Search

Hydrogen diffusion behaviour at the coherent and incoherent Σ3 grain boundaries (GBs) of pure polycrystalline Ni was observed in situ using a polyaniline-based hydrogen video imaging system. The hydrogen flux at the coherent Σ3 GBs, also referred to as twin boundaries, was found to be the same as that in the grain interior. In contrast, enhanced hydrogen diffusion was observed at the incoherent portions of the Σ3 GBs. Hydrogen diffusion was notably enhanced at the micro/nanoscale incoherent portion, and the deviation angle of Σ3 GBs was identified as a critical factor influencing the hydrogen flux therein.

Objectives: We performed preoperative evaluations of giant ovarian tumors in older adult patients using the comprehensive geriatric assessment (CGA) and estimation of physiologic ability and surgical stress (E-PASS) scoring systems. We report a case in which the Aron Alpha method was performed, and perioperative management was performed using enhanced recovery after surgery (ERAS). Materials and Methods: We performed preoperative evaluations using the E-PASS scoring system and CGA on older adult patients with giant ovarian tumors, followed by the minimally invasive Aron Alpha method and perioperative management using ERAS. Results: The mean patient age was 75.8 ± 8.8 years; comorbidities included hypertension in three patients, hyperlipidemia in two, angina pectoris in one, cholecystitis in one, and lower extremity varicose veins in one. The mean tumor size was 21.0 ± 5.4 cm. The E-PASS scoring system showed a preoperative risk score of 0.7 ± 0.4, a surgical stress score of 0, and a comprehensive risk score of 0.3 ± 0.3. CGA showed that two patients had problems with activities of daily living and cognitive function. The mean duration of surgery was 89.0 ± 16.6 min, and the mean blood loss was 56.0 ± 65.4 mL. No surgery-associated complications were observed. No patients had prolonged hospitalization or a decline in activities of daily living. Conclusion: We showed the usefulness of performing detailed preoperative evaluations using CGA and the E-PASS system, followed by the minimally invasive Aron Alpha surgical method and perioperative management using ERAS in improving surgical outcomes in older adult patients with giant ovarian tumors.

Abstract Background Disproportionately enlarged subarachnoid space hydrocephalus (DESH) is one of the neuroradiological characteristics of idiopathic normal pressure hydrocephalus (iNPH), which makes statistical analyses of brain images difficult. This study aimed to develop and validate methods of accurate brain segmentation and spatial normalisation in patients with DESH by using the Computational Anatomy Toolbox (CAT12). Methods Two hundred ninety-eight iNPH patients with DESH and 25 healthy controls (HCs) who underwent cranial MRI were enrolled in this study. We selected the structural images of 169 patients to create customised tissue probability maps and diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) templates for patients with DESH (DESH-TPM and DESH-Template). The structural images of 38 other patients were used to evaluate the validity of the DESH-TPM and DESH-Template. DESH-TPM and DESH-Template were created using the 114 well-segmented images after the segmentation processing of CAT12. In the validation study, we compared the accuracy of brain segmentation and spatial normalisation among three conditions: customised condition, applying DESH-TPM and DESH-Template to CAT12 and patient images; standard condition, applying the default setting of CAT12 to patient images; and reference condition, applying the default setting of CAT12 to HC images. Results In the validation study, we identified three error types during segmentation. (1) The proportions of misidentifying the dura and/or extradural structures as brain structures in the customised, standard, and reference conditions were 10.5%, 44.7%, and 13.6%, respectively; (2) the failure rates of white matter hypointensity (WMH) cancellation in the customised, standard, and reference conditions were 18.4%, 44.7%, and 0%, respectively; and (3) the proportions of cerebrospinal fluid (CSF)-image deficits in the customised, standard, and reference conditions were 97.4%, 84.2%, and 28%, respectively. The spatial normalisation accuracy of grey and white matter images in the customised condition was the highest among the three conditions, especially in terms of superior convexity. Conclusions Applying the combination of the DESH-TPM and DESH-Template to CAT12 could improve the accuracy of grey and white matter segmentation and spatial normalisation in patients with DESH. However, this combination could not improve the CSF segmentation accuracy. Another approach is needed to overcome this challenge.

