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Deformation of anodes upon reduction causes a cell stress evolution, possibly resulting in cell failure. We studied the effects of compositions on anode deformation and the mechanisms by monitoring anode dimensions and constructing three-dimensional structures. A new evaluation index, "the path length of particles connections (PLPC)", was defined to characterize the microstructure of the anodes, and a YSZ–Ni content diagram was constructed to clarify the relationship between deformation behavior and microstructure. The microstructure exerts significant effects on the deformation, and the deformation mechanisms are classified into four categories based on the PLPC results. The characteristic deformation behavior is discussed for each categories. The stress evolutions of the cell electrolyte upon reduction were examined by FEM analysis incorporating the anode deformation and creep behavior. The numerical analysis demonstrates that the larger the anode deformation, the higher the cell stress generated upon reduction, and the anode deformation may have an impact on mechanical reliability of cells. These results indicate that the cell stress change during reduction may be due to anode deformation and be prevented by selecting optimal anode composition. The YSZ–Ni content diagram is expected to provide fundamental and useful knowledge for designing optimal microstructure in anodes of SOFCs. • Deformation of Ni(O)-YSZ and cell stress change upon reduction are investigated. • Constructing 3D structure is useful for investigation of deformation factor. • Microstructure is an important factor for deformation amount and direction. • First systematically study of effect of composition on deformation behavior. • Anode deformation exerts significant stress change in cell electrolyte. [ABSTRACT FROM AUTHOR]

For commercialization of SOFCs, it is important to understand the deformation behavior of anode during reduction, which causes cell deformation and fracture. In this study, the factors of deformation and the effect of reduction conditions were investigated using NiO-YSZ. The samples with low Ni volume fraction shows expansion, while the samples with high Ni volume fraction shows shrinkage, indicating that the Ni volume fraction is one of the major factors. Furthermore, the SEM images show that this fact is due to the connectivity of Ni. Considering the results of previous studies, the boundary of Ni volume fraction between shrinkage and expansion is expected to be about 30%. We clarified that the expansion behavior is due to the release of the compressive residual stress on the YSZ side during the reduction. This is because the strain change in the NiO-YSZ during the reduction and the strain change calculated from the residual stress change on the YSZ side during the reduction match each other in both direction and amount. In addition, the reduction conditions do not affect the expansion mechanism of NiO-YSZ in the temperature of 700–900 °C and hydrogen concentration of 4%–15%. • Deformation behavior and factors of Ni(O)-YSZ during reduction are investigated. • Ni(O)-YSZ not only shrinks but also expands. • First proof that the expansion is caused by the release of residual stress. • Connectivity of Ni particles is an important factor for deformation direction. • Temperature and hydrogen concentration do not affect the expansion mechanism. [ABSTRACT FROM AUTHOR]

Background & Aims: Because of the lack of animal models developing spontaneous autoimmune hepatitis (AIH), the molecular mechanisms involved in the development of AIH are still unclear. This study aims to examine the regulatory roles of naturally arising CD4+ CD25 + regulatory T (Treg) cells and programmed cell death 1 (PD-1)-mediated signaling in the development of AIH. Methods: To induce a concurrent loss of Treg cells and PD-1-mediated signaling, neonatal thymectomy (NTx), which severely reduces the number of Treg cells, was performed on PD-1−/− mice. After the NTx, we performed histologic examination, assessed autoantibody production and infiltrating cells in the liver, and conducted adoptive transfer experiments. Results: In contrast to NTx mice and PD-1−/− mice, NTx-PD-1−/− mice produced antinuclear antibodies and developed fatal hepatitis characterized by a CD4+ and CD8+ T-cell infiltration invading the parenchyma with massive lobular necrosis. Induction of AIH in NTx-PD-1−/− mice was suppressed by transfer of Treg cells, even derived from PD-1−/− mice. Transfer of total but not CD4+ T-cell-depleted splenocytes from NTx-PD-1−/− mice into RAG2−/− mice induced the development of severe hepatitis. In contrast, the transfer of CD8+ T-cell-depleted splenocytes triggered only mononuclear infiltrates without massive necrosis of the parenchyma. Conclusions: NTx-PD-1−/− mice are the first mouse model of spontaneous fatal AIH. The concurrent loss of Treg cells and PD-1-mediated signaling can induce the development of fatal AIH. Autoreactive CD4+ T cells are essential for induction of AIH, whereas CD8+ T cells play an important role in progression to fatal hepatic damage. [Copyright &y& Elsevier]

