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Purpose: Currently, there is limited information regarding the utilization of pin-less augmented reality (AR) assistance in total hip arthroplasty (THA). This preliminary study aimed to evaluate the precision of acetabular cup placement in THA utilizing the AR Navigation “Pin-less” System (Pin-less AR navigation, prototype). Methods: A total of 72 consecutive primary THAs in 58 patients were categorized into two groups: the Pin-less AR navigation group and the conventional group. All THAs were conducted via the direct anterior approach. First, the absolute value of difference between the intra-operative and post-operative angles (absolute difference) was calculated in the Pin-less AR navigation group. Second, the absolute value of error between the post-operative angles and the target angles (absolute target error) was assessed both in the Pin-less AR navigation group and the conventional group. Results: The absolute difference in inclination and anteversion angles was 2.2 ​± ​1.4° and 2.4 ​± ​1.5°, respectively. The absolute target error in the Pin-less AR navigation group versus the conventional group was 1.9 ​± ​1.5° versus 4.2 ​± ​2.7° in inclination (P ​

Abstract Background The relationships between frailty and clinical outcomes in elderly Japanese patients with non‐valvular atrial fibrillation (NVAF) after catheter ablation (CA) have not been established. We evaluated the frailty rate of patients undergoing CA for NVAF, examined whether CA for NVAF improves frailty, and analyzed the CA outcomes of patients with and without frailty. Methods Elderly Japanese patients (≥65 years; mean age: 72.8 years) who participated in the real‐world ablation therapy with anti‐coagulants in management of atrial fibrillation registry and who responded to the frailty screening index survey were included (n = 213). Frailty and AF recurrence were assessed preoperatively and at 3 and 6 months after CA. Results Twenty‐six patients (12.8%) were frail, 109 (53.7%) were pre‐frail, and 68 (33.5%) were robust. Cardiovascular (frailty: 0.5%/person‐year; pre‐frailty: 0.1%/person‐year; robust: 0.1%/person‐year) and cardiac (frailty: 0.5%/person‐year; pre‐frailty: 0.1%/person‐year; robust: 0.1%/person‐year) events, as well as major bleeding (frailty: 0.3%/person‐year; pre‐frailty: 0.1%/person‐year; robust: 0.1%/person‐year), were numerically more frequent in the frailty group. No deaths from cardiovascular or stroke/systemic thromboembolic events occurred. A large proportion of patients did not experience 3‐month (frailty: 96.2%; pre‐frailty: 96.3%; robust: 88.2%) or 6‐month (frailty: 88.5%; pre‐frailty: 91.7%; robust: 86.8%) AF recurrence after CA. Weight loss, walking speed, and fatigue improved in the frailty and pre‐frailty groups after CA. Conclusion Japanese patients aged ≥65 years with frailty or pre‐frailty had improved frailty screening index components, such as weight loss, walking speed and fatigue, after CA. Therefore, elderly patients with frailty or pre‐frailty may benefit from CA for NVAF.

This paper aims to clarify the behavior and damage conditions of batteries when multi-rotor unmanned aerial vehicles (drones) in horizontal flight collide with a structure to obtain the engineering knowledge that serves to consider the method of the safety performance evaluation of drone batteries in the collision. Drones with maximum takeoff weight of 15.5 kg, 24.5 kg, and 50 kg for aerial photographing, agricultural chemical spraying, and material transporting were used in the experiment analysis. The drones were ejected from an ejection system and collided with a barrier. The behavior of the drones and the batteries were captured on high-speed cameras. In addition, collision loads on the barrier and accelerations of the drones and their batteries were measured. The behavior of the drones and the batteries were considered based on the analysis results of the high-speed cameras. When the drones collided with the barrier, the batteries attached to the drones with snap-fit, rubber bands, and hook-and-loop fasteners separated from the drones. The separated batteries subsequently collided with the barrier. In the collision of the batteries and the barrier, the acceleration of the battery attached to the front of the drone by snap-fit was maximum. The acceleration was approximately 2.2 times larger than the acceleration given to the battery by the impact testing machine in the JIS standard (JIS C62133-2) that defines the test method for the safe operation of lithium secondary batteries used for portable devices. The damage conditions of batteries were presented and discussed from the viewpoint of the collision safety of batteries.

Abstract Gastrointestinal (GI) bleeding control is critical in elderly patients with atrial fibrillation (AF) receiving oral anticoagulants (OAC). This subgroup analysis aimed to clarify the actual state and significance of GI bleeding in elderly non-valvular AF (NVAF) patients. We evaluated the incidence and risk factors of GI bleeding during the 2-year follow-up and examined the GI bleeding impact on mortality. Of the 32,275 patients in the ANAFIE Registry, 1139 patients (3.5%) experienced GI bleeding (incidence rate, 1.92 events per 100 person-years; mean follow-up, 1.88 years); 339 upper and 760 lower GI bleeding events occurred. GI bleeding risk factors included age ≥ 85 years, body mass index ≥ 25.0 kg/m2, prior major bleeding, hyperuricaemia, heart failure, P-glycoprotein inhibitor use, GI disease, and polypharmacy (≥ 5 drugs). No significant differences in GI bleeding risk were found between direct OAC (DOAC) vs warfarin users (adjusted hazard ratios [95% confidence interval], 1.01 [0.88–1.15]). The 1-year post-GI bleeding mortality rate was numerically higher in patients with upper (19.6%) than lower GI bleeding (8.9%). In elderly Japanese NVAF patients, this large-scale study found no significant difference in GI bleeding risk between DOAC vs. warfarin users or 1-year mortality after upper or lower GI bleeding.

Abstract Aims Atrial fibrillation (AF) and heart failure (HF) often coexist. Older age is strongly associated with stroke, HF, and mortality. The association between coexistence of HF and a risk of clinical outcomes and the effectiveness of anticoagulation therapy including direct oral anticoagulants (DOACs) in elderly patients with AF and HF have not been investigated. We aimed to evaluate 2 years of outcomes and to elucidate the efficacy of DOACs or warfarin in elderly AF patients in the All Nippon AF In the Elderly (ANAFIE) Registry with and without a history of HF. Methods and results The ANAFIE Registry is a multicentre, prospective observational study following elderly non‐valvular AF patients aged ≥75 years for 2 years. Hazard ratios (HRs) were calculated based on the presence or absence of an HF diagnosis and DOAC or warfarin use at enrolment. Among 32 275 eligible patients, 12 116 (37.5%) had been diagnosed with HF. Patients with HF had significantly higher rates of HF hospitalization or cardiovascular death (HR 1.94, P

Purpose: Postoperative periprosthetic femoral fracture (PPFF) is one of the major complications following total hip arthroplasty (THA). The purpose of this study was to investigate the epidemiology of early PPFF (within 90 days) after THA. Methods: Primary THA was performed for hip osteoarthritis through a direct anterior approach in 6769 cases. Among these, we retrospectively investigated the occurrence of postoperative PPFF that required surgical intervention. Results: Postoperative PPFF was seen in 29 hips (29/6769; 0.43%), and the mean period from primary THA to fracture occurrence was 9.2 ​± ​8.5 days. Of these, 13 (13/2170; 0.60%) fractures were observed in prosthesis with flat tapered-wedge stems, 7 (7/1652; 0.42%) in straight tapered stems, 4 (4/1082; 0.37%) in cemented stems, and 1 (1/1.060; 0.09%) in collared fully hydroxyapatite-coated stem. The prevalence of PPFF in collared fully hydroxyapatite-coated stems was significantly lower than that of flat tapered-wedge stems. Five hips (5/29; 17.2%) required re-surgical intervention. Conclusion: Our results indicate that, compared to the flat tapered-wedge stem, use of the collared fully hydroxyapatite-coated stem decreases the risk of early postoperative PPFF following direct anterior THA.

