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BackgroundParkinson’s disease (PD) is the most common neurodegenerative movement disorder. Pathological features of PD include dopaminergic neuron loss in the substantia nigra pars compacta (SNpc) and intraneuronal α-Synuclein (α-Syn) inclusions called Lewy bodies (LBs). Since there is no treatment to either halt or slow the progression of PD, it is highly demanded to establish a rodent model that recapitulates the clinicopathological features of PD within a short period to efficiently investigate the pathological mechanisms and test disease-modifying therapies (DMTs).MethodsWe injected human and mouse α-Syn-preformed fibrils (hPFFs and mPFFs, respectively) into the hemilateral dorsal striatum of wild-type mice, wild-type human α-Syn bacterial artificial chromosome (BAC) transgenic (WT BAC-SNCA Tg) mice, and A53T human α-Syn BAC transgenic (A53T BAC-SNCA Tg) mice, and conducted pathological and behavioral analyses.ResultsWT BAC-SNCA Tg and A53T BAC-SNCA Tg mice expressed a comparable amount of α-Syn (2.9 and 2.7-fold more α-Syn, respectively, than wild-type mice) in the brains. mPFF injections induced more severe α-Syn pathology in most brain regions, including the ipsilateral SNpc, than hPFF injections in all genotypes at 1 month post-injection. Among the mPFF-injected mice, the A53T BAC-SNCA Tg mice exhibited the most severe α-Syn pathology as early as 0.5 month (2 weeks) post-injection. Consistent with these observations, in vitro fibrillization assay revealed that a mixture of A53T human α-Syn and mouse α-Syn seeded with mPFFs aggregated most rapidly among the conditions tested. The mPFF-injected A53T BAC-SNCA Tg mice showed a 38% reduction in tyrosine hydroxylase (TH)-positive neurons in the ipsilateral SNpc, apomorphine-induced rotational behavior, and motor dysfunction at 2 months post-injection. Notably, the reduction in TH-positive density in the striatum and microglial activation preceded the obvious TH-positive neuron loss in the SNpc.Conclusions Our data indicate that the extent of α-Syn pathology induced by α-Syn PFF injection depends on the types of α-Syn PFFs and exogenously expressed α-Syn in Tg mice. The mPFF-injected A53T BAC-SNCA Tg mice recapitulate the pathological processes of PD more rapidly than previously reported mouse models, suggesting their usefulness for testing DMTs as well as analyzing the pathological mechanisms.

Hemorrhage inside the mammillary bodies (MMBs) is known to be one of the findings of Wernicke encephalopathy. Brain MRI of two patients with Wernicke-Korsakoff syndrome (WKS) demonstrated high susceptibility values representing hemosiderin deposition in MMBs by using quantitative susceptibility mapping (QSM). QSM provided additional information of susceptibility values to susceptibility-weighted imaging in diagnosis of WKS.

OBJECTIVES To characterise the clinical signs of suspected cerebrovascular disease in dogs. MATERIALS AND METHODS Medical records of one hospital were searched from November 2009 to December 2016 for dogs that suffered of cerebrovascular disease. We diagnosed cerebrovascular disease based on acute onset, clinical signs and magnetic resonance imaging findings. The medical history, clinical signs, concurrent disease, area of infarction, cerebrospinal fluid results, month at onset and outcome were investigated in the cerebrovascular disease group and in a control group (dogs with brain disorders other than cerebrovascular disease). RESULTS A total of 122 CVD cases were extracted from the 5312 patients that visited during the study period. Of these 122 cases, 66 (1.2%) matched the subject selection criteria of our study and were included in the analysis. Forebrain infarction was observed in 51 of 66 cases, of which 24 (47.1%) suffered from seizures. The number of dogs diagnosed with cerebrovascular disease was disproportionately high in August (nine of 59 cases) and December (13 of 59 cases). In the outcome survey, deterioration was observed in 11 of 55 cases. CLINICAL SIGNIFICANCE Seizure is an important clinical sign of cerebrovascular disease in dogs. There was a significant seasonal variation in the number of dogs diagnosed with cerebrovascular disease in Japan. Clinical features observed in this report differ from those of previous reports and highlight the need for additional research in this area.

