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Abstract Methionine adenosyltransferase 2 A (MAT2A) and MAT2B are essential for hepatic stellate cells (HSCs) activation. Forkhead box M1 (FOXM1) transgenic mice develop liver inflammation and fibrosis. Here we examine if they crosstalk in male mice. We found FOXM1/MAT2A/2B are upregulated after bile duct ligation (BDL) and carbon tetrachloride (CCl4) treatment in hepatocytes, HSCs and Kupffer cells (KCs). FDI-6, a FOXM1 inhibitor, attenuates the development and reverses the progression of CCl4-induced fibrosis while lowering the expression of FOXM1/MAT2A/2B, which exert reciprocal positive regulation on each other transcriptionally. Knocking down any of them lowers HSCs and KCs activation. Deletion of FOXM1 in hepatocytes, HSCs, and KCs protects from BDL-mediated inflammation and fibrosis comparably. Interestingly, HSCs from Foxm1 Hep−/−, hepatocytes from Foxm1 HSC−/−, and HSCs and hepatocytes from Foxm1 KC−/− have lower FOXM1/MAT2A/2B after BDL. This may be partly due to transfer of extracellular vesicles between different cell types. Altogether, FOXM1/MAT2A/MAT2B axis drives liver inflammation and fibrosis.

Abstract While physical reservoir computing is a promising way to achieve low power consumption neuromorphic computing, its computational performance is still insufficient at a practical level. One promising approach to improving its performance is deep reservoir computing, in which the component reservoirs are multi-layered. However, all of the deep-reservoir schemes reported so far have been effective only for simulation reservoirs and limited physical reservoirs, and there have been no reports of nanodevice implementations. Here, as an ionics-based neuromorphic nanodevice implementation of deep-reservoir computing, we report a demonstration of deep physical reservoir computing with maximum of four layers using an ion gating reservoir, which is a small and high-performance physical reservoir. While the previously reported deep-reservoir scheme did not improve the performance of the ion gating reservoir, our deep-ion gating reservoir achieved a normalized mean squared error of 9.08 × 10−3 on a second-order nonlinear autoregressive moving average task, which is the best performance of any physical reservoir so far reported in this task. More importantly, the device outperformed full simulation reservoir computing. The dramatic performance improvement of the ion gating reservoir with our deep-reservoir computing architecture paves the way for high-performance, large-scale, physical neural network devices.

Abstract Reservoir computing (RC) is a machine learning framework suitable for processing time series data, and is a computationally inexpensive and fast learning model. A physical reservoir is a hardware implementation of RC using a physical system, which is expected to become the social infrastructure of a data society that needs to process vast amounts of information. Ion-gating reservoirs (IGR) are compact and suitable for integration with various physical reservoirs, but the prediction accuracy and operating speed of redox-IGRs using WO3 as the channel are not sufficient due to irreversible Li+ trapping in the WO3 matrix during operation. Here, in order to enhance the computation performance of redox-IGRs, we developed a redox-based IGR using a (104) oriented LiCoO2 thin film with high electronic and ionic conductivity as a trap-free channel material. The subject IGR utilizes resistance change that is due to a redox reaction (LiCoO2 ⟺ Li1−x CoO2 + xLi+ + xe−) with the insertion and desertion of Li+. The prediction error in the subject IGR was reduced by 72% and the operation speed was increased by 4 times compared to the previously reported WO3, which changes are due to the nonlinear and reversible electrical response of LiCoO2 and the high dimensionality enhanced by a newly developed physical masking technique. This study has demonstrated the possibility of developing high-performance IGRs by utilizing materials with stronger nonlinearity and by increasing output dimensionality.

