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The link between changes in astrocyte function and the pathological progression of Alzheimer's disease (AD) has attracted considerable attention. Interestingly, activated astrocytes in AD show abnormalities in their lipid content and metabolism. In particular, the expression of apolipoprotein E (ApoE), a lipid transporter, is decreased. Because ApoE has anti-inflammatory and amyloid β (Aβ)-metabolizing effects, the nuclear receptors, retinoid X receptor (RXR) and LXR, which are involved in ApoE expression, are considered promising therapeutic targets for AD. However, the therapeutic effects of agents targeting these receptors are limited or vary considerably among groups, indicating the involvement of an unknown pathological factor that modifies astrocyte and ApoE function. Here, we focused on the signaling lipid, sphingosine-1-phosphate (S1P), which is mainly produced by sphingosine kinase 2 (SphK2) in the brain. Using astrocyte models, we found that upregulation of SphK2/S1P signaling suppressed ApoE induction by both RXR and LXR agonists. We also found that SphK2 activation reduced RXR binding to the APOE promoter region in the nucleus, suggesting the nuclear function of SphK2/S1P. Intriguingly, suppression of SphK2 activity by RNA knockdown or specific inhibitors upregulated lipidated ApoE induction. Furthermore, the induced ApoE facilitates Aβ uptake in astrocytes. Together with our previous findings that SphK2 activity is upregulated in AD brain and promotes Aβ production in neurons, these results indicate that SphK2/S1P signaling is a promising multifunctional therapeutic target for AD that can modulate astrocyte function by stabilizing the effects of RXR and LXR agonists, and simultaneously regulate neuronal pathogenesis.

Here the authors demonstrate that de novo DNA methylation mediated by DNMT3B is regulated by nitric oxide (NO). They also isolate a unique modulator (DBIC) that inhibits S-nitrosylation of DNMT3B, which mitigates cell proliferation and tumorigenic conversion in vivo.

Objective: The prognosis of and optimal treatment for grade 3 endometrioid endometrial carcinoma (G3EEC) currently remain unclear. This study aimed to clarify the baseline recurrence risk in patients with early-stage (stage I–II) G3EEC without adjuvant therapy and the prognosis of patients with advanced-stage (stage III–IV) G3EEC. Materials and methods: A total of 101 patients with pathologically confirmed G3EEC from 1997 to 2018 were identified. Their clinicopathological characteristics and survival outcomes were reviewed retrospectively. Disease-free survival and overall survival values were estimated according to the Kaplan–Meier method and compared using a log-rank test. Results: Recurrence was observed in eight (13%) of 63 patients with early-stage G3EEC, none of whom had received adjuvant therapy. The 5-year disease-free survival and 5-year overall survival rates for these patients were 86.7% and 96.4%, respectively. Recurrence was also observed in 12 (41%) of 29 patients with stage III G3EEC. The 5-year overall survival rates for stage III patients who underwent adjuvant chemotherapy and adjuvant radiotherapy were 85.6% and 42.9%, respectively. The 3-year overall survival rate among stage IVB patients was only 12.7% despite multidisciplinary treatment provision. Conclusion: Our study newly demonstrates that patients with early-stage G3EEC have a favorable prognosis and a low recurrence rate in the absence of adjuvant therapy. In patients with stage III G3EEC, adjuvant chemotherapy was more beneficial than adjuvant radiotherapy. The poor prognosis of patients with stage IV G3EEC indicates the need for more effective treatments. Unique therapeutic approaches based on staging are recommended for treatment of G3EEC.

Summary: Endosomal anomalies because of vesicular traffic impairment have been indicated as an early pathology of Alzheimer’| disease (AD). However, the mechanisms and therapeutic targets remain unclear. We previously reported that βCTF, one of the pathogenic metabolites of APP, interacts with TMEM30A. TMEM30A constitutes a lipid flippase with P4-ATPase and regulates vesicular trafficking through the asymmetric distribution of phospholipids. Therefore, the alteration of lipid flippase activity in AD pathology has got attention. Herein, we showed that the interaction between βCTF and TMEM30A suppresses the physiological formation and activity of lipid flippase in AD model cells, A7, and AppNL−G-F/NL−G-F model mice. Furthermore, the T-RAP peptide derived from the βCTF binding site of TMEM30A improved endosomal anomalies, which could be a result of the restored lipid flippase activity. Our results provide insights into the mechanisms of vesicular traffic impairment and suggest a therapeutic target for AD.

