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Simple Summary: As recurrence in glioblastoma is locally generated around the resection cavity, surviving glioma stem-like cells may cause recurrence. Glioma stem-like cells expressing high levels of CD44 are highly invasive and are required to change to less invasive, more proliferative types to generate a recurrent tumor. CD44 promotes both the invasion and proliferation of tumor cells via various signaling pathways. Among these, paired pathways show reciprocal activation of invasion and proliferation under different conditions of oxygenation. Severe hypoxia activates genes related to cell invasion, whereas moderate hypoxia activates genes related to cell proliferation. CD44 is associated with both pathways and plays a critical role in regulating the balance between the promotion of cell invasion and cell proliferation. These results may indicate that CD44 is a key molecule for executing tumor recurrence in glioblastoma. High invasiveness is a characteristic of glioblastoma (GBM), making radical resection almost impossible, and thus, resulting in a tumor with inevitable recurrence. GBM recurrence may be caused by glioma stem-like cells (GSCs) that survive many kinds of therapy. GSCs with high expression levels of CD44 are highly invasive and resistant to radio-chemotherapy. CD44 is a multifunctional molecule that promotes the invasion and proliferation of tumor cells via various signaling pathways. Among these, paired pathways reciprocally activate invasion and proliferation under different hypoxic conditions. Severe hypoxia (0.5–2.5% O2) upregulates hypoxia-inducible factor (HIF)-1α, which then activates target genes, including CD44, TGF-β, and cMET, all of which are related to tumor migration and invasion. In contrast, moderate hypoxia (2.5–5% O2) upregulates HIF-2α, which activates target genes, such as vascular endothelial growth factor (VEGF)/VEGFR2, cMYC, and cyclin D1. All these genes are related to tumor proliferation. Oxygen environments around GBM can change before and after tumor resection. Before resection, the oxygen concentration at the tumor periphery is severely hypoxic. In the reparative stage after resection, the resection cavity shows moderate hypoxia. These observations suggest that upregulated CD44 under severe hypoxia may promote the migration and invasion of tumor cells. Conversely, when tumor resection leads to moderate hypoxia, upregulated HIF-2α activates HIF-2α target genes. The phenotypic transition regulated by CD44, leading to a dichotomy between invasion and proliferation according to hypoxic conditions, may play a crucial role in GBM recurrence. [ABSTRACT FROM AUTHOR]

Recurrent glioblastoma multiforme (GBM) is largely attributed to peritumoral infiltration of tumor cells. As higher CD44 expression in the tumor periphery correlates with higher risk of GBM invasion, the present study analyzed the relationship between CD44 expression and magnetic resonance imaging (MRI)-based invasiveness of GBM on a large scale. We also quantitatively evaluated GBM invasion using 5-aminolevulinic acid (5-ALA) spectroscopy to investigate the relationship between CD44 expression and tumor invasiveness as evaluated by intraoperative 5-ALA intensity. Based on MRI, GBM was classified as high-invasive type in 28 patients and low-invasive type in 22 patients. High-invasive type expressed CD44 at a significantly higher level than low-invasive type and was associated with worse survival. To quantitatively analyze GBM invasiveness, the relationship between tumor density in the peritumoral area and the spectroscopic intensity of 5-ALA was investigated. Spectroscopy showed that the 5-ALA intensity of infiltrating tumor cells correlated with tumor density as represented by the Ki-67 staining index. No significant correlation between CD44 and degree of 5-ALA-based invasiveness of GBM was found, but invasiveness of GBM as evaluated by 5-ALA matched the classification from MRI in all except one case, indicating that CD44 expression at the GBM periphery could provide a reliable biomarker for invasiveness in GBM. [ABSTRACT FROM AUTHOR]

The Kelch-like ECH-associated protein 1–nuclear factor erythroid 2-related factor 2 (KEAP1–NRF2) system plays a central role in redox homeostasis and inflammation control. Oxidative stress or electrophilic compounds promote NRF2 stabilization and transcriptional activity by negatively regulating its inhibitor, KEAP1. We have previously reported that bromovalerylurea (BU), originally developed as a hypnotic, exerts anti-inflammatory effects in various inflammatory disease models. However, the molecular mechanism underlying its effect remains uncertain. Herein, we found that by real-time multicolor luciferase assay using stable luciferase red3 (SLR3) and green-emitting emerald luciferase (ELuc), BU potentiates NRF2-dependent transcription in the human hepatoblastoma cell line HepG2 cells, which lasted for more than 60 h. Further analysis revealed that BU promotes NRF2 accumulation and the transcription of its downstream cytoprotective genes in the HepG2 and the murine microglial cell line BV2. Keap1 knockdown did not further enhance NRF2 activity, suggesting that BU upregulates NRF2 by targeting KEAP1. Knockdown of Nfe2l2 in BV2 cells diminished the suppressive effects of BU on the production of pro-inflammatory mediators, like nitric oxide (NO) and its synthase NOS2, indicating the involvement of NRF2 in the anti-inflammatory effects of BU. These data collectively suggest that BU could be repurposed as a novel NRF2 activator to control inflammation and oxidative stress. [ABSTRACT FROM AUTHOR]

Activated microglia potentially cause neurodegeneration in Parkinson's disease (PD). Matrix metalloproteinase (MMP)-9 plays a crucial role in the pathogenesis of PD, but the modulator of microglial release of MMP-9 remains obscure. Given the modulatory effect of chloride intracellular channel protein 2 (CLIC2) on MMPs, we aimed to determine the role of CLIC2 in regulating microglial MMP expression and activation. We found that CLIC2 is expressed in microglia and neurons in rat brain tissue and focused on the function of CLIC2 in primary cultured microglia. Exposure to recombinant CLIC2 protein enhanced microglial invasion activity, and its knockdown abolished this activity. Moreover, increased activation of MMP-9 was confirmed by the addition of the CLIC2 protein, and CLIC2 knockdown eliminated this activation. Additionally, increased expression of CLIC2 was observed in PD-modeled tissue. In conclusion, CLIC2 increases MMP-9 activity in the microglia, which are involved in PD pathogenesis. [ABSTRACT FROM AUTHOR]

