Search

Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. To find potent S1PR1 antagonists, identification of the structural basis for drug efficacy is important. Here, we synthesized a novel antagonist, KSI-6666, that persistently inhibits S1PR1 activity and effectively suppresses pathogenic inflammation. Metadynamics simulation suggested that the interaction of a benzene ring moiety in KSI-6666 with a methionine residue in the ligand-binding pocket of S1PR1 inhibits the dissociation of KSI-6666 from S1PR1, generating a metastable binding state. Consistently,in vitrofunctional and mutational analyses revealed that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the methionine residue of the protein and substituents on the distal benzene ring of KSI-6666. Moreover,in vivostudy suggested that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666. These findings will contribute to the rational design of potent S1PR1 antagonists for the treatment of inflammatory disorders.

The thymus has the ability to regenerate from acute injury caused by radiation, infection, and stressors. In addition to thymocytes, thymic epithelial cells in the medulla (mTECs), which are crucial for T cell self-tolerance by ectopically expressing and presenting thousands of tissue-specific antigens (TSAs), are damaged by these insults and recover thereafter. However, given recent discoveries on the high heterogeneity of mTECs, it remains to be determined whether the frequency and properties of mTEC subsets are restored during thymic recovery from radiation damage. Here we demonstrate that acute total body irradiation with a sublethal dose induces aftereffects on heterogeneity and gene expression of mTECs. Single-cell RNA-sequencing (scRNA-seq) analysis showed that irradiation reduces the frequency of mTECs expressing AIRE, which is a critical regulator of TSA expression, 15 days after irradiation. In contrast, transit-amplifying mTECs (TA-mTECs), which are progenitors of AIRE-expressing mTECs, and Ccl21a-expressing mTECs, were less affected. Interestingly, detailed analysis of scRNA-seq data suggested that the proportion of a unique mTEC cluster expressing Ccl25 and high level of TSAs was severely decreased by irradiation. Overall, we propose that acute irradiation disturbs the heterogeneity and properties of mTECs, and may thereby impair TSA expression for thymic T cell selection.

One hallmark of some autoimmune diseases is the individual variability of symptoms. Organs affected by the disease differ between patients, making diagnosis of affected organs a challenge. Although numerous studies have investigated the correlation between T cell antigen receptor (TCR) repertoires and development of infectious and immune diseases, the correlation between TCR repertoires and variations in disease symptoms among individuals remains unclear. This study investigated correlation of TCR repertoires in blood T cells with severity of an autoimmune phenotype that varies among individuals. We sequenced TCR repertoires in the blood and stomachs of mice deficient in autoimmune regulator (Aire) (AIRE KO), a mouse model of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Data analysis revealed that degree of similarity in TCR repertoires between the blood and stomach differs among individual AIRE KO mice and reflects the severity of stomach inflammation. This suggests the existence of blood TCR repertoires that can be used to predict affected organs. Indeed, we identified a set of TCR sequences whose frequencies in blood correlated with severity of stomach manifestations. Our results highlight the potential of using TCR repertoires not just for diagnosis of disease development, but also for diagnosis of affected organs in autoimmune diseases.

Background Systemic inflammation has been reported to be associated with cancer progression and metastasis. Systemic inflammation score (SIS), calculated from preoperative serum albumin level and lymphocyte-to-monocyte ratio, has been shown to be a novel prognostic factor for several types of tumors. This study aimed to evaluate the prognostic value of the SIS in patients with pT2–4 resectable gastric cancer (GC). Methods Total 97 patients with pT2–4 GC who underwent curative surgery from 322 cases between 2009 and 2015 in Fukushima Medical University Hospital were included. We performed univariate and multivariate analyses to evaluate the usefulness of preoperative SIS and other prognostic factors for relapse-free survival (RFS) and overall survival (OS). Results The higher SIS score was associated with undifferentiated cancer and recurrence. Univariate analysis of RFS identified deeper tumor invasion and higher SIS were significant risk factors and multivariate analysis revealed that both of them were independent prognostic factors for RFS. As for OS, age, tumor invasion, SIS and LNR were significantly correlated with RFS. In multivariate analysis, tumor invasion, SIS and LNR were independent prognostic factors for OS. Conclusions SIS was an independent prognostic factor for RFS and OS in pT2–4 resectable gastric cancer patients who underwent curative gastrectomy.