Antipsychotic medications based on the dopamine hypothesis possess limited effects for negative symptoms and cognitive impairments of schizophrenia. Growing body of evidence suggests that redox dysregulation contributes to the pathophysiology of the illness. We synthesized new chemicals using apocynin and tandospirone as leading compounds, and tested their antioxidant properties. The new compounds (A-1, A-2, A-3, and A-4), olanzapine (OLA), and clozapine (CLZ) were examined in terms of the ⋅OH radical decreasing activity and the effects on intracellular reactive oxygen species (ROS) formation induced by X-irradiation in human lymphoma U937 cells. The effects of these drugs, given around the period of puberty (postnatal days; PD 49 to 62), on glutathione (GSH) levels, as well as the number of parvalbumin (PV)-positive γ-aminobutyric acid (GABA) interneurons were evaluated in the medial prefrontal cortex (mPFC) of rats transiently exposed to MK-801 in the neonatal period. A-2, A-3, A-4, OLA, and CLZ decreased intracellular ⋅OH and OCl−. The novel compounds reversed the decrease in GSH concentrations and reduction of PV-positive neurons in the mPFC in the model rats. CLZ only decreased GSH levels while OLA did not show a significant effect on either measure. These findings suggest that the new compounds derived from apocynin and tandospirone elicit antioxidant properties, and may provide a novel therapeutic approach for the treatment of schizophrenia and its spectrum disorders.

Aducanumab, co-developed by Eisai (Japan) and Biogen (U.S.), has received Food and Drug Administration approval for treating Alzheimer’s disease (AD). In addition, its successor antibody, lecanemab, has been approved. These antibodies target the aggregated form of the small peptide, amyloid-β (Aβ), which accumulates in the patient brain. The “amyloid hypothesis” based therapy that places the aggregation and toxicity of Aβ at the center of the etiology is about to be realized. However, the effects of immunotherapy are still limited, suggesting the need to reconsider this hypothesis. Aβ is produced from a type-I transmembrane protein, Aβ precursor protein (APP). One of the APP metabolites, the 99-amino acids C-terminal fragment (C99, also called βCTF), is a direct precursor of Aβ and accumulates in the AD patient’s brain to demonstrate toxicity independent of Aβ. Conventional drug discovery strategies have focused on Aβ toxicity on the “outside” of the neuron, but C99 accumulation might explain the toxicity on the “inside” of the neuron, which was overlooked in the hypothesis. Furthermore, the common region of C99 and Aβ is a promising target for multifunctional AD drugs. This review aimed to outline the nature, metabolism, and impact of C99 on AD pathogenesis and discuss whether it could be a therapeutic target complementing the amyloid hypothesis.

Abstract Background and Objectives The aim of this study was to determine whether peritoneal washing cytology (PWC) during interval debulking surgery (IDS) could predict the prognosis of patients with pelvic high‐grade serous carcinoma (HGSC) achieving R0 status. Methods Between January 2007 and May 2018, 110 patients with ovarian/tubal/primary peritoneal HGSC received platinum‐based neo‐adjuvant chemotherapy, followed by IDS at National Cancer Center Hospital, Japan. All the patients achieved R0 debulking status, defined as no macroscopic residual tumor in the peritoneal cavity at the completion of IDS. PWC was performed before debulking during IDS. The survival outcomes were compared between the PWC‐positive and PWC‐negative groups. Results The median progression free survival (PFS) for the entire cohort was 17 months (range, 5‐133 months). The median PFS for the PWC‐positive group was significantly shorter than that of the PWC‐negative group (16 vs 19 months, HR 2.04, 95% CI 1.22‐3.41, P‐value

A solitary pelvic tumor after treating a primary endometriosis-related neoplasm is usually considered a recurrence but may actually be a primary endometriosis-related peritoneal neoplasm. A Japanese woman in her late 60s was referred to our hospital for a solitary pelvic tumor. The tumor was suspected as a recurrence of a previously treated stage IA ovarian clear-cell carcinoma, and resected. Pathological analysis revealed that the tumor was a peritoneal seromucinous carcinoma associated with pelvic endometriosis. Both tumors displayed distinct histopathologies, although both neoplasms were endometriosis related. An apparent recurrent tumor after treating of an endometriosis-related neoplasm might not be a true recurrent tumor but a second primary endometriosis-related neoplasm. Histological confirmation is indicated in such cases. Keywords: Clear cell carcinoma, Endometriosis, Endometriosis-related neoplasm, Ovarian cancer, Seromucinous carcinoma

Screening methods for early detection of ovarian cancer is technically difficult. Here, the authors investigated circulating microRNA in human blood serum and developed a model using 10 microRNAs to discern between ovarian cancer and being ovarian tumors, solid tumors, and non-cancer patients.