Parkinson’s disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson’s disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson’s disease and a genome-wide association study in Parkinson’s disease has identified SNCA as a risk gene for Parkinson’s disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson’s disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson’s disease and a Rep1 polymorphism, all of which are causal of familial Parkinson’s disease or increase the risk of sporadic Parkinson’s disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson’s disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson’s disease that showed RBD-like behaviour and hyposmia without motor symptoms.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by the accumulation of TAR-DNA-binding protein 43 (TDP-43) aggregates in older adults. LATE coexists with Lewy body disease (LBD) as well as other neuropathological changes including Alzheimer’s disease (AD). We aimed to identify the pathological, clinical, and genetic characteristics of LATE in LBD (LATE-LBD) by comparing it with LATE in AD (LATE-AD), LATE with mixed pathology of LBD and AD (LATE-LBD + AD), and LATE alone (Pure LATE). We analyzed four cohorts of autopsy-confirmed LBD (n = 313), AD (n = 282), LBD + AD (n = 355), and aging (n = 111). We assessed the association of LATE with patient profiles including LBD subtype and AD neuropathologic change (ADNC). We studied the morphological and distributional differences between LATE-LBD and LATE-AD. By frequency analysis, we staged LATE-LBD and examined the association with cognitive impairment and genetic risk factors. Demographic analysis showed LATE associated with age in all four cohorts and the frequency of LATE was the highest in LBD + AD followed by AD, LBD, and Aging. LBD subtype and ADNC associated with LATE in LBD or AD but not in LBD + AD. Pathological analysis revealed that the hippocampal distribution of LATE was different between LATE-LBD and LATE-AD: neuronal cytoplasmic inclusions were more frequent in cornu ammonis 3 (CA3) in LATE-LBD compared to LATE-AD and abundant fine neurites composed of C-terminal truncated TDP-43 were found mainly in CA2 to subiculum in LATE-LBD, which were not as numerous in LATE-AD. Some of these fine neurites colocalized with phosphorylated α-synuclein. LATE-LBD staging showed LATE neuropathological changes spread in the dentate gyrus and brainstem earlier than in LATE-AD. The presence and prevalence of LATE in LBD associated with cognitive impairment independent of either LBD subtype or ADNC; LATE-LBD stage also associated with the genetic risk variants of TMEM106B rs1990622 and GRN rs5848. These data highlight clinicopathological and genetic features of LATE-LBD.

Background Patients with Parkinson's disease (PD) show motor symptoms as well as various non-motor symptoms. Postmortem studies of PD have suggested that initial alpha-synuclein (α-Syn) pathology develops independently in the olfactory bulb and lower brainstem, spreading from there stereotypically. However, it remains unclear how these two pathological pathways contribute to the clinicopathological progression of PD. Objective The objective of this study was to examine the clinicopathological contribution of α-Syn spread from the olfactory bulb. Methods We conducted pathological and behavioral analyses of human α-Syn bacterial artificial chromosome transgenic mice injected with α-Syn preformed fibrils into the bilateral olfactory bulb up to 10 months postinjection. Results α-Syn preformed fibril injections induced more widespread α-Syn pathology in the transgenic mice than that in wild-type mice. Severe α-Syn pathology in the transgenic mice injected with α-Syn preformed fibrils was initially observed along the olfactory pathway and later in the brain regions that are included in the limbic system and have connections with it. The α-Syn pathology was accompanied by regional atrophy, neuron loss, reactive astrogliosis, and microglial activation, which were remarkable in the hippocampus. Behavioral analyses revealed hyposmia, followed by anxiety-like behavior and memory impairment, but not motor dysfunction, depression-like behavior, or circadian rhythm disturbance. Conclusion Our data suggest that α-Syn spread from the olfactory bulb mainly affects the olfactory pathway and limbic system as well as its related regions, leading to the development of hyposmia, anxiety, and memory loss in PD. © 2021 International Parkinson and Movement Disorder Society.

N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2 R714G, I715D, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 sec than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.

