A Prospective Study of Long-term Outcomes in Female Patients with Nonalcoholic Steatohepatitis Using Age- and Body Mass Index-matched Cohorts

In patients with nonalcoholic steatohepatitis (NASH), the prevalence of cirrhosis is higher among women than men, and hepatocellular carcinoma (HCC) develops mainly in the cirrhotic stage among women. However, the long-term outcomes in female patients with NASH have not been fully elucidated, and age, gender and BMI were not simultaneously adjusted in previous studies on the prognosis of NASH. To elucidate the outcomes in female patients with NASH, we prospectively compared NASH patients with advanced fibrosis (advanced NASH) with hepatitis C virus-related advanced fibrosis (advanced CHC) patients and NASH patients with mild fibrosis (mild NASH) using study cohorts that were adjusted for body mass index (BMI) in addition to age. The median follow-up period was 92.5 months. Liver-related complication-free survival was significantly reduced in the advanced NASH group compared to the mild NASH group. No liver-related complications developed in the mild NASH group. The overall survival, liver-related complication- and cardiovascular/cerebrovascular disease-free survival were not significantly different between the advanced NASH and CHC groups. Female patients with NASH and advanced fibrosis may have a less favorable prognosis for liver-related complications than the matched cohorts with NASH and mild fibrosis, but may have a similar prognosis to the matched cohorts with CHC

3-years Occurrence Variability of Concentric Gravity Waves in the Mesopause Observed by IMAP/VISI

第6回極域科学シンポジウム分野横断型セッション：[IM] 横断　中層大気・熱圏11月17日（火）　統計数理研究所 セミナー室2（D304

Implication of extracellular zinc exclusion by recombinant human calprotectin (MRP8 and MRP14) from target cells in its apoptosis-inducing activity.

BACKGROUND: Calprotectin is a calcium-binding and zinc-binding protein complex that is abundant in the cytosol of neutrophils. This factor is composed of 8 and 14 kDa subunits, which have also been termed migration inhibitory factor-related proteins MRP8 and MRP14. We previously reported that rat calprotectin purified from inflammatory neutrophils induces apoptosis of various tumor cells or normal fibroblasts in a zinc-reversible manner. AIM: The present study was undertaken to elucidate which subunit is responsible for the apoptosis-inducing activity, and to explore the mechanism of zinc-reversible apoptosis induction. METHODS: The apoptosis-inducing activity of recombinant human MRP8 (rhMRP8) and recombinant human MRP14 (rhMRP14) was examined against EL-4 lymphoma cells in vitro. To determine whether zinc deprivation by calprotectin was essential for the cytotoxicity, the activity of calprotectin was tested under conditions where physical contact between the factor and the cells was precluded by a low molecular weight cut-off dialysis membrane. RESULTS: The cytotoxicity of rhMRP14 against EL-4 cells was first detected at 10 microM in a standard medium, whereas rhMRP8 caused only marginal cytotoxicity at 40 microM. A mixture of both proteins showed higher specific activity (onset of cytotoxicity at 5 microM). When the cells were cultured in divalent cation-depleted medium, each dose-response curve was shifted to about a four-fold lower concentration range. Calprotectin was found to induce cell death even when the complex and the target cells were separated by dialysis membrane. A membrane-impermeable zinc chelator, diethylenetriamine pentaacetic acid (DTPA), also induced target cell apoptosis in a similar time-course as calprotectin. Moreover, the activities of calprotectin and DTPA were completely inhibited by the presence of zinc ions. CONCLUSION: These data indicate that calprotectin has higher specific activity to induce apoptosis than the Individual subunits, and that the mechanism is exclusion of zinc from target cells

Diurnal metabolic regulation of isoflavones and soyasaponins in soybean roots

Isoflavones and soyasaponins are major specialized metabolites accumulated in soybean roots and secreted into the rhizosphere. Unlike the biosynthetic pathway, the transporters involved in metabolite secretion remain unknown. The developmental regulation of isoflavone and soyasaponin secretions has been recently reported, but the diurnal regulation of their biosynthesis and secretion still needs to be further studied. To address these challenges, we conducted transcriptome and metabolite analysis using hydroponically grown soybean plants at 6-hr intervals for 48 hr in a 12-hr-light/12-hr-dark condition. Isoflavone and soyasaponin biosynthetic genes showed opposite patterns in the root tissues; that is, the former genes are highly expressed in the daytime, while the latter ones are strongly induced at nighttime. GmMYB176 encoding a transcription factor of isoflavone biosynthesis was upregulated from ZT0 (6:00 a.m.) to ZT6 (12:00 a.m.), followed by the induction of isoflavone biosynthetic genes at ZT6. The isoflavone aglycone content in the roots accordingly increased from ZT6 to ZT18 (0:00 a.m.). The isoflavone aglycone content in root exudates was kept consistent throughout the day, whereas that of glucosides increased at ZT6, which reflected the decreased expression of the gene encoding beta-glucosidase involved in the hydrolysis of apoplast-localized isoflavone conjugates. Co-expression analysis revealed that those isoflavone and soyasaponin biosynthetic genes formed separate clusters, which exhibited a correlation to ABC and MATE transporter genes. In summary, the results in this study indicated the diurnal regulation of isoflavone biosynthesis in soybean roots and the putative transporter genes responsible for isoflavone and soyasaponin transport

Predictive Factors for Tracheal Intubation in Patients with Coronavirus Disease 2019 Treated Using a High-flow Nasal Cannula