The manufacturing industry has identified a new megatrend of mass customization, which is one of the essential goals of Industry 4.0. This megatrend requires the realization of manufacturing that can respond quickly and flexibly to various changing production requirements and ensure the achievement of various quality criteria. However, the manufacturing cannot be realized by conventional manufacturing systems in which reconfigurations need to be performed by skilled engineers. This paper proposes a new reconfigurable manufacturing system concept based on an ultra-flexible transfer system. Particularly, an autonomous mobile robotic manipulator, consisting of a high-performance automated guided vehicle module and a collaborative robotic manipulator module, represents a key component of the system concept. In this context, the focus is on the cooperative control between the modules of the autonomous mobile manipulator, which is essential for high-precision processes (e.g., machining, assembly, measurement, inspection), and its wide operating area. The experimental results confirm that the proposed cooperative control improves the positioning performance of the autonomous mobile manipulator, including the time required for positioning and the positioning accuracy.

SummaryMedullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by transcriptional regulator AIRE. Whereas AIRE-expressing (Aire+) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Integrative analysis of single-cell assays for transposase accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules CD80 (Aire+CD80hi). Proliferating Aire+CD80hi mTECs detected by using Fucci technology express a minimal level of Aire-dependent TSAs and are converted into quiescent Aire+CD80hi mTECs expressing high levels of TSAs after a transit amplification. These data provide evidence for the existence of transit amplifying Aire+mTEC precursors during Aire+mTEC differentiation process of the postnatal thymus.

Medullary thymic epithelial cells (mTECs) are critical for self-tolerance induction in T cells via promiscuous expression of tissue-specific antigens (TSAs), which are controlled by the transcriptional regulator, AIRE. Whereas AIRE-expressing (Aire+) mTECs undergo constant turnover in the adult thymus, mechanisms underlying differentiation of postnatal mTECs remain to be discovered. Integrative analysis of single-cell assays for transposase-accessible chromatin (scATAC-seq) and single-cell RNA sequencing (scRNA-seq) suggested the presence of proliferating mTECs with a specific chromatin structure, which express high levels of Aire and co-stimulatory molecules, CD80 (Aire+CD80hi). Proliferating Aire+CD80hi mTECs detected using Fucci technology express a minimal number of Aire-dependent TSAs and are converted into quiescent Aire+CD80hi mTECs expressing high levels of TSAs after a transit amplification. These data provide evidence for the existence of transit-amplifying Aire+mTEC precursors during the Aire+mTEC differentiation process of the postnatal thymus.

This paper proposes ROS-lite, a robot operating system (ROS) development framework for embedded many- core platforms based on network-on-chip (NoC) technology. Many-core platforms support the high processing capacity and low power consumption requirement of embedded systems. In this study, a self-driving software platform module is parallelized to run on many-core processors to demonstrate the practicality of embedded many-core platforms. The experimental results show that the proposed framework and the parallelized applications have met the deadline for low-speed self-driving systems.

The purpose of this research is to develop an assessment tool for reading aloud by pupils. We have proposed some metrics for evaluating reading fluency based on metrics of pauses in reading. In this paper, we developed a full-automated evaluation tool and a visualization method for reading using these indicators. We also propose a feedback interface based on heat-map method.

This paper presents Autoware on Board, a new profile of Autoware, especially designed to enable autonomous vehicles with embedded systems. Autoware is a popular open-source software project that provides a complete set of self-driving modules, including localization, detection, prediction, planning, and control. We customize and extend the software stack of Autoware to accommodate embedded computing capabilities. In particular, we use DRIVE PX2 as a reference computing platform, which is manufactured by NVIDIA Corporation for development of autonomous vehicles, and evaluate the performance of Autoware on ARM-based embedded processing cores and Tegra-based embedded graphics processing units (GPUs). Given that low-power CPUs are often preferred over high-performance GPUs, from the functional safety point of view, this paper focuses on the application of Autoware on ARM cores rather than Tegra ones. However, some Autoware modules still need to be executed on the Tegra cores to achieve load balancing and real-time processing. The experimental results show that the execution latency imposed on the DRIVE PX2 platform is capped at about three times as much as that on a high-end laptop computer. We believe that this observed computing performance is even acceptable for real-world production of autonomous vehicles in certain scenarios.

In embedded systems, high processing requirements and low power consumption need heterogeneous computing platforms. Considering embedded requirements, applications need to be designed based on scalable data allocation and parallel computing with non-uniform memory access (NUMA) many cores. In this paper, we use one of the embedded commercial off-the-shelf (COTS) multi/many-core components, the Massively Parallel Processor Arrays (MPPA) 256 developed by Kalray, and conduct evaluations of data transfer and parallelization of a practical application. We investigate currently achievable data transfer latencies between distributed memories on network-on-chip (NoC), memory access characteristics, and parallelization potential with many cores. Subsequently, we run a practical application, the core of the autonomous driving system, on many-core processors and acceleration by parallelization indicates practicality of many cores. By highlighting many-core computing capabilities, we explore the scalable data allocation and parallel computing on NoC-based embedded many cores.

