianas and those of each climbing type from subtropical to subboreal forests in the Japanese archipelago to better understand the geographical gradient of the liana community.We established six 400 m2 subplots within each of 19 forest plots and recorded the species, stem diameter, and climbing types of lianas with stem diameters ≥ 1 cm. We used generalised linear mixed effects models and model selection based on Akaike's information criterion to examine the effects of climate, soil, and forest structural attributes on liana stem density and basal area.Liana abundance varied substantially among the 19 plots and some forests were characterized by abundant lianas in temperate zones. Twining and root climbers were the major climbing types. Mean annual temperature positively affected the stem density of twining climbers and negatively affected the basal area of root climbers. Maximum snow depth positively affected the stem density of root climbers and negatively affected the basal area of twining climbers. Carbon:nitrogen ratio and dry mass of the soil organic layer had negative effects on the abundance of twining climbers and stem density of both climbers, respectively. Tree basal area positively affected the basal area of root climbers.This study demonstrated the effects of environmental factors, including unique factors such as snow accumulation, on liana distribution at a broad scale from the subtropical to the subboreal zone. Furthermore, the difference between climbing types in distribution may contribute to the gradient of forest ecosystem functions along the environmental factors.

Highly concentrated trehalose induces beneficial senescence-like state in fibroblasts and accelerates the proliferation of keratinocytes and angiogenesis to promote optimal wound repair, demonstrating its therapeutic potential in modulating fibroblast functions.

Background and aim The severity of atrophic gastritis is significantly associated with the risk of gastric cancer. Although the current gold standard for assessing the gastric cancer risk is esophagogastroduodenoscopy with a pathological examination, the development of less-invasive biomarkers is warranted for efficient risk stratification of gastric cancer. Serum pepsinogens (PGs) are biomarkers used to predict the extent of gastric mucosal atrophy; however, they are not an accurate reflection of gastric mucosal atrophy after Helicobacter pylori eradication. The present study was conducted to investigate the usefulness of plasma ghrelin levels as a marker for gastric mucosal atrophy, and as a risk stratification marker for gastric cancer, even after H. pylori eradication. Methods Patients who received H. pylori eradication treatment were enrolled in the study. The severity of gastric mucosal atrophy was evaluated both endoscopically and histologically. Serum pepsinogen and plasma ghrelin levels were measured before and at 1, 12, 24, and 48 weeks after treatment. The study was approved by the Research Ethics Committee of the Keio University School of Medicine (no. 20140102; 8 July 2014). Results Eighteen patients completed the study protocol. Total and acyl plasma ghrelin levels demonstrated no significant change from before treatment to 48 weeks after eradication; however, there was a significant difference between open-type and closed-type atrophic gastritis. The PG I/II ratio increased significantly from 48 weeks after H. pylori eradication. The severity of the histological intestinal metaplasia scores correlated inversely with plasma total ghrelin levels from before to 48 weeks after H. pylori eradication. Conclusion Plasma levels of ghrelin correlate well with the level of gastric mucosal atrophy, even after H. pylori eradication.KEY MESSAGES Ghrelin plasma levels are associated with the progression of endoscopic atrophic gastritis, even at 48 weeks after H. pylori eradication. Ghrelin plasma levels are also associated with increased severity of histological intestinal metaplasia 48 weeks after H. pylori eradication. Pepsinogen I/II ratios increased immediately after H. pylori eradication and are inappropriate for assessing atrophic gastritis after H. pylori eradication.

Abstract Body-centered-cubic (bcc) transition metals, such as $$\alpha $$ α -Fe and W, cleave along the {100} plane, even though the surface energy is the lowest along the {110} plane. To unravel the mechanism of this odd response, large-scale atomistic simulations of curved cleavage cracks of $$\alpha $$ α -Fe were conducted in association with stress intensity factor analyses of straight crack fronts using an interatomic potential created by an artificial neural network technique. The study provides novel findings: Dislocations are emitted from the crack fronts along the {110} cleavage plane, and this phenomenon explains why the {100} plane can be the cleavage plane. However, the simple straight crack-front analyses did not yield the same conclusion. It is suggested that atomistic modeling, at sufficiently large scales to capture the inherent complexities of materials using highly accurate potentials, is necessary to correctly predict the mechanical strength. The method adopted in this study is generally applicable to the cleavage problem of bcc transition metals and alloys.