Chronic constriction injury of the sciatic nerve is frequently considered as a cause of chronic neuropathic pain. Marked activation of microglia in the posterior horn (PH) has been well established with regard to this pain. However, microglial activation in the anterior horn (AH) is also strongly induced in this process. Therefore, in this study, we compared the differential activation modes of microglia in the AH and PH of the lumbar cord 7 days after chronic constriction injury of the left sciatic nerve in Wistar rats. Microglia in both the ipsilateral AH and PH demonstrated increased immunoreactivity of the microglial markers Iba1 and CD11b. Moreover, abundant CD68+ phagosomes were observed in the cytoplasm. Microglia in the AH displayed elongated somata with tightly surrounding motoneurons, whereas cells in the PH displayed a rather ameboid morphology and were attached to myelin sheaths rather than to neurons. Microglia in the AH strongly expressed NG2 chondroitin sulfate proteoglycan. Despite the tight attachment to neurons in the AH, a reduction in synaptic proteins was not evident, suggesting engagement of the activated microglia in synaptic stripping. Myelin basic protein immunoreactivity was observed in the phagosomes of activated microglia in the PH, suggesting the phagocytic removal of myelin. CCI caused both motor deficit and hyperalgesia that were evaluated by applying BBB locomotor rating scale and von Frey test, respectively. Motor defict was the most evident at postoperative day1, and that became less significant thereafter. By contrast, hyperalgesia was not severe at day 1 but it became worse at least by day 7. Collectively, the activation modes of microglia were different between the AH and PH, which may be associated with the difference in the course of motor and sensory symptoms. • Microglia are differently activated in the anterior and posterior horn after CCI. • Activated microglia in anterior horn may engage in synaptic stripping. • Activated microglia in posterior horn may engage in phagocytic removal of myelin. • Different activation modes of microglia may result in different symptoms after CCI. [ABSTRACT FROM AUTHOR]