Abstract Background Motor conversion disorders are characterized by movement symptoms without a neurological cause. A psychogenic etiology is presumed for these disorders, but little is known about their underlying neural mechanisms. Functional magnetic resonance imaging (fMRI) has been utilized to understand the mechanisms associated with unexplained motor symptoms. Here, we used fMRI to investigate the cerebral response to motor stimulation in a patient with conversion disorder with motor paralysis to determine the underlying neural mechanisms of this disorder. Methods Brain activation induced by movements of the bilateral ankle joints (repeated plantar flexion and dorsiflexion) was recorded using fMRI in a patient with conversion disorder with unexplained motor paralysis. We acquired 2 types of imaging data: (i) data obtained while motor paralysis remained present and (ii) data obtained after motor paralysis had completely improved. We used a within‐subject fMRI block design to compare the patient's brain activities during the motor task and at rest. Results Cerebral motor areas were significantly activated during the motor task relative to at rest, both when motor paralysis remained present and when paralysis had improved (FWE‐corrected P

Abstract Ayu fish form feeding territories during a non-breeding (growing) season. When the density of the fish increases, phases gradually change. In the early growing season, all fish can hold territories at low density. Once all territory sites are occupied, newcomers become floaters. As the density further increases, territory holders have to spend much more time in defending their own territory and lose the time to feed on algae. Eventually, all fish give up their own territories and then form a school. In contrast, when the density decreases, territories are directly reformed from the school. In short, ayu fish exhibit a different transition, called hysteresis, where the two transitions occur widely-apart from each other. The dynamics of this intrinsic phenomena has not been demonstrated in previous studies. We develop a rate equation to describe the population dynamics within territorial competition. Our model successfully reproduces territorial hysteresis and indicates that territory holders and floaters can coexist only in the process of population growth. Moreover, we also find that the two critical densities of territorial hysteresis are conspicuously different from each other when the increase of the density of floaters sharply influences (step-function-like) the territories.

Abstract Electrophiles can activate redox signal transduction pathways, through actions of effector molecules (e.g., kinases and transcription factors) and sensor proteins with low pKa thiols that are covalently modified. In this study, we investigated whether 1,4-naphthoquinone (1,4-NQ) could affect the phosphatase and tensin homolog (PTEN)–Akt signaling pathway and persulfides/polysulfides could modulate this adaptive response. Simultaneous exposure of primary mouse hepatocytes to Na2S4 and 1,4-NQ markedly decreased 1,4-NQ-mediated cell death and S-arylation of cellular proteins. Modification of cellular PTEN during exposure to 1,4-NQ was also blocked in the presence of Na2S4. 1,4-NQ, at up to 10 µM, increased phosphorylation of Akt and cAMP response element binding protein (CREB). However, at higher concentrations, 1,4-NQ inhibited phosphorylation of both proteins. These bell-shaped dose curves for Akt and CREB activation were right-shifted in cells treated with both 1,4-NQ and Na2S4. Incubation of 1,4-NQ with Na2S4 resulted in formation of 1,4-NQ–S–1,4-NQ-OH. Unlike 1,4-NQ, authentic 1,4-NQ-S-1,4-NQ-OH adduct had no cytotoxicity, covalent binding capability nor ability to activate PTEN-Akt signaling in cells. Our results suggested that polysulfides, such as Na2S4, can increase the threshold of 1,4-NQ for activating PTEN–Akt signaling and cytotoxicity by capturing this electrophile to form its sulfur adducts.

Cognitive impairments are a core feature in schizophrenia patients (SCZ) and are also observed in first-degree relatives (FR) of SCZ. However, substantial variability in the impairments exists within and among SCZ, FR and healthy controls (HC). A cluster-analytic approach can group individuals based on profiles of traits and create more homogeneous groupings than predefined categories. Here, we investigated differences in the Brief Assessment of Cognition in Schizophrenia (BACS) neuropsychological battery (six subscales) among SCZ, unaffected FR and HC. To identify three homogeneous and meaningful cognitive groups regardless of categorical diagnoses (SCZ, FR and HC), cognitive clustering was performed, and differences in the BACS subscales among the cognitive cluster groups were investigated. Finally, the effects of diagnosis and cognition on brain volumes were examined. As expected, there were significant differences in the five BACS subscales among the diagnostic groups. The cluster-analytic approach generated three meaningful subgroups: (i) neuropsychologically normal, (ii) intermediate impaired and (iii) widespread impaired. The cognitive subgroups were mainly affected by the clinical diagnosis, and significant differences in all BACS subscales among clusters were found. The effects of the diagnosis and cognitive clusters on brain volumes overlapped in the frontal, temporal and limbic regions. Frontal and temporal volumes were mainly affected by the diagnosis, whereas the anterior cingulate cortex (ACC) volumes were affected by the additive effects of diagnosis and cognition. Our findings demonstrate a cognitive continuum among SCZ, FR and HC and support the concept of cognitive impairment and the related ACC volumes as intermediate phenotypes in SCZ. Keywords: Schizophrenia, First-degree relative, Cognitive clustering, Brain volume, Anterior cingulate cortex