Background : In Japan, patients with coronavirus disease 2019 (COVID-19)＊ requiring a high-flow nasal cannula (HFNC) are often initially treated in non-specialized facilities and transferred to an intensive care unit if tracheal intubation is required. We aimed to investigate the factors associated with severe respiratory failure requiring tracheal intubation at an early stage in patients with COVID-19 treated using HFNCs. Methods : This retrospective cohort study compared the clinical features of consecutively enrolled patients with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus-2 infection admitted to two centers in Japan between early February 2020 and late June 2021. Results : A total of 35 patients with COVID-19 treated using HFNCs were included. Treatment success and failure occurred in 25 and 10 patients, respectively. The oxygen saturation (ROX) index (ratio of oxygen saturation [SpO2] to fraction of inspired oxygen [FiO2] and the respiratory rate) 12 h post-HFNC insertion was a useful predictor of HFNC failure (success group, 8.0 ; failure group, 6.5 : P＝0.0005). Moreover, the time from symptom onset to respiratory failure was significantly shorter in the failure group than in the success group (3.0 and 5.0 days, P＝0.004). Conclusions The ROX index and time from symptom onset to respiratory failure were useful predictors of HFNC failure.Article信州医学雑誌 71(6) : 403-409, (2023)journal articl

Regulatory Role of GRK2 in the TLR Signaling-Mediated iNOS Induction Pathway in Microglial Cells

G protein-coupled receptor kinase 2 (GRK2) is a ubiquitous member of the GRK family that restrains cellular activation by G protein-coupled receptor (GPCR) phosphorylation leading to receptor desensitization and internalization, but has been identified to regulate a variety of signaling molecules, among which may be associated with inflammation. In this study, we attempted to establish the regulatory role of GRK2 in the Toll-like receptor (TLR) signaling pathway for inducible nitric oxide synthase (iNOS) expression in microglial cells. When mouse MG6 cells were stimulated with the TLR4 ligands lipopolysaccharide (LPS) and paclitaxel, we found that interferon regulatory factor 1 (IRF1) protein expression and activation was upregulated, transcription of interferon-β (IFN-β) was accelerated, induction/activation of STAT1 and activation of STAT3 were promoted, and subsequently iNOS expression was upregulated. The ablation of GRK2 by small interfering RNAs (siRNAs) not only eliminated TLR4-mediated upregulation of IRF1 protein expression and nuclear translocation but also suppressed the activation of the STAT pathway, resulting in negating the iNOS upregulation. The TLR3-mediated changes in IRF1 and STAT1/3, leading to iNOS induction, were also abrogated by siRNA knockdown of GRK2. Furthermore, transfection of GRK2 siRNA blocked the exogenous IFN-β supplementation-induced increases in phosphorylation of STAT1 as well as STAT3 and abrogated the augmentation of iNOS expression in the presence of exogenous IFN-β. Taken together, our results show that GRK2 regulates the activation of IRF1 as well as the activation of the STAT pathway, leading to upregulated transcription of iNOS in activated microglial cells. Modulation of the TLR signaling pathway via GRK2 in microglia may be a novel therapeutic target for treatment of neuroinflammatory disorders

Tomato root-associated Sphingobium harbors genes for catabolizing toxic steroidal glycoalkaloids

トマト根に定着する細菌からトマトの毒を分解する酵素を発見 --土壌微生物が植物の分泌する有害成分を解毒するメカニズムの理解に貢献--. 京都大学プレスリリース. 2023-10-02.Roots of Bloody Mary. Tomato root-associated Sphingobium harbors genes for neutralizing toxic compound. 京都大学プレスリリース. 2023-10-06.Plant roots exude various organic compounds, including plant specialized metabolites (PSMs), into the rhizosphere. The secreted PSMs enrich specific microbial taxa to shape the rhizosphere microbiome, which is crucial for the healthy growth of the host plants. PSMs often exhibit biological activities; in turn, some microorganisms possess the capability to either resist or detoxify them. Saponins are structurally diverse triterpene-type PSMs that are mainly produced by angiosperms. They are generally considered as plant defense compounds. We have revealed that α-tomatine, a steroid-type saponin secreted from tomato (Solanum lycopersicum) roots, increases the abundance of Sphingobium bacteria. To elucidate the mechanisms underlying the α-tomatine-mediated enrichment of Sphingobium, we isolated Sphingobium spp. from tomato roots and characterized their saponin-catabolizing abilities. We obtained the whole-genome sequence of Sphingobium sp. RC1, which degrades steroid-type saponins but not oleanane-type ones, and performed a gene cluster analysis together with a transcriptome analysis of α-tomatine degradation. The in vitro characterization of candidate genes identified six enzymes that hydrolyzed the different sugar moieties of steroid-type saponins at different positions. In addition, the enzymes involved in the early steps of the degradation of sapogenins (i.e., aglycones of saponins) were identified, suggesting that orthologs of the known bacterial steroid catabolic enzymes can metabolize sapogenins. Furthermore, a comparative genomic analysis revealed that the saponin-degrading enzymes were present exclusively in certain strains of Sphingobium spp., most of which were isolated from tomato roots or α-tomatine-treated soil. Taken together, these results suggest a catabolic pathway for highly bioactive steroid-type saponins in the rhizosphere

Minority Carrier Trap in n-Type 4H–SiC Schottky Barrier Diodes

We present preliminary results on minority carrier traps in as-grown n-type 4H–SiC Schottky barrier diodes. The minority carrier traps are crucial for charge trapping and recombination processes. In this study, minority carrier traps were investigated by means of minority carrier transient spectroscopy (MCTS) and high-resolution Laplace-MCTS measurements. A single minority carrier trap with its energy level position at Ev + 0.28 eV was detected and assigned to boron- related defects