Nuclear IL-33 levels are high at the epidermal edges of skin wounds and facilitate wound healing. However, IL-33−mediated regulation of keratinocyte (KC) biology during wound healing remains poorly understood. During skin-wound healing, KC migration and re-epithelialization are mediated predominantly by EGFR signaling activation and depend on the function of signal transducer and activator of transcription 3 (STAT3). We found that migrating KCs at the leading edges of mouse skin wounds exhibited concomitant induction and nuclear colocalization of IL-33 and phosphorylated STAT3. In cultured human KCs, activation of EGFR signaling caused rapid elevation of nuclear IL-33, which directly interacts with phosphorylated STAT3, promoting STAT3 activation. In vitro KC migration and wound-healing assays revealed that high nuclear IL-33 levels were required for KC migration and wound closure. KC mobility associated with a lack of suprabasal epidermal keratins and extracellular matrix degradation mediated by matrix metalloproteinases (MMPs) control cell migration at the intracellular and extracellular levels, respectively. In EGFR-activated KCs, nuclear IL-33 mediated keratin 1 and 10 downregulation and MMP9 upregulation by promoting STAT3 activation and limited MMP1, MMP3, and MMP10 induction by suppressing NF-κB transactivation. Thus, epidermal nuclear IL-33 is involved in KC migration and wound closure by regulating the STAT3 and NF-κB pathways.

The impact of low-dose-rate radiation on genetics is largely unknown, particularly in natural environments. The Fukushima Dai-ich Nuclear Power Plant disaster resulted in the creation of contaminated natural lands. In this study, de novo mutations (DNMs) in germ line cells were surveyed from double-digest RADseq fragments in Japanese cedar and flowering cherry trees exposed to ambient dose rates ranging from 0.08 to 6.86 μGy h−1. These two species are among the most widely cultivated Japanese gymnosperm and angiosperm trees for forestry and horticultural purpose, respectively. For Japanese flowering cherry, open crossings were performed to produce seedlings, and only two candidate DNMs were detected from uncontaminated area. For Japanese cedar, the haploid megagametophytes were used as next generation samples. The use of megagametophytes from open crossing for next generation mutation screening had many advantages such as reducing exposure to radiation in contaminated areas because artificial crossings are not needed and the ease of data analysis owing to the haploid nature of megagametophytes. A direct comparison of the nucleotide sequences of parents and megagametophytes revealed an average of 1.4 candidate DNMs per megagametophyte sample (range: 0–40) after filtering procedures were optimized based on the validation of DNMs via Sanger sequencing. There was no relationship between the observed mutations and the ambient dose rate in the growing area or the concentration of 137Cs in cedar branches. The present results also suggest that mutation rates differ among lineages and that the growing environment has a relatively large influence on these mutation rates. These results suggested there was no significant increase in the mutation rate of the germplasm of Japanese cedar and flowering cherry trees growing in the contaminated areas.

Pseudomelanosis duodeni is a rare condition characterized by the endoscopic appearance of diffuse dark pigmentation of the duodenal mucosa. It is typically seen in older women and has been reported to be associated with hypertension, chronic renal disease, diabetes mellitus, gastrointestinal hemorrhage, and the use of medications such as oral iron, furosemide, thiazide, hydralazine, and propranolol. We present a case of pseudomelanosis duodeni appearing after 2 years of oral iron therapy in an 85-year-old woman. Although oral iron supplementation seemed the strongest possible etiology, our patient had multiple comorbidities and was on other medications that have been described as associations. The majority of individuals taking oral iron or under these clinical conditions do not develop this entity; some other factors in patients may be responsible for its occurrence.