Abstract The reflexive excitation of the sympathetic nervous system in response to psychological stress leads to elevated blood pressure, a condition that persists even after the stress has been alleviated. This sustained increase in blood pressure, which may contribute to the pathophysiology of hypertension, could be linked to neural plasticity in sympathetic nervous activity. Given the critical role of astrocytes in various forms of neural plasticity, we investigated their involvement in maintaining elevated blood pressure during the post-stress phase. Specifically, we examined the effects of arundic acid, an astrocytic inhibitor, on blood pressure and heart rate responses to air-jet stress. First, we confirmed that the inhibitory effect of arundic acid is specific to astrocytes. Using c-Fos immunohistology, we then observed that psychological stress activates neurons in cardiovascular brain regions, and that this stress-induced neuronal activation was suppressed by arundic acid pre-treatment in rats. By evaluating astrocytic process thickness, we also confirmed that astrocytes in the cardiovascular brain regions were activated by stress, and this activation was blocked by arundic acid pre-treatment. Next, we conducted blood pressure measurements on unanesthetized, unrestrained rats. Air-jet stress elevated blood pressure, which remained high for a significant period during the post-stress phase. However, pre-treatment with arundic acid, which inhibited astrocytic activation, suppressed stress-induced blood pressure elevation both during and after stress. In contrast, arundic acid had no significant impact on heart rate. These findings suggest that both neurons and astrocytes play integral roles in stress-induced blood pressure elevation and its persistence after stress, offering new insights into the pathophysiological mechanisms underlying hypertension.

Background & Aims: Hepatitis B virus (HBV)-DNA integration into the host genome contributes to hepatocellular carcinoma (HCC) development. KMT2B is the second most frequent locus of HBV-DNA integration in HCC; however, its role and function remain unclear. We aimed to clarify the impact of HBV-KMT2B integration in HCC development using a human genome-edited induced pluripotent stem cell (iPSCs) model. Methods: Based on the genetic information on HBV-KMT2B integration in HCC, we determined its complete DNA sequence and transcript variants. To exclude the effect of other oncogenic mutations, we reproduced HBV integration in healthy donor iPSCs with an intact genome and analyzed its effects using iPSC-derived hepatic progenitor cells (HPCs) and hepatocytes (iPS-Heps). Results: The reproduced HBV-KMT2B integration significantly upregulated the proliferation of hepatic cells. Comprehensive transcriptional and epigenetic analyses revealed enhanced expression of cell cycle-related genes in hepatic cells with HBV-KMT2B integration based on perturbation of histone 3 lysine 4 tri-methylation (H3K4me3), mimicking that in the original HCC sample. Long-read RNA-sequence detected the common KMT2B transcript variants in the HCC sample and HPCs. Overexpression of the truncated variant significantly enhanced proliferation of hepatic cells, whereas HBV-KMT2B fusion transcripts did not enhance proliferation. HBV-KMT2B-integrated HPCs exhibited replication stress and DNA damage, indicating that our model initiated the process of hepatocarcinogenesis due to abnormally promoted KMT2B function. Conclusions: Our disease model using genetically engineered iPSCs provides the first insight into both the KMT2B function in HCC development and the oncogenic processes by HBV-KMT2B integration. We clarified the novel oncogenic mechanism in HBV-related HCC due to aberrant KMT2B function.

The serotonergic neurons in the raphe nucleus are implicated in various cognitive functions such as learning and emotion. In vertebrates, the raphe nucleus is divided into the dorsal raphe and the median raphe. In contrast to the abundance of knowledge on the functions of the dorsal raphe, the roles of the serotonergic neurons in the median raphe are relatively unknown. The studies using zebrafish revealed that the median raphe serotonergic neurons receive input from the two distinct pathways from the habenula and the IPN. The use of zebrafish may reveal the function of the Hb-IPN-median raphe pathway. To clarify the functions of the median raphe serotonergic neurons, it is necessary to distinguish them from those in the dorsal raphe. Most median raphe serotonergic neurons originate from rhombomere 2 in mice, and we generated the transgenic zebrafish which can label the serotonergic neurons derived from rhombomere 2. In this study, we found the serotonergic neurons derived from rhombomere 2 are localized in the median raphe and project axons to the rostral dorsal pallium in zebrafish. This study suggests that this transgenic system has the potential to specifically reveal the function and information processing of the Hb-IPN-raphe-telencephalon circuit in learning.