Although there have been brilliant advancements in the practical application of therapies targeting immune checkpoints, achieving success in targeting the microenvironment remains elusive. In this study, we aimed to address this gap by focusing on Na+ / H+ exchanger 1 (NHE1) and Lysyl Oxidase Like 2 (LOXL2), which are upregulated in head and neck squamous cell carcinoma (HNSCC) cells. The malignancy of a metastatic human HNSCC cell line was assessed in a mouse tongue cancer xenograft model by knocking down (KD) NHE1, responsible for regulating intracellular pH, and LOXL2, responsible for extracellular matrix (ECM) reorganization via cross-linking of ECM proteins. In addition to assessing changes in PD-L1 levels and collagen accumulation following knockdown, the functional status of the PD-L1 / PD-1 immune checkpoint was examined through co-culture with NK92MI, a PD-1 positive phagocytic human Natural Killer (NK) cell line. The tumorigenic potential of each single KD cell line was similar to that of the control cells, whereas the potential was attenuated in cells with simultaneous KD of both factors (double knockdown [dKD]). Additionally, we observed decreased PD-L1 levels in NHE1 KD cells and compromised collagen accumulation in LOXL2 KD and dKD cells. NK92MI cells exhibited phagocytic activity toward HNSCC cells in co-culture, and the number of remaining dKD cells after co-culture was the lowest in comparison to the control and single KD cells. This study demonstrated the possibility of achieving efficient anti-tumor effects by simultaneously disturbing multiple factors involved in the modification of the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Objective: Bell's palsy is caused by the reactivation of herpes simplex virus type 1 (HSV-1). Using Balb/c mice inoculated with the KOS strain of HSV-1, we previously developed an animal disease model that simulated mild Bell's palsy. The current study developed an animal disease model of more severe facial palsy than that seen in the mouse model.Methods: Three-week-old female Wister rats weighing 60-80g were inoculated on the auricle with HSV-1 and acyclovir was administered intraperitoneally to deactivate the infected HSV-1. Instead of HSV-1, phosphate-buffered saline was used for inoculation as a negative control. Quantitative polymerase chain reaction (PCR), behavior testing (blink reflex), electroneuronography, histopathology of the peripheral nerve, and immunohistochemistry of the facial nerve nucleus were evaluated.Results: Facial palsy occurred 3-5 days after virus inoculation, and the severity of the facial palsy progressed for up to 7 days. Quantitative PCR showed an increase in HSV-1 DNA copies in the facial nerve from 24 to 72h, suggesting that HSV-1 infection occurred in the nerve. Electroneuronography values were 33.0±15.3% and 110.0±18.0% in HSV-1-inoculated and control rats, respectively. The histopathology of the peripheral nerve showed demyelination and loss of the facial nerve, and the facial nerve nucleus showed degeneration.Conclusion: Facial palsy developed in Wister rats following inoculation of the KOS strain of HSV-1 onto the auricles. The behavioral, histopathological, and electroneuronography data suggested that the severity of facial palsy was greater in our rats than in animals in the previous mouse disease model. [ABSTRACT FROM AUTHOR]

Background & Aims: To clarify mechanisms involved in the development of autoimmune hepatitis (AIH), we recently developed a mouse model of spontaneous AIH by inducing a concurrent loss of Foxp3+ regulatory T cells and programmed cell death 1 (PD-1)–mediated signaling. Fatal AIH in these mice was characterized by severe T-cell infiltration and huge production of antinuclear antibodies (Abs). This study aims to identify induction sites, responsible T-cell subsets, and key molecules for induction of AIH. Methods: To develop the mouse model of AIH, neonatal thymectomy (NTx) was performed on PD-1–deficient (PD-1−/−) mice. We then conducted neonatal splenectomy or in vivo administration of Abs to cytokines, chemokines, or cell-surface molecules. Results: In NTx-PD-1−/− mice, either neonatal splenectomy or in vivo CD4+ T-cell depletion suppressed CD4+ and CD8+ T-cell infiltration in the liver. In the induction phase of AIH, splenic CD4+ T cells were localized in B-cell follicles with huge germinal centers and showed the Bcl6+ inducible costimulator (ICOS)+ interleukin (IL)-21+ IL-21 receptor (IL-21R)+ follicular helper T (TFH) cell phenotype. Blocking Abs to ICOS or IL-21 suppressed TFH-cell generation and induction of AIH. In addition, IL-21 produced by TFH cells drove CD8+ T-cell activation. Splenic TFH cells and CD8+ T cells expressed CCR6, and CCL20 expression was elevated in the liver. Administration of anti-CCL20 suppressed migration of these T cells to the liver and induction of AIH. Conclusions: Dysregulated TFH cells in the spleen are responsible for the induction of fatal AIH, and CCR6-CCL20 axis-dependent migration of splenic T cells is crucial to induce AIH in NTx-PD-1 −/− mice. [ABSTRACT FROM AUTHOR]