The heartwood color of a major plantation tree Cryptomeria japonica shows high variability among clones and cultivars, and brighter heartwood has higher value in the usage of non-laminated wood such as in traditional construction, which makes heartwood color an important trait in breeding of this species. However, the genetic basis of the interactions between genetics and the environment on heartwood color has been understudied while these are necessary for effective breeding programs in multiple environmental condition. The objectives of the present study were to evaluate the effects of genetics and environments on heartwood color and how they interact in contrasting environments, and to identify genomic regions controlling heartwood color in C. japonica across multiple environments. Heartwood color in terms of L*a*b* color space and spectral reflectance was measured in common gardens established in three contrasting sites. Quantitative trait loci (QTL) that affect heartwood color were identified using previously constructed highly saturated linkage maps. Results found that heartwood color was largely genetically controlled, and genotype-by-environment interaction explained one-third of the total genetic variance of heartwood color. The effect of the environment was small compared to the effect of genetics, whereas environmental effects largely varied among heartwood color traits. QTL analysis identified a large number of QTLs with small to moderate effects (phenotypic variation explained of 6.6% on average). Some of these QTLs were stably expressed in multiple environments or had pleiotropic effects on heartwood color and moisture content. These results indicated that genetic variation in phenotypic plasticity plays an important role in regulating heartwood color and that the identified QTLs would maximize the breeding efficiency of heartwood color in C. japonica in heterogeneous environments.

An aortoesophageal fistula, an abnormal anatomical communication between the aorta and the esophagus, is a rare cause of upper gastrointestinal bleeding. The mortality rate of patients with this condition is very high. A 77-year-old man, who had undergone endovascular aortic repair for a ruptured abdominal aortic aneurysm, developed melena. An upper gastrointestinal endoscopy was performed. This detected an esophageal ulcer, which had the potential to develop into an aortoesophageal fistula. Therefore, thoracic endovascular aortic repair was performed on the following day. Thereafter, the course was uneventful. We encountered a rare case of an esophageal ulcer associated with a thoracoabdominal aortic aneurysm before it developed into an aortoesophageal fistula.

Since stroke-prone spontaneously hypertensive rats (SHRSP) develop hypertension and stroke without exception, the prevention or reduction of risk by various nutrients was tested on blood pressure and the mortality caused by stroke and cardiovascular diseases (CVD). In addition to sodium (Na) accelerating hypertension and stroke and potassium (K) counteracting the adverse effect of Na, taurine (Tau), rich in seafood, and magnesium (Mg) contained in soy, nuts, grains, etc., were proven to reduce stroke and CVD and improved survival. Therefore, the Cardiovascular Diseases and Alimentary Comparison Study was started in 1985 to explore the association of biomarkers of diet in 24 h urine(24U) with CVD risks, and about 100 males and 100 females aged 48–56 in each of 50 populations were studied until 1995. Linear regression analysis indicated that the 24U Tau/creatinine and Mg/creatinine ratios were inversely associated with body mass index, systolic and diastolic blood pressure, and total cholesterol. In comparison with six Euro-Western regions, 24U Tau and Mg collected from six regions, respectively, in Japan and the Mediterranean countries were significantly higher and were significantly associated with lower CVD risks. Diets rich in Tau and Mg were concluded to be contributory to the prevention of CVD in SHRSP and humans.

Although gasotransmitters nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) receive a bad connotation; in low concentrations these play a major governing role in local and systemic blood flow, stomach acid release, smooth muscles relaxations, anti-inflammatory behavior, protective effect and more. Many of these physiological processes are upstream regulated by gut peptides, for instance gastrin, cholecystokinin, secretin, motilin, ghrelin, glucagon-like peptide 1 and 2. The relationship between gasotransmitters and gut hormones is poorly understood. In this review, we discuss the role of NO, CO and H2S on gut peptide release and functioning, and whether manipulation by gasotransmitter substrates or specific blockers leads to physiological alterations.

Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are characterized by the concepts of lipo- and glucotoxicity. NAFLD is characterized by the accumulation of different lipidic species within the hepatocytes. Bile acids (BA), derived from cholesterol, and conjugated and stored in the gallbladder, help the absorption/processing of lipids, and modulate host inflammatory responses and gut microbiota (GM) composition. The latter is the new “actor” that links the GI tract and liver in NAFLD pathogenesis. In fact, the discovery and mechanistic characterization of hepatic and intestinal farnesoid X receptor (FXR) shed new light on the gut–liver axis. We conducted a search on the main medical databases for original articles, reviews, meta-analyses of randomized clinical trials, and case series using the following keywords, their acronyms, and their associations: farnesoid X receptor, bile acids metabolism, gut microbiota, dysbiosis, and liver steatosis. Findings on the synthesis, metabolism, and conjugation processes of BAs, and their action on FXR, change the understanding of NAFLD physiopathology. In detail, BAs act as ligands to several FXRs with GM modulation. On the other hand, the BAs pool is modulated by GM, thus, regulating FXRs functioning in the frame of liver fat deposition and fibrosis development. In conclusion, BAs passed from their role of simple lipid absorption and metabolism agents to messengers between the gut and liver, modulated by GM.

Background & Aims: CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. Methods: CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. Results: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori–infected gastric mucosa. Conclusions: CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells. Keywords: Autophagy, CagA, Cancer Stem Cells, CD44v9, Eradication Therapy

Functional dyspepsia (FD) and gastroparesis (GP) are common disorders of the upper gastrointestinal tract. The pathophysiology of these conditions is likely to be heterogenous, and factors such as altered motility, sensitivity and response to nutrition have been identified as putative underlying mechanisms. Motility, sensitivity as well as responses to nutrition can be influenced or mediated by peptide hormones and serotonin released from the gastrointestinal mucosa. This review summarizes the role of GI peptides in functional dyspepsia and gastroparesis. In most studies, the levels of somatostatin, ghrelin, and motilin did not differ between healthy volunteers and FD or GP patients, but higher symptom burden was often correlated with higher peptide levels. Ghrelin and motilin receptor agonists showed promising results in improvement of the gastric emptying, but the link with improvement of symptoms is less predictable. Serotonin agonists have a potential to improve symptoms in both FD and idiopathic gastroparesis. Drugs acting on the GLP-1 and on the PYY receptors deserve further investigation. There is a need for systematic large scale studies.

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and cryoballoon ablation was developed as a new treatment modality for symptomatic AF. Gastroparesis is rarely reported as a transient complication of ablation, and its frequency and risk are not clear. We experienced a rare case of gastroparesis after cryoballoon ablation followed by medication-induced recovery within 6 months.

Long-lived forest tree species experience a wide range of environmental conditions throughout their lifespan. Evaluation of the underlying growth and development mechanisms of these species is essential to predict tree growth under climate change. This study investigated climate sensitivity to temperature, precipitation, dry periods, and the associated genomic regions in Cryptomeria japonica, Japan's most commercially important tree. We used tree rings and common garden experiments with three clonal replicates planted in two contrasting environments in Kyushu (Kumamoto site) and Honshu (Chiba site), Japan. Tree growth showed a significant negative correlation with the dry period (>4 days) in March of the year of tree-ring formation at the Chiba site. In contrast, temperature and precipitation had little influence on tree growth. Quantitative trait locus (QTL) analysis was performed to investigate climate sensitivity to dry periods at the Chiba site, revealing 13 significant QTLs. One QTL showed a substantially large contribution to the overall climate sensitivity, accounting for 12.4% of the total phenotypic variation. The phenotypic variance explained (PVE) by other QTLs ranged from 0.9% to 2.9%, and the total PVE by all QTLs was 35.6%. These findings indicate that the tree population at the Chiba site could be vulnerable to drought in early spring and that the QTL showing the greatest impact on climate sensitivity may be closely related to genes associated with tolerance or adaptation to drought stress. The QTLs identified in this study could be useful for molecular breeding, forest management, and predicting the growth of C. japonica under a changing climate.