Background: Increased extracellular glutamate is known to cause epileptic seizures in patients with glioblastoma (GBM). However, predicting whether the seizure will be refractory is difficult. The present study investigated whether evaluation of the levels of various metabolites, including glutamate, can predict the occurrence of refractory seizure in GBM by quantitative measurement of metabolite concentrations on magnetic resonance spectroscopy (MRS). Methods: Forty patients were treated according to the same treatment protocol for primary GBM at Ehime University Hospital between April 2017 and July 2021. Of these patients, 23 underwent MRS to determine concentrations of metabolites, including glutamate, N-acetylaspartate, creatine, and lactate, in the tumor periphery by applying LC-Model. The concentration of each metabolite was expressed as a ratio to creatine concentration. Patients were divided into three groups: Type A, patients with no seizures; Type B, patients with seizures that disappeared after treatment; and Type C, patients with seizures that remained unrelieved or appeared after treatment (refractory seizures). Relationships between concentrations of metabolites and seizure types were investigated. Results: In 23 GBMs, seizures were confirmed in 11 patients, including Type B in four and Type C in seven. Patients with epilepsy (Type B or C) showed significantly higher glutamate and N-acetylaspartate values than did non-epilepsy patients (Type A) (p < 0.05). No significant differences in glutamate or N-acetylaspartate levels were seen between Types B and C. Conversely, Type C showed significantly higher concentrations of lactate than did Type B (p = 0.001). Cutoff values of lactate-to-creatine, glutamate-to-creatine, and N-acetylaspartate-to-creatine ratios for refractory seizure were > 1.25, > 1.09, and > 0.88, respectively. Conclusions: Extracellular concentrations of glutamate, N-acetylaspartate, and lactate in the tumor periphery were significantly elevated in patients with GBM with refractory seizures. Measurement of these metabolites on MRS may predict refractory epilepsy in such patients and could be an indicator for continuing the use of antiepileptic drugs. [ABSTRACT FROM AUTHOR]

Sepsis is a pathology accompanied by increases in myeloid cells and decreases in lymphoid cells in circulation. In a murine sepsis model induced by cecum ligation and puncture (CLP), increasing numbers of neutrophils and decreasing levels of B-cells in circulation are among the earliest changes in the immune system. However, to date, the mechanisms for these changes remain to be elucidated. The study here sought to elucidate mechanisms underlying the changes in the leukocyte levels after CLP and also to determine what, if any, role for an involvement of the sympathetic nervous system (SNS). Here, male C57/BL6 mice were subjected to CLP or sham-CLP (abdominal wall incised, but cecum was not punctured). The changes in the number of circulating leukocytes over time were then investigated using flow cytometry. The results showed that a sham-CLP led to increased polymorphonuclear cells (PMN; most of which are neutrophils) and decreased B-cells in the circulation to an extent similar to that induced by CLP. Effects of adrenergic agonists and antagonists, as well as of adrenalectomy, were also examined in mice that underwent CLP or sham-CLP. Administering adrenaline or a β2 adrenergic receptor agonist (clenbuterol) to mice 3 h before sacrifice produced almost identical changes to as what was seen 2 h after performing a sham-CLP. In contrast, giving a β2 adrenergic receptor antagonist ICI118,551 1 h before a CLP or sham-CLP suppressed the expected changes 2 h after the operations. Noradrenaline and an α1 adrenergic receptor agonist phenylephrine did not exert significant effects. Adrenalectomy 24 h before a sham-CLP significantly abolished the expected sham-CLP-induced changes seen earlier. Clenbuterol increased splenocyte expression of Cxcr4 (a chemokine receptor gene); adrenalectomy abolished sham-CLP-induced Cxcr4 expression. A CXCR4 antagonist AMD3100 repressed the sham-CLP-induced changes. From these results, it may be concluded that sepsis-induced activation of the SNS may be one cause for immune dysfunction in sepsis – regardless of the pathogenetic processes. [ABSTRACT FROM AUTHOR]

In addition to genetic factors, environmental factors play a role in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). This study used Lister hooded rats (LHRs) as ADHD model animals to evaluate the effects of environmental factors. Male LHR pups were kept in four rearing conditions from postnatal day 23 (4 rats in a standard cage; 12 rats in a large flat cage; and 4 or 12 rats in an enriched environment [EE]) until 9 weeks of age. EE rearing but not rearing in a large flat cage decreased the activity of LHRs in the open field test that was conducted for 7 consecutive days. In the drop test, most rats reared in an EE remained on a disk at a height, whereas most rats reared in a standard cage fell off. RNA sequencing revealed that the immediate-early gene expression in the medial prefrontal cortex of LHRs reared in an EE was reduced. cFos-expressing neurons were reduced in number in LHRs reared in an EE. These results suggest that growing in an EE improves ADHD-like behaviors and that said improvement is due to the suppression of neuronal activity in the mPFC. [ABSTRACT FROM AUTHOR]

Background Schizophrenia is a mental disorder caused by both environmental and genetic factors. Prenatal exposure to antipsychotics, an environmental factor for the fetal brain, induces apoptotic neurodegeneration and cognitive impairment of offspring similar to schizophrenia. The aim was to investigate molecular biological changes in the fetal hippocampus exposed to haloperidol (HAL) by RNA expression as a model of the disorder. Methods HAL (1 mg/kg/d) was administered to pregnant mice. Upregulated and downregulated gene expressions in the hippocampus of offspring were studied with RNA-sequencing and validated with the qPCR method, and micro-RNA (miR) regulating mRNA expressional changes was predicted by in silico analysis. An in vitro experiment was used to identify the miRNA using a dual-luciferase assay. Results There were significant gene expressional changes (1370 upregulated and 1260 downregulated genes) in the HAL group compared with the control group on RNA-sequencing analysis (P  < .05 and q < 0.05). Of them, the increase of Nr3c1 mRNA expression was successfully validated, and in silico analysis predicted that microRNA-137-3p (miR-137-3p) possibly regulates that gene's expression. The expression of miR-137-3p in the hippocampus of offspring was significantly decreased in the first generation, but it increased in the second generation. In vitro experiments with Neuro2a cells showed that miR-137-3p inversely regulated Nr3c1 mRNA expression, which was upregulated in the HAL group. Conclusions These findings will be key for understanding the impact of the molecular biological effects of antipsychotics on the fetal brain. [ABSTRACT FROM AUTHOR]