We previously reported that glioma stemlike cells (GSCs) exist in the area of the tumor periphery showing no gadolinium enhancement on magnetic resonance imaging. In the present work, we analyzed glucose metabolism to investigate whether lactate could be predictive of tumor invasiveness and of use in detection of the tumor invasion area in glioblastoma multiforme (GBM). The expression of lactate dehydrogenase A (LDH-A) and pyruvate dehydrogenase (PDH) was investigated in 20 patients. In GSC lines, LDH-A and PDH expression also was examined in parallel to assessments of mitochondrial respiration. We then investigated the relationship between lactate/creatine ratios in the tumor periphery measured by magnetic resonance spectroscopy, using learning-compression-model algorithms and phenotypes of GBMs. In 20 GBMs, high-invasive GBM expressed LDH-A at significantly higher expression than did low-invasive GBM, whereas low-invasive GBM showed significantly higher expression of PDH than did high-invasive GBM. The highly invasive GSC line showed higher expression of LDH-A and lower expression of PDH compared with low-invasive GSC lines. The highly invasive GSC line also showed the lowest consumption of oxygen and the lowest production of adenosine triphosphate. Lactate levels, as measured by magnetic resonance spectroscopy, showed a significant positive correlation with LDH-A transcript levels, permitting classification of the GBMs into high-invasive and low-invasive phenotypes based on a cutoff value of 0.66 in the lactate/creatine ratio. In the tumor periphery area of the highly invasive GBM, aerobic glycolysis was the predominant pathway for glucose metabolism, resulting in the accumulation of lactate. The level of lactate may facilitate prediction of the tumor-infiltrating area on GBM. [ABSTRACT FROM AUTHOR]

Microglia as a defensive arm of the nervous system emerged early in evolution. The surveilling microglia with motile and ramified processes are the main phenotype in the healthy CNS; the surveilling microglial patrol neuronal somata, dendrites, dendritic spines and axons. Increasing evidence suggests that microglia play fundamental roles in development, maturation and ageing of the brain, as well as contribute to a variety of physiological brain processes including sleep and circadian rhythm. Physiological state of microglia is tightly regulated by brain microenvironment and controlled by a sophisticated system of receptors and signalling cascades including ionotropic and metabotropic purinoceptors, pattern-recognition receptors, and receptors for chemokines and cytokines. Microglia also utilise ion channels and transporters in regulating ionic homeostasis and various aspects of microglial function. The major ion transporters expressed by microglia include Na+/H+ exchanger 1 and Na+/Ca2+ exchangers, which are involved in regulation of pH i and Ca2+ homeostasis during microglial physiological responses. Microglial cells control development, maturation and plasticity of neuronal ensembles through controlled physiological phagocytosis of synapses or synaptic fragments - processes known as synaptic pruning and trogocytosis. This special issue on "Physiological roles of microglia" is an assembly of papers written by the leading experts in this research field. We start this special issue with this snapshot of microglial physiological functions as a prelude to the indepth discussion of microglia in physiological processes in the nervous system. • Microglia form the defensive arm of the central nervous system. • Microglial cells acquire morphology and physiology of neural cells. • Microglia contributes to physiological functions including shaping neuronal ensembles and regulating synaptic transmission. [ABSTRACT FROM AUTHOR]