Background: Writing letters to the editor based on critical appraisal can serve as the first step in scholarly activity. The workshop in this study focused on educating physicians about the best ways to write letters to the editor. Methods: We conducted a 90-minute workshop as a part of scientific conference. Participants were physicians and medical students who chose to join this workshop. We developed the following learning outcomes for participants: 1) to be able to explain falsificationism; 2) to be able to explain how to check author instructions; 3) to be able to explain how to write a letter to the editor. Results: Twenty-eight participants, including three medical students, attended the workshop. Participants' satisfaction with the workshop had a mean of 4.5 points out of 5 (standard deviation: 0.5). Nearly 80% of participants achieved the learning outcomes. Four participants' groups submitted letters within a month after the workshop, and all four were published. These four groups encompassed a total of 13 authors. In addition, none of the first author of each letter had previously written a clinical research paper. Findings and Discussion: This workshop improved not only the participants' knowledge but it also led to the concrete result of four published letters. Japanese physicians would be able to use this framework to write letters to the editor.

Carbon nanotubes (CNTs) have desirable mechanical properties for use as biomaterials in orthopedic and dental area such as bone- and tooth- substitutes. Here, we demonstrate that a glass surface densely coated with single-walled carbon nanotubes (SWNTs) stimulate the osteogenic differentiation of rat bone marrow mesenchymal stem cells (MSCs). MSCs incubated on SWNT- and multi-walled carbon nanotube (MWNT)-coated glass showed high activities of alkaline phosphatase that are markers for early stage osteogenic differentiation. Expression of Bmp2, Runx2, and Alpl of MSCs showed high level in the early stage for MSC incubation on SWNT- and MWNT-coated surfaces, but only the cells on the SWNT-coated glass showed high expression levels of Bglap (Osteocalcin). The cells on the SWNT-coated glass also contained the most calcium, and their calcium deposits had long needle-shaped crystals. SWNT coating at high density could be part of a new scaffold for bone regeneration.

Background and study aims The efficacy of complete closure versus simple closure for perforations during endoscopic submucosal dissection (ESD) has never been evaluated. We evaluated the efficacy of complete closure and simple closure for perforations and muscular layer injuries incurred during ESD. Patients and methods Thirty-four consecutive patients who underwent “complete closure” or “simple closure” for correction of perforations and muscular layer injuries during colorectal ESD were enrolled in this study. Complete closure was performed by the mucosa-submucosa clip closure method using only conventional endo-clips. For simple closure, endo-clips are placed just for perforation or muscular layer injury, while leaving any mucosal defects open. Results Among the 15 patients in the complete closure group, eight developed perforations and seven developed muscular layer injuries. Among the 19 patients in the simple closure group, six developed perforations and 13 developed muscular layer injuries during the ESD procedure. There were no statistically significant differences between the two groups in inflammatory reactions, adverse events, or length of the hospital stay. Conclusion Complete closure and simple closure for perforations and muscular layer injuries during ESD seem to have similar efficacy. While simple closure for a perforation during ESD seems sufficient, further study will be required to confirm our results.

Thus far, no curved linear array endoscopic ultrasound (CLAEUS) findings were established as predictors of difficult selective bile duct cannulation (SBDC). This study aimed to identify CLAEUS findings to predict endoscopic retrograde cholangiopancreatography (ERCP) cases with difficult SBDC. This single-center, retrospective cohort study was conducted between July 2014 and June 2017. This study included all consecutive patients who underwent CLAEUS prior to naïve ERCP. A CLAEUS finding of the simultaneous depiction of bile and pancreatic ducts at the second portion of the duodenum (D2) (simultaneous depiction) was selected as a possible predictor of difficult SBDC, and the κ values in the evaluation of inter- and intra-observer variabilities for "simultaneous depiction" were 0.65 and 0.77, respectively, with substantial correlation. Among the 986 patients who underwent ERCP, 80 patients were relevant for evaluation. Logistic regression analysis revealed strong association between "simultaneous depiction" and difficult SBDC (odds ratio 15.4, 95% confidence interval 4.2-56.0; p