Background/Aims We aimed to investigate (1) promising clinical findings for the recognition of focal type autoimmune pancreatitis (FAIP) and (2) the impact of endoscopic ultrasound (EUS)-guided tissue acquisition (EUS-TA) on the diagnosis of FAIP. Methods Twenty-three patients with FAIP were involved in this study, and 44 patients with resected pancreatic ductal adenocarcinoma (PDAC) were included in the control group. Results (1) Multivariate analysis revealed that homogeneous delayed enhancement on contrast-enhanced computed tomography was a significant factor indicative of FAIP compared to PDAC (90% vs. 7%, p=0.015). (2) For 13 of 17 FAIP patients (76.5%) who underwent EUS-TA, EUS-TA aided the diagnostic confirmation of AIPs, and only one patient (5.9%) was found to have AIP after surgery. On the other hand, of the six patients who did not undergo EUS-TA, three (50.0%) underwent surgery for pancreatic lesions. Conclusions Homogeneous delayed enhancement on contrast-enhanced computed tomography was the most useful clinical factor for discriminating FAIPs from PDACs. EUS-TA is mandatory for diagnostic confirmation of FAIP lesions and can contribute to a reduction in the rate of unnecessary surgery for patients with FAIP.

Cachexia is a common cancer complication and is associated with weight loss and anorexia. In this study, we investigated the ameliorating effects of cystine and theanine on cancer cachexia using a mouse model. In mice carrying the colon cancer cell line C-26, there was a suppression of body weight increase and reduction in both internal fat and lower limb muscles. Repeated cystine and theanine administration significantly prevented weight loss, internal fat loss, lower limb muscle loss, and serum IL-6 increase in the cachexia model. These results suggested that cystine and theanine may be effective in ameliorating cancer cachexia.

Physical reservoir computing, which is a promising method for the implementation of highly efficient artificial intelligence devices, requires a physical system with nonlinearity, fading memory, and the ability to map in high dimensions. Although it is expected that spin wave interference can perform as highly efficient reservoir computing in some micromagnetic simulations, there has been no experimental verification to date. Herein, reservoir computing is demonstrated that utilizes multidetected nonlinear spin wave interference in an yttrium‐iron‐garnet single crystal. The subject computing system achieves excellent performance when used for hand‐written digit recognition, second‐order nonlinear dynamical tasks, and nonlinear autoregressive moving average (NARMA). It is of particular note that normalized mean square errors for NARMA2 and second‐order nonlinear dynamical tasks are 1.81 × 10−2 and 8.37 × 10−5, respectively, which are the lowest figures for any experimental physical reservoir so far reported. Said high performance is achieved with higher nonlinearity and the large memory capacity of interfered spin wave multidetection.

Background/Aims This study aimed to clarify the efficacy and safety of pancreatic duct lavage cytology combined with a cell-block method (PLC-CB) for possible pancreatic ductal adenocarcinomas (PDACs). Methods This study included 41 patients with suspected PDACs who underwent PLC-CB mainly because they were unfit for undergoing endoscopic ultrasonography-guided fine needle aspiration. A 6-Fr double lumen catheter was mainly used to perform PLC-CB. Final diagnoses were obtained from the findings of resected specimens or clinical outcomes during surveillance after PLC-CB. Results Histocytological evaluations using PLC-CB were performed in 87.8% (36/41) of the patients. For 31 of the 36 patients, final diagnoses (invasive PDAC, 12; pancreatic carcinoma in situ, 5; benignancy, 14) were made, and the remaining five patients were excluded due to lack of surveillance periods after PLC-CB. For 31 patients, the sensitivity, specificity, and accuracy of PLC-CB for detecting malignancy were 94.1%, 100%, and 96.8%, respectively. In addition, they were 87.5%, 100%, and 94.1%, respectively, in 17 patients without pancreatic masses detectable using endoscopic ultrasonography. Four patients developed postprocedural pancreatitis, which improved with conservative therapy. Conclusions PLC-CB has an excellent ability to detect malignancies in patients with possible PDACs, including pancreatic carcinoma in situ.

Objectives: The geriatric nutritional risk index (GNRI) is a nutrition-related risk index calculated easily from serum albumin and the ratio of body weight to ideal body weight. We investigated the prognostic values of the GNRI in elderly patients with obstructive colorectal cancer (OCRC) who had a self-expandable metallic stent inserted as a bridge to curative surgery. Methods: We retrospectively evaluated 61 patients aged 65 years with pathological stage I to III OCRC. Associations of preoperative GNRI and pre-stenting GNRI (ps-GNRI) with short- and long-term outcomes were examined. Results: Multivariate analyses revealed GNRI of

