Glutathione S-transferases Control astrocyte activation and neuronal health during neuroinflammation

Glutathione S-transferases (GST) are phase II detoxification enzymes of xenobiotic metabolism and readily expressed in the brain. Nevertheless, the current knowledge about their roles in the brain is limited. We have recently discovered that GSTM1 promotes the production of pro-inflammatory mediators by astrocytes and enhances microglial activation during acute brain inflammation. Here we report that GSTM1 significantly affects TNF-α-dependent transcriptional program in astrocytes and modulates neuronal activities and stress during brain inflammation. We have found that a reduced expression of GSTM1 in astrocytes downregulates the expression of pro-inflammatory genes while upregulating the expression of genes involved in interferon responses and fatty acid metabolism. Our data also revealed that GSTM1 reduction in astrocytes increased neuronal stress levels, attenuating neuronal activities during LPS-induced brain inflammation. Furthermore, we found that GSTM1 expression increased in the frontal cortex and hippocampus of aging mice. Thus, this study has further advanced our understanding of the role of Glutathione S-transferases in astrocytes during brain inflammation and paved the way for future studies to determine the critical role of GSTM1 in reactive astrocyte responses in inflammation and aging

Complexation of F⁻ by Li⁺ and Mg²⁺ Ions as Inorganic Anion Acceptors in Lactone-Based Li⁺/F⁻ and Mg²⁺/F⁻ Hybrid Electrolytes for Fluoride Shuttle Batteries

The development of high-quality fluoride-ion transporting electrolytes is a crucial demand for fluoride shuttle batteries (FSBs). However, the uncontrolled chemical and electrochemical activities of fluoride ions narrow the available potential window, hindering the development of high-voltage FSB cells. We present a method for upgrading recently developed lactone-based liquid fluoride electrolytes by complexation of F⁻ with Li⁺ and Mg²⁺ ions. In the resultant Li⁺/F⁻ and Mg²⁺/F⁻ hybrid electrolytes, Li2F+ and MgF+ were the most probable soluble complexes, and the effective fluoride concentrations could reach ∼0.15 M along with excess Li⁺(Mg²⁺) ions. Unique interactions between F⁻ and Li⁺(Mg²⁺) were observed using ¹⁹F nuclear magnetic resonance spectroscopy. Li⁺(Mg²⁺) ions thus served as inorganic anion acceptors with ultimate redox stabilities to expand the negative potential window of the electrolytes to near −3 V vs SHE. The proposed complex formation was also supported by a conductometric titration method. We demonstrated the superior and versatile electrochemical performances of the Li⁺/F⁻ hybrid electrolyte, which enabled reversible charge/discharge reactions of various metal electrodes and composite electrodes in a wide range of redox series. Further, the Li⁺/F⁻ hybrid electrolyte opened valid new reaction paths for aluminum, making it a promising negative electrode in high-voltage FSB cells

先新第三系中の鉛直回転軸を持つ摺曲（屈曲）

Various folds (bends) with subvertical/vertical axes are widely developed in the pre-Neogene terranes of Southwest Japan. They are variable in shape, conical folds, accordion folds, megakink bands and so on, and some of them are associated with strike-slip faults. Their size ranges from several meters to 10km or more in half-wavelength. Their deformation style indicate that they were produced under a brittle condition in a shallow level of the crust. They are superimposed on the pre-existing structures, and are regarded to have been formed mostly during the Middle Miocene contemporaneously at the time of the clockwise-rotation of Southwest Japan. The presence of them, thus, suggests that the upper crust of island arc is easily deformable around subvertical/vertical rotation axes to form various folds (bends) and locally strike-slip faults during its rotation

Efficacy of gilteritinib in comparison with alectinib for the treatment of ALK-rearranged non-small cell lung cancer

Gilteritinib is a multitarget tyrosine kinase inhibitor (TKI), approved for the treatment of FLT3-mutant acute myeloid leukemia, with a broad range of activity against several tyrosine kinases including anaplastic lymphoma kinase (ALK). This study investigated the efficacy of gilteritinib against ALK-rearranged non-small cell lung cancers (NSCLC). To this end, we assessed the effects of gilteritinib on cell proliferation, apoptosis, and acquired resistance responses in several ALK-rearranged NSCLC cell lines and mouse xenograft tumor models and compared its efficacy to alectinib, a standard ALK inhibitor. Gilteritinib was significantly more potent than alectinib, as it inhibited cell proliferation at a lower dose, with complete attenuation of growth observed in several ALK-rearranged NSCLC cell lines and no development of drug tolerance. Immunoblotting showed that gilteritinib strongly suppressed phosphorylated ALK and its downstream effectors, as well as mesenchymal-epithelial transition factor (MET) signaling. By comparison, MET signaling was enhanced in alectinib-treated cells. Furthermore, gilteritinib was found to more effectively abolish growth of ALK-rearranged NSCLC xenograft tumors, many of which completely receded. Interleukin-15 (IL-15) mRNA levels were elevated in gilteritinib-treated cells, together with a concomitant increase in the infiltration of tumors by natural killer (NK) cells, as assessed by immunohistochemistry. This suggests that IL-15 production along with NK cell infiltration may constitute components of the gilteritinib-mediated antitumor responses in ALK-rearranged NSCLCs. In conclusion, gilteritinib demonstrated significantly improved antitumor efficacy compared with alectinib against ALK-rearranged NSCLC cells, which can warrant its candidacy for use in anticancer regimens, after further examination in clinical trial settings