Background: The environment surrounding Helicobacter pylori eradication treatment is dramatically changing. Recently, vonoprazan, a first-in-class potassium-competitive acid blocker (P-CAB), was introduced onto the market in 2015. The aging of Japan’s demographic structure is becoming pronounced. In this study, we examined the trend of the eradication rate of H. pylori in the metropolitan area and examined factors concerning successful eradication. Methods: We collected data from 20 hospitals in the Tokyo metropolitan area on patients who received first-line eradication therapy with a proton-pump inhibitor (PPI)/P-CAB, amoxicillin, and clarithromycin for 1 week and second-line eradication therapy with a PPI/P-CAB, amoxicillin, and metronidazole for 1 week from 2013 to 2018. The annual eradication rate and associated factors for successful eradication were analyzed. Results: We collected data of 4097 and 3572 patients in the first- and second-line eradication therapies, respectively. The eradication rate decreased from 2013 to 2014 and increased again from 2015 to 2018 with the first-line therapy [the eradication rates in 2013, 2014, 2015, 2016, 2017 and 2018 were 71.8%, 63.7%, 78.5%, 84.6%, 89.7 and 90.1%, respectively, in the per protocol (PP)]. The second-line eradication rates were 90.0%, 82.6%, 88.8%, 87.5%, 91.8% and 90.1% in 2013, 2014, 2015, 2016, 2017 and 2018, respectively, in PP. Vonoprazan was an independent factor for successful eradication in not only first-line, but also second-line eradication. Age over 75 years was an independent factor for eradication failure in both first- and second-line eradication therapies. Conclusion: The eradication rate improved from 2015 to 2018 with the first-line therapy because of the introduction of vonoprazan in the market. The eradication rates with first- and second-line regimens in elderly patients were lower than those in younger patients.

This paper presents the results of several experiments identifying basal salts (BS) contained in maturation medium, polyethylene glycol (PEG) concentration, abscisic acid (ABA) concentration, additional supplementation with potassium chloride (KCl), amino acid (AA) concentration, and proliferation culture medium (PCM) as the main culture factors affecting somatic embryo maturation in sugi (Japanese cedar, Cryptomeria japonica, Cupressaceae). Highly efficient embryo maturation was achieved when embryogenic cell lines (ECLs) were cultured on media supplemented with a combination of PEG, ABA, and AAs. More than 1000 embryos per gram of fresh weight (FW) can be produced on EM maturation medium supplemented with 175 g L−1 PEG, 100 µM ABA, 2 g L−1 glutamine, 1 g L−1 asparagine, and 0.5 g L−1 arginine.

This study aimed to obtain information from several embryogenic cell (EC) genotypes analyzing the factors that affect somatic embryogenesis (SE) initiation in sugi (Cryptomeria japonica, Cupressaceae) to apply them in the improvement of protocols for efficient induction of embryogenic cell lines (ECLs). The results of several years of experiments including studies on the influence of initial explant, seed collection time, and explant genotype as the main factors affecting SE initiation from male-fertile, male-sterile, and polycross-pollinated-derived seeds are described. Initiation frequencies depending on the plant genotype varied from 1.35 to 57.06%. The best induction efficiency was achieved when seeds were collected on mid-July using the entire megagametophyte as initial explants. The extrusion of ECs started approximately after 2 weeks of culture, and the establishment of ECLs was observed mostly 4 weeks after extrusion on media with or without plant growth regulators (PGRs). Subsequently, induced ECLs were maintained and proliferated on media with PGRs by 2–3-week-interval subculture routines. Although, the initial explant, collection time, and culture condition played important roles in ECL induction, the genotype of the plant material of sugi was the most influential factor in SE initiation.

