The D-mannose/L-galactose pathway plays a predominant role in ascorbate biosynthesis in the liverwort Marchantia polymorpha but is not regulated by light and oxidative stress.

Ascorbate plays an indispensable role in plants, functioning as both an antioxidant and a cellular redox buffer. It is widely acknowledged that the ascorbate biosynthesis in the photosynthetic tissues of land plants is governed by light-mediated regulation of the D-mannose/L-galactose (D-Man/L-Gal) pathway. At the core of this light-dependent regulation lies the VTC2 gene, encoding the rate-limiting enzyme GDP-L-Gal phosphorylase. The VTC2 expression is regulated by signals via the photosynthetic electron transport system. In this study, we directed our attention to the liverwort Marchantia polymorpha, representing one of the basal land plants, enabling us to conduct an in-depth analysis of its ascorbate biosynthesis. The M. polymorpha genome harbors a solitary gene for each enzyme involved in the D-Man/L-Gal pathway, including VTC2, along with three lactonase orthologs, which may be involved in the alternative ascorbate biosynthesis pathway. Through supplementation experiments with potential precursors, we observed that only L-Gal exhibited effectiveness in ascorbate biosynthesis. Furthermore, the generation of VTC2-deficient mutants through genome editing unveiled the inability of thallus regeneration in the absence of L-Gal supplementation, thereby revealing the importance of the D-Man/L-Gal pathway in ascorbate biosynthesis within M.  polymorpha. Interestingly, gene expression analyses unveiled a distinct characteristic of M. polymorpha, where none of the genes associated with the D-Man/L-Gal pathway, including VTC2, showed upregulation in response to light, unlike other known land plants. This study sheds light on the exceptional nature of M. polymorpha as a land plant that has evolved distinctive mechanisms concerning ascorbate biosynthesis and its regulation.

Layer 5 Intratelencephalic Neurons in the Motor Cortex Stably Encode Skilled Movement.

The primary motor cortex (M1) and the dorsal striatum play a critical role in motor learning and the retention of learned behaviors. Motor representations of corticostriatal ensembles emerge during motor learning. In the coordinated reorganization of M1 and the dorsal striatum for motor learning, layer 5a (L5a) which connects M1 to the ipsilateral and contralateral dorsal striatum, should be a key layer. Although M1 L5a neurons represent movement-related activity in the late stage of learning, it is unclear whether the activity is retained as a memory engram. Here, using Tlx3-Cre male transgenic mice, we conducted two-photon calcium imaging of striatum-projecting L5a intratelencephalic (IT) neurons in forelimb M1 during late sessions of a self-initiated lever-pull task and in sessions after 6 d of nontraining following the late sessions. We found that trained male animals exhibited stable motor performance before and after the nontraining days. At the same time, we found that M1 L5a IT neurons strongly represented the well-learned forelimb movement but not uninstructed orofacial movements. A subset of M1 L5a IT neurons consistently coded the well-learned forelimb movement before and after the nontraining days. Inactivation of M1 IT neurons after learning impaired task performance when the lever was made heavier or when the target range of the pull distance was narrowed. These results suggest that a subset of M1 L5a IT neurons continuously represent skilled movement after learning and serve to fine-tune the kinematics of well-learned movement.SIGNIFICANCE STATEMENT Motor memory persists even when it is not used for a while. IT neurons in L5a of the M1 gradually come to represent skilled forelimb movements during motor learning. However, it remains to be determined whether these changes persist over a long period and how these neurons contribute to skilled movements. Here, we show that a subset of M1 L5a IT neurons retain information for skilled forelimb movements even after nontraining days. Furthermore, suppressing the activity of these neurons during skilled forelimb movements impaired behavioral stability and adaptability. Our results suggest the importance of M1 L5a IT neurons for tuning skilled forelimb movements over a long period.

Chloroplast dehydroascorbate reductase and glutathione cooperatively determine the capacity for ascorbate accumulation under photooxidative stress conditions.

Ascorbate is an indispensable redox buffer essential for plant growth and stress acclimation. Its oxidized form, dehydroascorbate (DHA), undergoes rapid degradation unless it is recycled back into ascorbate by glutathione (GSH)-dependent enzymatic or non-enzymatic reactions, with the enzymatic reactions catalyzed by dehydroascorbate reductases (DHARs). Our recent study utilizing an Arabidopsis quadruple mutant (∆dhar pad2), which lacks all three DHARs (∆dhar) and is deficient in GSH (pad2), has posited that these GSH-dependent reactions operate in a complementary manner, enabling a high accumulation of ascorbate under high-light stress. However, as Arabidopsis DHAR functions in the cytosol or chloroplasts, it remained unclear which isoform played a more significant role in cooperation with GSH-dependent non-enzymatic reactions. To further comprehend the intricate network of ascorbate recycling systems in plants, we generated mutant lines lacking cytosolic DHAR1/2 or chloroplastic DHAR3, or both, in another GSH-deficient background (cad2). A comprehensive comparison of ascorbate profiles in these mutants under conditions of photooxidative stress induced by various light intensities or methyl viologen unequivocally demonstrated that chloroplastic DHAR3, but not cytosolic isoforms, works in concert with GSH to accumulate ascorbate. Our findings further illustrate that imbalances between stress intensity and recycling capacity significantly impact ascorbate pool size and tolerance to photooxidative stress. Additionally, it was found that the absence of DHARs and GSH deficiency do not impede ascorbate biosynthesis, at least in terms of transcription or activity of biosynthetic enzymes. This study provides insights into the robustness of ascorbate recycling.

The lymphocyte/monocyte ratio predicts the efficacy of isatuximab plus pomalidomide in multiple myeloma patients.

BACKGROUND: Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab. OBJECTIVE: We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment. METHODS: We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment. RESULTS: Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/µL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen. CONCLUSION: We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results.

Evolutionary insights into strategy shifts for the safe and effective accumulation of ascorbate in plants.

Plants accumulate high concentrations of ascorbate, commonly in their leaves, as a redox buffer. While ascorbate levels have increased during plant evolution, the mechanisms behind this phenomenon are unclear. Moreover, has the increase in ascorbate concentration been achieved without imposing any detrimental effects on the plants? In this review, we focus on potential transitions in two regulatory mechanisms related to ascorbate biosynthesis and the availability of cellular dehydroascorbate (DHA) during plant evolution. The first transition might be that the trigger for the transcriptional induction of VTC2, which encodes the rate-limiting enzyme in ascorbate biosynthesis, has shifted from oxidative stress (in green algae) to light/photosynthesis (in land plants), probably enabling the continuous accumulation of ascorbate under illumination. This could serve as a preventive system against the unpredictable occurrence of oxidative stress. The second transition might be that DHA-degrading enzymes, which protect cells from the highly reactive DHA in green algae and mosses, have been lost in ferns or flowering plants. Instead, flowering plants may have increased glutathione concentrations to reinforce the DHA reduction capacity, possibly allowing ascorbate accumulation and avoiding the toxicity of DHA. These potential transitions may have contributed to strategies for plants' safe and effective accumulation of ascorbate.

Characterization of chloroplastic thioredoxin dependent glutathione peroxidase like protein in Euglena gracilis: biochemical and functional perspectives.

Euglena gracilis, a fascinating organism in the scientific realm, exhibits characteristics of both animals and plants. It maintains redox homeostasis through a variety of enzymatic and nonenzymatic antioxidant molecules. In contrast to mammals, Euglena possesses non-selenocysteine glutathione peroxidase homologues that regulate its intracellular pools of reactive oxygen species. In the present study, a full-length cDNA of chloroplastic EgGPXL-1 was isolated and subjected to biochemical and functional characterization. Recombinant EgGPXL-1 scavenged H2O2 and t-BOOH utilizing thioredoxin as an electron donor rather than glutathione. Despite its monomeric nature, EgGPXL-1 exhibits allosteric behavior with H2O2 as the electron acceptor and follows typical Michaelis-Menten kinetics with t-BOOH. Suppression of EgGPXL-1 gene expression under normal and high-light conditions did not induce critical situations in E. gracilis, suggesting the involvement of compensatory mechanisms in restoring normal conditions.

A study on the reliability and validity of the Japanese version of the Scenario Test for people with chronic stroke-induced aphasia: A cross-sectional study.