Although it is known that two coupled Wilson---Cowan models with reciprocal connections induce aperiodic oscillations, little attention has been paid to the dynamical mechanism for such oscillations so far. In this study, we aim to elucidate the fundamental mechanism to induce the aperiodic oscillations in the coupled model. First, aperiodic oscillations observed are investigated for the case when the connections are unidirectional and when the input signal is a periodic oscillation. By the phase portrait analysis, we determine that the aperiodic oscillations are caused by periodically forced state transitions between a stable equilibrium and a stable limit cycle attractors around the saddle-node and saddle separatrix loop bifurcation points. It is revealed that the dynamical mechanism where the state crosses over the saddle-node and saddle separatrix loop bifurcations significantly contributes to the occurrence of chaotic oscillations forced by a periodic input. In addition, this mechanism can also give rise to chaotic oscillations in reciprocally connected Wilson---Cowan models. These results suggest that the dynamic attractor transition underlies chaotic behaviors in two coupled Wilson---Cowan oscillators.

Lattice volume expansion or amorphization renders EuTiO3 ferromagnetic, although the stable phase of crystalline EuTiO3 is an antiferromagnet. The lattice volume expansion is induced into the crystalline EuTiO3 thin film by utilizing the lattice mismatch between the thin film and a substrate. The magnetization at low temperatures monotonically increases with an increase in lattice volume for the crystalline EuTiO3 thin film, coincident with the results of calculations based on the hybrid Hartree–Fock density functional approach. The ferromagnetic interaction between Eu2+ ions is enhanced by the amorphization as well; the amorphous EuTiO3 thin film becomes a ferromagnet, and the Curie temperature is higher for amorphous Eu2TiO4 than for its crystalline counterpart. The phenomenon, that is, the volume expansion- and amophization-induced ferromagnetism, is explained in terms of the competition between ferromagnetic and antiferromagnetic interactions among Eu2+ ions.

The axle counter which detects the position of the train is important railway signal device. This paper deals with a multi-objective optimization of the axle counter by 3D magnetic field analysis. In the optimization, we newly propose the introduction of the conductor plate and carry out its design optimization. It is revealed that the shape optimization of conductor plate enables us to well improve the detection performance of the axle counter from the multi-objective point of view.

Middleware for robotics development must meet demanding requirements in real-time distributed embedded systems. The Robot Operating System (ROS), open-source middleware, has been widely used for robotics applications. However, the ROS is not suitable for real-time embedded systems because it does not satisfy real-time requirements and only runs on a few OSs. To address this problem, ROS1 will undergo a significant upgrade to ROS2 by utilizing the Data Distribution Service (DDS). DDS is suitable for real-time distributed embedded systems due to its various transport configurations (e.g., deadline and fault-tolerance) and scalability. ROS2 must convert data for DDS and abstract DDS from its users; however, this incurs additional overhead, which is examined in this study. Transport latencies between ROS2 nodes vary depending on the use cases, data size, configurations, and DDS vendors. We conduct proof of concept for DDS approach to ROS and arrange DDS characteristic and guidelines from various evaluations. By highlighting the DDS capabilities, we explore and evaluate the potential and constraints of DDS and ROS2.

Cyber-Physical Systems (CPS) represent next generation distributed and embedded systems. Robot Operating System (ROS), an open-source middleware for robotics development, has been widely used for CPS applications. However, ROS is not suitable for real-time and embedded systems, because ROS does not support to meet real-time requirements, and runs only on a few kinds of OSs. Facing this problem, ROS is going to be significantly upgraded as ROS2 with utilizing Data Distribution Service (DDS). DDS is suitable for CPS due to its various transport configurations (e.g. reliability and durability). ROS2 needs to convert data for DDS and abstracting DDS from ROS2 users, which causes the overhead examined in this research. Transport latency between ROS2 nodes varies by transport situations, data size, and DDS vendors. We clarify the performance characteristics of currently-available data transport on ROS or ROS2 in various situations. Revealing the present capability of ROS2 depending on DDS vendors and DDS configurations, we explore and evaluate the facing constraints and potential of ROS2.

Bulk EuTiO3 is known as a compound in which spin and soft phonon mode is strongly coupled. Recent theoretical study suggests that application of stress or formation of strain leads to a drastic change in magnetic and dielectric properties of EuTiO3 and that so-called multiferroic properties emerge under such a situation. In the present study, effect of strain induced by a substrate, on which EuTiO3 thin film is deposited, on the magnetic properties of the film has been experimentally examined. By using a pulsed laser deposition method, EuTiO3 thin film has been deposited on different kinds of substrate, i.e., LaAlO3, SrTiO3, and DyScO3; the lattice parameter of these compounds is smaller than, just the same as, and larger than that of EuTiO3, respectively. X-ray diffraction analysis confirms that the strain induced in the plane of as-deposited EuTiO3 thin films on different substrates is coincident with the lattice parameter of the substrate compounds. Also, all the as-deposited EuTiO3 thin films manifest elongation of lattice in a direction perpendicular to the film surface. Temperature dependence of magnetization indicates that all the thin films exhibit ferromagnetic behavior at low temperatures. The magnetization at 2 K under a magnetic field of 100 Oe is the highest for EuTiO3 on DyScO3 and the lowest for EuTiO3 on LaAlO3. The experimental result is coincident with the first-principles calculations which predict that ferromagnetic spin configuration becomes more stable as the lattice volume of EuTiO3is increased.