Background and study aims We developed a new endoscopic closure technique using just conventional endoclips. The feasibility of endoscopic mucosa-submucosa clip closure method was evaluated in this clinical pilot study. Patients and methods This study involved consecutive 25 patients who underwent colorectal endoscopic submucosal dissection. Endoclips were placed at the edge of the mucosal defect. Each arm of the endoclip gripped the mucosa and submucosa, respectively. The direction in which the endoclip grips were placed was parallel to the short axis of the defect. Several endoclips were applied in this way. As a result, the mucosal defect was significantly reduced in size. Additional clips were placed to achieve complete closure. Results Mean size of resected specimen was 31.2 ± 11 mm. The success rate was 96 % (24/25). Mean procedure time was 9.6 ± 4.4 minutes. Mean number of endoclips was 9.3 ± 3.7. No complications were observed in any of the patients after the procedure. Conclusion Endoscopic mucosa-submucosa clip closure method could close mucosal defect of size around 2 – 4 cm completely using just conventional endoclips, and it seems easy, simple and low cost.

Background and study aims Although cold polypectomy (CP) is widely used for colorectal polyps 2B lesions were removed by EMR in compliance with the algorithm. Polypectomy outcomes were compared between the compliant and non-compliant groups. Histological outcomes were analyzed in accordance with JNET classification. Results Post-polypectomy bleeding rate in the compliant group (0 %) was lower than that in the non-compliant group (0.53 %, P

[This corrects the article DOI: 10.1371/journal.pone.0176039.].

In the World Health Organization (WHO)-coordinated Cardiovascular Disease and Alimentary Comparison Study, isoflavones (I; biomarker for dietary soy) and taurine (T; biomarker for dietary fish) in 24-hour-urine (24U) were inversely related to coronary heart disease (CHD) mortality. High levels of these biomarkers are found in Japanese people, whose CHD mortality is lowest among developed countries. We analyzed the association of these biomarkers with cardiovascular disease risk in the Japanese to know their health effects within one ethnic population. First, to compare the Japanese intake of I and T with international intakes, the ratios of 24UI and 24UT to creatinine from the WHO Study were divided into quintiles for analysis. The ratio for the Japanese was the highest in the highest quintiles for both I and T, reaching 88.1%, far higher than the average ratio for the Japanese (26.3%) in the total study population. Second, 553 inhabitants of Hyogo Prefecture, Japan, aged 30 to 79 years underwent 24-U collection and blood analyses. The 24UT and 24UI were divided into tertiles and adjusted for age and sex. The highest T tertile, compared with the lowest tertile, showed significantly higher levels of high-density lipoprotein-cholesterol (HDL-C), total cholesterol, 24U sodium (Na) and potassium (K). The highest I tertile showed significantly higher folate, 24UNa and 24UK compared with the lowest tertile. The highest tertile of both T and I showed significantly higher HDL-C, folate, and 24UNa and 24UK compared with the lowest tertile. Thus, greater consumption of fish and soy were significantly associated with higher HDL-C and folate levels, possibly a contributor to Japan having the lowest CHD mortality and longest life expectancy among developed countries. As these intakes were also associated with a high intake of salt, a low-salt intake of fish and soy should be recommended for healthy life expectancy.

It is difficult to remove well dispersed fine particles from dilute slurry, because filtration and evaporation process requires a lot of time and energy. Electrophoresis is known as a method of moving fine particles. Therefore, the electrophoresis technique is used to collect fine particles from such slurry as a paste of concentrated fine particles on electrodes. The viscous paste on the electrode is slowly falling down during electrophoresis process, finally drops from the electrode. This may affect recovery rate of the fine particles. In this paper, we studied transport phenomena of 5wt% alumina slurry under electric field for producing the concentrated particles from the alumina slurry. The concentration rate of the particles is evaluated from weight of the concentrated particles. Time-dependent behavior of the concentration rate shows a good agreement with the theoretical approach. Since the alumina slurry is a power-law fluid, we applied shear between electrodes. The concentration rate of the particles is successfully enhanced due to decreasing in the apparent viscosity. In addition, we measured rheological properties of the concentrated particles.