A comprehensive validation of very early rule-out strategies for non-ST-segment elevation myocardial infarction in emergency departments:protocol for a multicentre prospective cohort study

Introduction: Recent advances in troponin sensitivity enabled early and accurate judgement of ruling-out myocardial infarction, especially non-ST elevation myocardial infarction (NSTEMI) in emergency departments (EDs) with development of various prediction-rules and high-sensitive-troponin-based strategies (hs-troponin). Reliance on clinical impression, however, is still common, and it remains unknown which of these strategies is superior. Therefore, our objective in this prospective cohort study is to comprehensively validate the diagnostic accuracy of clinical impression-based strategies, prediction-rules and hs-troponin-based strategies for ruling-out NSTEMIs. Methods and analysis: In total, 1500 consecutive adult patients with symptoms suggestive of acute coronary syndrome will be prospectively recruited from five EDs in two tertiary-level, two secondary-level community hospitals and one university hospital in Japan. The study has begun in July 2018, and recruitment period will be about 1 year. A board-certified emergency physician will complete standardised case report forms, and independently perform a clinical impression-based risk estimation of NSTEMI. Index strategies to be compared will include the clinical impression-based strategy; prediction rules and hs-troponin-based strategies for the following types of troponin (Roche Elecsys hs-troponin T; Abbott ARCHITECT hs-troponin I; Siemens ADVIA Centaur hs-troponin I; Siemens ADVIA Centaur sensitive-troponin I). The reference standard will be the composite of type 1 MI and cardiac death within 30 days after admission to the ED. Outcome measures will be negative predictive value, sensitivity and effectiveness, defined as the proportion of patients categorised as low risk for NSTEMI. We will also evaluate inter-rater reliability of the clinical impression-based risk estimation. Ethics and dissemination: The study is approved by the Ethics Committees of the Kyoto University Graduate School and Faculty of Medicine and of the five hospitals where we will recruit patients. We will disseminate the study results through conference presentations and peer-reviewed journals

Re-arrangement of the Shallow-level structure of Southwest Japan Arc due to the collision of the Izu-Bonin Arc

The central part of the Honshu Arc collided in the South Fossa Magna (SFM) area with the crossing Izu-Bonin Arc (IBA), forming a cuspidate bend of the pre-Middle Miocene basement rocks of the Honshu Arc. This paper summarizes the effects of the collision on the basement rocks of the Southwest Japan Arc (SWJA), the southwestern segment of the Honshu Arc. The northward shift of the pre-Middle Miocene rocks in the Akaishi Mountains in the easternmost SWJA on the frontal side of the SFM collision zone reaches more than 160 km at a sub-vertical-axis, under counterclockwise rotation with N-S trending, left-lateral strike-slip faultings. The Mesozoic rocks of the Mino and Ryoke Belts to the north of the Akaishi Mountains at the rear side of the collision zone also shifted about 80 km northward about a sub-vertical rotation axis. These northward shifts also had some components of horizontal-axis rotation and resulted in the re-arrangement of geologic bodies in the shallow-crustal level of eastern SWJA. Chronological and paleomagnetic data clearly suggest that the northward bend occurred in a short period of the Middle Miocene around 15 Ma. This intra-arc bending originated from the combined effects of the clockwise rotation of SWJA in association with the rapid fan-shaped opening of the Sea of Japan, and the initial collision of SWJA with the northern tip of IBA, the Kushigatayama Block. The E-W compression due to the intra-arc bending of the eastern SWJA resulted in the formation of N-S trending, km-scale folds with the vertical axes at the inner side of the hinge area of this bending about 150-200 km west of the collision zone. These wide effects on the eastern SWJA probably occurred under a high geothermal regime that weakened its upper crust. Compared to the initial collision, the following Late Miocene and Pliocene collisions due to the north or northwestward advance of IBA did not severely affect the pre-existing structures in SWJA. The latest collision with the Izu Block since 1 Ma has caused a rapid uplift of left-stepping, en-echelon arranging mountain ranges on the eastern SWJA

腎, 副腎および後腹膜腫瘍に対する垂直切開を加えた上腹部横切開法

上腹部横切開に垂直切開を加えた切開法は, 腎腫瘍, 副腎腫瘍あるいは後腹膜腫瘍の手術の際に用いる胸膜を開くことなく広い術野が得られるという利点があった.1989年までの10年間に27例に対してこの切開法を用いた.この方法は腹腔を経由するので, 後腹膜腔から入る方法に比し合併症が多いように思われたが, 2例に軽い麻痺性イレウスが発生したのみであった.再手術を要するような重篤な合併症は生じなかったSubcostal transabdominal incision with midline extension is excellent for removal of large renal or adrenal tumors, or bilateral or retroperitoneal tumors. This incision is simple and gives a wide surgical field without involving the pleural cavity. No troublesome complications resulting from this approach have occurred