Herein, physical reservoir computing with a redox‐based ion‐gating reservoir (redox‐IGR) comprising LixWO3 thin film and lithium‐ion conducting glass ceramic (LICGC) is demonstrated. The subject redox‐IGR successfully solves a second‐order nonlinear dynamic equation by utilizing voltage pulse driven ion‐gating in a LixWO3 channel to enable reservoir computing. Under the normal conditions, in which only the drain current (ID) is used for the reservoir states, the lowest prediction error is 8.15 × 10−4. Performance is enhanced by the addition of IG to the reservoir states, resulting in a significant lowering of the prediction error to 5.39 × 10−4, which is noticeably lower than other types of physical reservoirs (memristors and spin torque oscillators) reported to date. A second‐order nonlinear autoregressive moving average (NARMA2) task, a typical benchmark of reservoir computing, is also performed with the IGR and good performance is achieved, with a normalized mean square error (NMSE) of 0.163. A short‐term memory task is performed to investigate an enhancement mechanism resulting from the IG addition. An increase in memory capacity, from 2.35 without IG to 3.57 with IG, is observed in the forgetting curves, indicating that enhancement of both high dimensionality and memory capacity is attributed to the origin of the performance improvement.

All-solid-state electric double layer transistors (ASS-EDLTs) have recently been attracting attention because of their huge potential for use in neuromorphic device applications. However, their low switching response speed is a significant drawback to their practical application. Here, we demonstrate ultrafast-switching of ASS-EDLTs, which was achieved by an excellent combination of hydrogenated diamond single crystal and a porous yttria stabilized zirconia thin film with extremely high proton conductivity. The switching response speed was investigated in response to gate voltage pulses. We achieved the ASS-EDLT that can operate at a very short response time of less than a hundred μs (i.e., 27 μs), even at room temperature. This is a far shorter time than that found in typical conventional ASS-EDLTs, which characteristically have response times measured in milliseconds or longer. Furthermore, the subject ASS-EDLT possessed characteristics that are similar to those of volatile memory devices. To demonstrate neuromorphic computing capability of the device, waveform transformation task has been performed. The results indicated that the ASS-EDLT, with its high operating speed, can contribute to the development of high-speed neuromorphic systems.

Physical reservoir computing (PRC) is useful for edge computing, although the challenge is to improve computational performance. In this study, we developed an inverted input method, the inverted input is additionally applied to a physical reservoir together with the original input, to improve the performance of the ion-gating reservoir. The error in the second-order nonlinear equation task was 7.3 × 10 ^−5 , the lowest error in reported PRC to date. Improvement of high dimensionality by the method was confirmed to be the origin of the performance enhancement. This inverted input method is versatile enough to enhance the performance of any other PRC.

Reservoir computing is a promising approach to implementing high-performance artificial intelligence that can process input data at lower computational costs than conventional artificial neural networks. Although reservoir computing enables real-time processing of input time-series data on artificial intelligence mounted on terminal devices, few physical devices are capable of high-speed operation for real-time processing. In this study, we introduce spin wave interference with a stepped input method to reduce the operating time of the physical reservoir, and second-order nonlinear equation task and second-order nonlinear autoregressive mean averaging, which are well-known benchmark tasks, were carried out to evaluate the operating speed and prediction accuracy of said physical reservoir. The demonstrated reservoir device operates at the shortest operating time of 13 ms/5000-time steps, compared to other compact reservoir devices, even though its performance is higher than or comparable to such physical reservoirs. This study is a stepping stone toward realizing an artificial intelligence device capable of real-time processing on terminal devices.

Abstract Background The efficacy of adjuvant chemotherapy for high-risk stage II colon cancer (CC) has not been well established. We compared the effects of surgery with and without oral uracil and tegafur plus leucovorin (UFT/LV) in patients with high-risk stage II CC, adjusting for potential risk factors. Methods We enrolled patients with histologically confirmed stage II colon adenocarcinoma with at least one of the following conditions: T4 disease, perforation/penetration, poorly differentiated adenocarcinoma/mucinous carcinoma, or