The flow interaction between bubbles is known to have an influence on acceleration of the bubbles rising velocity and the bubbles shape under static pressure field. We previously reported that pressure oscillation is effective for enhancing rising velocity of a small bubble in viscous shear-thinning fluid. In the present study, flow interaction between two small bubbles placed in the vertical direction under pressure-oscillating field, which is applied from the bottom side, is investigated experimentally. The three fluid types of different rheological properties, sodium polyacrylate, carboxy-methyl cellulose sodium salt and xanthan gum, are selected and tested. With a help of strobe scope lighting, we successfully monitor trace of the moving bubbles clearly through a high density video camera. Two non-dimensional parameters of each of the bubbles, normal rising velocity of bubble ε and non-dimensional acceleration Gb, are compared for the test fluids. It was found that the rising velocity of the lower bubble is higher than that of the upper bubble; that is strongly enhanced in the case of closer bubbles; and finally the bubbles move together and form a cluster, whereas natural rising velocity of the bubbles without pressure oscillation are the same. In addition, a ratio of distance between the bubbles center L and bubble diameter D and non-dimensional rising velocity ε are compared. After experiment we found that rising velocity of the lower bubble depends on the distance between bubbles and non-dimensional acceleration.

Background. Because of the epidemic of metabolic syndrome (MS) in Australian Aboriginals known for their higher cardiovascular mortality and shorter life expectancy, we analyzed the possible relationship of their MS risks with the current dietary custom. Methods. The subjects were 84 people aged 16–79 years. The health examination was conducted according to the basic protocol of WHO-CARDIAC (Cardiovascular Diseases and Alimentary Comparison) Study. Results. The highest prevalence among MS risks was abdominal obesity (over 60%). After controlling for age and sex, the odds of obesity decreased significantly with high level of urinary magnesium/creatinine ratio (Mg/cre) (OR, 0.11; 95% CI, 0.02–0.57; P

One of the newest and most promising methods for treating intractable neuronal diseases and injures is the transplantation of ex vivo-expanded human neural stem/progenitor cells (NSPCs). Human NSPCs are selectively expanded as free-floating neurospheres in serum-free culture medium containing fibroblast growth factor 2 (FGF2) and/or epidermal growth factor (EGF); however, the culture conditions still need to be optimized for performance and cost before the method is used clinically. Here, to improve the NSPC culture method for clinical use, we used an ATP assay to screen the effects of various reagents on human NSPC proliferation. Human NSPCs responded to EGF, FGF2, and leukemia inhibitory factor (LIF) in a dose-dependent manner, and the minimum concentrations eliciting maximum effects were 10 ng/ml EGF, 10 ng/ml FGF2, and 5 ng/ml LIF. EGF and LIF were stable in culture medium without NSPCs, although FGF2 was degraded. In the presence of human NSPCs, however, FGF2 and LIF were both degraded very rapidly, to below the estimated minimum concentration on day 3, but EGF remained above the minimum concentration for 5 days. Adding supplemental doses of each growth factor during the incubation promoted human NSPC proliferation. Among other supplements, insulin and transferrin promoted human NSPC growth, but progesterone, putrescine, selenite, D-glucose, and lactate were not effective and were cytotoxic at higher concentrations. Supplementing with conditioned medium from human NSPCs significantly increased human NSPC proliferation, but using a high percentage of the medium had a negative effect. These findings suggest that human NSPC culture is regulated by a balance in the culture medium between decreasing growth factor levels and increasing positive or negative factors derived from the NSPCs. Thus, in designing culture conditions for human NSPCs, it is useful to take the individual properties of each factor into consideration.

We report a case where tranexamic acid, which is an antifibrinolytic agent, was used to effectively treat bleeding tendency in a patient with immunoglobulin light chain (AL) amyloidosis. A male patient in his 80s without a history of bleeding disorders was admitted to our hospital for the examination of bleeding tendency and was diagnosed with a bleeding disorder due to AL amyloidosis. Blood tests revealed elevated plasmin-α2- plasmin inhibitor complex levels, suggesting fibrinolytic activation. Managing the bleeding was difficult; however, we suspected fibrinolytic activation associated with AL amyloidosis and initiated treatment with oral tranexamic acid, which markedly improved the bleeding disorder and abnormalities of the fibrinolytic system. Therefore, in cases of bleeding due to fibrinolytic activation of AL amyloidosis, tranexamic acid administration can be an effective treatment. [ABSTRACT FROM AUTHOR]