Introduction How to construct massive cardiac tissue and culture it with functional improvement may be crucial as cardiomyogenesis in failed heart. We previously presented that dynamic culture in a rotating wall vessel (RWV) bioreactor could provide a better culture environment for maintenance of the engineered 3D cardiac tissue. However, it is unknown about the effect of the tissue cultured in a RWV bioreactor on engraftment and improvement of function in the distressed rat heart. Hypothesis We hypothesized that the engineered 3D cardiac tissue cultured in a RWV bioreactor could improve its engraftment and lead recovery of cardiac function in rat infarction model. Methods We made engineered cardiac tissue by seeding 2.0 × 106 human induced pluripotent stem cell derived cardiomyocytes on the PLGA fiber sheet. It was cultured in the RWV bioreactor for seven days (RWV group). For the control, static culture has been done. After in vitro assessment, these tissues were transplanted to myocardial infarction model nude rats (sham, control, and RWV group, n=10, respectively) and cardiac performance was evaluated by ultrasonography. Four weeks after transplantation, we evaluated their hearts by histological analysis. Results The RWV group demonstrated maturation of cardiomyocytes evidenced by significantly higher expression of Troponin T (TnT), sarcomeric α actinin (SAA), connexin 43 (Cx43) and myosin heavy chain 7 (MYH7) than the control by Western blots (TnT; 2.7±1.0 vs. 1.0±0.4, p Conclusion Functional engineered 3D cardiac tissue cultured in a RWV bioreactor could induce angiogenesis and improved its engraftment, leading significant improvement of cardiac function in rat infarction model. Dynamic culture in a RWV bioreactor Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Japan Society for the Promotion of Science

N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2 R714G, I715D, or GD) that confers resistance to proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 sec than WT and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.

White matter (WM) disease is associated with disruption of the gliovascular unit, which involves breach of the blood–brain barrier (BBB). We quantified pericytes as components of the gliovascular unit and assessed their status in vascular and other common dementias. Immunohistochemical and immunofluorescent methods were developed to assess the distribution and quantification of pericytes connected to the frontal lobe WM capillaries. Pericytes with a nucleus were identified by collagen 4 (COL4) and platelet‐derived growth factor receptor‐β (PDGFR‐β) antibodies with further verification using PDGFR‐β‐specific ELISA. We evaluated a total of 124 post‐mortem brains from subjects with post‐stroke dementia (PSD), vascular dementia (VaD), Alzheimer’s disease (AD), AD‐VaD (Mixed) and post‐stroke non‐demented (PSND) stroke survivors as well as normal aging controls. COL4 and PDGFR‐β reactive pericytes adopted the characteristic “crescent” or nodule‐like shapes around capillary walls. We estimated densities of pericyte somata to be 225 ±38 and 200 ±13 (SEM) per COL4 mm2 area or 2.0 ± 0.1 and 1.7 ± 0.1 per mm capillary length in young and older aging controls. Remarkably, WM pericytes were reduced by ~35%–45% in the frontal lobe of PSD, VaD, Mixed and AD subjects compared to PSND and controls subjects (P

The stereotypical spread of pathological protein inclusions and clinicopathological heterogeneity are well described in neurodegenerative diseases. Accumulating evidence suggests that the former can be attributed to consecutive cell-to-cell transmission of pathological proteins between anatomically connected brain regions, while the latter has been hypothesized to result from the spread of conformationally distinct pathological protein aggregates, or strains. These emerging concepts have dramatically changed our understanding of neurodegenerative diseases. In this review, we first summarize the background and recent findings underpinning these concepts with a focus on two major pathological proteins: tau and α-synuclein. We then discuss their clinical implications for tauopathies and synucleinopathies and propose a working hypothesis for future research.

Zonisamide (ZNS) is an effective drug for not only motor symptoms but also non-motor symptoms in Parkinson's disease. However, the actions of ZNS as an anti-Parkinsonian drug are not well understood. To clarify the actions of ZNS in vivo, we administered ZNS to mice and examined the effects on neurotransmitter metabolism and behaviors, focusing on motor and non-motor symptoms. Administration of ZNS decreased dopamine (DA) turnover in various brain regions, including the striatum. In behavioral tests, ZNS enhanced locomotor activity and novelty seeking in the open field test, light-dark transition test, and the social interaction test. Consistent with these results of DA metabolism in ZNS-treated mice, monoamine oxidase activity was significantly inhibited by ZNS in primary neurons and astrocytes. Collectively, these data suggest that ZNS inhibits monoamine oxidase activity and decreases DA turnover, which increases locomotor activity and novelty seeking in mice. ZNS is potentially useful to improve not only motor symptoms but also neuropsychiatric non-motor symptoms such as apathy in PD.