Numerical simulations were generated to investigate the response of a very large floating airport to an airplane takeoff, using the set of nonlinear shallow water equations of velocity potential for water waves interacting with a floating thin plate. We have proposed two methods to reduce persistent airport vibration: reflectance reduction by decreasing the flexural rigidity in airport edge parts and amplification reduction by decreasing the still water depth partially under airport runways. First, when the flexural rigidity is uniformly decreased in an airport edge part, the reflectance of the floating body waves due to a B737 was reduced because of the multiple reflections. However, the wave reflectance for a B747 increased, depending on the conditions. A too-long edge part was not effective in reducing the wave reflectance. Conversely, when the flexural rigidity is linearly decreased in an airport edge part, the wave reflectance was reduced for both airplanes. Second, when the still water depth under an airport runway is partially reduced at the location where floating body waves are amplified, the wave heights of floating body waves tended to decrease as the still water depth in the shallower area decreased.

After being taught by teachers, learners often need to work independently in new situations. However, a teaching strategy that most efficiently fosters independent learning remains elusive. In this study, we developed a novel experimental paradigm to compare various teaching strategies. In addition, we formalized autonomy-supportive teaching and constructed an autonomy-support algorithm that estimates learners' mental states and aims to enhance both learners’ competence and autonomy. In the experiment, participants were taught through different teaching algorithms depending on the experimental conditions, after which they independently worked on a new set of tasks. Our results demonstrate that compared to the all- and no-teach algorithms, the autonomy-support algorithm enhances learners' engagement while being taught and enhances performance when learners independently work on a new set of tasks. Our findings contribute to the existing observational and interventional research on education by providing rigorous evidence in an experimentally controlled setting.

Diabetic heart disease remains the leading cause of death in individuals with type-2 diabetes mellitus (T2DM). Both insulin resistance and metabolic derangement, hallmark features of T2DM, develop early and progressively impair cardiovascular function. These factors result in altered cardiac metabolism and energetics, as well as coronary vascular dysfunction, among other consequences. Therefore, gaining a deeper understanding of the mechanisms underlying the pathophysiology of diabetic heart disease is crucial for developing novel therapies for T2DM-associated cardiovascular disease. Cardiomyocytes are equipped with the cholinergic machinery, known as the non-neuronal cardiac cholinergic system (NNCCS), for synthesizing and secreting acetylcholine (ACh) as well as possessing muscarinic ACh receptor for ACh binding and initiating signaling cascade. ACh from cardiomyocytes regulates glucose metabolism and energetics, endothelial function, and among others, in an auto/paracrine manner. Presently, there is only one preclinical animal model – diabetic db/db mice with cardiac-specific overexpression of choline transferase (Chat) gene - to study the effect of activated NNCCS in the diabetic heart. In this mini-review, we discuss the physiological role of NNCCS, the connection between NNCCS activation and cardiovascular function in T2DM and summarize the current knowledge of S-Nitroso-NPivaloyl-D-Penicillamine (SNPiP), a novel inducer of NNCCS, as a potential therapeutic strategy to modulate NNCCS activity for diabetic heart disease.