BACKGROUND: The Scenario Test is recognised for its effectiveness in assessing the interactive aspects of functional communication in people with post-stroke aphasia (PWA). AIMS: To develop a Japanese version of the Scenario Test (Scenario Test-JP) and assess its reliability and validity. METHODS & PROCEDURES: Among 66 participants, we selected 61 individuals: 34 PWA and 27 healthy controls (HCs). We modified the Scenario Test-JP based on the UK version and subsequently evaluated its reliability (internal consistency, test-retest and intra-rater and inter-rater reliabilities) and validity (convergent and discriminant) by comparing PWA and HCs. OUTCOMES & RESULTS: The Scenario Test-JP showed strong reliability with a Cronbach's α of 0.93, test-retest reliability with an intraclass correlation coefficient (ICC) of 0.97, intra-rater reliability with an ICC of 0.95-1.00, and inter-rater reliability with an ICC of 0.96. The validity of the test was confirmed with concurrent scores ranging from ρ = 0.37 to 0.76 (p < 0.05) and known-groups validity (p < 0.001, r = -0.56). CONCLUSIONS & IMPLICATIONS: The reliability and validity of the Scenario Test-JP align with those of the original Dutch version and the UK and Greek versions. Additionally, the assessment can now include extended alternative communication methods, such as digital devices, indicating the potential of the Scenario Test-JP for modern Japanese speech-language therapy. WHAT THIS PAPER ADDS: What is already known on the subject Interactive communication is a facet of functional communication and is crucial for evaluating engagement and participation of people with aphasia (PWA) in speech-language therapy. The Scenario Test provides valuable information for planning speech-language treatment strategies by assessing dialogic communication. What this study adds This study describes the development of the Scenario Test-JP for use with Japanese speakers and Japanese PWA, which is adapted from the Scenario Test UK version. This study evaluated the reliability and validity of this assessment tool and provided supporting evidence. What are the clinical implications of this work? The reliability and validity of the Scenario Test-JP were consistent with those of the Dutch, UK and Greek versions. The Scenario Test-JP contributes to speech-language therapy in Japan, where high-quality support for the activities and participation of PWA is required. PRACTITIONER POINTS: Insights from the Scenario Test The Scenario Test plays a crucial role in evaluating the functional communication skills of people with post-stroke aphasia (PWA). Enhancing functional communication has been linked to improved social engagement among PWA, which in turn influences their overall quality of life (QOL). Issues addressed by the Scenario Test The Scenario Test aids in delineating rehabilitation objectives for activities and participation among PWA, particularly concerning functional communication. The test facilitates tailored support for PWAs' interactive communication and forms the foundation for appropriate speech-language therapy interventions. Transformation of speech-language therapy (SLT) in Japan through the introduction of the Scenario Test-JP The integration of the Scenario Test-JP could enhance the SLT services provided to PWA in Japan. With Japan experiencing an unprecedented ageing population, the prevalence of social isolation and diminished QOL resulting from communication disorders like stroke-induced aphasia is expected to rise. Consequently, the SLT rehabilitation sector in Japan is actively seeking effective interventions to support functional communication among PWA. Hence, the adoption of the Scenario Test-JP is anticipated to streamline the evaluation of functional communication, facilitating the judicious selection and timely provision of assistance to PWA in SLT, including guidance on communication partner support and communication skill training.

Middle meatus microbiome in patients with eosinophilic chronic rhinosinusitis in a Japanese population.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease and is subdivided into eosinophilic and noneosinophilic forms. There are few reports investigating the nasal microbiome and its pathological functions in patients with CRS. OBJECTIVE: We sought to analyze factors contributing to variations of the nasal microbiome in CRS, and on the basis of these factors, to elucidate whether the bacterial metabolites were related to the pathogenesis. METHODS: Nasal swabs were collected, and the V3 to V4 variable region of the 16S ribosomal RNA gene was amplified and sequenced. Factors contributing to variations of the nasal microbiome in patients with CRS were compared. The most influential factor was whether CRS was eosinophilic, and we compared α- and ß-diversity, bacterial species, and predictive bacterial functions between the 2 patient groups. In addition, the metabolites of the key bacteria were extracted, and we evaluated the predicted bacterial functions in airway epithelial cells. RESULTS: In total, 110 patients with CRS and 33 control subjects were enrolled. On the basis of the factors of variation, it was found that patients with eosinophilic CRS (n = 65) had different microbiomes with weighted UniFrac ß-diversity and lower α-diversity compared with those with noneosinophilic CRS (n = 45). A higher abundance of Fusobacterium nucleatum and an increased LPS pathway were observed in patients with noneosinophilic CRS compared with those with eosinophilic CRS. In airway epithelial cells, LPS derived from F nucleatum suppressed the expression levels of ALOX15 induced by TH2 cytokines. CONCLUSIONS: The differences in the nasal microbiome may play a key role in the pathophysiology of CRS.