BackgroundA recent review reported that the median proportion of patients recovering from schizophrenia was 13.5% and that this did not change over time. Various factors including the duration of untreated psychosis, cognitive impairment, negative symptoms, and morphological changes in the brain influence the functional outcome of schizophrenia. The authors herein reviewed morphological changes in the brain of schizophrenia patients, effects of early intervention, and a direction of developing novel therapeutics to achieve significant improvement of the functional outcome.MethodsA selective review of the literature including studies from our department was performed.ResultsLongitudinal structural neuroimaging studies on schizophrenia revealed that volume reductions in the peri-Sylvian regions (e.g., superior temporal gyrus and insula), which are related to positive psychotic symptoms, progress around the onset (critical stage) of schizophrenia, but become stable in the chronic stage. On the other hand, morphological changes in the fronto-thalamic regions and lateral ventricle, which are related to negative symptoms, neurocognitive dysfunction, and the functional outcome, progress during both the critical and chronic stages. These changes in the peri-Sylvian and fronto-thalamic regions may provide a pathophysiological basis for Crow’s two-syndrome classification. Accumulated evidence from early intervention trials suggests that the transition risk from an at-risk mental state (ARMS) to psychosis is approximately 30%. Differences in the cognitive performance, event-related potentials (e.g., mismatch negativity), and brain morphology have been reported between ARMS subjects who later developed psychosis and those who did not. Whether early intervention for ARMS significantly improves the long-term recovery rate of schizophrenia patients remains unknown. With respect to the development of novel therapeutics, animal models of schizophrenia based on the N-methyl-d-aspartate receptor hypofunction hypothesis successfully mimicked behavioral changes associated with cognitive impairments characteristic of the disease. Furthermore, these animal models elicited histological changes in the brain similar to those observed in schizophrenia patients, i.e., decreased numbers of parvalbumin-positive interneurons and dendritic spines of pyramidal neurons in the frontal cortex. Some antioxidant compounds were found to ameliorate these behavioral and histological abnormalities.ConclusionEarly intervention coupled with novel therapeutics may offer a promising approach for substantial improvement of the functional outcome of schizophrenia patients.

In Japan, which is thought to be a rapidly growing super-aging society, a national campaign named "the Dementia Supporter Caravan" has been deployed. The aim of this study was to assess the educational benefits of the dementia supporter training program for nurses and nursing students. We conducted dementia supporter training, and measured knowledge and attitudes regarding people with dementia as educational benefits pre- and post-training. Data sets of 134 nursing students and 63 nurses were analyzed. The results indicated that the two groups gained knowledge, understanding, and the confidence to care for people with dementia after attending the dementia supporter training program. Moreover, the two groups derived different benefits from the program. Nursing students gained substantial knowledge and learnt the importance of early detection and treatment, to levels similar to those of nurses prior to training. The training program reduced the difficulties of nurses to interact with and care for people with dementia. We can conclude that the dementia supporter training program has considerable educational benefits for nurses and nursing students.

Although the aggregation of amyloid-β peptide (Aβ) clearly plays a central role in the pathogenesis of Alzheimer's disease (AD), endosomal traffic dysfunction is considered to precede Aβ aggregation and trigger AD pathogenesis. A body of evidence suggests that the β-carboxyl-terminal fragment (βCTF) of amyloid-β precursor protein (APP), which is the direct precursor of Aβ, accumulates in endosomes and causes vesicular traffic impairment. However, the mechanism underlying this impairment remains unclear. Here we identified TMEM30A as a candidate partner for βCTF. TMEM30A is a subcomponent of lipid flippase that translocates phospholipids from the outer to the inner leaflet of the lipid bilayer. TMEM30A physically interacts with βCTF in endosomes and may impair vesicular traffic, leading to abnormally enlarged endosomes. APP traffic is also concomitantly impaired, resulting in the accumulation of APP-CTFs, including βCTF. In addition, we found that expressed BACE1 accumulated in enlarged endosomes and increased Aβ production. Our data suggested that TMEM30A is involved in βCTF-dependent endosome abnormalities that are related to Aβ overproduction.