Simple Summary: Although chloride intracellular channel proteins (CLICs) have been identified as ion channel proteins, their true functions are still elusive. Recent in silico analyses show that CLICs may be prognostic markers in cancer. This review focuses on CLIC2 that plays preventive roles in malignant cell invasion and metastasis. CLIC2 is secreted extracellularly and binds to matrix metalloproteinase 14 (MMP14), while inhibiting its activity. As a result, CLIC2 may contribute to the development/maintenance of junctions between blood vessel endothelial cells and the inhibition of invasion and metastasis of tumor cells. CLIC2 may be a novel therapeutic target for malignancies. CLICs are the dimorphic protein present in both soluble and membrane fractions. As an integral membrane protein, CLICs potentially possess ion channel activity. However, it is not fully clarified what kinds of roles CLICs play in physiological and pathological conditions. In vertebrates, CLICs are classified into six classes: CLIC1, 2, 3, 4, 5, and 6. Recently, in silico analyses have revealed that the expression level of CLICs may have prognostic significance in cancer. In this review, we focus on CLIC2, which has received less attention than other CLICs, and discuss its role in the metastasis and invasion of malignant tumor cells. CLIC2 is expressed at higher levels in benign tumors than in malignant ones, most likely preventing tumor cell invasion into surrounding tissues. CLIC2 is also expressed in the vascular endothelial cells of normal tissues and maintains their intercellular adhesive junctions, presumably suppressing the hematogenous metastasis of malignant tumor cells. Surprisingly, CLIC2 is localized in secretory granules and secreted into the extracellular milieu. Secreted CLIC2 binds to MMP14 and inhibits its activity, leading to suppressed MMP2 activity. CLIC4, on the other hand, promotes MMP14 activity. These findings challenge the assumption that CLICs are ion channels, implying that they could be potential new targets for the treatment of malignant tumors. [ABSTRACT FROM AUTHOR]

This study proposes a stock handling system that combines an automatic shelf and a picking robot with the aim of reducing the labor required for stocking and disposing of items. The robot system was developed by referring to the rules of the robot competition WRS2020 F.C.S.C. The picking robot is a standard single-arm mobile manipulation robot and the automatic shelf is characterized by the fact that the shelves move up and down and back and forth automatically. Automatic movement of the shelves in the pull-out direction allows the end-effector of the manipulator to approach the item from above and select the grasping position from a number of candidates. This improves the stability of the grasping of the item and is expected to prevent the item from falling during transportation. When there are tall items at the front of the shelf, the end-effector can directly approach the items at the back of the shelf from above the shelf as the shelf plate automatically moves in the pull-out direction. We report the mechanical configuration of the automatic shelf and basic experimental results for stocking and disposal work by the proposed robot system. [ABSTRACT FROM AUTHOR]

Background: Eosinophilic enteritis is a chronic inflammatory disorder of the intestinal tract that is characterized by eosinophil infiltration. Cytomegalovirus (CMV), a common virus, has a broad infectivity range. CMV is retained in the host body after infection. Impairment of host immune defences may reactivate the latent CMV, leading to symptoms of overt disease.Case Presentation: A Japanese female in her 70 s was admitted to a hospital due to diarrhoea and then transferred to our hospital. Laboratory data showed hypoalbuminemia. Computed tomography (CT) revealed oedema of the small intestine. Lower gastrointestinal endoscopy revealed oedema of the submucosa, without any remarkable changes in the mucosa of the terminal ileum. Histological examination of the terminal ileum revealed infiltration of > 20 eosinophils per high-power field (HPF). These findings aided in diagnosing eosinophilic enteritis. We administered methylprednisolone (500 mg/day) for three days, followed by tapering prednisolone. However, the patient's general condition and hypoalbuminemia failed to improve. Immunoglobulin (Ig) G- CMV and IgM-CMV tests were positive. CMV antigenemia was extremely high. Therefore, we administered ganciclovir intravenously, which improved the patient's condition. Furthermore, azathioprine was administered to taper and discontinue prednisolone without relapse of eosinophilic enteritis. This treatment helped stabilize the patient's condition for approximately four years.Conclusion: We present a case of eosinophilic enteritis accompanied by CMV disease during prednisolone treatment. The patient's condition improved after administration of ganciclovir. Azathioprine aided in discontinuing prednisolone and stabilizing the patient's condition for approximately four years. [ABSTRACT FROM AUTHOR]

We propose a vacuum end effector with an expansion and contraction mechanism to realize a picking task for objects placed in a narrow space, such as a shelf. The proposed expansion and contraction mechanism consists of a tube and exoskeleton structure and is characterized by the use of a thin metal plate wound about itself to form a tubular exoskeleton. Expansion and contraction motions were realized by connecting the tube to a linear motion mechanism. The expansion and contraction mechanism can be easily extended by elastic force. In addition, the shape of the expansion and contraction mechanism is created by winding a thin metal plate around a predetermined axis, which ensures high rigidity even in the extended state. Even when an object to be picked from a shelf is located behind other objects, the end effector can efficiently hold the object because of its elongated shape and ability to freely change the position of the suction pad using a direction-changing linkage and the expansion and contraction mechanism. The developed end effector weighs about 1.46 kg and can carry a load of 0.56 kg when extended to 150 mm. Verification of the mechanism confirmed that the developed end effector is useful because it can perform the expected object-picking operation. [ABSTRACT FROM AUTHOR]