Objectives: Understanding the relationship between sarcopenia and malignancy is increasingly important since they inevitably affect the aging population. We investigated the clinical significance of sarcopenia in nonmetastatic obstructive colorectal cancer (OCRC) patients who were inserted self-expandable metallic stent and underwent curative surgery. Methods: Plain cross-sectional CT images obtained before stenting were retrospectively analyzed in 92 patients. Muscle volume loss (myopenia) and decreased muscle quality (myosteatosis) were evaluated as skeletal muscle index (SMI) and intramuscular adipose tissue content (IMAC), respectively. Results: This study included 54 men and 38 women, with a median age of 70.5 years. The median interval between SEMS placement and the surgery was 17 days (range, 5-47). There were 35 postoperative complications. The median postoperative hospital stay was 15.5 days (range, 8-77). Twenty-eight patients (41.3%) were classified as SMI-low, and 31 (34.1%) patients were classified as IMAC-high. In multivariate analysis, IMAC-high [hazard ratio (HR) = 7.68, 95% confidence interval (CI) 2.22-26.5, P = 0.001] and right-sided tumor (HR = 5.79, 95% CI 1.36-24.7, P = 0.018) were independent predictors of postoperative complications. IMAC-high (HR = 23.2, 95% CI 4.11-131, P < 0.001) and elevated modified Glasgow prognostic score (mGPS) (HR = 5.85, 95% CI 1.22-28.1, P = 0.027) were independent predictors of infectious complications. Relapse-free survival and overall survival were not significantly different regardless of the SMI or IMAC status. Conclusions: IMAC was associated with postoperative complications and infectious complications. Myosteatosis might be a stronger predictor of postoperative complications than myopenia.

The atomic scale switch, which operates on the principle of solid-state ionics, is an ultrafine device that takes advantage of the fact that the properties of materials can be changed significantly by the transport and chemical reaction of a small number of ions in a solid. The switch (e.g. ‘atomic switch’) actually works by using an ion-conducting solid electrolyte or an ion-/electron-conducting mixed-conductor as the device material, and by applying an external voltage to control local ion transport and electrochemical reaction. With the application of an external voltage, a bridge is formed as a conductive filament in the solid electrolyte or the mixed conductor between electrodes. The atomic structure of the point contact in said filament can be reversibly changed by precise control of the applied voltage. By controlling the atomic structure of the point contact, interesting functions are obtained, such as fast on/off resistive switching, switching between each state of quantized conductance and neuromorphic properties. This atomic scale switch has the potential to overcome the functional and performance limitations of conventional integrated circuits because it can be used in conjunction with extant semiconductor devices.

Objectives: It has been increasingly recognized that the progression of cancer is dependent not only on the tumor characteristics but also on the nutritious and inflammatory condition of the host. We investigated the relationship between the globulin-to-albumin ratio (GAR) and long-term outcomes in obstructive colorectal cancer (OCRC) patients who were inserted self-expandable metallic stent as a bridge to curative surgery. Methods: A total of 75 pathological stage II and III OCRC patients between 2013 and 2020 were retrospectively evaluated. The associations of the preoperative GAR with clinicopathological factors and patient survival were examined. Results: Receiver operating characteristic curve analysis demonstrated that the optimal cutoff value was 0.88. The GAR 0.88 status was significantly associated with the absence of lymph node metastasis (P = 0.011), longer postoperative hospital stay (17 days vs 15 days, P = 0.042), and not receiving adjuvant chemotherapy (P = 0.011). Relapse-free survival and cancer-specific survival were significantly shorter in the GAR 0.88 group (P = 0.007 and P = 0.023, respectively). Multivariate analyses revealed that the GAR 0.88 was independently associated with relapse-free survival [hazard ratio (HR) = 4.17, 95% confidence interval (CI) 1.32-13.14, P = 0.015)]. Moreover, CA19-9 37 (HR = 6.56, 95% CI 2.12-20.27, p = 0.001) and not receiving adjuvant chemotherapy (HR = 4.41, 95% CI 1.28-15.26, p = 0.019) were independent poor prognostic factors for relapse-free survival. Conclusions: The results demonstrated that the GAR was a significant prognostic factor for OCRC patients.

The effect of the electric double layer with solid electrolytes remains hard to characterize. In this study, the authors show how to evaluate the electric double layer effect with various lithium solid electrolytes using a hydrogenated diamond-based transistor.

