Failure of DNA double-strand break repair by tau mediates Alzheimer’s disease pathology in vitro

DNA double-strand break (DSB) is the most severe form of DNA damage and accumulates with age, in which cytoskeletal proteins are polymerized to repair DSB in dividing cells. Since tau is a microtubule-associated protein, we investigate whether DSB is involved in tau pathologies in Alzheimer’s disease (AD). First, immunohistochemistry reveals the frequent coexistence of DSB and phosphorylated tau in the cortex of AD patients. In vitro studies using primary mouse cortical neurons show that non-p-tau accumulates perinuclearly together with the tubulin after DSB induction with etoposide, followed by the accumulation of phosphorylated tau. Moreover, the knockdown of endogenous tau exacerbates DSB in neurons, suggesting the protective role of tau on DNA repair. Interestingly, synergistic exposure of neurons to microtubule disassembly and the DSB strikingly augments aberrant p-tau aggregation and apoptosis. These data suggest that DSB plays a pivotal role in AD-tau pathology and that the failure of DSB repair leads to tauopathy

Novel assay system for acidic Peptide:N-glycanase (aPNGase) activity in crude plant extract

Acidic peptide:N-glycanase (aPNGase) plays a pivotal role in plant glycoprotein turnover. For the construction of aPNGase-knockout or -overexpressing plants, a new method to detect the activity in crude plant extracts is required because endogenous peptidases present in the extract hamper enzyme assays using fluorescence-labeled N-glycopeptides as a substrate. In this study, we developed a new method for measuring aPNGase activity in crude extracts from plant material

Assessment of activities and the participation domain based on the ICF for the elderly requiring care

ICFの「活動と参加」の評価を通して,要介護高齢者における生活機能低下の全体像を把握することを目的に調査を実施した.要介護高齢者672名を対象に,ICFの「活動と参加」の第2レベル73項目について,「実行状況」と「能力」の両面から評価点を評価し,Item　Indexとしてそれぞれの困難度を求めた.「活動と参加」における領域ごとの比較では第5領域「セルフケア」のItem Indexが最も低くなり,「実行状況」で37.7,「能力」で34.4となった.逆に高くなったのは第6領域「家庭生活」であり,それぞれ89.6,77.7となった.本研究の結果は要介護高齢者の生活機能低下の現状と評価手段としてのICF活用の可能性を示すものである.The purpose of this study was to understand the degree of functioning and disability level in elderly requiring care through the evaluation of each domain of "activity and participation" in ICF. The study investigated 672 elderly requiring care. In the investigation, regarding the 2nd level of 73 "activity and participation" domains in the ICF, the elderly were evaluated from "performance" and "capacity", and then converted to the Item Index. Subsequently, each item was evaluated, and the degree of difficulty for both performance and capacity was determined. In the comparison of both performance and capacity, the Item Index of Chapter 5 "SELF-CARE" was the lowest, while "performance" was 37. 7, and "capacity" was 34. 4. Conversely, the Item Index of Chapter 6 "DOMESTIC LIFE" became higher: it was 89. 6 and 77. 7 respectively. The results indicate the degree of both dysfunction and disability of the elderly requiring care, and also demonstrate the possibility of the ICF as an assessment tool

STING signalling is terminated through ESCRT-dependent microautophagy of vesicles originating from recycling endosomes