PIM1 is a Poor Prognostic Factor for and Potential Therapeutic Target in Serous Carcinoma of the Endometrium.

Serous carcinoma (SC) is an aggressive histologic type of endometrial carcinoma (EMC) with a poor prognosis. The development of novel therapeutics for SC is an important issue. PIM1 is a serine/threonine kinase involved in various cellular functions, such as cell cycle progression, apoptosis, and transcriptional activation via the phosphorylation of many target proteins, including MYC. PIM1 is overexpressed in several cancers and has been associated with treatment-resistance. We investigated the expression and function of PIM1 in EMC, particularly SC. Immunohistochemical analysis in 133 EMC cases [103 endometrioid carcinomas (EC) and 30 SC] revealed the significantly stronger expression of PIM1 in SC than in EC and significantly shorter survival of patients with overexpression of PIM1 in all EMC cases, as well as in only SC cases. A multivariate analysis identified overexpression of PIM1 as an independent prognostic factor. The knockdown of PIM1 by siRNA in the SC cell line, ARK1, decreased the expression of phosphorylated MYC and reduced proliferation, migration, and invasion. The PIM1 inhibitor, SGI-1776, reduced cell viability in SC cell lines (ARK1, ARK2, and SPAC1L) with IC50 between 1 and 5 µM. SGI-1776 also reduced the migration and invasion of ARK1 cells. Moreover, the oral administration of SGI-1776 significantly suppressed subcutaneous ARK1 xenograft tumor growth in nude mice without impairing health. These results indicate that PIM1 is involved in the acquisition of aggressiveness and suggest the potential of PIM1 as a novel therapeutic target and SGI-1776 as a therapeutic agent for SC.

Eating behaviors and body self-esteem in couple's satisfaction during COVID-19 quarantine.

Background: Many experts agree that the Covid-19 pandemic and lockdown restriction have had an impact on relationships and eating habits in couples, but this hypothesis lacks evidence and empirical studies. Aim: The aim of the study was to investigate the relationship between satisfaction with the couple's relationship, body self-esteem, and eating behaviors during the Covid-19 lockdown. Method: Three hundred and eighty-one subjects, aged between 18 and 60 years (M = 26.88; SD = 9.22), of whom 89.8% women, participated in the survey. The online assessment included: the Relationship Assessment Scale; the Multidimensional Self Concept Scale and the Eating Disorder Examination Questionnaire. Results: The results showed that the relationship and the levels of couple's satisfaction are independent of respect to body experience and eating behavior. On the contrary, bodily experience is negatively correlated with diet, weight, body shape, and restriction attempts. However, the eating style of couple showed a change during the quarantine period, both in healthy and at-risk of ED subjects. Conclusion: The psychological impact of Covid-19 and its lockdown has had profound repercussions on the subjective relationship with body and food but have apparently preserved stable and satisfying bonds. The importance of the study confirmed the primary relation between self and body's satisfaction in subjective dimensions of life.

Lung Involvement in Adult T-Cell Lymphoma Diagnosed Using Bronchoscopic Cryobiopsy: A Case Report and Review of the Literature.

The diagnosis of pulmonary lymphoma using small tissue samples is difficult and often requires surgical procedures; thus, a less invasive sampling method is desirable. Moreover, pulmonary involvement in adult T-cell lymphoma (ATL) is often difficult to diagnose, especially in cases without characteristic flower cells. Here, we present the case of a 78-year-old man, in whom pathological examination of the transbronchial lung biopsy (TBLB) specimen did not reveal malignant findings; therefore, transbronchial lung cryobiopsy (TBLC) in combination with endobronchial ultrasonography (EBUS) was used to diagnose ATL based on the pathological findings. A literature review identified 18 cases of pulmonary lymphomas diagnosed using TBLC. Among the 19 cases, including our own, 16 cases were of B-cell lymphoma (84.2%), and the present case is the first case of ATL diagnosed using TBLC. Eighty percent of the cases underwent a biopsy (more than two samples) of the middle or lower lobe and were diagnosed without major complications. EBUS was used with TBLC in three cases to identify the location of the pulmonary lesions. In the present case, EBUS was also useful for avoiding vascular biopsy. Although large-scale prospective studies are required to establish precise guidelines for diagnosing pulmonary lymphomas using TBLC, our case report and review contributes to a deeper understanding of the diagnosis of rare diseases.