Abstract Parkinson's disease (PD) is a frequent neurodegenerative disease causing bradykinesia, tremor, muscle rigidity and postural instability. Although its main pathology is progressive dopaminergic (DArgic) neuron loss in the substantia nigra, motor deficits are thought not to become apparent until most DArgic neurons are lost, probably due to compensatory mechanisms that overcome the decline of DA level in the striatum. Even in animal PD models, it is difficult to detect motor deficits when most DArgic neurons are functional. In this study, we performed various behavioral tests (apomorphine-induced rotation, cylinder, forepaw adjustment steps (FAS), beam walking, rota-rod, and open-field), using 6-hydroxydopamine (OHDA) and lipopolysaccharide (LPS)-induced hemi-PD model rats with various striatal DA levels, to find the best way to predict the DA level from earlier disease stages. Different from the 6-OHDA-induced model, reduction in the striatal DA levels in the LPS-model was less significant. Among the behavioral tests, data from cylinder and FAS tests, which evaluate forelimb movements, best correlated with decline of the DA level. They also correlated well with decreased body weight gain. The beam and apomorphine tests showed less significant correlation than the cylinder and FAS tests. Open-field and rota-rod tests were not useful. Expressional levels of mRNA encoding tyrosine hydroxylase (TH), a marker of DArgic neurons, correlated well with the DA level. Metabotropic glutamate receptor 4 mRNA expression correlated with the striatal DA level and may be related to compensatory mechanisms. These results suggest that motor impairments of PD should be evaluated by forelimb movements, or hands and forearms in clinical settings, rather than movement of the body or large joints. The combination of cylinder and FAS tests may be the best to evaluate the rat PD models, in which many DArgic neurons survive. Graphical abstract Image 1 Highlights • The 6-OHDA- and LPS-induced Parkinson's disease (PD) rat models were used. • Cylinder and FAS tests are suitable to evaluate motor deficits of forelimbs. • Forelimb impairments correlated linearly with striatal dopamine (DA) decline. • Apomorphine-induced rotation was apparent when DArgic neurons were totally lost. • For early detection of PD, examination of hand and forearm movements is suitable. [ABSTRACT FROM AUTHOR]

Microglia play a central role in neuroinflammatory processes by releasing proinflammatory mediators. This process is tightly regulated along with neuronal activities, and neurotransmitters may link neuronal activities to the microglia. In this study, we showed that primary cultured rat microglia express the dopamine (DA) D1 receptor (D1R) and D4R, but not D2R, D3R, or D5R. In response to a D1R-specific agonist SKF-81297 (SKF), the cultured microglia exhibited increased intracellular cAMP levels. DA and SKF suppressed lipopolysaccharide (LPS)-induced expression of interleukin-1β (IL-1β) and tumor necrosis α (TNFα) in cultured microglia. Microglia in the normal mature rat prefrontal cortex (PFC) were sorted and significant expression of D1R, D2R, and D4R was observed. A delirium model was established by administering LPS intraperitoneally to mature male Wistar rats. The model also displayed sleep-wake disturbances as revealed by electroencephalogram and electromyogram recordings as well as increased expression of IL-1β and TNFα in the PFC. DA levels were increased in the PFC 21 h after LPS administration. Increased cytokine expression was observed in sorted microglia from the PFC of the delirium model; however, TNFα, but not IL-1β expression, was abruptly decreased 21 h after LPS administration in the delirium model, whereas DA levels were increased. A D1R antagonist SCH23390 partially abolished the TNFα expression change. This suggests that endogenous DA may play a role in suppressing neuroinflammation. Administration of the DA precursor L-DOPA or SKF to the delirium model rats inhibited the expression of IL-1β and TNFα. The simultaneous administration of clozapine, a D4R antagonist, strengthened the suppressive effects of L-DOPA. These results suggest that D1R mediates the suppressive effects of LPS-induced neuroinflammation, in which microglia may play an important role. Agonists for D1R may be effective for treating delirium. [Display omitted] • Rat microglia express dopamine receptors in vitro and in vivo. • The dopamine D1 receptor (D1R) mediates elevation of intracellular cAMP levels and anti-inflammatory actions. • A rat delirium model was prepared by intraperitoneal administration of LPS. • The delirium model exhibited sleep disturbances and increased IL-1β and TNFα expression. • DA suppressed cytokine expression in rat brains of the delirium model through D1R. [ABSTRACT FROM AUTHOR]