Aiming to expand the range of applications for parallel grippers, we propose an extension nail mechanism that can be mounted on a parallel gripper. We also propose an extension nail mechanism comprising a stainless steel belt, two transport belts, a triangular nail, and a drive unit. The triangular nail is connected to one end of the stainless steel belt, and the drive unit is connected near the other end. We achieve smooth sliding of the nails underneath objects by arranging the transport belts on either side of the stainless steel belt. By elastically winding one end of the stainless steel belt and each of the transport belts, the nail mechanism can be miniaturized while achieving large expansion and contraction. We achieve stable grasping operations by using the extension nail mechanism of the parallel gripper in accordance with the flexibility of the object. [ABSTRACT FROM AUTHOR]

We synthesized a series of phosphine–olefin-type chiral aminophosphines, and we confirmed that these each exists as two rotamers at the C(aryl)–N(amine) bond. We also investigated the ability of these aminophosphines to act as chiral ligands for Pd-catalyzed asymmetric allylic substitution reactions, such as the alkylation of allylic acetates with malonates or indoles, and we found they gave high enantio-selectivities (up to 98% ee). [ABSTRACT FROM AUTHOR]

Antiangiogenic therapy with bevacizumab (Bev), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), is a common treatment for recurrent glioblastoma (GBM), but its survival benefit is limited. Resistance to Bev is thought to be a major cause of ineffectiveness on Bev therapy. To optimize Bev therapy, identification of a predictive biomarker for responsiveness to Bev is required. Based on our previous study, we focused on the expression and functions of CD44 and VEGF in the Bev therapy. Here, we analyze a relationship between CD44 expression and responsiveness to Bev and elucidate the role of CD44 in anti‐VEGF therapy. CD44 and VEGF expression in the tumor core and periphery of 22 GBMs was examined, and the relationship between expression of these molecules and progression‐free time on Bev therapy was analyzed. The degree of CD44 expression in the tumor periphery was evaluated by the ratio of the mRNA expression in the tumor periphery to that in the tumor core (P/C ratio). VEGF expression was evaluated by the amount of the mRNA expression in the tumor periphery. To elucidate the roles of CD44 in the Bev therapy, in vitro and in vivo studies were performed using glioma stem‐like cells (GSCs) and a GSC‐transplanted mouse xenograft model, respectively. GBMs expressing high P/C ratio of CD44 were much more refractory to Bev than those expressing low P/C ratio of CD44, and the survival time of the former was much shorter than that of the latter. In vitro inhibition of VEGF with siRNA or Bev‐activated CD44 expression and increased invasion of GSCs. Bev showed no antitumor effects in mice transplanted with CD44‐overexpressing GSCs. The P/C ratio of CD44 expression may become a useful biomarker predicting responsiveness to Bev in GBM. CD44 reduces the antitumor effect of Bev, resulting in much more highly invasive tumors. [ABSTRACT FROM AUTHOR]

A volcanic slope in Izu Oshima Island in Japan experienced a profound rain-induced disaster in October 2013. Since this slope had been stable for centuries except for minor failures, a special investigation was carried out on the cause. Because of its volcanic origin, the failed slope consisted of layers of ash, sand and lava. While the investigation concerned many disciplines, the present paper addresses one part of the geotechnical studies. The particular emphasis was put on the reason why some part of the slope "did not" fail because the post-disaster construction of infrastructures in the affected area relied on the future stability of the affected mountain slope. In line with this, another focus of the study was on the geohydrological feature of the underlying lava layer that possibly controlled the instability of the volcanic slope. It was concluded finally that the lava layer is pervious and allows drainage of infiltrated rainwater and that, only during extremely heavy rain, the subsurface lava topography triggered slope failure only in its "valley" parts. For 7 years after the disaster, the remaining parts of the slope have been stable as judged and many local infrastructures have been reconstructed. [ABSTRACT FROM AUTHOR]

We propose a robotic finger with an exoskeleton-type structure that bends and extends by the deformation force of flat tubes. Our objective is to realize a disposable robot hand for gripping unsanitary objects. To reduce the cost of disposing of the robotic finger, a commercially available cable carrier chain was used for the exoskeleton component, and the flat tubes used in the pneumatic actuator were prepared by thermal processing of a commercially available tube. The driving joint of the robotic finger consists of a hollow link mechanism and two flat tubes, which are respectively arranged inside the hollow link mechanism and at the joint boundary. The proposed joint structure achieves both smooth drivability and good load-bearing capacity. The developed robotic finger weighs approximately 85 g and generates a fingertip force of approximately 4 N when a pressure of 0.25 MPa is applied. Because the developed robotic finger is pneumatically driven, it conforms to the object shape and is compliant to external force. Verification of the mechanism demonstrated that the developed robotic finger is useful because it was able to grasp six types of assumed objects. [ABSTRACT FROM AUTHOR]