Growth Promotion of Giant Duckweed Spirodela polyrhiza (Lemnaceae) by Ensifer sp. SP4 Through Enhancement of Nitrogen Metabolism and Photosynthesis.

Duckweeds (Lemnaceae) are representative producers in fresh aquatic ecosystems and also yield sustainable biomass for animal feeds, human foods, and biofuels, and contribute toward effective wastewater treatment; thus, enhancing duckweed productivity is a critical challenge. Plant-growth-promoting bacteria (PGPB) can improve the productivity of terrestrial plants; however, duckweed-PGPB interactions remain unclear and no previous study has investigated the molecular mechanisms underlying duckweed-PGPB interaction. Herein, a PGPB, Ensifer sp. strain SP4, was newly isolated from giant duckweed (Spirodela polyrhiza), and the interactions between S. polyrhiza and SP4 were investigated through physiological, biochemical, and metabolomic analyses. In S. polyrhiza and SP4 coculture, SP4 increased the nitrogen (N), chlorophyll, and ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) contents and the photosynthesis rate of S. polyrhiza by 2.5-, 2.5-, 2.7-, and 2.4-fold, respectively. Elevated photosynthesis increased the relative growth rate and biomass productivity of S. polyrhiza by 1.5- and 2.7-fold, respectively. Strain SP4 significantly altered the metabolomic profile of S. polyrhiza, especially its amino acid profile. N stable isotope analysis revealed that organic N compounds were transferred from SP4 to S. polyrhiza. These N compounds, particularly glutamic acid, possibly triggered the increase in photosynthetic and growth activities. Accordingly, we propose a new model for the molecular mechanism underlying S. polyrhiza growth promotion by its associated bacteria Ensifer sp. SP4, which occurs through enhanced N compound metabolism and photosynthesis. Our findings show that Ensifer sp. SP4 is a promising PGPB for increasing biomass yield, wastewater purification activity, and CO2 capture of S. polyrhiza.[Formula: see text] Copyright © 2021 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Dynamical Phase Transitions in the Photodriven Charge-Ordered Dirac-Electron System.

We study photoinduced phase transitions and charge dynamics in the interacting Dirac-electron system with a charge-ordered ground state theoretically by taking an organic salt α-(BEDT-TTF)_{2}I_{3}. By analyzing the extended Hubbard model for this compound using a combined method of numerical simulations based on the time-dependent Schrödinger equation and the Floquet theory, we observe successive dynamical phase transitions from the charge-ordered insulator to a gapless Dirac semimetal and, eventually, to a Chern insulator phase under irradiation with circularly polarized light. These phase transitions occur as a consequence of two major effects of circularly polarized light, i.e., closing of the charge gap through melting the charge order and opening of the topological gap by breaking the time-reversal symmetry at the Dirac points. We demonstrate that these photoinduced phenomena are governed by charge dynamics of driven correlated Dirac electrons.

Investigating optimal region for thermal and electrical properties of epoxy nanocomposites under high frequencies and temperatures.

This research investigates the optimal region to achieve balanced thermal and electrical insulation properties of epoxy (EP) under high frequency (HF) and high temperature (HT) via integration of surface-modified hexagonal boron nitride (h-BN) nanoparticles. The effects of nanoparticle content and high temperature on various electrical (DC, AC, and high frequency) and thermal properties of EP are investigated. It is found that the nano h-BN addition enhances thermal performance and weakens electrical insulation properties. On the other side, under HF and HT stress, the presence of h-BN nanoparticles significantly improves the electrical performance of BN/EP nanocomposites. The EP has superior insulation properties at low temperature and low frequency, whereas the BN/EP nanocomposites exhibit better insulation performance than EP under HF and HT. The factors such as homogeneous nanoparticle dispersion in EP, enhanced thermal conductivity, nanoparticle surface modification, weight percent of nanoparticles, the mismatch between the relative permittivity of EP and nano h-BN, and the presence of voids in nanocomposites play the crucial role. The optimal nanoparticle content and homogenous dispersion can produce suitable EP composites for the high frequency and high temperature environment, particularly solid-state transformer applications.