Abstract Objective This study examined the hepatitis B virus (HBV) and hepatitis C virus (HCV) infection rates and vaccination rates for hepatitis B (HB) among dental healthcare workers (DHCWs) in the Oita prefecture, Japan. Methods Hepatitis virus testing was conducted on 1920 participants (486 dentists and 1434 dental staff). Anonymous data on age, gender, occupation, hepatitis B surface antigen (HBsAg), antibodies to hepatitis B surface antigen (anti‐HBs), antibodies to HCV (anti‐HCV), history of HB vaccination, and antiviral treatment for individuals with positive anti‐HCV were collected. Results The positivity rates for HBsAg, anti‐HBs, and anti‐HCV were 0.5%, 39.7%, and 0.6%, respectively. Dentists had significantly higher rates of anti‐HBs positivity (53.9% vs. 34.9%; p

Abstract Background This ANAFIE Registry sub-analysis investigated 2-year outcomes and oral anticoagulant (OAC) use stratified by glycated hemoglobin (HbA1c) levels among Japanese patients aged ≥ 75 years with non-valvular atrial fibrillation (NVAF) with and without clinical diagnosis of diabetes mellitus (DM). Methods The ANAFIE Registry was a large-scale multicenter, observational study conducted in Japan; this sub-analysis included patients with baseline HbA1c data at baseline. The main endpoints evaluated (stroke/systemic embolic events [SEE], major bleeding, intracranial hemorrhage, cardiovascular death, all-cause death, and net clinical outcome [a composite of stroke/SEE, major bleeding, and all-cause death]) were stratified by HbA1c levels (

Abstract Risk assessment is one of the important processes in the social implementation of robots. In risk assessment and safety design of systems with various stakeholders, modeling and visualization of related elements are important not only for designers but also for users. We examined the use of SafeML in the process and proposed its extension for the purpose for missing elements.

ABSTRACT: This study discusses robust control problems related to the fall of two-wheel motor vehicles during parking or low-speed driving. The robotic motorcycle includes a new rotary axis that can vary the position of the total center of gravity. Some authors have already reported preliminary control demonstrations using a typical PID controller and simple LQR. Moreover, the mathematical model of a robotic motorcycle derived using multibody dynamics methods and its optimal regulator simulation were developed. However, an experimental investigation of a robust control strategy for practical implementation has not yet been conducted. Therefore, this study proposes a practical method based on applying a sliding mode controller (SMC) to improve robust stability in a real usage environment. Here, we introduce the control system design combining a novel mathematical model, including a minor PID control loop and the SMC, with its hyperplane designed by the frequency-shaped optimal regulator. Finally, its effectiveness is verified by experiments using an actual robotic motorcycle.

Abstract Carbon catabolite repression (CCR) enables preferential utilization of easily metabolizable carbon sources, implying the presence of mechanisms to ensure discriminatory gene repression depending on the ambient carbon sources. However, the mechanisms for such hierarchical repression are not precisely understood. In this report, we examined how deletion of pkaA and ganB, which encode cAMP signaling factors, and creA, which encodes a well-characterized repressor of CCR, affects CCR of hemicellulase genes in the filamentous fungus Aspergillus nidulans. β-Xylanase production increased not only in ΔcreA but also in ΔpkaA and ΔganB, with the highest level observed in their double deletants, irrespective of the presence or absence of d-glucose. Expression of the β-xylanase genes in the presence of d-glucose was de-repressed in all the deletion mutants, with significantly higher tolerance against d-glucose repression in ΔpkaA and ΔganB than in ΔcreA. In the presence of galactomannan and d-glucose, partial de-repression of β-mannanase production was detected in ΔcreA, but not in ΔpkaA and ΔganB. The double deletion of creA/pkaA and creA/ganB led to earlier production. Release from d-glucose repression of the β-mannanase genes was partial in the single deletants, while nearly full de-repression was observed in ΔcreAΔpkaA and ΔcreAΔganB. The contribution of PkaA and GanB to CCR by d-xylose of the β-mannanase genes was very minor compared to that of CreA. Consequently, the present study revealed that cAMP signaling plays a major role in CCR of hemicellulase gene expression in a manner that is clearly independent from CreA.

Objectives: In this study, we investigated the impact of critical care outreach implemented to overcome the problem of rapid response system (RRS) activation. The aim was to evaluate the impact of nurse-led proactive rounding on the rate of adverse events in a hospital setting using an automatic early-warning score system, without a call-activated team. Methods: This observational study was conducted at a university hospital in Japan. Beginning in September 2019, critical care outreach via nurse-led proactive rounding of the general ward was conducted, using an automatic early-warning score system. We retrospectively assessed the computerised records of all inpatient days (N = 497,284) of adult inpatients admitted to the hospital from September 2017 to 2020. We compared the adverse event occurrences before and after implementation of the critical care outreach program. The main outcome measures were: unexpected death in the general ward, code blue (an in-hospital resuscitation request code directed towards all staff via broadcast) for non-intensive care unit inpatients and unexpected intensive care unit admissions from the general ward. The secondary outcome was the proportion of patients who received respiratory rate measurement. Results: The incidence rate ratios of the occurrence of unexpected deaths (0.19, 95% confidence interval: 0.04–0.57) and code blue in the general ward (0.15, 95% confidence interval: 0.025–0.50) decreased. There was no change in unexpected intensive care unit admissions from the general ward (1.25, confidence interval: 0.84–1.82). The proportion of patients who received respiratory rate measurement increased (10.2% vs 16.2%). Conclusion: Our results suggest that in RRSs, drastic control of the failure of the mechanism to activate a response team may produce positive outcomes. Proactive rounding that bypasses the mechanism to activate a response team component of RRSs may relieve ward nurses of activation failure responsibility and help them overcome the hierarchical hospital structure.

