担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation. METHODS: An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses. FINDINGS: Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children. INTERPRETATION: Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology. FUNDING: This study was supported mainly by MEXT, Japan.

添付ファイル： 1-s2.0-S2352396420302929-main.pdf

DOI： 10.1016/j.ebiom.2020.102917

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Recent discussions of human brain evolution have largely focused on increased neuron numbers and changes in their connectivity and expression. However, it is increasingly appreciated that oligodendrocytes play important roles in cognitive function and disease. Whether both cell types follow similar or distinctive evolutionary trajectories is not known. We examined the transcriptomes of neurons and oligodendrocytes in the frontal cortex of humans, chimpanzees, and rhesus macaques. We identified human-specific trajectories of gene expression in neurons and oligodendrocytes and show that both cell types exhibit human-specific up-regulation. Moreover, oligodendrocytes have undergone more pronounced accelerated gene expression evolution in the human lineage compared to neurons. We highlighted human-specific coexpression networks with specific functions. Our data suggest that oligodendrocyte human-specific networks are enriched for alternative splicing and transcriptional regulation. Oligodendrocyte networks are also enriched for variants associated with schizophrenia and other neuropsychiatric disorders. Such enrichments were not found in neuronal networks. These results offer a glimpse into the molecular mechanisms of oligodendrocytes during evolution and how such mechanisms are associated with neuropsychiatric disorders.

添付ファイル： berto-et-al-accelerated-evolution-of-oligodendrocytes-in-the-human-brain.pdf

DOI： 10.1073/pnas.1907982116

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The importance of cell type-specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generate cell type-specific whole-genome methylomes (N = 95) and transcriptomes (N = 89) from neurons and oligodendrocytes obtained from brain tissue of patients with schizophrenia and matched controls. RESULTS: The methylomes of the two cell types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation differences between cases and controls are subtle compared to cell type differences, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell type differentially methylated sites, highlighting the significance of cell type-specific epigenetic dysregulation in a complex neuropsychiatric disorder. CONCLUSIONS: Our results provide novel and comprehensive methylome and transcriptome data from distinct cell populations within patient-derived brain tissues. This data clearly demonstrate that cell type epigenetic-differentiated sites are preferentially targeted by disease-associated epigenetic dysregulation. We further show reduced cell type epigenetic distinction in schizophrenia.

添付ファイル： s13059-019-1747-7.pdf

DOI： 10.1186/s13059-019-1747-7

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Copy-number variants of chromosome 16 region 16p11.2 are linked to neuropsychiatric disorders and are among the most prevalent in autism spectrum disorders. Of many 16p11.2 genes, Kctd13 has been implicated as a major driver of neurodevelopmental phenotypes. The function of KCTD13 in the mammalian brain, however, remains unknown. Here we delete the Kctd13 gene in mice and demonstrate reduced synaptic transmission. Reduced synaptic transmission correlates with increased levels of Ras homolog gene family, member A (RhoA), a KCTD13/CUL3 ubiquitin ligase substrate, and is reversed by RhoA inhibition, suggesting increased RhoA as an important mechanism. In contrast to a previous knockdown study, deletion of Kctd13 or kctd13 does not increase brain size or neurogenesis in mice or zebrafish, respectively. These findings implicate Kctd13 in the regulation of neuronal function relevant to neuropsychiatric disorders and clarify the role of Kctd13 in neurogenesis and brain size. Our data also reveal a potential role for RhoA as a therapeutic target in disorders associated with KCTD13 deletion.

添付ファイル： nature24470.pdf

DOI： 10.1038/nature24470

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The molecular mechanisms underlying human brain evolution are not fully understood; however, previous work suggested that expression of the transcription factor CLOCK in the human cortex might be relevant to human cognition and disease. In this study, we investigated this novel transcriptional role for CLOCK in human neurons by performing chromatin immunoprecipitation sequencing for endogenous CLOCK in adult neocortices and RNA sequencing following CLOCK knockdown in differentiated human neurons in vitro. These data suggested that CLOCK regulates the expression of genes involved in neuronal migration, and a functional assay showed that CLOCK knockdown increased neuronal migratory distance. Furthermore, dysregulation of CLOCK disrupts coexpressed networks of genes implicated in neuropsychiatric disorders, and the expression of these networks is driven by hub genes with human-specific patterns of expression. These data support a role for CLOCK-regulated transcriptional cascades involved in human brain evolution and function.

添付ファイル： Genes Dev.-2017-Fontenot-2121-35.pdf

DOI： 10.1101/gad.305813.117

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

The molecular mechanisms driving brain development at risk in autism spectrum disorders (ASDs) remain mostly unknown. Previous studies have implicated the transcription factor FOXP1 in both brain development and ASD pathophysiology. However, the specific molecular pathways both upstream of and downstream from FOXP1 are not fully understood. To elucidate the contribution of FOXP1-mediated signaling to brain development and, in particular, neocortical development, we generated forebrain-specific Foxp1 conditional knockout mice. We show that deletion of Foxp1 in the developing forebrain leads to impairments in neonatal vocalizations as well as neocortical cytoarchitectonic alterations via neuronal positioning and migration. Using a genomics approach, we identified the transcriptional networks regulated by Foxp1 in the developing neocortex and found that such networks are enriched for downstream targets involved in neurogenesis and neuronal migration. We also uncovered mechanistic insight into Foxp1 function by demonstrating that sumoylation of Foxp1 during embryonic brain development is necessary for mediating proper interactions between Foxp1 and the NuRD complex. Furthermore, we demonstrated that sumoylation of Foxp1 affects neuronal differentiation and migration in the developing neocortex. Together, these data provide critical mechanistic insights into the function of FOXP1 in the developing neocortex and may reveal molecular pathways at risk in ASD.