Abstract Designing suitable anion exchange ionomers is critical to improving the performance and in situ durability of anion exchange membrane water electrolyzers (AEMWEs) as one of the promising devices for producing green hydrogen. Herein, highly gas‐permeable and dimensionally stable anion exchange ionomers (QC6xBA and QC6xPA) are developed, in which bulky cyclohexyl (C6) groups are introduced into the polymer backbones. QC650BA‐2.1 containing 50 mol% C6 composition shows 16.6 times higher H2 permeability and 22.3 times higher O2 permeability than that of QC60BA‐2.1 without C6 groups. Through‐plane swelling of QC650BA‐2.1 decreases to 12.5% from 31.1% (QC60BA‐2.1) while OH− conductivity slightly decreases (64.9 and 56.2 mS cm−1 for QC60BA‐2.1 and QC650BA‐2.1, respectively, at 30 °C). The water electrolysis cell using the highly gas permeable QC650BA‐2.1 ionomer and Ni0.8Co0.2O in the anode catalyst layer achieves two times higher performance (2.0 A cm−2 at 1.69 V, IR‐included) than those of the previous cell using in‐house ionomer (QPAF‐4‐2.0) (1.0 A cm−2 at 1.69 V, IR‐included). During 1000 h operation at 1.0 A cm−2, the QC650BA‐2.1 cell exhibits nearly constant cell voltage with a decay rate of 1.1 µV h−1 after the initial increase of the cell voltage, proving the effectiveness of the highly gas permeable and dimensionally stable ionomer in AEMWEs.

The nomenclature used to describe animals working in roles supporting people can be confusing. The same term may be used to describe different roles, or two terms may mean the same thing. This confusion is evident among researchers, practitioners, and end users. Because certain animal roles are provided with legal protections and/or government-funding support in some jurisdictions, it is necessary to clearly define the existing terms to avoid confusion. The aim of this paper is to provide operationalized definitions for nine terms, which would be useful in many world regions: "assistance animal", "companion animal", "educational/school support animal", "emotional support animal", "facility animal", "service animal", "skilled companion animal", "therapy animal", and "visiting/visitation animal". At the International Society for Anthrozoology (ISAZ) conferences in 2018 and 2020, over 100 delegates participated in workshops to define these terms, many of whom co-authored this paper. Through an iterative process, we have defined the nine terms and explained how they differ from each other. We recommend phasing out two terms (i.e., "skilled companion animal" and "service animal") due to overlap with other terms that could potentially exacerbate confusion. The implications for several regions of the world are discussed.

Vascular endothelial cells play an important role in regulating peripheral circulation by modulating arterial tone in the microvasculature. Elevated intracellular Ca2+ levels are required in endothelial cells to induce smooth muscle relaxation via endothelium-dependent mechanisms such as nitric oxide production, prostacyclin, and endothelial cell hyperpolarization. It is well established that exogenous administration of acetylcholine can increase intracellular Ca2+ concentrations, followed by endothelium-dependent vasodilation. Although endogenous acetylcholine's regulation of vascular tone remains debatable, recent studies have reported that endogenously derived acetylcholine, but not neuronal cell-derived acetylcholine, is a key modulator of endothelial cell function. In this minireview, we summarize the current knowledge of the non-neuronal cholinergic system (NNCS) in vascular function, particularly vascular endothelial cell function, which contributes to blood pressure regulation. We also discuss the possible pathophysiological impact of endothelial NNCS, which may induce the development of vascular diseases due to endothelial dysfunction, and the potential of endothelial NNCS as a novel therapeutic target for endothelial dysfunction in the early stages of metabolic syndrome, diabetes, and hypertension.

Abstract Inflammatory myofibroblastic tumor (IMT) is an intermediate malignancy with myofibroblast proliferation and inflammatory cell infiltration with malignant potential. Primary IMTs are predominantly reported in the lungs, while gastric IMTs are very rare. Therefore, no guidelines exist for the diagnosis and treatment of gastric IMTs. The present case is a 39‐year‐old man diagnosed with an asymptomatic gastric submucosal tumor. Considering the malignancy of the tumor, we selected non‐exposed endoscopic wall‐inversion surgery as the resection method and successfully performed local resection. Histopathological analysis showed myofibroblast proliferation and inflammatory cell infiltration, with a diagnosis of primary gastric IMT and negative resection margins. Immunohistochemical staining was negative for anaplastic lymphoma kinase. To the best of our knowledge, including our case, there have been 52 reported cases of primary gastric IMTs that have been treated, with several recurrent cases. In this study, we report the first case of local resection of gastric IMT using non‐exposed endoscopic wall‐inversion surgery, with a literature review.