Subcortical small vessel disease (SVD) is characterized by white matter damage resulting from arteriolosclerosis and chronic hypoperfusion. Transforming growth factor beta 1 (TGFB1) is dysregulated in the hereditary SVD, CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). However, very little is known about the role of the largest group in the TGFB superfamily - the bone morphogenetic proteins (BMPs) - in SVD pathogenesis. The aim of this study was to characterize signaling abnormalities of BMPs in sporadic SVD. We examined immunostaining of TGFB1 and BMPs (BMP2/BMP4/BMP6/BMP7/BMP9) in a total of 19 post-mortem human brain samples as follows: 7 SVD patients (4 males, 76-90 years old); 6 Alzheimer's disease (AD) patients (2 males, 67-93 years old) and 6 age-matched disease controls (3 males, 68-78 years old). We subsequently investigated the effects of oxygen-glucose deprivation and BMP4 addition on cultured cells. Furthermore, adult mice were subjected to chronic cerebral hypoperfusion using bilateral common carotid artery stenosis, followed by continuous intracerebroventricular infusion of the BMP antagonist, noggin. In the SVD cases, BMP4 was highly expressed in white matter pericytes. Oxygen-glucose deprivation induced BMP4 expression in cultured pericytes in vitro. Recombinant BMP4 increased the number of cultured endothelial cells and pericytes and converted oligodendrocyte precursor cells into astrocytes. Chronic cerebral hypoperfusion in vivo also upregulated BMP4 with concomitant white matter astrogliogenesis and reduced oligodendrocyte lineage cells, both of which were suppressed by intracerebroventricular noggin infusion. Our findings suggest ischemic white matter damage evolves in parallel with BMP4 upregulation in pericytes. BMP4 promotes angiogenesis, but induces astrogliogenesis at the expense of oligodendrocyte precursor cell proliferation and maturation, thereby aggravating white matter damage. This may explain white matter vulnerability to chronic hypoperfusion. The regulation of BMP4 signaling is a potential therapeutic strategy for treating SVD.

Synucleinopathies are composed of Parkinson disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Alpha-synuclein (α-Syn) forms aggregates mainly in neurons in PD and DLB, while oligodendroglial α-Syn aggregates are characteristic of MSA. Recent studies have demonstrated that injections of synthetic α-Syn preformed fibrils (PFFs) into the brains of wild-type (WT) animals induce intraneuronal α-Syn aggregates and the subsequent interneuronal transmission of α-Syn aggregates. However, injections of α-Syn PFFs or even brain lysates of patients with MSA have not been reported to induce oligodendroglial α-Syn aggregates, raising questions about the pathogenesis of oligodendroglial α-Syn aggregates in MSA. Here, we report that WT mice injected with mouse α-Syn (m-α-Syn) PFFs develop neuronal α-Syn pathology after short postinjection (PI) intervals on the scale of weeks, while oligodendroglial α-Syn pathology emerges after longer PI intervals of several months. Abundant oligodendroglial α-Syn pathology in white matter at later time points is reminiscent of MSA. Furthermore, comparison between young and aged mice injected with m-α-Syn PFFs revealed that PI intervals rather than aging correlate with oligodendroglial α-Syn aggregation. These results provide novel insights into the pathological mechanisms of oligodendroglial α-Syn aggregation in MSA.

Parkinson’s disease (PD) is pathologically characterized by intraneuronal α-synuclein (α-Syn) aggregates called Lewy bodies (LBs) as well as the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). On the basis of autopsy studies, Braak et al. hypothesized that Lewy pathology initially occurs in the enteric nervous system, subsequently spreading to the dorsal motor nucleus of the vagus nerve (dmX) and then ascending in the brainstem to the SNpc. However, this hypothetical progression lacks adequate experimental evidence. We previously reported that inoculation of α-Syn preformed fibrils (PFFs) into the gastric wall of wild-type (WT) mice induced LB-like α-Syn aggregates in the dmX via the vagus nerve. However, α-Syn pathology did not spread beyond the dmX up to 12 months postinoculation. In the present study, we inoculated α-Syn PFFs into the gastric wall of bacterial artificial chromosome (BAC) transgenic mice harboring the human α-Syn gene with an A53 T mutation and analyzed the pathology. The transgenic mice had ∼1.5-fold overexpression of α-Syn in the brains and ∼6-fold overexpression of α-Syn in the stomach compared with WT mice. After inoculation of α-Syn PFFs, the transgenic mice developed a higher number of phosphorylated α-Syn (p-α-Syn)–positive neurons in the dmX compared with similarly inoculated WT mice. However, the number of p-α-Syn–positive neurons in the dmX decreased over time, and α-Syn pathology was not observed in other brain regions except in the ambiguous nucleus up to 8 months postinoculation. Taken together, BAC transgenic expression of α-Syn facilitated induction of α-Syn pathology in the brainstem, but not subsequent caudo-rostral spread in accordance with Braak’s hypothesis.