Objectives: The secretory enzyme lysyl oxidase like 2 (LOXL2) is speculated to contribute to tumor progression through its functions in the remodeling of extracellular matrix and epithelial-mesenchymal transition. We previously identified elevated expression of LOXL2 in metastatic human head and neck squamous cell carcinoma (HNSCC) cells in a mouse lymph node metastases model. Here we performed a case series study examining LOXL2 expression levels in human serum from HNSCC patients to evaluate whether LOXL2 is worth evaluation in a large cohort study.Methods: LOXL2 protein levels in three serum samples from HNSCC patients were assessed by immunoblotting and LOXL2 tissue expression was examined in one human tongue squamous cell carcinoma (SCC) tissue by immunohistochemistry as a representative of HNSCC tissue. Serum samples were further fractionated in exosomes and supernatants by ultracentrifugation, which were then subjected to immunoblot and in vitro LOX activity analyses. Exosomal LOXL2 levels of 36 serum samples from HNSCC patients and seven healthy volunteers were measured using polymer sedimentation exosome preparation followed by ELISA measurement and subjected to statistical analyses.Results: Immunoblot analyses revealed that LOXL2 was present in serum exosomal fractions from three HNSCC patients, and we observed approximately threefold higher levels of LOXL2 in HNSCC patients compared with three healthy volunteers. Immunohistochemical LOXL2 staining was detected in HNSCC cells in addition to non-cancerous lipid tissues and some muscles in human tongue HNSCC tissue. Further measurements of exosomal LOXL2 by ELISA showed over ninefold higher mean LOXL2 levels in patients compared with controls. Statistical analysis revealed a correlation between elevated serum exosomal LOXL2 levels and low-grade, but not high-grade, HNSCC.Conclusions: Our case series study that elevated serum exosomal LOXL2 levels exhibited a correlation with low-grade HNSCCs. A follow-up large cohort clinical study will be required to determine the potential clinical utility of LOXL2 as a new biomarker and/or therapy target for HNSCCs.Level Of Evidence: 4 Laryngoscope, 130:E327-E334, 2020. [ABSTRACT FROM AUTHOR]

This paper proposes a portable compact suction pad unit for the parallel grippers of a mobile manipulation robot to place items for product display. In addition, this paper includes verification of the unit's mechanism. Given that robots have to hold various items, we propose an operation method by which the parallel gripper holding the compact suction pad unit switches between a pinching mode and a vacuum suction mode depending on the item being placed. The compact suction pad unit is self-contained, with all the devices necessary for the suction operation inside the unit. The suction operation is switched on and off wirelessly by an external host system controller. The compact suction pad unit produced a suction force of about 5.6 N at an allowable inclination angle of 15°. We demonstrated in a competition that our proposed operation method of the compact suction pad unit is useful by having it place a beverage in a cup with lid and a boxed lunch. [ABSTRACT FROM AUTHOR]

This paper describes a vacuum suction-type end effector for depalletizing robots in distribution centers. The developed end effector has multiple suction pad units to which a bellows pneumatic actuator is applied as the support mechanism. Load-bearing capacity is improved due to a high-strength wire provided inside the bellows, and the contraction force is improved due to ring members placed inside of the ridges of the rubber bellows. The developed end effector is attached to the arm of a linear motion-type depalletizing robot, and its real-world performance is verified. Verification results confirm that the suction pad units tolerate cardboard box inclination and differences in box height by a simple lowering motion of the arm, and multiple cardboard boxes can be simultaneously unloaded. Moreover, as compared with conventional end effectors, the developed end effector achieves large expansion and contraction in a thin structure. The developed end effector is expected to broaden applications for depalletizing robots. [ABSTRACT FROM AUTHOR]

To improve noise and vibration of Electric Power Steering (EPS) system, we focus on the reduction of the sixth‐order radial force of an EPS motor by regulating its harmonic current. Because an EPS system is operated in a wide speed range, a reduction method is required to work even for dynamic motor speed. In this article, we introduce our method and report its test result to show the reduction of sixth‐order radial vibration of an EPS motor. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most aggressive malignant brain tumor and a subpopulation of glioma stem-like cells (GSCs) is likely responsible for the invariable recurrence following maximum resection and chemoradiotherapy. As most GSCs that are located in the perivascular and perinecrotic niches should be removed during tumor resection, it is very important to know where surviving GSCs are localized. Here, we investigated the existence and functions of GSCs in the tumor periphery, which is considered to constitute the invasion niche for GSCs in GBM, by analyzing expression of stem cell markers and stem cell-related molecules and measuring particular activities of cultured GSCs. In addition, the relationship between GSCs expressing particular stem cell markers and pathological features on MRI and prognosis in GBM patients was analyzed. We showed that GSCs that express high levels of CD44 are present in the tumor periphery. We also found that vascular endothelial growth factor (VEGF) is characteristically expressed at a high level in the tumor periphery. Cultured GSCs obtained from the tumor periphery were highly invasive and have enhanced migration phenotype, both of which were markedly inhibited by CD44 knockdown. Higher expression of CD44 in the tumor periphery than in the core was correlated with a highly invasive feature on MRI and was associated with early tumor progression and worse survival, whereas lower expression of CD44 in the tumor periphery corresponded to low invasion and was associated with longer survival. The low invasion type on MRI tended to show high levels of VEGF expression in the tumor periphery, thus presenting the tumor with high proliferative activity. These results imply the significance of GSCs with high levels of CD44 expression in the tumor periphery compared to the core, not only in tumor invasion but also rapid tumor progression and short survival in patients with GBM. [ABSTRACT FROM AUTHOR]

Levels of high mobility group box 1 (HMGB1), an important inflammatory mediator, are high in the serum of febrile seizure (FS) patients. However, its roles in FS and secondary epilepsy after prolonged FS are poorly understood. We demonstrate HMGB1's role in the pathogenesis of hyperthermia-induced seizures (HS) and secondary epilepsy after prolonged hyperthermia-induced seizures (pHS). In the first experiment, 14-15-day-old male rats were divided into four groups: high-dose HMGB1 (100 μg), moderate-dose (10 μg), low-dose (1 μg), and control. Each rat was administered HMGB1 intranasally 1 h before inducing HS. Temperature was measured at seizure onset with electroencephalography (EEG). In the second experiment, 10-11-day-old rats were divided into four groups: pHS + HMGB1 (10 μg), pHS, HMGB1, and control. HMGB1 was administered 24 h after pHS. Video-EEGs were recorded for 24 h at 90 and 120 days old; histological analysis was performed at 150 days old. In the first experiment, the temperature at seizure onset was significantly lower in the high- and moderate-dose HMGB1 groups than in the control group. In the second experiment, the incidence of spontaneous epileptic seizure was significantly higher in the pHS + HMGB1 group than in the other groups. Comparison between pHS + HMGB1 groups with and without epilepsy revealed that epileptic rats had significantly enhanced astrocytosis in the hippocampus and corpus callosum. In developing rats, HMGB1 enhanced HS and secondary epilepsy after pHS. Our findings suggest that HMGB1 contributes to FS pathogenesis and plays an important role in the acquired epileptogenesis of secondary epilepsy associated with prolonged FS. [ABSTRACT FROM AUTHOR]