The low molecular weight organic compound bromovalerylurea (BU) has long been used as a hypnotic/sedative. In the present study, we found that BU suppressed mRNA expression of proinflammatory factors and nitric oxide release in lipopolysaccharide (LPS)-treated rat primary microglial cell cultures. BU prevented neuronal degeneration in LPS-treated neuron-microglia cocultures. The anti-inflammatory effects of BU were as strong as those of a synthetic glucocorticoid, dexamethasone. A rat hemi-Parkinsonian model was prepared by injecting 6-hydroxydopamine into the right striatum. BU was orally administered to these rats for 7 days, which ameliorated the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and alleviated motor deficits. BU suppressed the expression of mRNAs for interferon regulatory factors (IRFs) 1, 7 and 8 in the right (lesioned) ventral midbrain as well as those for proinflammatory mediators. BU increased mRNA expression of various neuroprotective factors, including platelet-derived growth factor and hepatocyte growth factor, but it did not increase expression of alternative activation (M2) markers. In microglial culture, BU suppressed the LPS-induced increase in expression of IRFs 1 and 8, and it reduced LPS-induced phosphorylation of JAK1 and STATs 1 and 3. Knockdown of IRFs 1 and 8 suppressed LPS-induced NO release by microglial cells. These results suggest that suppression of microglial IRF expression by BU prevents neuronal cell death in the injured brain region, where microglial activation occurs. Because many Parkinsonian patients suffer from sleep disorders, BU administration before sleep may effectively ameliorate neurological symptoms and alleviate sleep dysfunction. [ABSTRACT FROM AUTHOR]

Noradrenaline (NA) has marked anti-inflammatory effects on activated microglial cells. The present study was conducted to elucidate the mechanisms underlying the NA effects using rat primary cultured microglial cells. NA, an α1 agonist, phenylephrine (Phe) and a β2 agonist, terbutaline (Ter) suppressed lipopolysaccharide (LPS)-induced nitric oxide (NO) release by microglia and prevented neuronal degeneration in LPS-treated neuron-microglia coculture. The agents suppressed expression of mRNA encoding proinflammatory mediators. Both an α1-selective blocker terazocine and a β2-selective blocker butoxamine overcame the suppressive effects of NA. cAMP-dependent kinase (PKA) inhibitors did not abolish the suppressive NA effects. LPS decreased IκB leading to NFκB translocation into nuclei, then induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) and expression of interferon regulatory factor 1 (IRF1). NA inhibited LPS-induced these changes. When NFκB expression was knocked down with siRNA, LPS-induced STAT1 phosphorylation and IRF1 expression was abolished. NA did not suppress IL-6 induced STAT1 phosphorylation and IRF1 expression. These results suggest that one of the critical mechanisms underlying the anti-inflammatory effects of NA is the inhibition of NFκB translocation. Although inhibitory effects of NA on STAT1 phosphorylation and IRF1 expression may contribute to the overall suppressive effects of NA, these may be the downstream events of inhibitory effects on NFκB. Since NA, Phe and Ter exerted almost the same effects and PKA inhibitors did not show significant antagonistic effects, the suppression by NA might not be dependent on specific adrenergic receptors and cAMP-dependent signaling pathway. [ABSTRACT FROM AUTHOR]

We conducted water column surveys to search for hydrothermal plumes over the spreading axes in the Gulf of Aden between 45°35′E and 52°42′E. We measured light transmission and chemical tracers Mn, Fe, CH 4 and δ 13 C of CH 4 in seawater taken using a CTD-Carrousel multi-sampling system at 12 locations including a control station in the Arabian Sea. We recognized three types of hydrothermal plumes at depths of ~650 to ~900 m (shallow plumes), ~1000 to ~1200 m (intermediate plumes), and >1500 m (deep plumes). The shallow plumes were apparently originated from newly discovered twin seamounts (12°03–06′N and 45°35–41′E) at the westernmost survey area, where two-dimensional distributions of light transmission and Mn were mapped by tow-yo observations of the CTD-sampling system with an in situ auto-analyzer GAMOS. The maximum concentrations of Mn, Fe, and CH 4 of 46 nM, 251 nM, and 15 nM, respectively, were observed for collected seawater within the shallow plumes. The intermediate plumes were characterized by anomalies of light transmission, Mn, Fe, and δ 13 C of CH 4 , but by little CH 4 anomalies, suggesting that CH 4 had been consumed down to the background level during the aging of the plumes. Anomalies of δ 3 He already reported by the World Ocean Circulation Experiment (WOCE) program exhibited a hydrothermal plume-like peak at ~2000 m depth in the Gulf of Aden, which seems to coincide with the deep plumes observed in this study. The endmember δ 13 C–CH 4 values for the shallow and the deep plumes were estimated to be in a range between −10‰ and −15‰, demonstrating that the sources of CH 4 are not biogenic but magmatic as similarly observed at sediment-starved mid-oceanic ridges. [ABSTRACT FROM AUTHOR]

