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Accumulation of amyloid β peptides (Aβ) is thought to be one of the causal factors of Alzheimer's disease (AD). The aspartyl protease β-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate-limiting protease for Aβ production, and therefore, BACE1 inhibition is a promising therapeutic approach for the treatment of AD. Starting with a dihydro-1,3-thiazine-based lead, Compound J, we discovered atabecestat 1 (JNJ-54861911) as a centrally efficacious BACE1 inhibitor that was advanced into the EARLY Phase 2b/3 clinical trial for the treatment of preclinical AD patients. Compound 1 demonstrated robust and dose-dependent Aβ reduction and showed sufficient safety margins in preclinical models. The potential of reactive metabolite formation was evaluated in a covalent binding study to assess its irreversible binding to human hepatocytes. Unfortunately, the EARLY trial was discontinued due to significant elevation of liver enzymes, and subsequent analysis of the clinical outcomes showed dose-related cognitive worsening.

Synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome and chronic recurrent multifocal osteomyelitis (CRMO) have been described as disorders of chronic osteoarthritic inflammation frequently associated with skin manifestations, and SAPHO and CRMO (SAPHO/CRMO) are rare autoinflammatory disorders of unknown etiology. SAPHO tends to occur in adults and CRMO predominantly occurs in children and adolescents. SAPHO/CRMO can affect any skeletal region (e.g., anterior chest wall, spine, or long bones). As SAPHO/CRMO are diagnoses of exclusion, the diagnoses might be difficult if skin manifestations are not clearly evident. However, knowledge of the imaging findings of skeletal disorders is helpful for correcting the diagnosis and avoiding unnecessary invasive procedures, as well as in facilitating early diagnosis and adequate treatment. This pictorial review describes the appearance of increased skeletal uptake for SAPHO/CRMO on bone scintigraphy along with findings from radiography, computed tomography, and magnetic resonance imaging.

In recent years, street parking in prohibited areas has become a serious social problem, particularly in metropolitan and tourist areas where there are many on-street parked cars. In addition, because on-street parking can cause traffic congestion and accidents, real-time detection is considered necessary. In previous studies, fixed-point cameras have been mainly used for traffic control; however, a major disadvantage of these systems is their limited detection area. In this study, we developed a system that can detect and visualize on-street parking in real-time using video data captured by dashboard cameras, which have become widely used in recent years. We created a learned model to detect on-street parking and to recognize cars using an edge device. By displaying the location information of on-street parked cars on a map, their location can be visualized. This system could be used to obtain statistical data for crackdowns on on-street parking and to identify areas where on-street parking occurs.

In this study, the finite element analysis of the string planes of badminton racquets was investigated to evaluate the effect of the mechanical characteristics of polymer strings. The nonlinear mechanical characteristics of commercially available polymer strings were obtained by the uniaxial loading tests experimentally. The effects of the strain rate on the mechanical characteristics of the polymer strings were also investigated to consider the dynamic effect on the numerical simulation. The numerical simulation code used to analyze the string planes of the badminton racquets was developed originally. A nonlinear elastic model (Yeoh model) was applied to the mechanical characteristics of the polymer string. Simulated results were compared with the experimental results. The effect of the mechanical characteristics of the polymer strings and the geometrical shape of the badminton racquets on the out-of-plane stiffnesses were investigated.

In this paper, 3-axial knee joint torques given by compression sports tights were performed by numerical simulations using 3-dimensional computer graphics of a human model. Running motions of the human model were represented as the 3-dimensional computer graphics, and the running motions were determined by the motion capturing system of human subjects. Strain distribution on the surface of the 3-dimentional computer graphics of the human model was applied to the boundary conditions of the numerical simulations. An anisotropic hyperelastic model considering stress softening of fabric materials was implemented to reproduce the mechanical characteristics of the compression sports tights. Based on the strain-time relationships, knee joint torques in 3-dimentional coordinates given by the compression sports tights were calculated. As a result, the three types of knee joint torque generated by the compression sports tights in running motions were calculated. From the calculated results, the maximum value of flexion/extension, varus/valgus, and internal/external knee joint torques were given as 2.52, 0.59, and 0.31 Nm, respectively. The effect of compression sports tights on the knee joint was investigated.