BackgroundAlthough anticoagulants are indicated for many elderly patients with non-valvular atrial fibrillation (NVAF), some patients do not receive anticoagulant therapy, whose characteristics and outcomes are diverse.Methods and resultsIn this sub-analysis of the All Nippon AF In the Elderly (ANAFIE) Registry, the phenotypes of patients who were not receiving anticoagulants at baseline were evaluated by cluster analysis using Ward's linkage hierarchical algorithm. Of 32,275 enrolled patients, 2445 (7.6%) were not receiving anticoagulants. Two clusters were identified: (1) elderly paroxysmal AF (PAF) patients with a high proportion of catheter ablation history (57%) and (2) very elderly patients with a high prevalence of previous major bleeding (43%). Respective mean ages were 80.9 and 84.2 years, mean CHA2DS2-VASc scores were 3.8 and 4.9, PAF prevalences were 100.0% and 31.4%, proportions of patients with catheter ablation history were 21.0% and 7.9%, and proportions of patients with a history of major bleeding were 4.0% and 10.8%. Annual incidence rates were 2.72% and 8.81% for all-cause death, 1.66% and 5.85% for major adverse cardiovascular or neurological events, 1.08% and 3.30% for stroke or systemic embolism, and 0.69% and 1.19% for major bleeding, respectively.ConclusionsIn this cohort of elderly NVAF patients from the ANAFIE Registry who were not receiving anticoagulants, over half had PAF with a high proportion of catheter ablation history and a low incidence of adverse outcomes; for them, non-prescription of anticoagulants may be partially understandable, but they should be carefully monitored regarding AF burden or atrial cardiomyopathy and be adequately anticoagulated when adverse findings are detected. The remaining were very elderly patients with a high prevalence of previous major bleeding and a high incidence of adverse outcomes; for them, non-prescription of anticoagulants is inappropriate because of the high thromboembolic risk.Trial registrationRegistration: http://www.umin.ac.jp/; Unique identifier: UMIN000024006.

Background This subcohort study of All Nippon AF In the Elderly (ANAFIE) Registry based on 33 275 elderly patients (aged ≥75 years) with non-valvular atrial fibrillation (NVAF) investigated the relationship between cognitive function and 2-year clinical outcomes.Methods A total of 2963 (mean age, 81.4 years) patients participated in this subcohort study and were classified as having normal cognition (Mini-Mental State Examination (MMSE) score ≥24/30) or cognitive impairment (score ≤23/30) at baseline. Patients with a decrease of >2 points after 24 months were classified as having cognitive decline.Results At baseline, 586 (19.8%) patients had cognitive impairment. These patients tended to be older and had poorer general conditions than patients with normal cognition. The 2-year probability of stroke/systemic embolic events (SEEs), major bleeding and intracranial haemorrhage was numerically higher; those of cardiovascular death, all-cause death and net clinical outcome (composite of stroke/SEE, major bleeding and all-cause death) were significantly higher (all p

Introduction: This subanalysis aimed to provide real-world data on venous thromboembolism (VTE) from patients with lung cancer in the Cancer-VTE Registry. Methods: The primary outcome was the number of baseline VTE events in patients with lung cancer. The 1-year cumulative incidences of symptomatic VTE; composite VTE (symptomatic and incidental VTE requiring treatment); bleeding; cerebral infarction, transient ischemic attack, and systemic embolic events; and all-cause death were calculated. Clinical trial registration: UMIN000024942. Results: The study enrolled a total of 2377 patients with lung cancer; of these, 119 (5.0%) had VTE (six [0.3%], symptomatic, and 113 [4.8%], asymptomatic) and 14 (0.6%) had pulmonary embolism at baseline. During the follow-up period (mean, 337.7 d), the incidence was 0.6% for symptomatic VTE, 1.8% for composite VTE, 1.5% for bleeding events, 1.3% for cerebral infarction, transient ischemic attack, and systemic embolism, and 19.1% for all-cause death. Composite VTE frequency did not vary by anticancer drug type. Patients with (versus without) VTE at baseline had higher hazard ratios (HRs) for composite VTE (unadjusted HR: 5.29; Gray test p < 0.001) and symptomatic VTE (unadjusted HR: 4.89; Gray test p = 0.007). Patients with VTE at baseline had higher HRs for bleeding events (unadjusted HR: 3.27; Gray test p = 0.010) and all-cause death (unadjusted HR: 2.73; log-rank test p < 0.001) than patients without. In multivariable analysis, patients with baseline VTE prevalence and Eastern Cooperative Oncology Group Performance Status of 2 had increased composite VTE risk during cancer therapy. There were no other risk factors for composite VTE. Conclusions: Our findings emphasize the importance of VTE screening at cancer diagnosis.

Abstract Background Data are limited on patient background characteristics associated with catheter ablation (CA)-related bleeding events in Japanese patients with non-valvular atrial fibrillation receiving uninterrupted periprocedural edoxaban. This subanalysis of the KYU-RABLE study focused on univariate and multivariate analyses to identify correlations between bleeding events and baseline patient demographics and CA-related characteristics. Methods Patients with non-valvular atrial fibrillation (NVAF) enrolled from the KYU-RABLE study were included in the study. We performed univariate and multivariate analyses to investigate the correlation of major, minor, and clinically relevant non-major bleeding events with the patient baseline data at enrollment, and with CA procedures. Results A total of 513 NVAF patients were included in the full analysis set. Univariate analysis showed that the incidence of the bleeding events was higher in patients with HAS-BLED score ≥ 3 compared with those with a score 50 mL/min (OR: 10.59, 95% CI: 3.65–30.79; p

Myosin II–mediated contractility is required for leukocyte migration. Here, authors show that lysosomes are involved in leukocyte migration by providing the platform where Ragulator complex interacts with the myosin phosphatase Rho-interacting protein (MPRIP) independently of mTORC1 and interferes with the interaction between MPRIP and a subunit of myosin light chain phosphatase (MLCP).

Abstract Background Catheter ablation (CA) for atrial fibrillation (AF) can be associated with a risk of thromboembolism and bleeding. We recently demonstrated that uninterrupted edoxaban with one dose delayed on the CA procedural day is associated with a low risk of periprocedural complications. Previous reports have indicated that some specific subgroups of patients undergoing CA have an increased risk of bleeding and thromboembolic complications. This subanalysis of the KYU‐RABLE study assessed the changes in plasma concentrations of edoxaban and coagulation biomarkers during the periprocedural period of CA in subgroups stratified by the risk of thromboembolism assessed by CHADS2 score (

Abstract In the ANAFIE Registry home blood pressure subcohort, we evaluated 5204 patients aged ≥75 years with non‐valvular atrial fibrillation (NVAF) to assess blood pressure (BP) control, prevalence of masked hypertension, and anticoagulant use. Mean clinic (C) and home (H) systolic/diastolic BP(SBP/DBP) was 128.5/71.3 and 127.7/72.6 mm Hg, respectively. Overall, 77.5% of patients had hypertension; of these, 27.7%, 13.4%, 23.4%, and 35.6% had well‐controlled, white coat, masked, and sustained hypertension, respectively. Masked hypertension prevalence increased with diabetes, decreased renal function, age ≥80 years, current smoker status, and chronic obstructive pulmonary disease. By morning/evening average, 59.0% of patients had mean H‐SBP ≥ 125 mm Hg; 48.9% had mean C‐SBP ≥ 130 mm Hg. Early morning hypertension (morning H‐SBP ≥ 125 mm Hg) was found in 65.9% of patients. Although 51.1% of patients had well‐controlled C‐SBP, 52.5% of these had uncontrolled morning H‐SBP. In elderly NVAF patients, morning H‐BP was poorly controlled, and masked uncontrolled morning hypertension remains significant.