Summary: Objective: To study vascular anatomy on oral cancer-draining lymph nodes before metastasis in mice. Material and methods: Cell lines: highly lymph metastatic oral squamous cell carcinoma SASL1m and non-metastatic human adenoid cystic carcinoma ACC2. Bone marrow transplants and xenografts: Nude mice were lethally irradiated and transplanted with bone marrow cells from EGFP+ mice. SASL1m or ACC2 cells were implanted in the tongue. Non-xenografted mice were used as controls. In addition, we injected conditioned medium from SASL1m or ACC2 in transplanted mice. Immunohistochemistry: Primary tumors and neck lymph nodes were resected and stained with anti-mouse Podoplanin and CD31. Images were visualized in a confocal microscope. Image analysis: Areas covered by EGFP, CD31 and Podoplanin were measured and compared statistically. Expression microarrays: Transcriptomic microarray analysis compared SASL1 to ACC2 cells. Interactomes were generated to reveal altered pathways. Results: SASL1m cells induced the assemblage of blood vessels in cancer-free, tumor-draining lymph nodes. These blood vessels incorporated bone marrow-derived EGFP+CD31+ cells. Notably, SASL1m-conditioned medium induced a similar reaction. Non-metastatic cells failed to produce any change. Microarray and pathway analyses revealed the upregulation of Transforming Growth Factor-β, Lysyl Oxidase-like 2, Slit homolog 3 and Protease Serine 22. The upregulation of these genes was confirmed in xenografts. Conclusions: This study suggests that a blood supply for new tumors is established in lymph nodes before metastasis. It also suggests that premetastatic vasculogenesis and primary tumor angiogenesis may be mediated by different mechanisms. [ABSTRACT FROM AUTHOR]

The axon initial segment (AIS) is a structural neuronal compartment of the proximal axon that plays key roles in sodium channel clustering, action potential initiation, and signal propagation of neuronal outputs. Mutations in constitutive genes of the AIS, such as ANK3, have been identified in patients with neurodevelopmental disorders. Nevertheless, morphological changes in the AIS in neurodevelopmental disorders have not been characterized. In this study, we investigated the length of the AIS in rodent models of attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). We observed abnormalities in AIS length in both animal models. In ADHD model rodents, we observed shorter AIS length in layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC) and primary somatosensory barrel field (S1BF). Further, we observed shorter AIS length in S1BF L5 neurons. In ASD model mice, we observed shorter AIS length in L2/3 and L5 neurons of the S1BF. These results suggest that impairments in AIS length are common phenomena in neurodevelopmental disorders such as ADHD and ASD and may be conserved across species. Our findings provide novel insight into the potential contribution of the AIS to the pathophysiology and pathogenesis of neurodevelopmental disorders. • In mouse and rat models of ADHD, mPFC & S1BF neurons have shorter AIS lengths. • In ASD model mice, S1BF neurons have shorter AIS lengths. • A disorder-specific AIS phenotype may be conserved across species. • AIS abnormalities in S1BF neurons are common phenotypes in ADHD & ASD. [ABSTRACT FROM AUTHOR]