Background Intraneuronal α-synuclein (α-Syn) aggregates known as Lewy bodies (LBs) and the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) are the pathological hallmarks of Parkinson’s disease (PD). Braak’s hypothesis based on autopsy studies suggests that Lewy pathology initially occurs in the enteric nervous system (ENS) and then travels retrogradely to the dorsal motor nucleus of the vagus nerve (dmX), proceeding from there in a caudo-rostral direction. Recent evidence that α-Syn aggregates propagate between interconnected neurons supports this hypothesis. However, there is no direct evidence demonstrating this transmission from the ENS to the dmX and then to the SNpc. Methods We inoculated α-Syn preformed fibrils (PFFs) or phosphate-buffered saline (PBS) into the mouse gastric wall and analyzed the progression of the pathology. Results The mice inoculated with α-Syn PFFs, but not with PBS, developed phosphorylated α-Syn (p-α-Syn)–positive LB-like aggregates in the dmX at 45 days postinoculation. This aggregate formation was completely abolished when vagotomy was performed prior to inoculation of α-Syn PFFs, suggesting that the aggregates in the dmX were retrogradely induced via the vagus nerve. Unexpectedly, the number of neurons containing p-α-Syn–positive aggregates in the dmX decreased over time, and no further caudo-rostral propagation beyond the dmX was observed up to 12 months postinoculation. P-α-Syn–positive aggregates were also present in the myenteric plexus at 12 months postinoculation. However, unlike in patients with PD, there was no cell-type specificity in neurons containing those aggregates in this model. Conclusions: These results indicate that α-Syn PFF inoculation into the mouse gastrointestinal tract can induce α-Syn pathology resembling that of very early PD, but other factors are apparently required if further progression of PD pathology is to be replicated in this animal model. Electronic supplementary material The online version of this article (10.1186/s13024-018-0257-5) contains supplementary material, which is available to authorized users.

Subcortical small vessel disease (SVD) is characterized by white matter damage resulting from arteriolosclerosis and chronic hypoperfusion. Transforming growth factor beta 1 (TGFB1) is dysregulated in the hereditary SVD, CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). However, very little is known about the role of the largest group in the TGFB superfamily – the bone morphogenetic proteins (BMPs) – in SVD pathogenesis. The aim of this study was to characterize signaling abnormalities of BMPs in sporadic SVD. We examined immunostaining of TGFB1 and BMPs (BMP2/BMP4/BMP6/BMP7/BMP9) in a total of 19 post‐mortem human brain samples as follows: 7 SVD patients (4 males, 76–90 years old); 6 Alzheimer's disease (AD) patients (2 males, 67–93 years old) and 6 age‐matched disease controls (3 males, 68–78 years old). We subsequently investigated the effects of oxygen–glucose deprivation and BMP4 addition on cultured cells. Furthermore, adult mice were subjected to chronic cerebral hypoperfusion using bilateral common carotid artery stenosis, followed by continuous intracerebroventricular infusion of the BMP antagonist, noggin. In the SVD cases, BMP4 was highly expressed in white matter pericytes. Oxygen–glucose deprivation induced BMP4 expression in cultured pericytes in vitro. Recombinant BMP4 increased the number of cultured endothelial cells and pericytes and converted oligodendrocyte precursor cells into astrocytes. Chronic cerebral hypoperfusion in vivo also upregulated BMP4 with concomitant white matter astrogliogenesis and reduced oligodendrocyte lineage cells, both of which were suppressed by intracerebroventricular noggin infusion. Our findings suggest ischemic white matter damage evolves in parallel with BMP4 upregulation in pericytes. BMP4 promotes angiogenesis, but induces astrogliogenesis at the expense of oligodendrocyte precursor cell proliferation and maturation, thereby aggravating white matter damage. This may explain white matter vulnerability to chronic hypoperfusion. The regulation of BMP4 signaling is a potential therapeutic strategy for treating SVD.