In this paper, mechanical properties of thermoplastic elastomers were investigated to expand the applicability of thermoplastic elastomers to the impact load reduction for the sports equipment. The thermoplastic elastomers show both thermoplastic and elastomeric properties. These are expected to apply to the impact load reduction in sports equipment due to good processability and less-smell. In this study, thermoplastic elastomers were applied for monotonic and cyclic tensile loading tests. The thermoplastic elastomer (TPE) materials in this study were newly developed for the specific purpose of impact load reduction. The nonlinear hyperelastic model considering the viscosity and damage model was applied to the tensile loading test results. finite element analysis (FEA) results of TPE specimens with periodic geometric shapes to reduce impact load were investigated.

Organic anion-transporting polypeptides (OATPs) mediate the uptake of various drugs from blood into the liver in the basolateral membrane of hepatocytes. Positron emission tomography (PET) is a potentially powerful tool to assess the activity of hepatic OATPs in vivo, but its utility critically depends on the availability of transporter-selective probe substrates. We have shown before that among the three OATPs expressed in hepatocytes (OATP1B1, OATP1B3, and OATP2B1), [11C]erlotinib is selectively transported by OATP2B1. In contrast to OATP1B1 and OATP1B3, OATP2B1 has not been thoroughly explored yet, and no specific probe substrates are currently available. To assess if the prototypical OATP inhibitor rifampicin can inhibit liver uptake of [11C]erlotinib in vivo, we performed [11C]erlotinib PET scans in six healthy volunteers without and with intravenous pretreatment with rifampicin (600 mg). In addition, FVB mice underwent [11C]erlotinib PET scans without and with concurrent intravenous infusion of high...

To assess the hepatic disposition of erlotinib, we performed positron emission tomography (PET) scans with [11 C]erlotinib in healthy volunteers without and with oral pretreatment with a therapeutic erlotinib dose (300 mg). Erlotinib pretreatment significantly decreased the liver exposure to [11 C]erlotinib with a concomitant increase in blood exposure, pointing to the involvement of a carrier-mediated hepatic uptake mechanism. Using cell lines overexpressing human organic anion-transporting polypeptides (OATPs) 1B1, 1B3, or 2B1, we show that [11 C]erlotinib is selectively transported by OATP2B1. Our data suggest that at PET microdoses hepatic uptake of [11 C]erlotinib is mediated by OATP2B1, whereas at therapeutic doses OATP2B1 transport is saturated and hepatic uptake occurs mainly by passive diffusion. We propose that [11 C]erlotinib may be used as a hepatic OATP2B1 probe substrate and erlotinib as an OATP2B1 inhibitor in clinical drug-drug interaction studies, allowing the contribution of OATP2B1 to the hepatic uptake of drugs to be revealed.

Positron emission tomography (PET) imaging with radiolabeled drugs holds great promise to assess the influence of membrane transporters on hepatobiliary clearance of drugs. To exploit the full potential of PET, quantitative pharmacokinetic models are required. In this study, we evaluated the suitability of different compartment models to describe the hepatic disposition of [11C]erlotinib as a small-molecule model drug which undergoes transporter-mediated hepatobiliary excretion. We analyzed two different, previously published data sets in healthy volunteers, in which a baseline [11C]erlotinib PET scan was followed by a second PET scan either after oral intake of unlabeled erlotinib (300 mg) or after intravenous infusion of the prototypical organic anion-transporting polypeptide inhibitor rifampicin (600 mg). We assessed a three-compartment (3C) and a four-compartment (4C) model, in which either a sampled arterial blood input function or a mathematically derived dual input function (DIF), which takes the contribution of the portal vein to the liver blood supply into account, was used. Both models provided acceptable fits of the observed PET data in the liver and extrahepatic bile duct and gall bladder. Changes in model outcome parameters between scans were consistent with the involvement of basolateral hepatocyte uptake and canalicular efflux transporters in the hepatobiliary clearance of [11C]erlotinib. Our results demonstrated that inclusion of a DIF did not lead to substantial improvements in model fits. The models developed in this work represent a step forward in applying PET as a tool to assess the impact of hepatic transporters on drug disposition and their involvement in drug-drug interactions. Electronic supplementary material The online version of this article (10.1208/s12248-019-0323-0) contains supplementary material, which is available to authorized users.

In recent years, street parking in prohibited areas has become a social problem, especially in urban and tourist areas. In addition, because street parking can cause traffic congestion and accidents, real-time detection is required. The detection of street parking has been previously implemented on the basis of comparisons of videos recorded by fixed-point cameras. However, this approach has a limited detection area and low accuracy. To overcome these problems, this study aims towards a real-time street parking detection system that uses dashboard camera videos. We propose a machine learning method based on the characteristics of on-street parked vehicles derived by transforming images into text. The object detection model YOLOv3 was used to analyze videos. We created a dataset based on the coordinate information of 1765 vehicles and the recording vehicle information. We also created a model using random forest and logistic regression algorithms and evaluated it using the holdout and stratified 5-fold validation methods. F-measure values of up to 92% and 89% were obtained for the two types of model, respectively. These results confirm the effectiveness of the proposed street parking detection method based on bounding boxes and recording vehicle data.

Organic anion-transporting polypeptides (OATPs) mediate the uptake of various drugs from blood into the liver in the basolateral membrane of hepatocytes. Positron emission tomography (PET) is a potentially powerful tool to assess the activity of hepatic OATPs in vivo, but its utility critically depends on the availability of transporter-selective probe substrates. We have shown before that among the three OATPs expressed in hepatocytes (OATP1B1, OATP1B3, and OATP2B1), [

Naldemedine tosylate, a peripherally acting μ-opioid receptor antagonist, is indicated for treatment of opioid induced constipation in both Japan and US. Naldemedine has limited ability to affect the central analgesic effect of opioid analgesics. In this study, we investigated the contribution of P-glycoprotein (P-gp) on the brain distribution of naldemedine. Naldemedine tosylate showed acceptable oral absorption in rats. Following a single oral administration of [14C]-naldemedine tosylate to rats and ferrets, little radioactivity was detected in the region protected by the blood-brain barrier (BBB). In the assessment using Caco-2 cells, it was determined that naldemedine is a substrate for P-gp. The contribution of P-gp to the brain distribution of naldemedine was assessed using multidrug resistance 1a/b (mdr1a/b) knockout mice. While the brain-to-plasma concentration ratio (brain Kp) of naldemedine in the mdr1a/b knockout mice was 4-fold of that in the wild-type mice, the brain Kp in the mdr1a/b knockout mice was quite low (brain Kp

This paper presents the application, technology and design of recent Flexible AC Transmission System (FACTS) projects in the USA, including a brief overview of three case study examples that describe recent FACTS applications. Renewable integration, generation retirement, and applied system reliability standards to the U. S. transmission system are currently the primary drivers for most applications.

The effect of string pattern on the mechanical characteristics of a tennis racket were simulated numerically. A numerical simulation program to evaluate deformation of the string bed of a tennis racket was developed using the finite element method. The formulation of a numerical simulation code is described in this paper. The applicability of the developed simulation program was investigated by comparing experimental results of loading tests on string bed specimens, for which the distance between strings was 12 mm. The out-of-plane stiffness and sliding characteristics of strings of an actual racket were simulated using the developed simulation code.

Foamed rubbers are widely used for the shoe-soles, shin-guards, protectors and so on. The complex microstructure of foamed rubber consists of rubber matrix and pores. Therefore, foamed rubbers show good shock-absorbing properties in addition to good formability and lightweight. The mechanical characteristics of foamed rubber are determined by the mechanical characteristics of rubber matrix and its microstructure. In this study, a homogenization numerical analysis of mechanical characteristics of foamed rubber considering the rubber matrix and microstructure was shown. In order to develop the evaluation method, the microstructure of the foamed rubber was assumed to have the periodical holes, and a homogenization FEM code for formed rubber was developed based on homogenization theory with hyperelasticity. To verify the applicability of our developed code, rectangular rubber specimens with periodically holes were prepared to observe stress distributions of periodical inner structure. Incompressible hyperelasticity was applied to the rubber matrix. The material parameters of hyperelasticity for rubber matrix were identified by the biaxial tensile test results. Compression test of the rubber specimen reproducing FEM model was conducted to verify the applicability of the analysis code. The analysis result showed good agreement with the compression test result in the low strain region.