Application of objective structured clinical examination (OSCE) for the evaluation of Kampo medicine training.

BACKGROUND: The purpose of this study was to develop an objective, content-valid, and reliable assessment method for Kampo medicine using an objective structured clinical examination (OSCE) for the assessment of clinical competence in Kampo medicine. METHODS: We developed a blueprint followed by a list of 47 assessment items and three task scenarios related to clinical competence in Kampo medicine. An eight-member test committee checked the relevance of the assessment items on a Likert scale. We calculated a content validity index and content validity ratio, and used the Angoff method to set the passing threshold. We trained a total of nine simulated patients with three assigned to each scenario. We conducted an OSCE for 11 candidates with varying medical abilities, and conducted three stations per person, which were evaluated by one evaluator in one room by direct observation. We used video recordings to test the inter-rater reliability of the three raters. We used the test results to verify the reliability of the assessment chart. RESULTS: The inter-rater reliability (intraclass correlation coefficient [2,1]) was 0.973. The reliability of the assessment chart for each scenario (Cronbach's α) was 0.86, 0.89, and 0.85 for Scenarios 1, 2, and 3, respectively. The reliability of the assessment chart for the whole OSCE (Cronbach's α) was 0.90. CONCLUSIONS: We developed a content-valid new OSCE assessment method for Kampo medicine and obtained high inter-rater and test reliabilities. Our findings suggest that this is one of the most reliable evaluation methods for assessing clinical competence in Kampo medicine.

Electrical and thermal performances of epoxy-based micro-nano hybrid composites at different electric fields and temperatures.

This paper investigates the electrical and thermal properties of pure epoxy resin (EP) and its micro-nano hybrid composites (20 wt% micro-AlN fillers with 1 wt% and 3 wt% nano-Al2O3fillers; 50% micro-AlN with 3% nano-Al2O3fillers) for power electronic packaging applications. Electrical properties such as space charge distribution, electrical conductivity and surface potential decay are measured. The thermal performance of the fabricated samples is estimated using thermal analysis devices. The hybrid composite consisting of 20 wt% micro-AlN and 1 wt% nano-Al2O3fillers exhibits the least space charge accumulation, higher thermal conductivity and better thermal stability. However, the excessive addition adversely affects space charge and electrical conductivity properties. The micro-nano hybrid composites significantly exhibit higher electrical conductivity than pure EP. The microfiller addition from 20 wt% to 50 wt% significantly improves the thermal conductivity of the EP. The reduced space charge injection and accumulation in the hybrid micro-nano composites are attributed to the enhancement of the injection barrier and reduction of the charge carrier traps in these materials. A theoretical mechanism of the charge dynamics inside the samples under different test conditions is proposed to support the experimental results.

Evaluation system for cell-permeable CYP3A4 inhibitory activity using 1α,25-dihydroxy-vitamin D3-induced intestinal cell lines.

We developed an assay system to evaluate the cytochrome P450 (CYP) 3A4-inhibitory activity of compounds, taking account of their cellular permeability, using intestine-derived cell lines pre-treated with the CYP3A4 inducer 1α,25-dihydroxy-vitamin D3 (250 nM).Ketoconazole (KTZ), saquinavir (SQV), naringin, naringenin (NGE), bergamottin (BG), 6',7'-dihydroxybergamottin (DHBG), epigallocatechin gallate (EGCG), and resveratrol (RES) were evaluated as known CYP3A4 inhibitors. The apparent IC50 (IC50,app) values of known inhibitors were determined in Caco-2 cells with 10 µM midazolam as a CYP3A4 substrate, and compared with the IC50 values in a human liver microsome assay.SQV and BG with high lipophilicity and good membrane permeability show similar concentrations inside and outside the cells, and consequently IC50,app and IC50 are similar.KTZ, EGCG, DHBG, NGE, and RES showed a difference between IC50 and IC50,app. This is considered to result from a difference between the intracellular and extracellular concentrations of the compound, which is likely due to the involvement of efflux and/or influx transporters.This method to evaluate CYP inhibition taking account of membrane permeation should be helpful to assess the potential clinical relevance of drug-drug or drug-food interactions in the gastrointestinal tract.