To investigate the effect of cross‐linking on partially fluorinated anion exchange membranes tethered with trimethylpropyl side chains (QPAF‐C3), styrene‐based cross‐linker is introduced into the precursor copolymers and then cross‐linked via free radical reaction. The one‐pot cross‐linking and quaternization reactions are successful as confirmed through nuclear magnetic resonance spectra. By solution casting, the resulting polymers provide flexible membranes (xQPAF‐C3‐VB) with 9.1–36.0% degree of cross‐linking. The cross‐linking results in smaller hydrophilic/hydrophobic phase‐separated morphology as confirmed by transmission electron microscopy images. The cross‐linking effect on the membrane properties is observed in the suppressed water uptake and decreased hydroxide ion conductivity. Among the cross‐linked membranes, xQPAF‐C3‐VB membranes with 17.4% degree of cross‐linking and 1.16 meq g−1 of ion exchange capacity exhibit the highest hydroxide ion conductivity (56 mS cm−1 at 30 °C) that is comparable to that of the pristine membrane (54 mS cm−1). The cross‐linking contributes to improving the thermomechanical properties with higher glass transition temperature. The cross‐linked xQPAF‐C3‐VB is applied to alkaline water electrolyzer to achieve high efficiency (74%) and reasonable performance (1.67 V at 1.0 A cm−2).

The non-neuronal cholinergic system of the cardiovascular system has recently gained attention because of its origin. The final product of this system is acetylcholine (ACh) not derived from the parasympathetic nervous system but from cardiomyocytes, endothelial cells, and immune cells. Accordingly, it is defined as an ACh synthesis system by non-neuronal cells. This system plays a dispensable role in the heart and cardiomyocytes, which is confirmed by pharmacological and genetic studies using murine models, such as models with the deletion of vesicular ACh transporter gene and modulation of the choline acetyltransferase (ChAT) gene. In these models, this system sustained the physiological function of the heart, prevented the development of cardiac hypertrophy, and negatively regulated the cardiac metabolism and reactive oxygen species production, resulting in sustained cardiac homeostasis. Further, it regulated extra-cardiac organs, as revealed by heart-specific ChAT transgenic (hChAT tg) mice. They showed enhanced functions of the blood-brain barrier (BBB), indicating that the augmented system influences the BBB through the vagus nerve. Therefore, the non-neuronal cardiac cholinergic system indirectly influences brain function. This mini-review summarizes the critical cardiac phenotypes of hChAT tg mice and focuses on the effect of the system on BBB functions. We discuss the possibility that a cholinergic signal or vagus nerve influences the expression of BBB component proteins to consolidate the barrier, leading to the downregulation of inflammatory responses in the brain, and the modulation of cardiac dysfunction-related effects on the brain. This also discusses the possible interventions using the non-neuronal cardiac cholinergic system.

Abstract Purpose To investigate whether seminal plasma (SP)/serum ratios of multiple trace elements (TEs) can classify patients with male subfertility. Methods SP/serum ratios of 20 TEs (lithium, sodium, magnesium, phosphorus, sulfur, potassium, calcium, manganese, iron, cobalt, copper, zinc, arsenic, selenium, rubidium, strontium, molybdenum, cesium, barium, and thallium) were calculated for healthy volunteers (n = 4) and those consulting for male subfertility (n = 245). Volunteer semen samples were collected by split ejaculation into early and subsequent fractions, and SP/serum ratio data were compared between fractions. The patients' SP/serum ratio data were used in an unsupervised clustering analysis and qualitatively compared with the data from the fractions of ejaculation from the volunteers. Semen quality parameters and pregnancy outcomes were compared between patient clusters. Results The early fraction of volunteers was characterized by lower phosphorus and arsenic and 18 other higher TEs than the subsequent fraction. Cluster analysis classified patients into four distinct clusters, one sharing characteristics with the early fraction and another with the subsequent fraction. One cluster with the early fraction characteristics had significantly lower semen volume and higher pregnancy rates from spontaneous pregnancies or intrauterine insemination. Conclusions Classification of patients based on SP/serum ratios of multiple TEs represents the dominance of fractions of ejaculation samples.