NF-κB-inducing kinase (NIK) plays critical roles in the development of lymph nodes and Peyer’s patches, and microarchitecture of the thymus and spleen via NF-κB activation. Alymphoplasia ( aly / aly ) mice have a point mutation in the NIK gene that causes a defect in the activation of an NF-κB member RelB. Here, we developed a novel method to determine the aly mutation by genetic typing using PCR. This method facilitated the easy establishment of a congeneic aly / aly mouse line. Indeed, we generated a mouse line with aly mutation on a BALB/cA background (BALB/cA- aly / aly ). BALB/cA- aly / aly mice showed significant splenomegaly with extramedullary hemopoiesis, which was not significant in aly / aly mice on a C57BL/6 background. Interestingly, the splenomegaly and extramedullary hemopoiesis caused by the aly mutation was gender-dependent. These data together with previous reports on extramedullary hemopoiesis in RelB-deficient mice suggest that NIK–RelB signaling may be involved in the suppression of extramedullary hemopoiesis in adult mice.

Regulatory T cells (Tregs), a subset of CD4(+) helper T cells, are crucial for immunological self-tolerance. Defect in development or function of Tregs results in autoimmune disease in human and mice. Whereas it is known that Tregs mainly develop in the thymus, the molecular mechanism underlying development of Treg is not fully understood. TRAF6-deficient mice showed a severe defect in the Treg development in thymus. In vitro fetal thymic organ culture experiments indicated that the defect is ascribed to the absence of TRAF6 in thymic cells. Moreover, mixed fetal liver transfer experiments revealed that the development of Foxp3(+) cells differentiated from Traf6(-/-) hematopoietic cells was specifically impaired in the thymus, indicating cell-intrinsic requirement for TRAF6 in the Treg development. On the other hand, TRAF6 is not required for the development of conventional CD4(+) T cell. In addition, TGFβ-dependent induction of Foxp3 in CD4(+) T cells in vitro was not impaired by the absence of TRAF6. Overall, our data indicate that TRAF6 plays an essential role on the commitment of immature thymocytes to thymic Tregs in cell-intrinsic fashion.

Regulatory T cells (Tregs), a subset of CD4(+) helper T cells, are crucial for immunological self-tolerance. Defect in development or function of Tregs results in autoimmune disease in human and mice. Whereas it is known that Tregs mainly develop in the thymus, the molecular mechanism underlying development of Treg is not fully understood. TRAF6-deficient mice showed a severe defect in the Treg development in thymus. In vitro fetal thymic organ culture experiments indicated that the defect is ascribed to the absence of TRAF6 in thymic cells. Moreover, mixed fetal liver transfer experiments revealed that the development of Foxp3(+) cells differentiated from Traf6(-/-) hematopoietic cells was specifically impaired in the thymus, indicating cell-intrinsic requirement for TRAF6 in the Treg development. On the other hand, TRAF6 is not required for the development of conventional CD4(+) T cell. In addition, TGFβ-dependent induction of Foxp3 in CD4(+) T cells in vitro was not impaired by the absence of TRAF6. Overall, our data indicate that TRAF6 plays an essential role on the commitment of immature thymocytes to thymic Tregs in cell-intrinsic fashion.

Medullary thymic epithelial cells (mTECs) establish T cell self-tolerance through the expression of autoimmune regulator (Aire) and peripheral tissue-specific self-antigens. However, signals underlying mTEC development remain largely unclear. Here, we demonstrate crucial regulation of mTEC development by receptor activator of NF-kappaB (RANK) and CD40 signals. Whereas only RANK signaling was essential for mTEC development during embryogenesis, in postnatal mice, cooperation between CD40 and RANK signals was required for mTEC development to successfully establish the medullary microenvironment. Ligation of RANK or CD40 on fetal thymic stroma in vitro induced mTEC development in a tumor necrosis factor-associated factor 6 (TRAF6)-, NF-kappaB inducing kinase (NIK)-, and IkappaB kinase beta (IKKbeta)-dependent manner. These results show that developmental-stage-dependent cooperation between RANK and CD40 promotes mTEC development, thereby establishing self-tolerance.