Abstract Background Dual therapy with a direct oral anticoagulant (DOAC) plus a P2Y12 receptor inhibitor is recommended in patients with nonvalvular atrial fibrillation who undergo percutaneous coronary intervention. Thus, we evaluated the effects of DOAC edoxaban plus P2Y12 receptor inhibitor prasugrel on bleeding time (BT), and pharmacodynamics (PD) and pharmacokinetics (PK) of edoxaban in healthy elderly Japanese male subjects. Methods A single-center, clinical pharmacology study with randomized, open-label, repeated dosing enrolled 24 participants in two groups of 12 receiving 30 mg edoxaban once daily for 3 days; then 30 mg edoxaban plus 2.5 mg prasugrel (Group 1) or 30 mg edoxaban plus 3.75 mg prasugrel (Group 2) once daily for 5 days. Primary endpoint was BT by the Ivy method. Secondary endpoints were the PD parameters of prothrombin time (PT), activated partial thromboplastin time (aPTT), prothrombin fragment F1 + 2 (F1 + 2), and P2Y12 reaction units (PRU), and PK profiles of edoxaban alone and in combination with prasugrel. Results Geometric least squares mean of BT ratios (vs. baseline) for 3-day edoxaban treatment were 1.097 (90% confidence interval (CI) 0.911–1.321) in Group 1 and 1.327 (90% CI 1.035–1.703) in Group 2; for 5-day edoxaban plus 2.5 mg and 3.75 mg prasugrel, they were 1.581 (90% CI 1.197–2.087) and 1.996 (90% CI 1.482–2.690), respectively. Contributions of prasugrel to the effects (edoxaban + prasugrel/edoxaban) were 1.442 (90% CI 1.096–1.897) in Group 1 and 1.504 (90% CI 1.172–1.930) in Group 2. Edoxaban prolonged PT and aPTT and decreased F1 + 2. Adding on prasugrel did not appreciably change PT, aPTT, or F1 + 2. Prasugrel reduced PRU, whereas edoxaban had no effect on PRU. We recorded 26 adverse events; 23 were treatment-emergent (positive fecal occult blood test). All participants with adverse events recovered during follow-up. Conclusions Coadministration of 2.5 mg and 3.75 mg prasugrel with 30 mg edoxaban prolonged BT in healthy elderly Japanese male subjects. The effect was dependent on the dose of prasugrel. Prasugrel did not affect PD or PK profiles of edoxaban. Edoxaban had no effect on PD of prasugrel. Trial registration Japan Registry of Clinical Trials No. jRCTs071190006 ; registration date, 26-April-2019.

Abstract Background A majority of women from all cultures and socioeconomic levels experience myriad symptoms known as premenstrual syndrome during the days prior to menstruation. The present study investigated commonly reported symptoms in the premenstrual phase among college students. The authors further scrutinized potential factors, including subjective perceptions of health, which may be related to the premenstrual-symptom constellation. Methods We conducted a cross-sectional survey, which included 200 participants (mean age: 19.8 ± 0.1 years old). The subjects completed a rating of their premenstrual experiences relative to 46 symptoms in eight categories of the self-reporting menstrual distress questionnaire (MDQ) to evaluate the prevalence and severity of premenstrual symptoms. The participants also answered a standardized health questionnaire regarding subjective perceptions of health, self-rating stress, lifestyle, and demographic variables. Results Regardless of severity, the 10 symptoms most often occurring among the participants included skin disorders, irritability, fatigue, mood swings, general aches and pains, lowered school or work performance, backache, painful breasts, weight gain, and swelling. Stepwise multiple regression analysis revealed subjective perception of health (β = 0.28; p

Two manganese peroxidases (MnPs), MnP1 and MnP2, and a laccase, Lac1, were purified from Trametes polyzona KU-RNW027. Both MnPs showed high stability in organic solvents which triggered their activities. Metal ions activated both MnPs at certain concentrations. The two MnPs and Lac1, played important roles in dye degradation and pharmaceutical products deactivation in a redox mediator-free system. They completely degraded Remazol brilliant blue (25 mg/L) in 10–30 min and showed high degradation activities to Remazol navy blue and Remazol brilliant yellow, while Lac1 could remove 75% of Remazol red. These three purified enzymes effectively deactivated tetracycline, doxycycline, amoxicillin, and ciprofloxacin. Optimal reaction conditions were 50 °C and pH 4.5. The two MnPs were activated by organic solvents and metal ions, indicating the efficacy of using T. polyzona KU-RNW027 for bioremediation of aromatic compounds in environments polluted with organic solvents and metal ions with no need for redox mediator supplements.

Abstract Background This study involved a sensory evaluation of edoxaban orally disintegrating (OD) tablets in patients with nonvalvular atrial fibrillation who had been receiving the existing edoxaban film-coated tablets before the study. Methods Edoxaban OD tablets 30 or 60 mg were prescribed for patients who had been receiving the existing 30- or 60-mg edoxaban film-coated tablets before the study. Each dose group was randomized into groups taking the tablets with or without water. After ingestion of the edoxaban OD tablet, each patient was asked to complete a sensory evaluation questionnaire (12 items). Results In the evaluation of satisfaction with edoxaban OD tablets, 52.8% of the patients perceived “no difference” from the existing edoxaban film-coated tablets and 34.9% indicated that they were more satisfied with the OD tablets, thus demonstrating a relatively high degree of satisfaction. When asked about convenience and reliability in using edoxaban OD tablets, about half of the patients perceived “no difference” from the existing edoxaban film-coated tablets and the remaining half indicated preference for the OD tablets. Responses about taste, flavor, ease of ingestion, and motivation to continue taking edoxaban indicated the overall acceptance of the OD tablets. Recognition of edoxaban OD tablets was rated as “easy” by about half of the patients and “difficult” by the remaining half. Among all patients, 49.5% preferred a change to edoxaban OD tablets. The degree of satisfaction with taste, flavor, and ease of ingestion, as well as overall satisfaction, tended to be greater when the OD tablets were taken with rather than without water, and the percentage of patients who preferred a change was higher in the group taking the OD tablets with water. Conclusions This study indicated that the degree of satisfaction with taste, flavor, ease of ingestion, and convenience, as well as overall satisfaction, in addition to motivation to continue drug intake and sense of confidence were greater for OD tablets than for the existing edoxaban film-coated tablets. Edoxaban OD tablet is a promising formulation for inducing greater patient adherence to medication and therefore ensures better treatment response. Trial registration UMIN-CTR UMIN000028788, registered 23-Aug-2017.