Myasthenic crisis, a life-threatening exacerbation of myasthenia gravis, is a significant clinical challenge, particularly when refractory to standard therapies. Here, we described a case of myasthenic crisis in which the patient transitioned from refractory myasthenic crisis to minimal symptom expression after receiving add-on treatment with efgartigimod, a novel neonatal Fc receptor antagonist. A 54 years-old woman who was diagnosed with anti-acetylcholine receptor antibody-positive myasthenia gravis experienced respiratory failure necessitating mechanical ventilation. Despite aggressive treatment with plasmapheresis, intravenous immunoglobulins, and high-dose corticosteroids, her condition continued to deteriorate, culminating in persistent myasthenic crisis. Efgartigimod was administered as salvage therapy. Remarkable improvement in neuromuscular function was observed within days, allowing for successful weaning from mechanical ventilation. Over the subsequent weeks, the patient’s symptoms continued to ameliorate, ultimately reaching a state of minimal symptom expression. Serial assessments of her serum anti-acetylcholine receptor antibody titer showed a consistent decline in parallel with this clinical improvement. This case highlights efgartigimod’s potential as an effective therapeutic option for refractory myasthenic crisis, offering new hope for patients facing this life-threatening condition.

Background/aimAntiviral hepatitis and systemic therapies for hepatocellular carcinoma (HCC) remarkably progressed in the recent 10 years. This study aimed to reveal the actual transition and changes in the prognosis and background liver disease in non-advanced HCC in the past 20 years.MethodsThis retrospectively recruited 566 patients who were diagnosed with non-advanced HCC from February 2002 to February 2022. The prognosis was analyzed by subdividing according to the diagnosis date (period I: February 2002-April 2009 and period Ⅱ: May 2009-February 2022).ResultsPatients in period II (n = 351) were significantly older, with lower albumin-bilirubin (ALBI) scores and alpha-fetoprotein (AFP) and more anti-viral therapy, systemic therapy, and hepatic arterial infusion chemotherapy as compared with those in period I (n = 215). The etiology ratio of the background liver disease revealed decreased hepatitis C virus from 70.6% to 49.0% and increased non-B, non-C from 17.7% to 39.9% from periods I to Ⅱ. The multivariate analysis revealed older age and higher ALBI score in Barcelona Clinic Liver Cancer (BCLC) 0/A stage, AFP of >20 ng/mL, and higher ALBI score in BCLC B stage as independent prognosis factors. Fine-Gray competing risk model analysis revealed that liver-related deaths significantly decreased in period II as compared to period I, especially for BCLC stage 0/A (HR: 0.656; 95%CI: 0.442-0.972, P = 0.036).ConclusionThe characteristics of patients with non-advanced HCC have changed over time. Appropriate background liver management led to better liver-related prognoses in BCLC 0/A.

We have previously reported the identification of a novel splicing variant of the mouse peroxisome proliferator-activated receptor-γ (Pparγ), referred to as Pparγ1sv. This variant, encoding the PPARγ1 protein, is abundantly and ubiquitously expressed, playing a crucial role in adipogenesis. Pparγ1sv possesses a unique promoter and 5′ untranslated region (5′UTR), distinct from those of the canonical mouse Pparγ1 and Pparγ2 mRNAs. We observed a significant increase in DNA methylation at two CpG sites within the proximal promoter region (-733 to -76) of Pparγ1sv during adipocyte differentiation. Concurrently, chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) using antibodies against H3K4me3 and H3K27ac indicated marked elevations in both methylation and acetylation of histone H3, while the repressive histone mark H3K9me2 significantly decreased, at the transcription start sites of both Pparγ1sv and Pparγ2 following differentiation. Knocking down Pparγ1sv using specific siRNA also led to a decrease in Pparγ2 mRNA and PPARγ2 protein levels; conversely, knocking down Pparγ2 resulted in reduced Pparγ1sv mRNA and PPARγ1 protein levels, suggesting synergistic transcriptional regulation of Pparγ1sv and Pparγ2 during adipogenesis. Furthermore, our experiments utilizing the CRISPR-Cas9 system identified crucial PPARγ-binding sites within the Pparγ gene locus, underscoring their significance in adipogenesis. Based on these findings, we propose a model of positive feedback regulation for Pparγ1sv and Pparγ2 expression during the adipocyte differentiation process in 3T3-L1 cells.