Accumulating evidence indicates a pivotal role for neuroinflammation in ischemic and excitotoxic brain injury. Cytokine-induced neutrophil chemoattractant-1 (CINC-1) is a CXC chemokine implicated in the infiltration of inflammatory cells into the brain parenchyma. In this study, we investigated the effect of N-methyl-D-aspartate (NMDA)-induced neuronal injury on CINC-1 production in the organotypic cortico-striatal slice cultures. Treatment with 50 μM NMDA for 3 – 4 h caused devastating neuronal damage and increased CINC-1 production. Immunohistochemical analysis revealed that the CINC-1 immunoreactivity was predominantly detected in astrocytes. NMDA failed to induce CINC-1 production in enriched astrocyte cultures or neuron-depleted slice cultures, suggesting that NMDA acted on neuronal cells to induce astrocytic CINC-1 production. NMDA-induced CINC-1 mRNA expression was significantly inhibited by U0126, a mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor. These results suggest that NMDA-evoked neuronal injury induced astrocytic CINC-1 production via a MEK/ERK signaling pathway. Manipulation of this signaling pathway may serve as a target for suppressing neuroinflammation and, thereby, treating ischemic brain injury. Keywords:: astrocyte, chemokine, N-methyl-D-aspartate (NMDA), mitogen-activated protein (MAP) kinase, organotypic slice culture

The number of patients with schizophrenia has increased over the past decade. Previously, many studies have been performed to establish its diagnostic criteria, prophylactic methods, and effective therapies. In this study, we analyzed whether the ratios of DNA methylation in CpG islands of the Shati/Nat8l is decreased in model mice of schizophrenia-like phenotype using genomic DNA collected from brain regions and peripheral blood, since the mouse model of schizophrenia-like phenotype, mice treated repeatedly with methamphetamine showed increase of Shati/Nat8l mRNA expression in our previous experiment. The ratios of Shati/Nat8l CpG island methylation were significantly decreased in both the nucleus accumbens and the peripheral blood of model mice compared with those of control mice. We also investigated Shati/Nat8l methylation in the blood of patients with schizophrenia. We found that Shati/Nat8l CpG island methylation ratios were lower in the patients with schizophrenia than in the healthy controls, which is consistent with our findings in the mice model. To our knowledge, this is the first study to show similar alterations in methylation status of a particular genomic DNA site in both the brain and peripheral blood of mice. Furthermore, the same phenomenon was observed in corresponding human genomic sequences of the DNA extracted from the peripheral blood of patients with schizophrenia. Based on our findings, DNA methylation profiles of the CpG island of Shati/Nat8l might be a diagnostic biomarker of schizophrenia.

The conservation of aquatic plants in river ecosystems should consider the wash-out (away) problem resulting from severe rainfall. The aquatic plant Schoenoplectus gemmifer is an endangered species endemic to Japan. Our previous study reported that the population size of S. gemmifer in Hamamatsu city, Japan, had decreased by one-tenth because many individuals had been washed out by a series of heavy rains in 2004. However, there is insufficient information on the ecological nature of this endangered aquatic plant for adequate conservation. In this paper, we report the population dynamics of one population in Hamamatsu city from 2004 to 2012 in relation to rainfall. We surveyed the number and growing location of all living individuals in the population 300 times during the study period. To examine the temporal changes of individual plants, we also counted the number of culms for 38 individuals in four observations among 300 records. Decreases and increases in the population size of this plant were associated with washing out and the settlement of gemmae (vegetative propagation), respectively. The major cause of the reduction in the population size was an increase in the number of washed-out individuals and not the decreased settlement of gemmae. The wash-out rates for small and large individuals were not significantly different. Small individuals having a stream form with linear leaves resisted flooding, and large individuals were often partially torn off by flooding events. Modification of river basins to reduce the flow velocity may be effective for the conservation of S. gemmifer.

Tropical rainforests are known for their extreme biodiversity, posing a challenging problem in tropical ecology. Many hypotheses have been proposed to explain the diversity of tree species, yet our understanding of this phenomenon remains incomplete. Here, we consider the contribution of animal seed dispersers to the species diversity of trees. We built a multi-layer lattice model of trees whose animal seed dispersers are allowed to move only in restricted areas to disperse the tree seeds. We incorporated the effects of seed dispersers in the traditional theory of allopatric speciation on a geological time scale. We modified the lattice model to explicitly examine the coexistence of new tree species and the resulting high biodiversity. The results indicate that both the coexistence and diversified evolution of tree species can be explained by the introduction of animal seed dispersers.