Ingredients of Jelly Products Affect Aspiration-Related Pulmonary Inflammation; in an Animal Study.

Diet modification is an important intervention in the management of patients with dysphagia. Food entering the airway, same as oral bacterium, causes pulmonary inflammation; therefore, the elucidation of inflammatory responses to different foods is important. This study aimed to investigate the differences in the severity of inflammatory response induced by intratrachial injection of foods with different nutritional components. Two jelly products, the one containing only carbohydrates (KURIN jelly: Isocal Jelly KURIN®) and the other containing carbohydrates, proteins, and lipids (HC jelly: Isocal Jelly HC®), were prepared. These jelly products (dilution with saline, 50% volume/volume) and saline, as control, were intratracheally administered to Sprague-Dawley rats at a dose of 1 ml/kg (KURIN group (n = 15), HC group (n = 15), Saline group (n = 15)). At 1, 2 and 7 days after administration, lungs were harvested and histological analysis was performed. The severity of induced inflammation was evaluated using the Acute Lung Injury (ALI) score with hematoxylin-eosin staining, and the expression of IL-1ß, IL-6 and TNF-α, markers of airway inflammation, were observed with immunostaining. The ALI score in the HC jelly group was significantly higher than the KURIN jelly group and the Saline group (P < 0.01) at 1 and 2 days after administration, while the ALI score in the KURIN jelly group was higher than Saline group only at 2 day after administration. Numerous positive cells for IL-1ß, IL-6 and TNF-α were observed only in the HC jelly group at 1 and 2 days after administration. There were no significant histological differences between the three groups at 7 days after administration. Our data suggests that the severity of inflammation caused by aspiration differs depending on the ingredients of the foods, and the nutrients contained in foods might be considered in dietary management for the patients with dysphagia.

Endoscopic Endonasal Orbital Floor Fracture Repair With Mucosal Preservation to Reinforce the Fractured Bone.

ABSTRACT: Treatment of orbital floor fracture is often needed to cure diplopia and enophthalmos. However, the available surgical methods have many limitations. An endoscopic endonasal reduction is a familiar approach for otolaryngologists; however, reconstruction of the orbital floor may pose certain problems. Here, the authors developed the endoscopic endonasal orbital floor fracture repair with mucosal preservation procedure (mucosal preservation procedure). This study aims to evaluate outcomes after the mucosal preservation procedure. The authors analyzed 18 patients who had their orbital floor repaired using the mucosal preservation procedure. Pre- and post-operative ocular motility range was measured with a Hess screen test, and the percentage of Hess area ratio (HAR%) was used for all statistical comparisons. The distance between the fractured bone and orbital floor (DBFO) on computed tomography was measured before and four months after surgery. Overall, diplopia, and pain improved after surgery in all patients. Diplopia and pain completely disappeared in 17 patients, while only mild diplopia remained in one. HAR% increased significantly, whereas DBFO reduced significantly after the operation. In conclusion, the outcome of the mucosal preservation procedure was favorable without any major complications. Further studies with larger numbers of patients are needed to verify our technique.

Motor learning requires myelination to reduce asynchrony and spontaneity in neural activity.

Myelination increases the conduction velocity in long-range axons and is prerequisite for many brain functions. Impaired myelin regulation or impairment of myelin itself is frequently associated with deficits in learning and cognition in neurological and psychiatric disorders. However, it has not been revealed what perturbation of neural activity induced by myelin impairment causes learning deficits. Here, we measured neural activity in the motor cortex during motor learning in transgenic mice with a subtle impairment of their myelin. This deficit in myelin impaired motor learning, and was accompanied by a decrease in the amplitude of movement-related activity and an increase in the frequency of spontaneous activity. Thalamocortical axons showed variability in axonal conduction with a large spread in the timing of postsynaptic cortical responses. Repetitive pairing of forelimb movements with optogenetic stimulation of thalamocortical axon terminals restored motor learning. Thus, myelin regulation helps to maintain the synchrony of cortical spike-time arrivals through long-range axons, facilitating the propagation of the information required for learning. Our results revealed the pathological neuronal circuit activity with impaired myelin and suggest the possibility that pairing of noninvasive brain stimulation with relevant behaviors may ameliorate cognitive and behavioral abnormalities in diseases with impaired myelination.