Objective To explore anticoagulant usage patterns stratified by stroke and bleeding risk in elderly patients with non-valvular atrial fibrillation (NVAF).Design Prospective, multicentre, observational cohort study.Setting The real-world All Nippon AF In the Elderly (ANAFIE) registry.Participants Japanese patients aged ≥75 years with NVAF (n=32 726).Outcome measures The distribution of stroke and bleeding risk scores, and the selection of anticoagulant regimen for patients at high stroke and bleeding risk.Results Overall, 18 185 (55.6%) patients had a high risk of stroke (CHADS2 score ≥3). Of these, 12 561 (38.4% of the total ANAFIE population) had a low bleeding risk (HAS-BLED ≤2) and 5624 (17.2%) had a high bleeding risk (HAS-BLED ≥3). Significant differences were noted between the high versus low bleeding risk groups in sex, height, weight, systolic blood pressure and rates of abnormality of lipid metabolism, gastrointestinal disease, cerebrovascular disorders, chronic kidney disease, angina pectoris, respiratory disease, primary malignant tumour, dementia and fall history within the past year (all p

The real-world status of proton pump inhibitor (PPI) use in patients with atrial fibrillation (AF) receiving antithrombotic treatment is largely unknown. The All Nippon AF In the Elderly (ANAFIE) Registry, a prospective, multicenter, observational study, aimed to determine treatment patterns, risk factors, and outcomes among elderly (aged ≥75 years) Japanese non-valvular AF (NVAF) patients in the real-world clinical setting. The present subanalysis of the ANAFIE Registry determined the PPI prescription status of 32,490 elderly Japanese NVAF patients. Patients were stratified by PPI use (PPI+) or no PPI use (PPI-). Risk scores for stroke (CHADS2, CHA2DS2-VASc) and bleeding (HAS-BLED), anticoagulant use, time in therapeutic range (TTR) for warfarin, and anticoagulant/antiplatelet combination use were evaluated. PPIs were used in 11,981 (36.9%) patients. Compared with the PPI- group, the PPI+ group included a greater proportion of female patients (45.2% vs 41.3%; P

Abstract The aggregation mechanism of phosphorylated tau is an important therapeutic target for tauopathies, including Alzheimer’s disease, although the mechanism by which aggregation occurs is still unknown. Because the phosphorylation process of tau is involved in the trafficking of AMPA receptors, which accompanies the long-term depression (LTD) of synapses, we examined the effect of LTD-inducing low-frequency stimulation (LFS) on the formation of pathological tau aggregates in adult and aged wild-type mice. Our biochemical analysis demonstrated that LFS led to the formation of sarkosyl-insoluble (SI) tau oligomers in aged hippocampi but not in adult hippocampi in wild-type mice. In parallel, electrophysiological experiments showed an increased contribution of the autophagy-lysosomal pathway (ALP) to LTD during aging, although the other properties of LFS-induced LTD that we investigated were not altered. Thus, we anticipate that the increased contribution of the ALP to the LTD cascade is involved in the age-dependent formation of tau oligomers that results from LFS. Analysis of the LC3 ratio, an indicator of autophagosome formation, showed that LFS increased cleaved LC3 (type II) in the aged hippocampus relative to type I LC3, suggesting potentiation of the ALP accompanied by LTD. Pharmacological inhibition of autophagosome formation depressed LFS-induced oligomerization of tau. Prevention of lysosomal function in the ALP enhanced the formation of tau oligomers by LFS. These results suggest the importance of the autophagosome for the LFS-induced oligomerization of tau and suggest a reason for its age dependency. Interestingly, the lysosomal disturbance promoted the formation of the fibrillar form of aggregates consisting of hyper-phosphorylated tau. The LTD-ALP cascade potentially acts as one of the suppliers of pathological aggregates of tau in aged neurons.

Abstract The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer’s disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.

Background: The purpose of this study was to evaluate the clinical results following intra-articular knee injection of Stromal Vascular Fraction (SVF cell therapy). Methods: This study involved 13 consecutive patients who had received SVF cell therapy at our clinic before November 2015 and completed the 6-month post-treatment follow-up period. For each treatment, approximately 200 mL or more of subcutaneous adipose tissue was harvested using tumescent liposuction technique and manual aspiration of tissue from the lower abdomen using a suction cannula under local anesthesia in the operating room. The adipose tissue harvested was processed using the Celution Centrifuge IV in the cell processing room of our clinic. These cells were injected into the articular cavity of both knees directly. Outcome was assessed on the basis of patient questionnaires using VAS for pain, the Japanese Knee Osteoarthritis Measure (JKOM), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Results: The 13 patients (26 knee joints), consisting of 2 men and 11 women, had a mean age of 74.5 ± 5.4 years. Eleven patients (9 women, 2 men) presented Grade IV knee OA according to the KL classification. The remaining two patients, both women, had Grade III. Pre-operative scores of JKOM, WOMAC, VAS, and BS-POP (for patients) were 55.9 ± 21.0, 49.6 ± 20.4, 72.7 ± 18.2, and 18.5 ± 2.0. No serious adverse events were reported. One month after injection of SVF, all the scores of JKOM, WOMAC, and VAS were significantly improved over baseline (P

Exercise-induced changes in executive function affect the control of action in a dynamic environment. This study aimed to examine the effect of sustained high-intensity exercise on executive function. Nine healthy male and female participants (age, 21-28 years) completed an exercise session with 65-min treadmill running at 75% VO2max. Executive function was assessed before and after exercise with the Stroop Color and Word Test that included congruent and incongruent conditions. The reaction time and response accuracy of the test were measured, and the task difficulty was controlled by adjusting the stimulus duration so that each participant could maintain at least 80% response accuracy to exclude the effect of a speed–accuracy trade-off. The levels of plasma norepinephrine and adrenocorticotropic hormone were examined. A significant interaction with the reaction time was found (condition × time, P = 0.024), in which the reaction time significantly increased after exercise only in the incongruent condition (P = 0.019). The response accuracy was not significantly different between before and after exercise in both conditions, which indicated that the response accuracy was controlled as intended. The levels of plasma norepinephrine and adrenocorticotropic hormone were significantly increased after exercise (P < 0.05). These results demonstrated that the reaction time in the incongruent condition increased after sustained high-intensity exercise with a cognitive function test with the response accuracy controlled, indicating a decline in executive function. Increased levels of plasma norepinephrine and adrenocorticotropic hormone may contribute, at least in part, to such decline in executive function.