添付ファイル： Genes Dev.-2017-Usui-2039-55.pdf

DOI： 10.1101/gad.305037.117

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Mutations in the gene encoding the transcription factor forkhead box P2 (FOXP2) result in brain developmental abnormalities, including reduced gray matter in both human patients and rodent models and speech and language deficits. However, neither the region-specific function of FOXP2 in the brain, in particular the cerebellum, nor the effects of any posttranslational modifications of FOXP2 in the brain and disorders have been explored. METHODS: We characterized sumoylation of FOXP2 biochemically and analyzed the region-specific function and sumoylation of FOXP2 in the developing mouse cerebellum. Using in utero electroporation to manipulate the sumoylation state of FOXP2 as well as Foxp2 expression levels in Purkinje cells of the cerebellum in vivo, we reduced Foxp2 expression approximately 40% in the mouse cerebellum. Such a reduction approximates the haploinsufficiency observed in human patients who demonstrate speech and language impairments. RESULTS: We identified sumoylation of FOXP2 at K674 (K673 in mice) in the cerebellum of neonates. In vitro co-immunoprecipitation and in vivo colocalization experiments suggest that PIAS3 acts as the small ubiquitin-like modifier E3 ligase for FOXP2 sumoylation. This sumoylation modifies transcriptional regulation by FOXP2. We demonstrated that FOXP2 sumoylation is required for regulation of cerebellar motor function and vocal communication, likely through dendritic outgrowth and arborization of Purkinje cells in the mouse cerebellum. CONCLUSIONS: Sumoylation of FOXP2 in neonatal mouse cerebellum regulates Purkinje cell development and motor functions and vocal communication, demonstrating evidence for sumoylation in regulating mammalian behaviors.

添付ファイル： 1-s2.0-S0006322316000950-main.pdf

DOI： 10.1016/j.biopsych.2016.02.008

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The recent Zika virus (ZIKV) outbreak in the Western hemisphere is associated with severe pathology in newborns, including microcephaly and brain damage. The mechanisms underlying these outcomes are under intense investigation. Here, we show that a 2015 ZIKV isolate replicates in multiple cell types, including primary human fetal neural progenitors (hNPs). In immortalized cells, ZIKV is cytopathic and grossly rearranges endoplasmic reticulum membranes similar to other flaviviruses. In hNPs, ZIKV infection has a partial cytopathic phase characterized by cell rounding, pyknosis, and activation of caspase 3. Despite notable cell death, ZIKV did not activate a cytokine response in hNPs. This lack of cell intrinsic immunity to ZIKV is consistent with our observation that virus replication persists in hNPs for at least 28 days. These findings, supported by published fetal neuropathology, establish a proof-of-concept that neural progenitors in the developing human fetus can be direct targets of detrimental ZIKV-induced pathology.

添付ファイル： 1-s2.0-S221112471630688X-main.pdf

DOI： 10.1016/j.celrep.2016.05.075

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sensory neurons possess the central and peripheral branches and they form unique spinal neural circuits with motoneurons during development. Peripheral branches of sensory axons fasciculate with the motor axons that extend toward the peripheral muscles from the central nervous system (CNS), whereas the central branches of proprioceptive sensory neurons directly innervate motoneurons. Although anatomically well documented, the molecular mechanism underlying sensory-motor interaction during neural circuit formation is not fully understood. To investigate the role of motoneuron on sensory neuron development, we analyzed sensory neuron phenotypes in the dorsal root ganglia (DRG) of Olig2 knockout (KO) mouse embryos, which lack motoneurons. We found an increased number of apoptotic cells in the DRG of Olig2 KO embryos at embryonic day (E) 10.5. Furthermore, abnormal axonal projections of sensory neurons were observed in both the peripheral branches at E10.5 and central branches at E15.5. To understand the motoneuron-derived factor that regulates sensory neuron development, we focused on neurotrophin 3 (Ntf3; NT-3), because Ntf3 and its receptors (Trk) are strongly expressed in motoneurons and sensory neurons, respectively. The significance of motoneuron-derived Ntf3 was analyzed using Ntf3 conditional knockout (cKO) embryos, in which we observed increased apoptosis and abnormal projection of the central branch innervating motoneuron, the phenotypes being apparently comparable with that of Olig2 KO embryos. Taken together, we show that the motoneuron is a functional source of Ntf3 and motoneuron-derived Ntf3 is an essential pre-target neurotrophin for survival and axonal projection of sensory neurons.