Blood vessels in brain tumors, particularly glioblastomas, have been shown to express CD90. CD90+ cells in and around blood vessels in cancers including brain tumors have been identified as endothelial cells, cancer stem cells, fibroblasts or pericytes. In this study, we aimed to determine the nature or type(s) of cells that express CD90 in human brain tumors as well as an experimental rat glioma model by double immunofluorescence staining. The majority of CD90+ cells in human glioblastoma tissue expressed CD31, CD34 and von Willebrand factor, suggesting that they were endothelial cells. Vasculatures in a metastatic brain tumor and meningioma also expressed CD90. CD90+ cells often formed glomeruloid structures, typical of angiogenesis in malignant tumors, not only in glioblastoma but also in metastatic tumors. Some cells in the middle and outer layers of the vasculatures expressed CD90. Similar results were obtained in the rat glioma model. There were cells expressing both α-smooth muscle actin and CD90 in the middle layer of blood vessels, indicating that smooth muscle cells and/or pericytes may express CD90. CD90+ vasculatures were surrounded by tumor-associated macrophages (TAMs). Thus, in addition to endothelial cells, some other types of cells, such as smooth muscle cells, pericytes and fibroblasts constituting the vasculature walls in brain tumors expressed CD90. Because CD90 has been shown to interact with integrins expressed by circulating monocytes, CD90 might be involved in angiogenesis through recruitment and functional regulation of TAMs in tumors. CD90+ vasculatures may also interact with tumor cells through interactions with integrins. Because CD90 was not expressed by vasculatures in normal brain tissue, it might be a possible therapeutic target to suppress angiogenesis and tumor growth. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that the expression level of Oct-3/4, a self-renewal regulator in stem cells, is positively correlated with the progression of various solid tumors. However, little is known regarding the influence of Oct-3/4 in the tumor angiogenesis of glioblastomas. In the present study, we subcutaneously transplanted Oct-3/4-overexpressing human glioblastoma U251 (U251/EGFP-Oct-3/4) cells into the right thighs of nude mice to evaluate the roles of Oct-3/4 in the tumor angiogenesis. Both tumor size and the number of large vessels growing in the tumor were markedly increased. In an in vitro model of angiogenesis, the conditioned media from U251/EGFP-Oct-3/4 cells significantly accelerated capillary-like tube formation compared with that of U251/EGFP cells. In comparison with U251/EGFP cells, U251/EGFP-Oct-3/4 cells had markedly elevated the expression of vascular endothelial growth factor mRNA under the control of hypoxia-inducible factor (HIF) 1α. In U251/EGFP-Oct-3/4 cells, enhanced protein expression and nuclear translocation of HIF1α were observed. Furthermore, we demonstrated that the involvement of AKT, an oncogenic signaling molecule, in the Oct-3/4 induced upregulation of HIF1α protein. Our findings suggest that Oct-3/4-expressing glioblastoma cells have the ability to adapt to low-oxygen environments within tumor masses by promoting tumor angiogenesis through AKT-HIF1 pathway. [ABSTRACT FROM AUTHOR]

It is possible to examine bilateral primary motor cortex (M1) activation during a sustained motor task using near-infrared spectroscopy (NIRS), in which it is assumed that increased oxygenation reflects cortical activation. The purpose of this study was to examine bilateral M1 activation in response to graded levels of force production during a unilateral finger task. Ten healthy right-handed male subjects participated in this study. NIRS probes were placed over the cortex to measure M1 activity while the subjects performed the finger task. The subjects performed a 10 s finger task at 20%, 40%, and 60% of the maximal voluntary contraction (MVC). Symmetrical activation was found over both M1 areas at all force levels investigated. In the contralateral M1, there were significant differences in oxygenation between 20% and 60% MVC, as well as between 40% and 60% MVC. In the ipsilateral M1, there were significant differences among all force levels. These results indicate the ipsilateral M1 takes part in muscle force control. [ABSTRACT FROM AUTHOR]

Febrile seizures (FS) is the most common convulsive disorder in children, but there have been no clinical and experimental studies of the possible treatment of FS with herbal medicines, which are widely used in Asian countries. Paeoniflorin (PF) is a major bioactive component of Radix Paeoniae alba, and PF- containing herbal medicines have been used for neuromuscular, neuropsychiatric, and neurodegenerative disorders. In this study, we analyzed the anticonvulsive effect of PF and Keishikashakuyaku-to (KS; a PF-containing herbal medicine) for hyperthermia-induced seizures in immature rats as a model of human FS. When immature (P5) male rats were administered PF or KS for 10 days, hyperthermia- induced seizures were significantly suppressed compared to control rats. In cultured hippocampal neurons, PF suppressed glutamate-induced elevation of intracellular Ca2+ ([Ca2+]i), glutamate receptor-mediated membrane depolarization, and glutamate-induced neuronal death. In addition, PF partially suppressed the elevation in [Ca2+]i induced by activation of the metabotropic glutamate receptor 5 (mGluR5), but not that mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid (AMPA) or N-methyl-D-aspartate (NMDA) receptors. However, PF did not affect production or release of γ-aminobutyric acid (GABA) in hippocampal neurons. These results suggest that PF or PF-containing herbal medicines exert anticonvulsive effects at least in part by preventing mGluR5-dependent [Ca2+]i elevations. Thus, it could be a possible candidate for the treatment of FS in children. [ABSTRACT FROM AUTHOR]