Abstract: Brain ischemia causes the death of neurons and glial cells. Such brain cells are believed to inevitably undergo degeneration in the core of ischemic lesions, whereas neurons and glial cells may survive in the region surrounding the core that is often referred to as the ischemic penumbra. However, many cells, particularly immune cells infiltrate and survive in the core. 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 90min. At 7 days post-reperfusion, we observed macrophage-like cells expressing CD200, a cell surface glycoprotein belonging to an immunoglobulin superfamily and that elicits suppressive effects on myeloid cells including microglia by interacting with the CD200 receptor (CD200R). RT-PCR and immunoblot analyses revealed the presence of CD200-mRNA and protein in the ischemic core as well as in the contralateral region. As revealed by immunohistochemistry, CD200 is located on the cell membrane of spherical Iba1+ cells with many cytoplasmic granules. CD200−/Iba1+ macrophage-like cells were also present, which have a more irregular shape than CD200+/Iba1+ cells. CD200 was detected in isolated spherical Iba1+ macrophage-like cells. Thus, CD200 is expressed in some populations of macrophage-like cells that may be responsible for the suppression of CD200R+ myeloid cell functions in the ischemic core. [Copyright &y& Elsevier]

Abstract: Heparanase is an enzyme that cleaves heparan sulfate proteoglycans, an important component of the extracellular matrix to generate heparan sulfate fragments, leading to the remodeling of the extracellular matrix and the basement membrane particularly during cancer metastasis. A growing body of evidence suggests that heparanase serves multiple functions in normal tissues including the central nervous system. In this study, we showed that heparanase is expressed in reactive astrocytes in the peri-infarct lesion of a rat brain whose middle cerebral artery was transiently occluded for 90min. RT-PCR and Western blot analyses revealed that heparanase expression was markedly upregulated during the subacute phase of ischemia (from 3 to 7 days post-reperfusion (dpr)). As revealed by immunohistochemical study, heparanase was localized in astrocytes located in the peri-infarct region. Heparanase+ astrocytes expressed nestin that is known as a marker of reactive astrocytes. Infiltrated neutrophils were weakly heparanase+. After 7 dpr, the expression level of heparanase+ astrocytes considerably decreased. Therefore, the maximum expression of heparanase by astrocytes may correlate with the time of migration of reactive astrocytes toward the ischemic core, which may result in astrogliosis. These findings suggest a novel role of heparanase in the pathophysiology of brain ischemia. [Copyright &y& Elsevier]

Microglial cells rapidly become activated in response to even minor damage of neurons, suggestive of the intimate interactions between neurons and microglial cells. Although mediators for microglia–neuron interactions have not been well identified, neurotransmitters are possible candidates transmitting signals from neurons to microglial cells. Among the neurotransmitters, we focused on the effects of norepinephrine and other adrenergic agonists on the functions of rat cultured microglial cells. Reverse transcriptase polymerase chain reaction studies revealed that microglial cells expressed mRNAs encoding α1A, α2A, β1 and β2 receptors. Norepinephrine and a β2 adrenergic agonist terbutaline elevated intracellular cAMP level of microglial cells. Norepinephrine, an α1 agonist phenylephrine, a β1 agonist dobutamine and terbutaline suppressed the expressions of mRNAs encoding pro-inflammatory cytokines, interleukin-6 and tumor necrosis factor α. Release of tumor necrosis factor α and nitric oxide was suppressed by norepinephrine, phenylephrine, dobutamine and terbutaline. An α2 agonist clonidine and dobutamine upregulated the expression of mRNA encoding catechol-O-methyl transferase, an important enzyme to degrade norepinephrine. Norepinephrine, dobutamine and terbutaline upregulated the expressions of mRNA encoding 3-phospshoglycerate dehydrogenase, an essential enzyme for synthesis of l-serine and glycine, which are amino acids necessary for neuronal survival. Clonidine upregulated the expression of mRNA encoding an anti-apoptotic factor Bcl-xL. These results suggest that norepinephrine participates in the regulation of brain function at least partly by modulating the functions of microglia. [Copyright &y& Elsevier]