STING炎症シグナルの終結分子機構 --新規細胞内分解システムの発見--. 京都大学プレスリリース. 2023-03-14.Stimulator of interferon genes (STING) is essential for the type I interferon response against a variety of DNA pathogens. Upon emergence of cytosolic DNA, STING translocates from the endoplasmic reticulum to the Golgi where STING activates the downstream kinase TBK1, then to lysosome through recycling endosomes (REs) for its degradation. Although the molecular machinery of STING activation is extensively studied and defined, the one underlying STING degradation and inactivation has not yet been fully elucidated. Here we show that STING is degraded by the endosomal sorting complexes required for transport (ESCRT)-driven microautophagy. Airyscan super-resolution microscopy and correlative light/electron microscopy suggest that STING-positive vesicles of an RE origin are directly encapsulated into Lamp1-positive compartments. Screening of mammalian Vps genes, the yeast homologues of which regulate Golgi-to-vacuole transport, shows that ESCRT proteins are essential for the STING encapsulation into Lamp1-positive compartments. Knockdown of Tsg101 and Vps4, components of ESCRT, results in the accumulation of STING vesicles in the cytosol, leading to the sustained type I interferon response. Knockdown of Tsg101 in human primary T cells leads to an increase the expression of interferon-stimulated genes. STING undergoes K63-linked ubiquitination at lysine 288 during its transit through the Golgi/REs, and this ubiquitination is required for STING degradation. Our results reveal a molecular mechanism that prevents hyperactivation of innate immune signalling, which operates at REs

Preoperative Biliary Drainage in Cases of Borderline Resectable Pancreatic Cancer Treated with Neoadjuvant Chemotherapy and Surgery

Objective. To elucidate the optimum preoperative biliary drainage method for patients with pancreatic cancer treated with neoadjuvant chemotherapy (NAC). Material and Methods. From January 2010 through December 2014, 20 patients with borderline resectable pancreatic cancer underwent preoperative biliary drainage and NAC with a plastic or metallic stent and received NAC at Hiroshima University Hospital. We retrospectively analyzed delayed NAC and complication rates due to biliary drainage, effect of stent type on perioperative factors, and hospitalization costs from diagnosis to surgery. Results. There were 11 cases of preoperative biliary drainage with plastic stents and nine metallic stents. The median age was 64.5 years; delayed NAC occurred in 9 cases with plastic stent and 1 case with metallic stent (p=0.01). The complication rates due to biliary drainage were 0% (0/9) with metallic stents and 72.7% (8/11) with plastic stents (p=0.01). Cumulative rates of complications determined with the Kaplan-Meier method on day 90 were 60% with plastic stents and 0% with metallic stents (log-rank test, p=0.012). There were no significant differences between group in perioperative factors or hospitalization costs from diagnosis to surgery. Conclusions. Metallic stent implantation may be effective for preoperative biliary drainage for pancreatic cancer treated with NAC

High-Dose Barium Impaction Therapy Is Useful for the Initial Hemostasis and for Preventing the Recurrence of Colonic Diverticular Bleeding Unresponsive to Endoscopic Clipping

Most cases of colonic diverticular bleeding stop spontaneously, but some patients experience massive bleeding that requires emergency treatment. Endoscopy can be useful when the bleeding source is identified. However, bleeding sometimes recurs within a short period despite the successful endoscopic treatment. Under such conditions, more invasive therapy such as interventional angiography or surgery is required and can prolong hospitalization and involve frequent blood transfusions. We report the case of a 68-year-old woman who presented with massive hematochezia. The patient was in hemorrhagic shock and required 16 units of blood transfusion to recover to general condition. We performed multidetector row computed tomography, but it showed no sites of bleeding. We conducted colonoscopy and identified the source of bleeding as colonic diverticula. We treated the bleeding with endoscopic hemoclips and achieved hemostasis, but bleeding recurred the next day. Four units of blood transfusion were required. We tried high-dose barium impaction therapy to avoid further blood transfusion and surgery. No complications or recurrent bleeding was observed for an 18-month period. Therapeutic barium enema is an option for colonic diverticular bleeding unresponsive to endoscopic clipping and may be effective for preventing recurrent bleeding

Molecular Dynamics in Two-Dimensional Supramolecular Systems Observed by STM

Since the invention of scanning tunneling microscopy (STM), 2D supramolecular architectures have been observed under various experimental conditions. The construction of these architectures arises from the balance between interactions at the medium-solid interface. This review summarizes molecular motion observed in 2D-supramolecular structures on surfaces using nanospace resolution STM. The observation of molecular motion on surfaces provides a visual understanding of intermolecular interactions, which are the major driving force behind supramolecular arrangement