This report describes synthesis of binary BiTe and ternary BiSbTe single crystals using the halide chemical vapor transport technique. For synthesis of ternary BiSbTe, BiBr is a more effective transport agent compared with iodine I. The single crystal includes a few atomic percent of Br. The BiSbTe crystal shows p-type conduction and has a comparatively large residual resistivity ratio. The crystal exhibits relatively high electrical resistivity and high Seebeck coefficient. These high values are attributed to decrease of the hole concentration p due to doping of the transport agent Br. [ABSTRACT FROM AUTHOR]

Purpose: Thymic stromal lymphopoietin (TSLP) is released by intestinal epithelial cells (IECs), and TSLP-conditioned dendritic cells appear to be involved in immune homeostasis of intestine and immunoglobulin A (IgA) class-switching in the physiological condition. In contrast, TSLP activates dendritic cells to induce strong T-cell proliferation and is involved in inflammatory T helper (Th) 2 responses in human allergic diseases. However, it is not clear how TSLP production by IECs is regulated in ulcerative colitis (UC), which appears to involve inflammatory Th2 responses. The aim of this study is to examine how TSLP production by IECs is regulated in ulcerative colitis.Results: We show here that expression of TSLP was enhanced in mucosal lesions from UC patients in which inflammatory Th2 cytokine production was predominant. In addition, using a human colonic epithelial cell line, we demonstrated that a combination of tumor necrosis factor-alpha (TNF-alpha) and interleukin-4 (IL-4) induced TSLP expression and that TSLP expression by TNF-alpha + IL-4 was further enhanced by either Toll-like receptor 3 ligand or interferon (IFN)-gamma.Conclusions: Taken together, as in human allergic diseases, an inflammatory Th2 condition in the mucosal lesions of UC patients may trigger increased TSLP expression by IECs, resulting in exacerbation of UC. [ABSTRACT FROM AUTHOR]

In a transient 90-min middle cerebral artery occlusion (MCAO) model of rats, a large ischemic lesion is formed where macrophage-like cells massively accumulate, many of which express a macrophage marker, Iba1, and an oligodendrocyte progenitor cell marker, NG2 chondroitin sulfate proteoglycan (NG2); therefore, the cells were termed BINCs (Brain Iba1+/NG2+ Cells). A bone marrow transplantation experiment using green-fluorescent protein-transgenic rats showed that BINCs were derived from bone marrow. 5-Fluorouracil (5FU) injection at 2 days post reperfusion (2 dpr) markedly reduced the number of BINCs at 7 dpr, causing enlargement of necrotic volumes and frequent death of the rats. When isolated BINCs were transplanted into 5FU-aggravated ischemic lesion, the volume of the lesion was much reduced. Quantitative real-time RT-PCR showed that BINCs expressed mRNAs encoding bFGF, BMP2, BMP4, BMP7, GDNF, HGF, IGF-1, PDGF-A, and VEGF. In particular, BINCs expressed IGF-1 mRNA at a very high level. Immunohistochemical staining showed that IGF-1-expressing BINCs were found not only in rat but also human ischemic brain lesions. These results suggest that bone marrow-derived BINCs play a beneficial role in ischemic brain lesions, at least in part, through secretion of neuroprotective factors. [ABSTRACT FROM AUTHOR]

Although neurons and glia inevitably undergo degeneration in the core of ischemic lesions, many cells, particularly immune cells, infiltrate the core and survive in it. Such infiltrating cells may play certain roles in the regeneration and repair of damaged brain tissues. In this study, we characterized macrophage-like cells that accumulated in the ischemic core of a rat brain whose right middle cerebral artery was transiently occluded for 90 mins. Many of the accumulated macrophage-like cells expressed Iba1, a marker of macrophages/microglia, as well as NG2 chondroitin sulfate proteoglycan (NG2), which has been recognized as a marker of oligodendrocyte progenitor cells. Such macrophage-like cells were termed BINCs (brain Iba1+/NG2+ cells) to distinguish them from NG2−/Iba1+ or NG2+/Iba1− cells that were also present in the perilesion and the contralateral hemisphere. Electron microscopy showed the localization of NG2 along the plasma membrane of cells that had many phagosomes and irregular-shaped or reniform heterochromatin-rich nuclei, which are characteristics of monocytes/macrophages. Brain Iba1+/NG2+ cells were highly proliferative and their number peaked at 7 days post-reperfusion. An immunoblot analysis of NG2 revealed the presence of two NG2s: one expressed by BINCs with a molecular weight of 300 kDa, and the other found in the contralateral hemisphere with a molecular weight of 290 kDa. Taken the various functions of NG2, BINCs may be involved in not only phagocytosis of degenerated cells but also the healing and regeneration of lesion cores.Journal of Cerebral Blood Flow & Metabolism (2008) 28, 149–163; doi:10.1038/sj.jcbfm.9600519; published online 13 June 2007 [ABSTRACT FROM AUTHOR]

Background: Although previous studies have reported important roles of CD4+ type1-helper T cells and regulatory T cells in Helicobacter-associated gastritis, the significance of CD8+ cytotoxic T cells remains unknown. To study the roles of CD8+ T cells, we examined the immune response in the gastric mucosa of Helicobacter felis-infected major histocompatibility complex (MHC) class II-deficient (II−/–) mice, which lack CD4+ T cells. Materials and methods: Stomachs from H. felis-infected wild-type and infected MHC II−/– mice were examined histologically and immunohistochemically. Gastric acidity and serum levels of anti- H. felis antibodies were measured. The expression of pro-inflammatory and anti-inflammatory cytokine, Fas-ligand, perforin, and Foxp3 genes in the gastric mucosa was investigated. Results: H. felis-infected MHC II−/– mice developed severe gastritis, accompanied by marked infiltration of CD8+ cells. At 1 and 2 months after inoculation, mucosal inflammation and atrophy were more severe in MHC II−/– mice, although gastritis had reached similar advanced stages at 3 months after inoculation. There was little infiltration of CD4+ cells, and no Foxp3-positive cells were detected in the gastric mucosa of the infected MHC II−/– mice. The expression of the interleukin-1β and Fas-ligand genes was up regulated, but that of Foxp3 was down regulated in the infected MHC II−/– mice. Serum levels of anti- H. felis antibodies were lower in the infected MHC II−/– mice, despite severe gastritis. Conclusions: The present study suggests that cross-primed CD8+ cytotoxic T cells can induce severe H.-associated gastritis in the absence of CD4+ helper T cells and that Foxp3-positive cells may have an important role in the control of gastric inflammation. [ABSTRACT FROM AUTHOR]