Abstract A pancreatic β-cell line MIN6 was previously established in our lab from an insulinoma developed in an IT6 transgenic mouse expressing the SV40 T antigen in β-cells. This cell line has been widely used for in vitro analysis of β-cell function, but tends to lose the mature β-cell features, including glucose-stimulated insulin secretion (GSIS), in long-term culture. The aim of this study was to develop a stable β-cell line that retains the characteristics of mature β-cells. Considering that mice derived from a cross between C3H and C57BL/6 strains are known to exhibit higher insulin secretory capacity than C57BL/6 mice, an IT6 male mouse of this hybrid background was used to isolate insulinomas, which were independently cultured. After 7 months of continuous culturing, we obtained the MIN6-CB4 β-cell line, which stably maintains its GSIS. It has been noted that β-cell lines express the glucagon (Gcg) gene at certain levels. MIN6-CB4 cells were utilized to assess the effects of differential Gcg expression on β-cell function. Our data show the functional importance of Gcg expression and resulting basal activation of the GLP-1 receptor in β-cells. MIN6-CB4 cells can serve as an invaluable tool for studying the regulatory mechanisms of insulin secretion, such as the GLP-1/cAMP signaling, in β-cells.

MoS2 is a promising two-dimensional material for optoelectronics. Here, MoS2 phototransistors with a dual-functioning HfO2 dielectric and charge-trapping layer achieve a responsivity of 1.1×106, due to an enhanced photogating effect from band edge alignment with oxygen vacancies.

Artificial synapses capable of mimicking the fundamental functionalities of biological synapses are critical to the building of efficient neuromorphic systems. We have developed a H _x WO _3 -based artificial synapse that replicates such synaptic functionalities via an all-solid-state redox transistor mechanism. The subject synaptic-H _x WO _3 transistor, which operates by current pulse control, exhibits excellent synaptic properties including good linearity, low update variation and conductance modulation characteristics. We investigated the performance of the device under various operating conditions, and the impact of the characteristics of the device on artificial neural network computing. Although the subject synaptic-H _x WO _3 transistor showed an insufficient recognition accuracy of 66% for a handwritten digit recognition task with voltage pulse control, it achieved an excellent accuracy of 88% with current pulse control, which is approaching the 93% accuracy of an ideal synaptic device. This result suggests that the performance of any redox-transistor-type artificial synapse can be dramatically improved by current pulse control, which in turn paves the way for further exploration and the evolution of advanced neuromorphic systems, with the potential to revolutionize the artificial intelligence domain. It further marks a significant stride towards the realization of high-performance, low-power consumption computing devices.

In the present paper, development of an automatic spinach harvester is discussed. Our research group has been developing a prototype harvester and many filed tests have been successfully executed. The field test results show that spinach can be picked up automatically without being grasped after their roots being cut at specified position in soil. The harvester equips two degrees of freedom control units, such as the arm length control unit and the arm angle control unit, for controlling a root-cutting blade which follows the specified path under the ground. In the present paper, modeling and control design for the arm length control is discussed. First, a control design model is developed by several system identification techniques. Next, an I-PD controller is designed by the robust control design procedure. Control performance is verified by numerical simulations and field tests.

Stereocontrolled syntheses of biotin-labeled oligosaccharide portions containing the Galβ1-3GalNAc core of the TES-glycoprotein antigen obtained from larvae of the parasite Toxocara and their analogues have been accomplished. Trisaccharides Fuc2Meα1-2Gal4Meβ1-3GalNAcα1-OR (A), Fucα1-2Gal4Meβ1-3GalNAcα1-OR (B), Fuc2Meα1-2Galβ1-3GalNAcα1-OR (C), Fucα1-2Galβ1-3GalNAcα1-OR (D) and a disaccharide Fuc2Meα1-2Gal4Meβ1-OR (E) (R = biotinylated probe) were synthesized by block synthesis using 5-(methoxycarbonyl)pentyl-2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl-(1®3)-2-azide-4-O-benzyl-2-deoxy-α-D-galactopyranoside as a common glycosyl acceptor. We examined the antigenicity of these five oligosaccharides by enzyme linked immunosorbent assay (ELISA). Our results demonstrate that the O-methyl groups in these oligosaccharides are important for their antigenicity and the biotinylated oligosaccharides A, B, C and E have high serodiagnostic potential to detect infections caused by Toxocara larvae.