To evaluate the long-range cross-correlation in non-stationary bi-variate time-series, detrending-operation-based analysis methods such as the detrending moving-average cross-correlation analysis (DMCA), are widely used. However, its mathematical foundation has not been well established. In this paper, we propose a generalized theory to form the foundation of DMCA-type methods and introduce the higher-order DMCA in which Savitzky-Golay filters are employed as the detrending operator. Using this theory, we can understand the mathematical basis of DMCA-type methods. Our theory establishes a rigorous relationship between the DMCA-type analysis, the cross-correlation function analysis, and the cross-power spectral analysis. Based on the mathematical validity, we provide a practical guide for the use of higher-order DMCA. Additionally, we present illustrative results of a numerical and real-world analysis. To achieve reliable and accurate detection of the long-range cross-correlation, we emphasize the importance of time-lag estimation and time scale correction in DMCA, which has not been pointed out in the previous studies. Keywords: Long memory process, Complex system interaction, Cross-spectral analysis

Each year, increasing amounts of plastic waste are generated, causing environmental pollution and resource loss. Recycling is a solution, but recycled plastics often have inferior mechanical properties to virgin plastics. However, studies have shown that holding polymers in the melt state before extrusion can restore the mechanical properties; thus, we propose a twin-screw extruder with a molten resin reservoir (MSR), a cavity between the screw zone and twin-screw extruder discharge, which retains molten polymer after mixing in the twin-screw zone, thus influencing the polymer properties. Re-extruded recycled polyethylene (RPE) pellets were produced, and the tensile properties and microstructure of virgin polyethylene (PE), unextruded RPE, and re-extruded RPE moldings prepared with and without the MSR were evaluated. Crucially, the elongation at break of the MSR-extruded RPE molding was seven times higher than that of the original RPE molding, and the Young’s modulus of the MSR-extruded RPE molding was comparable to that of the virgin PE molding. Both the MSR-extruded RPE and virgin PE moldings contained similar striped lamellae. Thus, MSR re-extrusion improved the mechanical performance of recycled polymers by optimizing the microstructure. The use of MSRs will facilitate the reuse of waste plastics as value-added materials having a wide range of industrial applications.

The role of nutrient-sensing pathways in regulation of innate immune response is unexplored. Here the authors show that IL-4 activates the amino-acid sensing pathway in macrophages and leads to polarization of anti-inflammatory M2 macrophages via the transcription factor liver X receptor.

We report a case with compression myelopathy due to proliferative changes around the C2 pars defects without instability. A 69-year-old man presented with progressive clumsy hands and spastic gait. Plain radiographs showed bilateral spondylolysis (pars defects) at C2 and fusion between C2 and C3 spinous processes. Dynamic views revealed mobility through the pars defects, but there was no apparent instability. Computed tomography showed proliferative changes at the pars defects, which protruded into spinal canal. On magnetic resonance imaging, the spinal cord was compressed and intramedullary high signal change was found. A diagnosis of compression myelopathy due to proliferative changes around the C2 pars defects was made. We performed posterior decompression. Postoperatively, symptoms have been alleviated and images revealed sufficient decompression and no apparent instability. In patients with the cervical spondylolysis, myelopathy caused by instability or slippage have been periodically reported. The present case involving C2 spondylolysis is extremely rare.

To better understand the light regulation of ligninolytic systems in Trametes polyzona KU-RNW027, ligninolytic enzymes-encoding genes were identified and analyzed to determine their transcriptional regulatory elements. Elements of light regulation were investigated in submerged culture. Three ligninolytic enzyme-encoding genes, mnp1, mnp2, and lac1, were found. Cloning of the genes encoding MnP1 and MnP2 revealed distinct deduced amino acid sequences with 90% and 86% similarity to MnPs in Lenzites gibbosa, respectively. These were classified as new members of short-type hybrid MnPs in subfamily A.2 class II fungal secretion heme peroxidase. A light responsive element (LRE), composed of a 5′-CCRCCC-3′ motif in both mnp promoters, is reported. Light enhanced MnP activity 1.5 times but not laccase activity. The mnp gene expressions under light condition increased 6.5- and 3.8-fold, respectively. Regulation of laccase gene expression by light was inconsistent with the absence of LREs in their promoter. Blue light did not affect gene expressions but impacted their stability. Reductions of MnP and laccase production under blue light were observed. The details of the molecular mechanisms underlying enzyme production in this white-rot fungus provide useful knowledge for wood degradation relative to illumination condition. These novel observations demonstrate the potential of enhancing ligninolytic enzyme production by this fungus for applications with an eco-friendly approach to bioremediation.

Background A decline in executive function could have a negative influence on the control of actions in dynamic situations, such as sports activities. Mouth rinsing with a carbohydrate solution could serve as an effective treatment for preserving the executive function in exercise. The purpose of this study was to examine the effects of mouth rinsing with a carbohydrate solution on executive function after sustained moderately high-intensity exercise. Methods Eight young healthy participants completed 65 min of running at 75% V̇O2max with two mouth-rinsing conditions: with a carbohydrate solution (CHO) or with water (CON). Executive function was assessed before and after exercise by using the incongruent task of the Stroop Color and Word Test. The levels of blood glucose; and plasma adrenocorticotropic hormone (ACTH), epinephrine, and norepinephrine (NE) were evaluated. A two-way repeated-measures ANOVA, with condition (CHO and CON) and time (pre-exercise and post-exercise) as factors, was used to examine the main and interaction effects on the outcome measures. Results The reaction time in the incongruent condition of the Stroop test significantly increased after exercise in CON (pre-exercise 529 ± 45 ms vs. post-exercise 547 ± 60 ms, P = 0.029) but not in CHO (pre-exercise 531 ± 54 ms vs. post-exercise 522 ± 80 ms), which resulted in a significant interaction (condition × time) on the reaction time (P = 0.028). The increased reaction time in CON indicates a decline in the executive function, which was attenuated in CHO. Increases in plasma epinephrine and NE levels demonstrated a trend toward attenuation accompanying CHO (P

Vast numbers of proteins work cooperatively to exert their functions in various cells. In order to understand the functions and molecular mechanisms of these proteins in plants, analyses of transgenic plants that concomitantly express two protein-coding genes are often required. We developed a novel Gateway cloning technology-compatible binary vector system, the R4 dual-site (R4DS) Gateway cloning system, which enables the easy and efficient cloning of two desired sets of promoters and open reading frames (ORFs) into a binary vector using promoter and ORF entry clones. In this system, C-terminal fusions with 17 kinds of tags including visible reporters and epitope tags are available for each ORF, and selection by four kinds of resistance markers is possible. We verified that the R4DS Gateway cloning system functioned well in Arabidopsis thaliana by observing the expression and localization patterns of fluorescent proteins fused with organelle-targeting signals and driven by stomatal-lineage specific promoters. We also confirmed that the two cloning sites in the R4DS Gateway cloning system were equivalent and independently regulated. The results obtained indicate that the R4DS Gateway cloning system facilitates detailed comparisons of the expression patterns of two promoters as well as co-localization and interaction analyses of two proteins in specific cells in plants.