In this paper, we describe an approach to the analysis and design of power grid dynamic performance based on hybrid systems theory. Power grid is a large-scale cyber-physical system for transmission of electrical energy. The joint dynamics of physical processes and cyber elements in power grids are typical of a mixture of continuous and discrete behaviors, that is, hybrid dynamics. We address problems on stability that are basic concerns in the performance of current and future power grids with the hybrid dynamics. Measures for stability of power grids are interpreted as safety specifications in hybrid system models and are translated into restrictions on the systems' reachable sets of states. Algorithmic reachability analysis of hybrid systems enables analysis of safe initial states and hence quantitative estimation of stability regions. Also it contributes to synthesis of safe initial states as well as switching conditions in order to satisfy safety specifications in a power grid. We demonstrate the approach for two problems on transient stability of the single machine/infinite bus (SMIB) system and on fault release control of a multimachine power grid.

Amaranth seeds can be popped under suitable heating conditions. On the basis of experimental results obtained in our laboratory, we have developed a prototype of a continuous processing system for commercial application. In addition, the effects of gas temperature, flow rate, and feed speed on the popping quality of seeds, such as their volume expansion ratio and yield, were examined. The experimental results showed that the undersized yield ratio increased with the flow speed, whereas it decreased with an increase in the gas temperature. In addition, to achieve a high expansion ratio and maximum output, the feed speed was increased with the gas temperature. Furthermore, measuring the differential pressure in the test section of the experimental apparatus enabled the estimation of the quantity of seeds therein during the popping experiment.

To improve the pinched-off characteristics of an AlGaN/GaN heterojunction field effect transistor (HJFET), the conduction band potential of an incorporated ALxGa1-xN buffer is designed to be upwardly convex in a band diagram. This approach utilizes the polarization effects specific to GaN-based materials by lowering the Al content x from 30% to 5% almost linearly toward the front side. Fabricated field effect transistors (FETs) adopting the designed buffer have demonstrated the following advanced characteristics in comparison to those of a FET adopting a conventional GaN buffer: less than one-tenth of the buffer leakage current, a gate-to-drain breakdown voltage BVgd twice or more as high, and remarkably improved carrier confinement and pinched-off behavior. The FETs are operated in an enhancement mode with a gate-to-channel distance thick enough to prevent tunneling current through the gate.

The structural and magnetic properties of Co2Cr0.6Fe0.4Al (CCFA) thin films epitaxially grown on GaAs substrates by sputtering were investigated. The CCFA film directly grown on GaAs showed a cube-on-cube crystallographic relation, while it was rotated by 45° in the (001) plane when a thin MgO layer was inserted between the CCFA and GaAs. Both samples showed strong magnetic anisotropy, in which a uniaxial anisotropy with an easy axis of [110]GaAs or [1–10]GaAs dominated with a slight cubic anisotropy having easy axes of 〈110〉CCFA superimposed. The uniaxial anisotropy constants were approximately 1.6 times as large as the cubic anisotropy constants for both samples.

Pericytes are embedded within basal lamina and play multiple roles in the perivascular niche in brain. Recently, oligodendrocyte precursor cells (OPCs) have also been reported to associate with cerebral endothelium. Is it possible that within this gliovascular locus, there may also exist potential spatial and functional interactions between pericytes and OPCs? Here, we demonstrated that in the perivascular region of cerebral white matter, pericytes and OPCs may attach and support each other. Immunostaining showed that pericytes and OPCs are localized in close contact with each other in mouse white matter at postnatal days 0, 60 and 240. Electron microscopic analysis confirmed that pericytes attached to OPCs via basal lamina in the perivascular region. The close proximity between these two cell types was also observed in postmortem human brains. Functional interaction between pericytes and OPCs was assessed by in vitro media transfer experiments. When OPC cultures were treated with pericyte-conditioned media, OPC number increased. Similarly, pericyte number increased when pericytes were maintained in OPC-conditioned media. Taken together, our data suggest a potential anatomical and functional interaction between pericytes and OPCs in cerebral white matter.