BACKGROUND: Cyclooxygenase-2 (COX-2) is a key enzyme in the conversion of arachidonic acid to prostanoids, and its activation is associated with carcinogenesis as well as inflammation. The antitumor effect of selective COX-2 inhibitors has been noted in various malignancies. Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue sarcoma for which effective treatments have not yet been established. The purpose of this study was to investigate a potential therapeutic role of COX-2 in MPNST. METHODS: We evaluated the expression of COX-2 in 44 cases of high-grade MPNST using immunohistochemical staining and compared the staining results with the characteristics and outcome of the patients. We also investigated the antitumor effect of etodolac, a selective COX-2 inhibitor, on MPNST cells in vitro using the MPNST cell line, FMS-1. RESULTS: Overexpression of COX-2 (≥50% positive cells) was observed in 29 cases (65.9%), was significantly associated with a poor overall survival (P = 0.0495), and was considered an independent risk factor for a poor outcome by the results of both univariate and multivariate analysis. Etodolac induced apoptosis of FMS-1 cells through the activation of caspase-8, -9, and -3. Moreover, several caspase inhibitors significantly inhibited etodolac-induced apoptosis. CONCLUSIONS: Selective COX-2 inhibitors including etodolac had an antitumor effect on MPNST cells, and their use holds promise as a novel therapeutic strategy for patients with MPNST to improve their prognoses.

In situ hard x-ray photoemission spectroscopy (HX-PES) and soft x-ray absorption spectroscopy (SX-XAS) have been employed to investigate a local redox reaction at the carbon/Gd-doped CeO2 (GDC) thin film heterointerface under applied dc bias. In HX-PES, Ce3d and O1s core levels show a parallel chemical shift as large as 3.2 eV, corresponding to the redox window where ionic conductivity is predominant. The window width is equal to the energy gap between donor and acceptor levels of the GDC electrolyte. The Ce M-edge SX-XAS spectra also show a considerable increase of Ce3+ satellite peak intensity, corresponding to electrochemical reduction by oxide ion migration. In addition to the reversible redox reaction, two distinct phenomena by the electrochemical transport of oxide ions are observed as an irreversible reduction of the entire oxide film by O2 evolution from the GDC film to the gas phase, as well as a vigorous precipitation of oxygen gas at the bottom electrode to lift off the GDC film. These in situ spectroscopic observations describe well the electrochemical polarization behavior of a metal/GDC/metal capacitor-like two-electrode cell at room temperature.

Background and study aims: Since more than a few patients having intraductal papillary mucinous neoplasms of the pancreas (IPMNs) with mural nodules (MNs) are benign, clinical plans should be determined by using histocytological specimens especially for those patients with high-risk for surgery or with a small MN. Patients and methods: This study included 27 patients to evaluate the efficacy of peroral pancreatoscopy using a SpyGlass DS system (POPS-DS) for patients with MN-positive IPMN, mainly focusing on the ability of POPS-DS to detect malignancy. Results: Biopsy specimens obtained under POPS-DS guidance could be used for the histological evaluations of all patients with MNs in the main pancreatic duct and 67% of the patients with MNs in the branch ducts, whereas fluid specimens collected during POPS-DS could be used for histocytological evaluations for all patients. For the 13 patients who underwent surgery just after POPS-DS, the sensitivity, specificity, and accuracy of POPS-DS to detect malignancy were 89%, 100%, and 92%, respectively. For the 12 patients who underwent surveillance without surgery, the cumulative 3-year progression rates for 9 benign IPMNs and 3 malignant ones determined using POPS-DS were 0% and 100%, respectively. However, the sensitivity of POPS to detect IPMN epithelium in the resection margin was 20%. Only one patient developed procedure-related pancreatitis (mild). Conclusions: POPS-DS could be used to accurately detect malignancy for patients with MN-positive IPMN. Therefore, histocytological evaluations using POPS-DS can contribute to the selection of patients for whom surgery would be appropriate.