BackgroundElderly patients with atrial fibrillation are at higher risk of both ischemic and bleeding events compared to younger patients. In a prespecified analysis from the ENGAGE AF‐TIMI 48 trial, we evaluate clinical outcomes with edoxaban versus warfarin according to age. Methods and ResultsTwenty‐one thousand one‐hundred and five patients enrolled in the ENGAGE AF‐TIMI 48 trial were stratified into 3 prespecified age groups:

This paper describes a novel mechanism with passive crawlers that will realize a stair-climbing rescue robot with simple system. The proposed mechanism is called “SMART-III”, it is named after “Simple Mechanism Adaptive for Rough Terrain”. Some quasi-static dynamic analysis were implemented and effectiveness of limitation for crawler rotation angle were verified. A prototype robot with the SMART-III mechanism had been improved. Experimental results show the effectiveness and performance of the proposed mechanism against a step and continuous stairs.

We present a case of a 53-year-old woman with subchondral insufficiency fracture (SIF) of the femoral head without history of severe osteoporosis or overexertion. Plain radiographs showed acetabular overcoverage with excessive lateralization of the acetabular rim. A diagnosis of SIF was made by typical MRI findings of SIF. The lesion occurred at the antipodes of the extended rim. Increased mechanical stress over the femoral head due to impingement against the excess bone was suspected as a cause of SIF. The distinct femoral head deformity is consistent with this hypothesis. This is the first report of SIF associated with acetabular overcoverage.

Nature Communications 7 Article number: 13130 (2016); Published 12 October 2016; Updated 27 February 2017 In this Article, there are errors in the labelling of the x axis in Fig. 5g,h that were introduced during the production process. The second label on the x axis of each graph in Fig. 5g should have been ‘ΦWT’ instead of ‘ΦKO’.

Tauopathies differ in terms of the brain regions that are affected. In Alzheimer's disease, basal forebrain and hippocampus are mainly involved, while frontotemporal lobar degeneration affects the frontal and temporal lobes and subcortical nuclei including striatum. Over 90% of human cases of tauopathies are sporadic, although the majority of established tau-transgenic mice have had mutations. This prompted us to establish transgenic mice expressing wild-type human tau (Tg601). Old (>14 months old) Tg601 mice displayed decreased anxiety in the elevated plus maze test and impaired place learning in the Morris water maze test. Immunoblotting of brain tissue identified that soluble tau multimer was increased with aging even though insoluble tau was not observed. In the striatum of old Tg601, the level of AT8- or AT180-positive tau was decreased compared with that of other regions, while PHF-1-positive tau levels remained equal. Phosphorylated tau-positive axonal dilations were present mainly in layers V and VI of the prefrontal cortex. Loss of synaptic dendritic spine and decreased immunohistochemical level of synaptic markers were observed in the nucleus accumbens. In vivo 2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography analysis also showed decreased activity exclusively in the nucleus accumbens of living Tg601 mice. In Tg601 mice, the axonal transport defect in the prefrontal cortex–nucleus accumbens pathway may lead to decreased anxiety behavior. Differential distribution of hyperphosphorylated tau may cause region-specific neurodegeneration.

In a competitive sport, the outcome of a game is determined by an athlete's relationship with an unpredictable and uncontrolled opponent. We have previously analyzed the preparatory state of ground reaction forces (GRFs) dividing non-weighted and weighted states (i.e., vertical GRFs below and above 120% of body weight, respectively) in a competitive ballgame task and demonstrated that the non-weighted state prevented delay of the defensive step and promoted successful guarding. However, the associated kinetics of lower extremity joints during a competitive sports task remains unknown. The present study aims to investigate the kinetic characteristics of a real-time competitive sport before movement initiation. As a first kinetic study on a competitive sport, we initially compared the successful defensive kinetics with a relatively stable preparatory state and the choice-reaction sidestep as a control movement. Then, we investigated the kinetic cause of the outcome in a 1-on-1 dribble in terms of the preparatory states according to our previous study. The results demonstrated that in successful defensive motions in the non-weighted state guarding trial, the times required for the generation of hip abduction and three extension torques for the hip, knee, and ankle joints were significantly shortened compared with the choice-reaction sidestep, and hip abduction and hip extension torques were produced almost simultaneously. The sport-specific movement kinetics emerges only in a more-realistic interactive experimental setting. A comparison of the outcomes in the 1-on-1 dribble and preparatory GRF states showed that, in the non-weighted state, the defenders guarded successfully in 68.0% of the trials, and the defender's initiation time was earlier than that in the weighted state (39.1%). In terms of kinetics, the root mean squares of the derivative of hip abduction and three extension torques in the non-weighted state were smaller than those in the weighted state, irrespective of the outcome. These results indicate that the preparatory body state as explained by short-term joint torque fluctuations before the defensive step would help explain the performance in competitive sports, and will give insights into understanding human adaptive behavior in unpredicted and uncontrolled environments.

In recent years, the study of resting state neural activity has received much attention. To better understand the roles of different brain regions in the regulation of behavioral activity in an arousing or a resting period, we developed a novel behavioral paradigm (8-arm food-foraging task; 8-arm FFT) using the radial 8-arm maze and examined how AcbC lesions affect behavioral execution and learning. Repetitive training on the 8-arm FFT facilitated motivation of normal rats to run quickly to the arm tips and to the center platform before the last-reward collection. Importantly, just after this point and before confirmation of no reward at the next arm traverse, locomotor activity decreased. This indicates that well-trained rats can predict the absence of the reward at the end of food seeking and then start another behavior, namely planned resting. Lesions of the AcbC after training selectively impaired this reduction of locomotor activity after the last-reward collection without changing activity levels before the last-reward collection. Analysis of arm-selection patterns in the lesioned animals suggests little influence of the lesion in the ability to predict the reward absence. AcbC lesions did not change exploratory locomotor activity in an open-field test in which there were no rewards. This suggests that the AcbC controls the activity level of planned resting behavior shaped by the 8-arm FFT. Rats receiving training after AcbC lesioning showed a reduction in motivation for reward seeking. Thus, the AcbC also plays important roles not only in controlling the activity level after the last-reward collection but also in motivational learning for setting the activity level of reward-seeking behavior.

Squid can rapidly change the chromatic patterns on their body. The patterns are created by the expansion and retraction of chromatophores. The chromatophore consists of a central pigment-containing cell surrounded by radial muscles that are controlled by motor neurons located in the central nervous system (CNS). In this study we used semi-intact squid (Sepioteuthis lessoniana) displaying centrally controlled natural patterns to analyze spatial and temporal activities of chromatophores located on the dorsal mantle skin. We found that chromatophores oscillated with miniature expansions/retractions at various frequencies, even when the chromatic patterns appear macroscopically stable. The frequencies of this miniature oscillation differed between "feature" and "background" areas of chromatic patterns. Higher frequencies occurred in feature areas, whereas lower frequencies were detected in background areas. We also observed synchronization of the oscillation during chromatic pattern expression. The expansion size of chromatophores oscillating at high frequency correlated with the number of synchronized chromatophores but not the oscillation frequency. Miniature oscillations were not observed in denervated chromatophores. These results suggest that miniature oscillations of chromatophores are driven by motor neuronal activities in the CNS and that frequency and synchrony of this oscillation determine the chromatic pattern and the expansion size, respectively.