In this study, a numerical design method for high-performance sports spats was proposed. The effect of sports spats on the human body during running motions was calculated. An anisotropic hyperelastic model considering stress softening was implemented to reproduce the mechanical characteristics of the sports spats fabric. Also, cyclic tensile loading tests were conducted to evaluate the mechanical characteristics of the sports spats fabric, which was composed of tricot fiber. The stiffness changed with loading direction, and the stiffness was softened depending on previous maximum stretch. The material parameters of the sports spats were identified using the cyclic loading test results. The theoretical calculations showed good agreement with experimental results. The anisotropic hyperelastic model was applied to a 3D-CG human model and running motion data were also introduced into the human model. The proposed numerical design method enabled calculation of the stress induced by the sports spats during running motions. Also, the joint torque generated in each knee was calculated using the stress calculation. The effect of high-performance sports spats on the human body was thus evaluated numerically.

In this paper, joint torque powers of lower limbs in bicycle pedaling were investigated numerically. An approximation method of relationship between the angle of the ankle and normal force in the rotation direction of a bicycle crank while pedaling was investigated To calculate the joint torque power of lower limbs, a free body diagram of the motion of the lower limbs was formulated in the 2-dimensional plane. We assumed that the movements of the greater trochanters while pedaling were too small to consider. Also, bicycle shoes were supposed to be fixed to binding pedals. The free body diagram of one leg has two degrees of freedom, the crank angle and the ankle angle, when it is assumed that the greater trochanters are relatively motionless during bicycle pedaling. In previous research, the ankle angle during bicycle pedaling was obtained directly from image analysis using high-speed cameras each time the pedaling output or cadence changes. However, the relationship proposed here does not require image analysis software with high-speed cameras each time the pedaling output or cadence changes: All positions of the lower limb segments, the joint torques and the joint torque powers were calculated from the lower-limb model. The analytical system for bicycle pedaling comprised cleat-shape biaxial load cells and a program to evaluate pedaling effectiveness, joint torque and joint torque power. The plastic cleats between shoe-sole and binding pedal were replaced with biaxial load cells, which measured the biaxial-forces of right and left legs independently. Evaluations of the joint torques of the lower limbs were conducted with five male subjects to demonstrate the applicability of the proposed method.

This study aims to present a method for detecting conflict scenes during negotiations through negative-attitude recognition using multimodal features of face-to-face negotiation interactions. This research is conducted based on a new multimodal data corpus that includes annotation of the participants’ negative attitude during the conflicting scenes. Semantic orientation (positive/negative) of the words used by the participants in the negotiation dialog, as well as the speaking turn and prosodic features, are extracted as multimodal features. Linear SVM was used to fuse the multimodal features, and the latest fusion technique was used for estimating the negative attitudes. When the proposed method is applied, classification accuracy of negative/non-negative attitude detection reaches 62.8%; recall is 0.641, precision is 0.645, and F value is 0.638.

Recently, there have been many developments in compression sportswear and swimwear. The main purpose of compression sportswear is to keep athletes’ muscles warm to prevent muscle strain and fatigue. Now, some compression sportswear has been developed to include a joint protection function. In this study, a design method for joint torque generated by compression sportswear such as competitive swimwear and compression long running tights is proposed. Information on the joint torque generated by sportswear would be useful for compression sportswear design. The proposed method calculates stress-strain relationships of sportswear fabrics using the anisotropic hyperelastic model, and calculates the frictional displacement between the human body and sportswear using a 3D-CG human model. In order to accurately calculate stress, anisotropic material modeling and a stress-softening model were applied to the mechanical characteristics of compression sportswear fabrics. The frictional displacement between the human body and swimwear during swimming was also considered for stress calculations. Typical sportswear fabrics exhibit anisotropic mechanical behavior depending on tensile direction. Also, the stiffness of the fabrics is softened by the maximum strain experienced in each warp and weft fiber. To accurately calculate the joint torques generated by compression sportswear, the anisotropy and stress softening of sportswear fabrics are considered for numerical modeling.

The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration–time profiles and P-glycoprotein (Pgp)–mediated brain drug–drug interactions between the model Pgp substrate ( R )-[ 11 C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [ 11 C]tariquidar (TQD), and the Pgp inhibitor tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration–time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration–time profiles and rank the magnitude of the Pgp-mediated brain drug–drug interaction potential for both Pgp and Pgp/BCRP substrates in humans.