添付ファイル： 1125.pdf

DOI： 10.1242/dev.069997

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

添付ファイル： s41598-025-10476-2.pdf

DOI： 10.1038/s41598-025-10476-2

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その他リンク： https://www.nature.com/articles/s41598-025-10476-2

担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

Neurotoxins have been extensively investigated, particularly in the field of neuroscience. They induce toxic damage, oxidative stress, and inflammation on neurons, triggering neuronal dysfunction and neurodegenerative diseases. Here we demonstrate the neuroprotective effect of a silicon (Si)-based hydrogen-producing agent (Si-based agent) in a juvenile neurotoxic mouse model induced by 6-hydroxydopamine (6-OHDA). The Si-based agent produces hydrogen in bowels and functions as an antioxidant and anti-inflammatory agent. However, the effects of the Si-based agent on neural degeneration in areas other than the lesion and behavioral alterations caused by it are largely unknown. Moreover, the neuroprotective effects of Si-based agent in the context of lactation and use during infancy have not been explored in prior studies. In this study, we show the neuroprotective effect of the Si-based agent on 6-OHDA during lactation period and infancy using the mouse model. The Si-based agent safeguards against the degradation and neuronal cell death of dopaminergic neurons and loss of dopaminergic fibers in the striatum (STR) and ventral tegmental area (VTA) caused by 6-OHDA. Furthermore, the Si-based agent exhibits a neuroprotective effect on the length of axon initial segment (AIS) in the layer 2/3 (L2/3) neurons of the medial prefrontal cortex (mPFC). As a result, the Si-based agent mitigates hyperactive behavior in a juvenile neurotoxic mouse model induced by 6-OHDA. These results suggest that the Si-based agent serves as an effective neuroprotectant and antioxidant against neurotoxic effects in the brain, offering the possibility of the Si-based agent as a neuroprotectant for nervous system diseases.

添付ファイル： 1-s2.0-S0166432824001967-main.pdf

DOI： 10.1016/j.bbr.2024.115040

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Sociality is an instinctive property of organisms that live in relation to others and is a complex characteristic of higher order brain functions. However, the evolution of the human brain to acquire higher order brain functions, such as sociality, and the neural basis for executing these functions and their control mechanisms are largely unknown. Several studies have attempted to evaluate how human sociality was acquired during the course of evolution and the mechanisms controlling sociality from a neurodevelopment viewpoint. This review discusses these findings in the context of human brain evolution and the pathophysiology of autism spectrum disorder (ASD). Comparative genomic studies of postmortem primate brains have demonstrated human-specific regulatory mechanisms underlying higher order brain functions, providing evidence for the contribution of oligodendrocytes to human brain function. Functional analyses of the causative genes of ASD in animal models have demonstrated that the neural basis of social behavior is associated with layer 6 (L6) of the neocortex and oligodendrocytes. These findings demonstrate that both neurons and oligodendrocytes contribute to the neural basis and molecular mechanisms underlying human brain evolution and social functioning. This review provides novel insights into sociability and the corresponding neural bases of brain disorders and evolution.

添付ファイル： s12565-023-00747-1.pdf

DOI： 10.1007/s12565-023-00747-1

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その他リンク： https://link.springer.com/article/10.1007/s12565-023-00747-1/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

添付ファイル： 1-s2.0-S2666354623000443-main.pdf

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

添付ファイル： 1-s2.0-S0278584623000696-main.pdf

DOI： 10.1016/j.pnpbp.2023.110783

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

添付ファイル： ijms-24-05487-v2.pdf

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

添付ファイル： ijms-24-02203-v2.pdf

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Methamphetamine (METH) is a psychostimulant drug that induces addiction. Previous epidemiological studies have demonstrated that maternal METH abuse during pregnancy causes low birthweight (LBW) in the offspring. As a source of essential nutrients, in particular glucose, the placenta plays a key role in fetal development. LBW leads to health problems such as obesity, diabetes, and neurodevelopmental disorders (NDDs). However, the detailed mechanism underlying offspring’s LBW and health hazards caused by METH are not fully understood. Therefore, we investigated the effects of prenatal METH exposure on LBW and fetal-placental relationship by focusing on metabolism. We found dysfunction of insulin production in the pancreas of fetuses exposed to METH. We also found a reduction of the glycogen cells (GCs) storing glycogens in the junctional zone of placenta, all of which suggest abnormal glucose metabolism affects the fetal development. These results suggest that dysfunction in fetal glucose metabolism may cause LBW and future health hazards. Our findings provide novel insights into the cause of LBW via the fetal-placental crosstalk.

添付ファイル： fendo-13-1023984.pdf

DOI： 10.3389/fendo.2022.1023984

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

添付ファイル： 1-s2.0-S0006291X22009949-main.pdf

DOI： 10.1016/j.bbrc.2022.07.027

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Recent breakthroughs in sequencing technology and technological developments have made it easier to analyze the entire human genome than ever before. In addition to disease-specific genetic mutations and chromosomal aberrations, epigenetic alterations in individuals can also be analyzed using genomics. Autism spectrum disorder (ASD) is a neurodevelopmental disorder (NDD) caused by genetic and/or environmental factors. More than a thousand genes associated with ASD have been identified which are known to be involved in brain development. However, it is difficult to decode the roles of ASD-associated genes without in vitro and in vivo validations, particularly in the process of brain development. In this review, we discuss genomic strategies for understanding the pathological mechanisms underlying ASD. For this purpose, we discuss ASD-associated genes and their functions, as well as analytical strategies and their strengths and weaknesses in cellular and animal models from a basic research perspective.