BackgroundThe M(5) muscarinic acetylcholine receptor is known to play a crucial role in mediating acetylcholine dependent dilation of cerebral blood vessels. Previously, we reported that male M(5) muscarinic acetylcholine knockout mice (M5R(-/-) mice) suffer from a constitutive constriction of cerebral arteries, reduced cerebral blood flow, dendritic atrophy, and short-term memory loss, without necrosis and/or inflammation in the brain.Methodology/principal findingsWe employed the Magnetic Resonance Angiography to study the area of the basilar artery in male and female M5R(-/-) mice. Here we show that female M5R(-/-) mice did not show the reduction in vascular area observed in male M5R(-/-) mice. However, ovariectomized female M5R(-/-) mice displayed phenotypic changes similar to male M5R(-/-) mice, strongly suggesting that estrogen plays a key role in the observed gender differences. We found that 17beta-estradiol (E2) induced nitric oxide release and ERK activation in a conditional immortalized mouse brain cerebrovascular endothelial cell line. Agonists of ERalpha, ERbeta, and GPR30 promoted ERK activation in this cell line. Moreover, in vivo magnetic resonance imaging studies showed that the cross section of the basilar artery was restored to normal in male M5R(-/-) mice treated with E2. Treatment with E2 also improved the performance of male M5R(-/-) mice in a cognitive test and reduced the atrophy of neural dendrites in the cerebral cortex and hippocampus. M5R(-/-) mice also showed astrocyte swelling in cortex and hippocampus using the three-dimensional reconstruction of electron microscope images. This phenotype was reversed by E2 treatment, similar to the observed deficits in dendrite morphology and the number of synapses.Conclusions/significanceOur findings indicate that M5R(-/-) mice represent an excellent novel model system to study the beneficial effects of estrogen on cerebrovascular function and cognition. E2 may offer new therapeutic perspectives for the treatment of cerebrovascular insufficiency related memory dysfunction.

Activation of GSK-3beta is presumed to be involved in various neurodegenerative diseases, including Alzheimer's disease (AD), which is characterized by memory disturbances during early stages of the disease. The normal function of GSK-3beta in adult brain is not well understood. Here, we analyzed the ability of heterozygote GSK-3beta knockout (GSK+/-) mice to form memories. In the Morris water maze (MWM), learning and memory performance of GSK+/- mice was no different from that of wild-type (WT) mice for the first 3 days of training. With continued learning on subsequent days, however, retrograde amnesia was induced in GSK+/- mice, suggesting that GSK+/- mice might be impaired in their ability to form long-term memories. In contextual fear conditioning (CFC), context memory was normally consolidated in GSK+/- mice, but once the original memory was reactivated, they showed reduced freezing, suggesting that GSK+/- mice had impaired memory reconsolidation. Biochemical analysis showed that GSK-3beta was activated after memory reactivation in WT mice. Intraperitoneal injection of a GSK-3 inhibitor before memory reactivation impaired memory reconsolidation in WT mice. These results suggest that memory reconsolidation requires activation of GSK-3beta in the adult brain.

Recent in vitro and in vivo studies suggest that destabilized proteins with defective folding induce aggregation and toxicity in protein-misfolding diseases. One such unstable protein state is called amyloid oligomer, a precursor of fully aggregated forms of amyloid. Detection of various amyloid oligomers with A11, an anti-amyloid oligomer conformation-specific antibody, revealed that the amyloid oligomer represents a generic conformation and suggested that toxic beta-aggregation processes possess a common mechanism. By using A11 antibody as a probe in combination with mass spectrometric analysis, we identified GroEL in bacterial lysates as a protein that may potentially have an amyloid oligomer conformation. Surprisingly, A11 reacted not only with purified GroEL but also with several purified heat shock proteins, including human Hsp27, 40, 70, 90; yeast Hsp104; and bovine Hsc70. The native folds of A11-reactive proteins in purified samples were characterized by their anti-beta-aggregation activity in terms of both functionality and in contrast to the beta-aggregation promoting activity of misfolded pathogenic amyloid oligomers. The conformation-dependent binding of A11 with natively folded Hsp27 was supported by the concurrent loss of A11 reactivity and anti-beta-aggregation activity of heat-treated Hsp27 samples. Moreover, we observed consistent anti-beta-aggregation activity not only by chaperones containing an amyloid oligomer conformation but also by several A11-immunoreactive non-chaperone proteins. From these results, we suggest that the amyloid oligomer conformation is present in a group of natively folded proteins. The inhibitory effects of A11 antibody on both GroEL/ES-assisted luciferase refolding and Hsp70-mediated decelerated nucleation of Abeta aggregation suggested that the A11-binding sites on these chaperones might be functionally important. Finally, we employed a computational approach to uncover possible A11-binding sites on these targets. Since the beta-sheet edge was a common structural motif having the most similar physicochemical properties in the A11-reactive proteins we analyzed, we propose that the beta-sheet edge in some natively folded amyloid oligomers is designed positively to prevent beta aggregation.

Advanced age and mutations in the genes encoding amyloid precursor protein (APP) and presenilin (PS1) are two serious risk factors for Alzheimer's disease (AD). Finding common pathogenic changes originating from these risks may lead to a new therapeutic strategy. We observed a decline in memory performance and reduction in hippocampal long-term potentiation (LTP) in both mature adult (9-15 months) transgenic APP/PS1 mice and old (19-25 months) non-transgenic (nonTg) mice. By contrast, in the presence of bicuculline, a GABA(A) receptor antagonist, LTP in adult APP/PS1 mice and old nonTg mice was larger than that in adult nonTg mice. The increased LTP levels in bicuculline-treated slices suggested that GABA(A) receptor-mediated inhibition in adult APP/PS1 and old nonTg mice was upregulated. Assuming that enhanced inhibition of LTP mediates memory decline in APP/PS1 mice, we rescued memory deficits in adult APP/PS1 mice by treating them with another GABA(A) receptor antagonist, picrotoxin (PTX), at a non-epileptic dose for 10 days. Among the saline vehicle-treated groups, substantially higher levels of synaptic proteins such as GABA(A) receptor alpha1 subunit, PSD95, and NR2B were observed in APP/PS1 mice than in nonTg control mice. This difference was insignificant among PTX-treated groups, suggesting that memory decline in APP/PS1 mice may result from changes in synaptic protein levels through homeostatic mechanisms. Several independent studies reported previously in aged rodents both an increased level of GABA(A) receptor alpha1 subunit and improvement of cognitive functions by long term GABA(A) receptor antagonist treatment. Therefore, reduced LTP linked to enhanced GABA(A) receptor-mediated inhibition may be triggered by aging and may be accelerated by familial AD-linked gene products like Abeta and mutant PS1, leading to cognitive decline that is pharmacologically treatable at least at this stage of disease progression in mice.