We have investigated photoluminescence (PL) properties of a high quality GaN thin film grown by metalorganic vapor phase epitaxy under intense excitation conditions in a wide temperature range from 10 to 300 K. It is found that there are two types of PL band peculiar to intense excitation conditions. In a low temperature region below 80 K, the exciton-exciton scattering dominates the PL, the so-called P emission. On the other hand, in a high temperature region above ∼120 K, a PL band, which is different from the P emission, appears. The energy spacing between the new PL band and the fundamental A exciton linearly increases with an increase in temperature. In addition, the energy spacing is estimated to be zero at absolute zero temperature by extrapolation of the temperature dependence. These PL profiles indicate that the PL band observed in the high temperature regime originates from the exciton-electron scattering. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

A small single bubble was generated with a single-hole nozzle facing upward in a water bath contained in a rotating cylindrical vessel. The bubble size falls in the surface tension force dominant regime. The vertical, radial, and tangential migration velocities of the bubble were measured with two CCD cameras and a high-speed video camera. The tangential velocity component of water flow was measured with particle image velocimetry. A helical motion of the bubble was observed under every experimental condition. The direction of the helical motion was the same as that of the tangential velocity component. This helical motion is associated with the large initial shape deformation of the bubble near the nozzle exit and the subsequent regular shedding of vortices behind it. The period and amplitude of the helical motion were obtained by analyzing the trajectory of the bubble. These quantities were non-dimensionalized by the volume equivalent bubble diameter and the terminal bubble velocity in the vertical direction and correlated as functions of the Eotvos number. Empirical equations were proposed for the period and amplitude.

A three-valued D-flip-flop (D-FF) circuit and a two-stage shift register built from InGaAs-based multiple-junction surface tunnel transistors (MJSTT) and Si-based metal-oxide-semiconductor field effect transistors (MOSFET) have been demonstrated. Due to the combination of the MJSTT's latching function and the MOSFET's switching function, the number of devices required for the D-FF circuit was greatly reduced to two from the thirty required for the FET-only circuit.

Effects of annealing ambient of an oxygen and nitrogen mixed gas on the electrical properties were studied for Au-based ohmic contacts (NiAu, CoAu, CuAu, PdAu, and PtAu) to p-type GaN. Addition of oxygen to the nitrogen gas reduced the specific contact resistances (ρc) and resitivities of the p-GaN epilayers (ρs) of the contacts after annealing at temperatures of 500–600°C. The microstructural analysis at the p-GaN/metal interfaces did not detect the heterostructural intermediate semiconductor layer at the GaN/metal interfaces. The reason for reduction of both the ρc and ρs values by the oxygen gas addition was believed to be due to formation of the p-GaN epilayer with high hole concentrations, caused by removal of hydrogen atoms which bonded with Mg atoms.

Fatigue tests were carried out on a shipbuilding-grade rolled steel, prestrained to various degrees up to 85% of its static tensile fracture strain. It is observed that prestraining degrades the fatigue life in the domain of low-cycle fatigue, but this effect is not apparent in the medium-to-high cycle fatigue regime. A set of equations has been developed to assess the behaviour of tensile prestrained materials for the entire range from low-to-high cycle fatigue. The data acquired in this study validate the authenticity of these formulae sufficiently well.

In Japan, elderly disorders and diseases have markedly increased in recent years, because of rapid aging and an increasing number of older persons. The situation is creating serious social and community problems. These disorders, particularly dysuria and urinary incontinence (UI), disturb the quality of life (QOL) in latelife. Few reports on UI have been published, but precise investigation into the community level remains to be made. Our presentation is the development, implementation and evaluation of elderly UI in Kumamoto Prefecture. This study includes 2,304 people (male: 856, female: 1,448), over 65 years of age, living in two different communities; one is an urban (K) and the other is a typical rural area (S). The rate of UI was in homebound elderly persons, male: 4.7%, female: 11.3%, and in nursing home residents, male: 16.2%, female: 23.2%. The condition of UI was: almost Urinary Urgency in male (61.5%), and Stress Incontinence (such as, caused by coughing, sneezing, and exercise) in female (46.3%). The influence of UI on the activity of daily life was investigated. Most of the male cases were giving concerns for family and community. In contrast, females hesited to participate in group excursions and outdoor exercise, and had a tendency to live alone or indoors. However, most persons (81.5%) with UI did not visit a physician. From this investigation, we conclude that a community health care program and public support system are essential for proper understanding and solution of the elderly UI problem.