添付ファイル： fnmol-15-930941.pdf

DOI： 10.3389/fnmol.2022.930941

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Maternal immune activation (MIA) is triggered by infection or autoimmune predisposition during pregnancy, and cytokines produced by MIA are transmitted through the placenta to the fetal brain, implicating in the onset risks and vulnerability for the developmental and psychiatric disorders such as autism spectrum disorder (ASD) and schizophrenia. To address these kinds of problem in the child health, we have developed a silicon (Si)-based hydrogen-producing antioxidant (Si-based agent) that continuously and effectively produces hydrogen in the body. Medical hydrogen is known to have antioxidative, anti-inflammatory, and antiapoptotic effects, therefore we applied our Si-based agent as a potential therapeutic agent to MIA. Using a MIA mouse model, we found that Si-based agent improved social communication of MIA offspring mice. We also found that the Si-based agent suppressed the expressions of inflammation associated genes Ifna1 and Il-6 in the mouse brain. These results demonstrate that Si-based agent is an effective prophylactic agent against MIA during pregnancy, suggesting that our Si-based agent may be a preventative or therapeutic agent for ASD and other disease risks in the child health by suppressing MIA damage.

添付ファイル： fpsyt-13-872302.pdf

DOI： 10.3389/fpsyt.2022.872302

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担当区分：最終著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

添付ファイル： fgene-13-874350.pdf

DOI： 10.3389/fgene.2022.874350

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

The internal and external environment of the mother during the developmental stages of the fetus affects the offspring’s health. According to the developmental origins of health and disease (DOHaD) theory, environmental factors influence the offspring and also affect health in adulthood. Recently, studies based on this theory have gained attracted attention because of their clinical utility in identifying the risk groups for various diseases. Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) can be caused by exposure to certain prenatal environments during pregnancy. This review describes the latest findings on the effect of prenatal environment on the onset mechanism of NDDs based on the DOHaD theory. Unravelling the molecular mechanisms underlying the pathogenesis of NDDs is important, because there are no therapeutic drugs for these disorders. Furthermore, elucidating the relationship between the DOHaD theory and NDDs will contribute to the popularization of preventive medicine.

添付ファイル： fnins-16-871979.pdf

DOI： 10.3389/fnins.2022.871979

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

The internal and external environment of the mother during the developmental stages of the fetus affects the offspring’s health. According to the developmental origins of health and disease (DOHaD) theory, environmental factors influence the offspring and also affect health in adulthood. Recently, studies based on this theory have gained attracted attention because of their clinical utility in identifying the risk groups for various diseases. Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) can be caused by exposure to certain prenatal environments during pregnancy. This review describes the latest findings on the effect of prenatal environment on the onset mechanism of NDDs based on the DOHaD theory. Unravelling the molecular mechanisms underlying the pathogenesis of NDDs is important, because there are no therapeutic drugs for these disorders. Furthermore, elucidating the relationship between the DOHaD theory and NDDs will contribute to the popularization of preventive medicine.

添付ファイル： fendo-13-860110.pdf

DOI： 10.3389/fendo.2022.860110

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

添付ファイル： 1-s2.0-S0197018621003193-main.pdf

DOI： 10.1016/j.neuint.2021.105273

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers Media SA  

Early life stress (ELS), such as abuse, neglect, and maltreatment, exhibits a strong impact on the brain and mental development of children. However, it is not fully understood how ELS affects social behaviors and social-associated behaviors as well as developing prefrontal cortex (PFC). In this study, we performed social isolation on weaned pre-adolescent mice until adolescence and investigated these behaviors and PFC characteristics in adolescent mice. We found the ELS induced social impairments in social novelty, social interaction, and social preference in adolescent mice. We also observed increases of anxiety-like behaviors in ELS mice. In histological analysis, we found a reduced number of neurons and an increased number of microglia in the PFC of ELS mice. To identify the gene associated with behavioral and histological features, we analyzed transcriptome in the PFC of ELS mice and identified 15 differentially expressed genes involved in transcriptional regulation, stress, and synaptic signaling. Our study demonstrates that ELS influences social behaviors, anxiety-like behaviors through cytoarchitectural and transcriptomic alterations in the PFC of adolescent mice.

添付ファイル： fgene-12-754198.pdf

DOI： 10.3389/fgene.2021.754198

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Early life stress (ELS), such as neglect and maltreatment, exhibits a strong impact on the mental and brain development of children. However, it is not fully understood how ELS affects the body and behavior of children. Therefore, in this study, we performed social isolation on weaned pre-adolescent mice and investigated how ELS could affect gut microbiota and mouse behavior. Using the metagenomics approach, we detected an overall ELS-related change in the gut microbiota and identified Bacteroidales and Clostridiales as significantly altered bacterial groups. These metagenomic alterations impaired social behavior in ELS mice, which also correlated with the abundance of Bacteroidales and Clostridiales. Our results demonstrate that ELS alters the gut microbiota and reduces social behavior in adolescent mice.

添付ファイル： brainsci-11-00913.pdf

DOI： 10.3390/brainsci11070913

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Frontiers  

添付ファイル： fmedt-03-665506.pdf

DOI： 10.3389/fmedt.2021.665506

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

We have reported that a subpopulation of patients with schizophrenia have lower levels of vitamin B₆ (VB6) in peripheral blood than do healthy controls. In a previous study, we found that VB6 level was inversely proportional to the patient’s positive and negative symptom scale (PANSS) score for measuring symptom severity, suggesting that the loss of VB6 might contribute to the development of schizophrenia symptoms. In the present study, to clarify the relationship between VB6 deficiency and schizophrenia, we generated VB6-deficient (VB6(−)) mice through feeding with a VB6-lacking diet as a mouse model for the subpopulation of schizophrenia patients with VB6 deficiency. After feeding for 4 weeks, plasma VB6 level in VB6(−) mice decreased to 3% of that in control mice. The VB6(−) mice showed social deficits and cognitive impairment. Furthermore, the VB6(−) mice showed a marked increase in 3-methoxy-4-hydroxyphenylglycol (MHPG) in the brain, suggesting enhanced noradrenaline (NA) metabolism in VB6(−) mice. We confirmed the increased NA release in the prefrontal cortex (PFC) and the striatum (STR) of VB6(−) mice through in vivo microdialysis. Moreover, inhibiting the excessive NA release by treatment with VB6 supplementation into the brain and α2A adrenoreceptor agonist guanfacine (GFC) suppressed the increased NA metabolism and ameliorated the behavioral deficits. These findings suggest that the behavioral deficits shown in VB6(−) mice are caused by enhancement of the noradrenergic (NAergic) system.

添付ファイル： s41398-021-01381-z.pdf

DOI： 10.1038/s41398-021-01381-z

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その他リンク： http://www.nature.com/articles/s41398-021-01381-z

記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

添付ファイル： pain_like_behavior_in_mice_can_be_induced_by_the.11.pdf

DOI： 10.1097/wnr.0000000000001607

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>This case–control study aimed to assess oxidative stress alterations in autism spectrum disorder (ASD). We used the MULTIS method, an electron spin resonance-based technique measuring multiple free radical scavenging activities simultaneously, in combination with conventional oxidative stress markers to investigate the ability of this MULTIS approach as a non-behavioural diagnostic tool for children with ASD. Serum samples of 39 children with ASD and 58 age-matched children with typical development were analysed. The ASD group showed decreased hydroxyl radical (^·OH) and singlet oxygen scavenging activity with increased serum coenzyme Q10 oxidation rate, indicating a prooxidative tendency in ASD. By contrast, scavenging activities against superoxide (O₂^·−) and alkoxyl radical (RO^·) were increased in the ASD group suggesting antioxidative shifts. In the subgroup analysis of 6-year-olds or younger, the combination of ^·OH, O₂^·−, and RO^· scavenging activities predicted ASD with high odds ratio (50.4), positive likelihood (12.6), and percentage of correct classification (87.0%). Our results indicate that oxidative stress in children with ASD is not simply elevated but rather shows a compensatory shift. MULTIS measurements may serve as a very powerful non-behavioural tool for the diagnosis of ASD in children.

添付ファイル： s41598-020-77328-z.pdf

DOI： 10.1038/s41598-020-77328-z

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その他リンク： http://www.nature.com/articles/s41598-020-77328-z

掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Detection of early-stage hepatocellular carcinoma (HCC) is beneficial for prolonging patient survival. However, the serum markers currently used show limited ability to identify early-stage HCC. In this study, we explored human serum N-glycans as sensitive markers to diagnose HCC in patients with cirrhosis. Using a simplified fluorescence-labeled N-glycan preparation method, we examined non-sialylated and sialylated N-glycan profiles from 71 healthy controls and 111 patients with hepatitis and/or liver cirrhosis (LC) with or without HCC. We found that the level of serum N-glycan A2G1(6)FB, a biantennary N-glycan containing core fucose and bisecting GlcNAc residues, was significantly higher in hepatitis C virus (HCV)-infected cirrhotic patients with HCC than in those without HCC. In addition, A2G1(6)FB was detectable in HCV-infected patients with early-stage HCC and could be a more accurate marker than alpha-fetoprotein (AFP) or protein induced by vitamin K absence or antagonists-II (PIVKA-II). Moreover, there was no apparent correlation between the levels of A2G1(6)FB and those of AFP or PIVKA-II. Thus, simultaneous use of A2G1(6)FB and traditional biomarkers could improve the accuracy of HCC diagnosis in HCV-infected patients with LC, suggesting that A2G1(6)FB may be a reliable biomarker for early-stage HCC patients.

添付ファイル： ijms-21-08913-v3.pdf

DOI： 10.3390/ijms21238913

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

添付ファイル： 1-s2.0-S1750946720301203-main.pdf

DOI： 10.1016/j.rasd.2020.101630

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Public Library of Science (PLoS)  

添付ファイル： file.pdf

DOI： 10.1371/journal.pone.0191706

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Genetic perturbations of the transcription factor Forkhead Box P1 (FOXP1) are causative for severe forms of autism spectrum disorder that are often comorbid with intellectual disability. Recent work has begun to reveal an important role for FoxP1 in brain development, but the brain-region-specific contributions of Foxp1 to autism and intellectual disability phenotypes have yet to be determined fully. Here, we describe Foxp1 conditional knock-out (Foxp1cKO) male and female mice with loss of Foxp1 in the pyramidal neurons of the neocortex and the CA1/CA2 subfields of the hippocampus. Foxp1cKO mice exhibit behavioral phenotypes that are of potential relevance to autism spectrum disorder, including hyperactivity, increased anxiety, communication impairments, and decreased sociability. In addition, Foxp1cKO mice have gross deficits in learning and memory tasks of relevance to intellectual disability. Using a genome-wide approach, we identified differentially expressed genes in the hippocampus of Foxp1cKO mice associated with synaptic function and development. Furthermore, using magnetic resonance imaging, we uncovered a significant reduction in the volumes of both the entire hippocampus as well as individual hippocampal subfields of Foxp1cKO mice. Finally, we observed reduced maintenance of LTP in area CA1 of the hippocampus in these mutant mice. Together, these data suggest that proper expression of Foxp1 in the pyramidal neurons of the forebrain is important for regulating gene expression pathways that contribute to specific behaviors reminiscent of those seen in autism and intellectual disability. In particular, Foxp1 regulation of gene expression appears to be crucial for normal hippocampal development, CA1 plasticity, and spatial learning.SIGNIFICANCE STATEMENT Loss-of-function mutations in the transcription factor Forkhead Box P1 (FOXP1) lead to autism spectrum disorder and intellectual disability. Understanding the potential brain-region-specific contributions of FOXP1 to disease-relevant phenotypes could be a critical first step in the management of patients with these mutations. Here, we report that Foxp1 conditional knock-out (Foxp1cKO) mice with loss of Foxp1 in the neocortex and hippocampus display autism and intellectual-disability-relevant behaviors. We also show that these phenotypes correlate with changes in both the genomic and physiological profiles of the hippocampus in Foxp1cKO mice. Our work demonstrates that brain-region-specific FOXP1 expression may relate to distinct, clinically relevant phenotypes.

添付ファイル： 10917.full.pdf

DOI： 10.1523/JNEUROSCI.1005-17.2017

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The role of post-transcriptional gene regulation in human brain development and neurodevelopmental disorders remains mostly uncharacterized. ELAV-like RNA-binding proteins (RNAbps) are a family of proteins that regulate several aspects of neuronal function including neuronal excitability and synaptic transmission, both critical to the normal function of the brain in cognition and behavior. Here, we identify the downstream neuronal transcriptional and splicing networks of ELAVL2, an RNAbp with previously unknown function in the brain. Expression of ELAVL2 was reduced in human neurons and RNA-sequencing was utilized to identify networks of differentially expressed and alternatively spliced genes resulting from haploinsufficient levels of ELAVL2. These networks contain a number of autism-relevant genes as well as previously identified targets of other important RNAbps implicated in autism spectrum disorder (ASD) including RBFOX1 and FMRP. ELAVL2-regulated co-expression networks are also enriched for neurodevelopmental and synaptic genes, and include genes with human-specific patterns of expression in the frontal pole. Together, these data suggest that ELAVL2 regulation of transcript expression is critical for neuronal function and clinically relevant to ASD.

添付ファイル： ddw110.pdf

DOI： 10.1093/hmg/ddw110

PubMed

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Identification of genetic and molecular factors responsible for the specialized cognitive abilities of humans is expected to provide important insights into the mechanisms responsible for disorders of cognition such as autism, schizophrenia and Alzheimer's disease. Here, we discuss the use of comparative genomics for identifying salient genes and gene networks that may underlie cognition. We focus on the comparison of human and non-human primate brain gene expression and the utility of building gene coexpression networks for prioritizing hundreds of genes that differ in expression among the species queried. We also discuss the importance of and methods for functional studies of the individual genes identified. Together, this integration of comparative genomics with cellular and animal models should provide improved systems for developing effective therapeutics for disorders of cognition.

添付ファイル： 000365182.pdf

DOI： 10.1159/000365182

PubMed

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Members of the CarA/LitR family are MerR-type transcriptional regulators that contain a C-terminal cobalamin-binding domain. They are thought to be involved in light-induced transcriptional regulation in a wide variety of nonphototrophic bacteria. Based on the distribution of this kind of regulator, the current study examined carotenoid production in Thermus thermophilus, and it was found to occur in a light-induced manner. litR and carotenoid and cobalamin biosynthesis genes were all located on the large plasmid of this organism. litR or cobalamin biosynthesis gene knockout mutants were unable to switch off carotenoid production under dark conditions, while a mutant with a mutation in the downstream gene adjacent to litR (TT_P0055), which encodes a CRP/FNR family transcriptional regulator, was unable to produce carotenoids, irrespective of light conditions. Overall, genetic and biochemical evidence indicates that LitR is bound by cobalamin and associates with the intergenic promoter region between litR and crtB (phytoene synthase gene), repressing the bidirectional transcription of litR and crtB. It is probable that derepression of LitR caused by some photodependent mechanism induces the expression of TT_P0055 protein, which serves as a transcriptional activator for the crtB operon and hence causes the expression of carotenoid biosynthesis and the DNA repair system under light condition.

添付ファイル： takano-et-al-involvement-of-cara-litr-and-crp-fnr-family-transcriptional-regulators-in-light-induced-carotenoid.pdf

DOI： 10.1128/JB.01125-10

PubMed

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Tamoxifen-inducible Cre (CreER) has become a powerful tool for in vivo manipulation of the genome. Here, we investigated opposing effects of tamoxifen on apoptosis during embryogenesis using Olig2-CreER knock-in mice, namely, tamoxifen-induced apoptosis through CreER-mediated toxicity and cytoprotective activity of tamoxifen independent of CreER. First, we examined tamoxifen-induced apoptosis; in the homozygous mice, we observed region-specific apoptosis in the ventral neural tube, with no obvious increase in the heterozygotes. Next, we detected a cytoprotective effect on apoptosis in the homozygous dorsal root ganglia (DRG). This apoptosis is a secondary phenotype of Olig2-null mice, as Olig2/CreER is not expressed in the DRG. The cytoprotective effect is DRG-specific, because tamoxifen did not rescue apoptosis in the interdigital mesenchyme. These data indicate that tamoxifen has multiple effects on apoptosis during development and caution that careful examination is necessary when interpreting results obtained from tamoxifen-induced recombination: in Olig2-CreER mice, heterozygotes are usable for lineage-tracing experiment without obvious toxicity, while homozygotes show efficient recombination, despite enhanced apoptosis.

添付ファイル： Genesis - 2008 - Takebayashi - Tamoxifen modulates apoptosis in multiple modes of action in CreER mice.pdf

DOI： 10.1002/dvg.20461

PubMed

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担当区分：最終著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

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担当区分：最終著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：医歯薬出版株式会社  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

Autism spectrum disorder (ASD) is a heterogeneous disorder characterized by impaired social communication and restricted repetitive behaviors, however the biological mechanisms remain unclear. Although trace elements play essential roles in the living body, it is unclear how alterations of trace elements in ASD are involved in pathogenesis. Here we analyzed the plasma metallome and identified the alterations of 11 elements in individuals with ASD. The copper decrease was negatively correlated with ASD symptom scores. A copper-deficient mouse model reflecting the condition showed ASD-like behaviors and impaired oligodendrocyte development. In copper-deficient mice, mechanistic target of rapamycin (mTOR) signaling was reduced, and its activation by agonist improved social impairment and oligodendrocyte developmental defects. Supporting these results, white matter volumes were negatively correlated with social symptoms in individuals with ASD. Our results demonstrate that copper-deficiency contributes to ASD by causing oligodendrocytes impairment via mTOR signaling. Our findings indicate that the effects of copper-deficiency and mTOR imbalance are relevant to the pathogenesis of ASD and are potential therapeutic targets.

DOI： 10.1101/2023.12.16.23300061

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）   出版者・発行元：新興医学出版社  

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記述言語：英語  

DOI： 10.1111/jnc.15675

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：中外医学社  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究発表ペーパー・要旨（全国大会，その他学術会議）  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（大学・研究所紀要）  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

Recent genetic studies have underscored the pleiotropic effects of single genes to multiple cognitive disorders. Mutations of ZBTB16 are associated with autism spectrum disorder (ASD) and schizophrenia (SCZ), but how the function of ZBTB16 is related to ASD or SCZ remains unknown. Here we show the deletion of Zbtb16 in mice leads to both ASD- and SCZ-like behaviors such as social impairment, repetitive behaviors, risk-taking behaviors, and cognitive impairment. To elucidate the mechanism underlying the behavioral phenotypes, we carried out histological studies and observed impairments in thinning of neocortical layer 6 (L6) and a reduction of TBR1+ neurons in the prefrontal cortex (PFC) of Zbtb16 KO mice. Furthermore, we found increased dendritic spines and microglia as well as developmental defects in oligodendrocytes and neocortical myelination in the PFC of Zbtb16 KO mice. Using a genomics approach, we identified the Zbtb16-transcriptome that includes genes involved in both ASD and SCZ pathophysiology and neocortical maturation such as neurogenesis and myelination. Co-expression networks further identified Zbtb16-correlated modules that are unique to ASD or SCZ respectively. Our study provides insight into the differential role of ZBTB16 in ASD and SCZ.

DOI： 10.1101/2020.08.09.233270

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担当区分：筆頭著者   記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）  

DOI： 10.2139/ssrn.3582706

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

Cell-type specific epigenetic modifications are critical for brain development and neuropsychiatric diseases. Here we elucidate evolutionary origins of neuron- and oligodendrocyte-specific DNA methylation in human prefrontal cortex, and demonstrate dynamic and distinctive changes of CG and CH methylation. We show that the human brain has experienced pronounced reduction of CG methylation during evolution, which significantly contributed to cell-type specific active regulatory regions. On the other hand, a substantial increase of CH methylation occurred during human brain evolution, associated with fine-tuning expression in development and neuronal subtypes. The majority of differential CG methylation between neurons and oligodendrocytes originated before the divergence of hominoids and catarrhine monkeys, and carries strong signal for genetic risk for schizophrenia. Remarkably, a substantial portion of differential CG methylation between neurons and oligodendrocytes emerged in the human lineage and harbors additional genetic risk for schizophrenia, implicating epigenetic evolution of human cortex in increased vulnerability to neuropsychiatric diseases.

DOI： 10.1101/2020.07.14.203034

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記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

Methylglyoxal (MG) is a cytotoxic α-dicarbonyl byproduct of glycolysis. Our bodies have several bio-defense systems to detoxify MG, including an enzymatic system by glyoxalase (GLO) 1 and a scavenge system by vitamin B6 (VB6). We know a population of patients with schizophrenia impaired MG detoxification systems. However, the molecular mechanism connecting them remains poorly understood. We created a novel mouse model for MG detoxification deficits by feeding Glo1 knockout mice VB6-lacking diets (KO/VB6(-)) and evaluated the effects of impaired MG detoxification systems on brain function. KO/VB6(-) mice accumulated MG in the prefrontal cortex (PFC), hippocampus, and striatum, and displayed schizophrenia-like behavioral deficits. Furthermore, we found aberrant gene expression related to mitochondria function in the PFC of the KO/VB6(-) mice. We demonstrated respiratory deficits in mitochondria isolated from the PFC of KO/VB6(-) mice. These findings suggest that MG detoxification deficits might cause schizophrenia-like behavioral deficits via mitochondrial dysfunction in the PFC.

DOI： 10.1101/2020.07.08.192906

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1016/j.biopsych.2020.02.176

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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担当区分：筆頭著者   記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

The importance of cell-type specific epigenetic variation of non-coding regions in neuropsychiatric disorders is increasingly appreciated, yet data from disease brains are conspicuously lacking. We generated cell-type specific whole-genome methylomes (N=95) and transcriptomes (N=89) from neurons and oligodendrocytes from brains of schizophrenia and matched controls. The methylomes of these two cell-types are highly distinct, with the majority of differential DNA methylation occurring in non-coding regions. DNA methylation difference between control and schizophrenia brains is subtle compared to cell-type difference, yet robust against permuted data and validated in targeted deep-sequencing analyses. Differential DNA methylation between control and schizophrenia tends to occur in cell-type differentially methylated sites, highlighting the significance of cell-type specific epigenetic dysregulation in a complex neuropsychiatric disorder. Our resource provides novel and comprehensive methylome and transcriptome data from distinct cell populations from schizophrenia brains, further revealing reduced cell-type epigenetic distinction in schizophrenia.

DOI： 10.1101/609131

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担当区分：筆頭著者   記述言語：英語   掲載種別：速報，短報，研究ノート等（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

Recent discussions of human brain evolution have largely focused on increased neuron numbers and changes in their connectivity and expression. However, it is increasingly appreciated that oligodendrocytes play important roles in cognitive function and disease. Whether both cell-types follow similar or distinctive evolutionary trajectories is not known. We examined the transcriptomes of neurons and oligodendrocytes in the frontal cortex of humans, chimpanzees, and rhesus macaques. We identified human-specific trajectories of gene expression in neurons and oligodendrocytes and show that both cell-types exhibit human-specific upregulation. Moreover, oligodendrocytes have undergone accelerated gene expression evolution in the human lineage compared to neurons. The signature of acceleration is enriched for cell type-specific expression alterations in schizophrenia. These results underscore the importance of oligodendrocytes in human brain evolution.

DOI： 10.1101/601062

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記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）   出版者・発行元：Wiley  

DOI： 10.1002/ana.25331

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（その他）  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）   出版者・発行元：金芳堂  

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：記事・総説・解説・論説等（学術雑誌）  

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1016/j.neures.2011.07.572

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担当区分：筆頭著者   記述言語：英語   掲載種別：記事・総説・解説・論説等（国際会議プロシーディングズ）  

DOI： 10.1111/j.1471-4159.2011.07325.x

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1016/j.neures.2010.07.126

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1111/j.1471-4159.2009.06238.x

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1016/j.neures.2009.09.739

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究発表ペーパー・要旨（国際会議）  

DOI： 10.1016/j.neures.2008.05.002

Web of Science

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（招待・特別）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：口頭発表（招待・特別）  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：口頭発表（一般）  

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出願人：国立大学法人大阪大学

出願番号：中国202280038824.0  出願日：2022年5月

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出願人：国立大学法人大阪大学

出願番号：特願2021-097781  出願日：2021年6月

出願国：国内  

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出願人：国立大学法人大阪大学

出願番号：PCT/JP2021/16176  出願日：2021年4月

出願国：外国  

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出願人：国立大学法人大阪大学

出願番号：PCT/JP2021/15738  出願日：2021年4月

出願国：外国   取得国：外国

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出願人：国立大学法人大阪大学

出願番号：PCT/JP2021/15020  出願日：2021年4月

出願国：外国   取得国：外国

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出願人：国立大学法人大阪大学

出願番号：PCT/JP2021/14332  出願日：2021年4月

出願国：外国   取得国：外国

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出願人：国立大学法人大阪大学

出願番号：欧州出願19815281.1  出願日：2020年12月

特許番号/登録番号：欧州特許3804732  登録日：2024年11月 

出願国：外国   取得国：外国

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出願人：国立大学法人大阪大学

出願番号：米国17/113886  出願日：2020年12月

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出願人：国立大学法人大阪大学

出願番号：特願2020-077075  出願日：2020年4月

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出願人：国立大学法人大阪大学

出願番号：特願2020-076561  出願日：2020年4月

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出願人：国立大学法人大阪大学

出願番号：特願2020-070882  出願日：2020年4月

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出願人：国立大学法人大阪大学

出願番号：特願2020-068534  出願日：2020年4月

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出願人：国立大学法人大阪大学

出願番号：特願2019-213065  出願日：2019年11月

特許番号/登録番号：特許7461009  登録日：2024年3月 

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出願人：国立大学法人大阪大学

出願番号：特願2019-212972  出願日：2019年11月

特許番号/登録番号：特許7461006  登録日：2024年3月 

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出願人：国立大学法人大阪大学

出願番号：特願2019-212973  出願日：2019年11月

特許番号/登録番号：特許7461007  登録日：2024年3月 

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出願人：国立大学法人大阪大学

出願番号：特願2019-212971  出願日：2019年11月

特許番号/登録番号：特許7461005  登録日：2024年3月 

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出願人：国立大学法人大阪大学

出願番号：特願2019-213066  出願日：2019年11月

特許番号/登録番号：特許7461010  登録日：2024年3月 

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出願番号：特願2019-212974  出願日：2019年11月

特許番号/登録番号：特許7461008  登録日：2024年3月 

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出願人：国立大学法人大阪大学

出願番号：特願2019-210724  出願日：2019年11月

特許番号/登録番号：特許7461004  登録日：2024年3月 

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出願人：国立大学法人大阪大学

出願番号：中国201980038513.2  出願日：2019年6月

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出願人：国立大学法人大阪大学

出願番号：PCT/JP2019/022558  出願日：2019年6月

出願国：外国   取得国：外国

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出願人：国立大学法人大阪大学

出願番号：特願2019-106147  出願日：2019年6月

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