To investigate the effects of suppressors of cytokine signaling 3 (SOCS3) on neural stem cell fate, stem cells were infected with an adenoviral vector expressing SOCS3. Three days later, western blot analysis and immunocytochemical analysis revealed that the protein level of MAP2 and the number of MAP2-positive cells were significantly increased in SOCS3-transfected cells, whereas the protein level of GFAP and the number of GFAP-positive cells were significantly decreased. Furthermore, promoter assay revealed a significant reduction in the transcriptional level of signal transducer and activator of transcription 3 (Stat3) in the transfected cells. In addition, the mRNA levels of Notch family member (notch1) and inhibitory basic helix-loop-helix (bHLH) factors (hes5 and id3) were significantly up-regulated 1 day after overexpression of SOCS3. Three days after transfection, the mRNA level of hes5 was significantly decreased, whereas that of notch1 was still up-regulated. Moreover, all of SOCS3-positive cells expressed Nestin protein but did not express MAP2 or GFAP proteins. These data indicate that overexpression of SOCS3 induced neurogenesis and inhibited astrogliogenesis in neural stem cells. Our data also show that SOCS3 promoted maintenance of neural stem cells. [ABSTRACT FROM AUTHOR]

Almost all agents that exhibit neuroprotection when administered into the cerebral ventricles are ineffective or much less effective in rescuing damaged neurons when infused into the blood stream. Search for an intravenously infusible drug with a potent neuroprotective action is essential for the treatment of millions of patients suffering from acute brain diseases. Here, we report that postischemic intravenous infusion of a ginseng saponin, ginsenoside Rb1 (gRb1) (C54H92O23, molecular weight 1109.46) to stroke-prone spontaneously hypertensive rats with permanent occlusion of the middle cerebral artery distal to the striate branches significantly ameliorated ischemia-induced place navigation disability and caused an approximately 50% decrease in the volume of the cortical infarct lesion in comparison with vehicle-infused ischemic controls. In subsequent studies that focused on gRb1-induced expression of gene products responsible for neuronal death or survival, we showed that gRb1 stimulated the expression of the mitochondrion-associated antiapoptotic factor Bcl-xL in vitro and in vivo. Moreover, we revealed that a Stat5 responsive element in the bcl-x promoter became active in response to gRb1 treatment. Ginsenoside Rb1 appears to be a promising agent not only for the treatment of cerebral stroke, but also for the treatment of other diseases involving activation of mitochondrial cell death signaling.Journal of Cerebral Blood Flow & Metabolism (2006) 26, 708–721. doi:10.1038/sj.jcbfm.9600225; published online 14 September 2005 [ABSTRACT FROM AUTHOR]

Although it was reported that protein 4.1 G, a cytoskeletal protein characterized by its general expression in the body, interacts with some signal transduction molecules in the central nervous system (CNS), its distribution and significance in vivo remained to be elucidated. In the present study, we have identified 4.1 G-positive cells in the rodent CNS, and demonstrated its immunolocalization in the developing mouse CNS. In the rodent CNS, 4.1 G was colocalized with markers for microglia, such as CD45, OX-42 and ionized calcium-binding adapter molecule 1 (Iba1), but not with markers for neuronal or other glial cells. Additionally, colocalization of 4.1 G and A1 adenosine receptor was observed in the mouse cerebrum. In a mixed glial culture, most OX-42-positive microglia were positive for 4.1 G, and 4.1 G isoforms of the same molecular weight as in the rat brain were expressed in cultured microglia, where 4.1 G mRNA was detected by RT-PCR. In the developing mouse cerebral cortex, 4.1 G was detected in immature microglia, which were positive for Iba1. These results indicate that 4.1 G in the CNS is mainly distributed in microglia in vivo. Considering the interactions between 4.1 G and the signal transduction molecules, putative roles have been propsed for 4.1 G in microglial functions in the CNS. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether the onset kinetics of muscle oxygenation in localized working muscle (mOxy) was affected by differences in exercise intensity. Five healthy male subjects exercised for 6 min at 125 W, 150 W, and 175 W, and 1 min at 300 W on a cycle ergometer. mOxy was estimated by near-infrared spectroscopy (NIRS) with a continuous wave photometer. The NIRS probe was positioned on the vastus lateralis muscle of the right leg. The relative change in mOxy was calculated from the relative change of the oxygenated hemoglobin (OxyHb) and deoxygenated hemoglobin (DeoxyHb) concentration from their resting values ([mOxy]=Δ[OxyHb]-Δ[DeoxyHb]). Assuming an exponential time course with time delay, the time constants of the mOxy were 5.7 (SD 2.2) s at 125 W, 5.6 (SD 1.9) s at 150 W, 6.0 (SD 2.2) s at 175 W, and 5.6 (SD 2.1) s at 300 W. The time delays of the mOxy were 6.7 (SD 4.2) s at 125 W, 8.6 (SD 1.6) s at 150 W, 6.4 (SD 3.0) s at 175 W, and 5.4 (SD 2.9) s at 300 W. The mean response times of the mOxy were 12.5 (SD 2.7) s at 125 W, 14.2 (SD 2.4) s at 150 W, 12.4 (SD 4.4) s at 175 W, and 11.0 (SD 3.1) s at 300 W. These results indicate that the kinetics of mOxy were not affected by differences in exercise intensity. [ABSTRACT FROM AUTHOR]