Mitochondrial fission in hepatocytes as a potential therapeutic target for nonalcoholic steatohepatitis

[Aim] The mitochondria are highly plastic and dynamic organelles; mitochondrial dysfunction has been reported to play causative roles in diabetes, cardiovascular diseases, and nonalcoholic fatty liver disease (NAFLD). However, the relationship between mitochondrial fission and NAFLD pathogenesis remains unknown. We aimed to investigate whether alterations in mitochondrial fission could play a role in the progression of NAFLD. [Methods] Mice were fed a standard diet or choline-deficient, L-amino acid-defined (CDAA) diet with vehicle or mitochondrial division inhibitor-1. [Results] Substantial enhancement of mitochondrial fission in hepatocytes was triggered by 4 weeks of feeding and was associated with changes reflecting the early stage of human nonalcoholic steatohepatitis (NASH), steatotic change with liver inflammation, and hepatocyte ballooning. Excessive mitochondrial fission inhibition in hepatocytes and lipid metabolism dysregulation in adipose tissue attenuated liver inflammation and fibrogenesis but not steatosis and the systemic pathological changes in the early and chronic fibrotic NASH stages (4- and 12-week CDAA feeding). These beneficial changes due to the suppression of mitochondrial fission against the liver and systemic injuries were associated with decreased autophagic responses and endoplasmic reticulum stress in hepatocytes. Injuries to other liver cells, such as endothelial cells, Kupffer cells, and hepatic stellate cells, were also attenuated by the inhibition of mitochondrial fission in hepatocytes. [Conclusions] Taken together, these findings suggest that excessive mitochondrial fission in hepatocytes could play a causative role in NAFLD progression by liver inflammation and fibrogenesis through altered cell cross-talk. This study provides a potential therapeutic target for NAFLD

Variation of Heating Efficiency of Magnetically Sheared CHS Plasmas by Polarization Control of 106GHz EC-Wave

To clarify the effect of polarization on electron cyclotron heating (ECH) in magnetized plasmas, experiment controlling the polarization of injected EC-waves is carried out in Compact Helical System (CHS). In the experiment, plasmas are generated and sustained only with 106.4 GHz ECH power. Magnetic field at the magnetic axis is 1.9 T so that the wave frequency is second harmonic. The optimum direction of linear polarization for the shortest time-delay of density start-up from the start of power injection and the optimum direction for the highest electron temperature and plasma stored energy during plasma duration show clear difference. The difference is attributed to the CHS magnetic configuration with strong shear and the plasma volume expansion from magnetic axis to the last closed flux surface

Determination of the Major Impurity Radiators in the Reheat Mode Discharges in the Compact Helical System

Radiation brightness and impurity behaviors have been studied for reheat mode discharges in the Compact Helical System (CHS) by three different types of impurity diagnostics. Total radiation power measured by a pyroelectric detector significantly reduces after entering the reheat mode, whereas the line-averaged radiation brightness measured by an absolute extreme ultraviolet (AXUV) photodiode array increases especially for a center viewing chord due to the impurity accumulation in the plasma core. One possible reason for this opposite behavior between the two bolometric detectors is the reduced sensitivity of the AXUV photodiode for lower energy photons in vacuum ultraviolet (VUV) region. This speculation is supported by temporal evolutions of VUV spectra measured by a grazing incidence spectrometer. These results demonstrate that the comparison of three impurity diagnostics would be beneficial to the determination of the major impurity radiators and a comprehensive understanding of impurity behaviors in the reheat mode discharges

Polaprezinc Protects Mice against Endotoxin Shock

Polaprezinc (PZ), a chelate compound consisting of zinc and l-carnosine (Car), is an anti-ulcer drug developed in Japan. In the present study, we investigated whether PZ suppresses mortality, pulmonary inflammation, and plasma nitric oxide (NO) and tumor necrosis factor (TNF)-α levels in endotoxin shock mice after peritoneal injection of lipopolysaccharide (LPS), and how PZ protects against LPS-induced endotoxin shock. PZ pretreatment inhibited the decrease in the survival rate of mice after LPS injection. PZ inhibited the increases in plasma NO as well as TNF-α after LPS. Compatibly, PZ suppressed LPS-induced inducible NO synthase mRNA transcription in the mouse lungs. PZ also improved LPS-induced lung injury. However, PZ did not enhance the induction of heat shock protein (HSP) 70 in the mouse lungs after LPS. Pretreatment of RAW264 cells with PZ suppressed the production of NO and TNF-α after LPS addition. This inhibition likely resulted from the inhibitory effect of PZ on LPS-mediated nuclear factor-κB (NF-κB) activation. Zinc sulfate, but not Car, suppressed NO production after LPS. These results indicate that PZ, in particular its zinc subcomponent, inhibits LPS-induced endotoxin shock via the inhibition of NF-κB activation and subsequent induction of proinflammatory products such as NO and TNF-α, but not HSP induction

Development of Music Classes on Gagaku in Elementary and Junior High School

The purpose of this study is to develop music classes using Etenraku, which is one of the oldest existing music in Japan called Gagaku (traditional Japanese court music), as a material in elementary and junior high school. The main points of view on developing music classes are as follows: (1) to pursue the musical substance, (2) to center a proactive and action-oriented learning of students, and (3) to promote and enhance language activity. The music class in elementary school has two goals. One is that students develop an understanding for a mechanism of producing sounds with double reed through the activity to make hand-made musical instrument. The other is that students understand the role of hichiriki (a kind of flute) in Gagaku ensemble, discovering sound aspects of hichiriki, and expressing the sound aspects with their own words. The music class in junior high school has two goals. One is that students understand the musical style of Gagaku through creating rhythm patterns of percussion section for the melody of Etenraku. When creating, students write musical note using composition software. The other is that students engage in entire learning process with language activity, for example, talking together about what they want to express in their work, describing their intention put into their work, or expressing what they feel when they listen other's work

Christopher Simpson The Division-Viol, or The Art of PLAYING Ex tempore upon a GROUND. EDITIO SECVNDA Part III "The Method of ordering Division to a Ground" (3)

本訳稿はChristopher Simpson (1605頃－1669) 著 The Division-Viol, or, The Art of PLAYING Ex tempore upon a GROUND. DIVIDED INTO THREE PARTS. EDITIO SECVNDA, London, 1665 のPart III "The Method of ordering Division to a Ground" より§13～§16(pp.57-61)の全訳である

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements