記述言語：英語   掲載種別：研究論文（学術雑誌）  

INTRODUCTION: The mechanisms underlying obesity are not fully understood, necessitating the creation of novel animal models for the investigation of metabolic disorders. We have previously found that neurosecretory protein GL (NPGL), a newly identified hypothalamic neuropeptide, is involved in feeding behavior and fat accumulation in rats. However, the impact of NPGL on obesity remains unclear in any animal model. The present investigation sought to elucidate whether NPGL causes obesity in the obesity-prone mouse strain C57BL/6J. METHODS: We overexpressed the NPGL-precursor gene (Npgl) in the hypothalamus using adeno-associated virus in male C57BL/6J mice fed normal chow (NC) or a high-calorie diet (HCD). After 9 weeks of Npgl overexpression, we measured adipose tissues, muscle, and several organ masses in addition to food intake and body mass. To assess the effects of Npgl overexpression on peripheral tissues, we analyzed mRNA expression of lipid metabolism-related genes by quantitative RT-PCR. Whole body energy consumption was assessed using an O2/CO2 metabolism measurement before an apparent increase in body mass. RESULTS: Npgl overexpression increased food intake, body mass, adipose tissues and liver masses, and food efficiency under both NC and HCD, resulting in obesity observable within 8 weeks. Furthermore, we observed fat accumulation in adipose tissues and liver. Additionally, mRNA expression of lipid metabolism-related factors was increased in white adipose tissue and the liver after Npgl overexpression. Npgl overexpression inhibited energy expenditure during a dark period. CONCLUSION: Taken together, the present study suggests that NPGL can act as an obesogenic factor that acts within a short period of time in mice. As a result, this Npgl overexpression-induced obesity can be widely applied to study the etiology of obesity from genes to behavior.

DOI： 10.1159/000518969

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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 medial preoptic area, which plays an essential role in the control of sexual behavior in rats, contains a sexually dimorphic nucleus that consists of neurons expressing calbindin-D28 K (Calb) that is referred to as the CALB-SDN. The CALB-SDN is larger and contains more Calb neurons in males than in females. The physiological functions of the CALB-SDN are not fully understood; however, CALB-SDN neurons are activated during sexual behavior in males, suggesting that the male CALB-SDN is involved in regulation of sexual behavior. However, no information exists about the physiological functions of the female CALB-SDN. In the present study, we performed an immunohistochemical analysis of c-Fos, a neuronal activity marker, in the CALB-SDN of female and male rats that had copulated with conspecifics of the opposite sex to determine whether neurons of the female CALB-SDN are activated during copulation and whether the neuronal activity of the CALB-SDN differs between sexes. The numbers of c-Fos-immunoreactive cells with or without Calb-immunoreactivity (c-Fos+/Calb+ and c-Fos+/Calb- cells) were greater in the CALB-SDN of rats that had copulated than in rats that had not copulated in each sex. Although the number of Calb+ cells in the CALB-SDN was smaller in females than in males, the increase in the number of c-Fos+/Calb+ cells in the female CALB-SDN with copulation was comparable to that in the male CALB-SDN with copulation. The increase in the number of c-Fos+/Calb- cells in the CALB-SDN with copulation was more prominent in males than in females. These results suggest that CALB-SDN neurons are activated during copulation in both sexes. The patterns of neuronal activation in the CALB-SDN during copulation may differ between sexes.

DOI： 10.1016/j.neulet.2021.135915

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Two types of nuclear estrogen receptors, ERα and ERβ, have been shown to be differentially involved in the regulation of various types of behaviors. Due to a lack of tools for identifying ERβ expression, detailed anatomical distribution and neurochemical characteristics of ERβ expressing cells and cellular co-expression with ERα remain unclear. We have generated transgenic mice ERβ-RFPtg, in which RFP was inserted downstream of ERβ BAC promotor. We verified RFP signals as ERβ by confirming: (1) high ERβ mRNA levels in RFP-expressing cells collected by fluorescence-activated cell sorting; and (2) co-localization of ERβ mRNA and RFP proteins in the paraventricular nucleus (PVN). Strong ERβ-RFP signals were found in the PVN, medial preoptic area (MPOA), bed nucleus of the stria terminalis, medial amygdala (MeA), and dorsal raphe nucleus (DRN). In the MPOA and MeA, three types of cell populations were identified; those expressing both ERα and ERβ, and those expressing exclusively either ERα or ERβ. The majority of PVN and DRN cells expressed only ERβ-RFP. Further, ERβ-RFP positive cells co-expressed oxytocin in the PVN, and tryptophan hydroxylase 2 and progesterone receptors in the DRN. In the MeA, some ERβ-RFP positive cells co-expressed oxytocin receptors. These findings collectively suggest that ERβ-RFPtg mice can be a powerful tool for future studies on ERβ function in the estrogenic regulation of social behaviors.

DOI： 10.1016/j.neuroscience.2020.04.047

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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 calbindin-sexually dimorphic nucleus (CALB-SDN) and calbindin-principal nucleus of the bed nucleus of the stria terminalis (CALB-BNSTp) show male-biased sex differences in calbindin neuron number. The ventral part of the BNSTp (BNSTpv) exhibits female-biased sex differences in noncalbindin neuron number. We previously reported that prepubertal gonadectomy disrupts the masculinization of the CALB-SDN and CALB-BNSTp and the feminization of the BNSTpv. This study aimed to determine the action mechanisms of testicular androgens on the masculinization of the CALB-SDN and CALB-BNSTp and whether ovarian estrogens are the hormones that have significant actions in the feminization of the BNSTpv. We performed immunohistochemical analyses of calbindin and NeuN, a neuron marker, in male mice orchidectomized on postnatal day 20 (PD20) and treated with cholesterol, testosterone, estradiol, or dihydrotestosterone during PD20-70, female mice ovariectomized on PD20 and treated with cholesterol or estradiol during PD20-70, and PD70 mice gonadectomized on PD56. Calbindin neurons number in the CALB-SDN and CALB-BNSTp in males treated with testosterone or dihydrotestosterone, but not estradiol, was significantly larger than that in cholesterol-treated males. Noncalbindin neuron number in the BNSTpv in estradiol-treated females was significantly larger than that in cholesterol-treated females. Gonadectomy on PD56 had no significant effect on neuron numbers. Additionally, an immunohistochemical analysis revealed the expression of androgen receptors in the CALB-SDN and CALB-BNSTp of PD30 males and estrogen receptors-α in the BNSTpv of PD30 females. These results suggest that peripubertal testicular androgens act to masculinize the CALB-SDN and CALB-BNSTp without aromatization, and peripubertal ovarian estrogens act to feminize the BNSTpv.

DOI： 10.1210/endocr/bqaa063

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Developmental exposure to environmental chemicals with estrogen-like activity is suspected to permanently impair women's health. In this study, a mouse model was used to evaluate whether tris(2,6-dimethylphenyl) phosphate (TDMPP), a chemical with a putative estrogen-like action, impairs sexual differentiation of the brain. Either TDMPP and 17β-estradiol (E2) as positive controls or sesame oil as a negative control were administered subcutaneously to dams from gestational day (GD) 14 to parturition, and to pups from postnatal day (PND) 0 to 9. Precocious puberty, irregular estrous cycles, and a lowered lordosis response were found in the TDMPP- and E2-treated groups. A certain amount of TDMPP and its metabolites in the perinatal brain and the masculinization of sexual dimorphic nuclei in the hypothalamus of female mice after treatment were also detected. The experimental evidence demonstrates that TDMPP directly enters the fetal and neonatal brain, thereby inducing changes of sex-related brain structures and impairing female reproductive functions.

DOI： 10.1016/j.envint.2020.105662

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Testicular androgens during the perinatal period play an important role in the sexual differentiation of the brain of rodents. Testicular androgens transported into the brain act via androgen receptors or are the substrate of aromatase, which synthesizes neuroestrogens that act via estrogen receptors. The latter that occurs in the perinatal period significantly contributes to the sexual differentiation of the brain. The preoptic area (POA) and the bed nucleus of the stria terminalis (BNST) are sexually dimorphic brain regions that are involved in the regulation of sex-specific social behaviors and the reproductive neuroendocrine system. Here, we discuss how neuroestrogens of testicular origin act in the perinatal period to organize the sexually dimorphic structures of the POA and BNST. Accumulating data from rodent studies suggest that neuroestrogens induce the sex differences in glial and immune cells, which play an important role in the sexually dimorphic formation of the dendritic synapse patterning in the POA, and induce the sex differences in the cell number of specific neuronal cell groups in the POA and BNST, which may be established by controlling the number of cells dying by apoptosis or the phenotypic organization of living cells. Testicular androgens in the peripubertal period also contribute to the sexual differentiation of the POA and BNST, and thus their aromatization to estrogens may be unnecessary. Additionally, we discuss the notion that testicular androgens that do not aromatize to estrogens can also induce significant effects on the sexually dimorphic formation of the POA and BNST.

DOI： 10.3389/fnins.2020.00797

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The medial preoptic nucleus (MPN) plays an essential role in the control of male sexual behavior. In rats, the central part of the MPN (MPNc) contains a sexually dimorphic nucleus exhibiting male-biased morphological sex differences. Although it has been suggested that the MPNc of male rats functions to induce sexual arousal, the mechanisms by which male rats are sexually aroused to successfully achieve copulation are poorly understood. We recently showed that increased neuronal activity in the MPNc of male rats during copulation is higher at their first copulation compared with later copulations, indicating that a plastic change in excitatory synaptic transmission occurs with copulatory experience. In this study, we tested the hypothesis that changes to dendritic spines at structural and molecular levels occur following copulatory experience. First, we examined the effects of at least two copulations on the morphology of dendrites and spines in the MPNc and in the lateral and medial parts of the MPN (MPNlm) of male rats. In the MPNc, the total number of dendrites and their branches, and the surface area of dendrites were not significantly affected by copulation. However, the copulatory experience, specifically experience of ejaculation, significantly reduced the density of mushroom spines but not of filopodia, thin or stubby spines in the MPNc. In the MPNlm, the copulatory experience, specifically experience of ejaculation, significantly increased the surface area of dendrites, although there was no significant effect of copulation on spine density. Next, we measured the mRNA levels of genes encoding actin-binding proteins related to spinogenesis after male rats had copulated for their first and second times. Copulatory stimuli, especially stimuli from ejaculation, significantly reduced the mRNA levels of drebrin A and spinophilin in the MPNc but not in the MPNlm. These results indicate that copulatory experiences, especially experience of ejaculation, reduce spine density in the MPNc of male rats, which may result, in part, from downregulation of genes encoding actin-binding proteins.

DOI： 10.1016/j.psyneuen.2019.05.025

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The bed nucleus of the stria terminalis (BNST) contains the highest density of corticotropin-releasing factor (CRF)-producing neurons in the brain. CRF-immunoreactive neurons show a female-biased sexual dimorphism in the dorsolateral BNST in the rat. Since CRF neurons cannot be immunostained clearly with available CRF antibodies in the mouse, we used a mouse line, in which modified yellow fluorescent protein (Venus) was inserted to the CRF gene, and the Neo cassette was removed, to examine the morphological characteristics of CRF neurons in the dorsolateral BNST. Developmental changes of CRF neurons were examined from postnatal stages to adulthood. Gonadectomy (GDX) was carried out in adult male and female mice to examine the effects of sex steroids on the number of CRF neurons in the dorsolateral BNST. METHODS: The number of Venus-expressing neurons, stained by immunofluorescence, was compared between male and female mice over the course of development. GDX was carried out in adult mice. Immunohistochemistry, in combination with Nissl staining, was carried out, and the effects of sex or gonadal steroids were examined by estimating the number of Venus-expressing neurons, as well as the total number of neurons or glial cells, in each BNST subnucleus, using a stereological method. RESULTS: Most Venus-expressing neurons co-expressed Crf mRNA in the dorsolateral BNST. They constitute a group of neurons without calbindin immunoreactivity, which makes a contrast to the principal nucleus of the BNST that is characterized by calbindin immunostaining. In the dorsolateral BNST, the number of Venus-expressing neurons increased across developmental stages until adulthood. Sexual difference in the number of Venus-expressing neurons was not evident by postnatal day 5. In adulthood, however, there was a significant female predominance in the number of Venus expressing neurons in two subnuclei of the dorsolateral BNST, i.e., the oval nucleus of the BNST (ovBNST) and the anterolateral BNST (alBNST). The number of Venus-expressing neurons was smaller significantly in ovariectomized females compared with proestrous females in either ovBNST or alBNST, and greater significantly in orchiectomized males compared with gonadally intact males in ovBNST. The total number of neurons was also greater significantly in females than in males in ovBNST and alBNST, but it was not affected by GDX. CONCLUSION: Venus-expressing CRF neurons showed female-biased sexual dimorphism in ovBNST and alBNST of the mouse. Expression of Venus in these subnuclei was controlled by gonadal steroids.

DOI： 10.1186/s13293-019-0221-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sex steroids play a major role in sexually dimorphic brain development during not only the perinatal period but also the pubertal period. We previously showed that, in male mice, the estrogen receptor-α (Esr1) and aromatase (Cyp19a1) genes are essential to the sexually dimorphic formation of the anteroventral periventricular nucleus (AVPV) and the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), but the estrogen receptor-β (Esr2) gene is not necessary. We also showed that the androgen receptor (Ar) gene is essential to the sexually dimorphic formation of the BNSTp. These genes are expressed in the AVPV and BNSTp of perinatal mice. However, it remains unknown whether these genes are expressed in the AVPV and BNSTp during puberty, and whether the expression, if any, differs by sex, age, and brain region. Here, we dissected the AVPV and BNSTp from Nissl-stained brain sections of male and female mice on postnatal day (PD) 20 (prepuberty), PD30 (puberty onset in females), PD40 (puberty onset in males), and PD60 (young adult) using a laser microdissection system. We then examined the mRNA levels of Esr1, Esr2, Cyp19a1, and Ar in these brain regions. In the AVPV, Esr1 mRNA levels were greater in females than males during PD20-60. Esr2 and Ar mRNA expressions did not differ between sexes. Ar mRNA levels were higher at PD30 than PD20. Cyp19a1 mRNA was not detected in the AVPV at PD20-60. In the BNSTp, Esr1 and Esr2 mRNA levels were higher in females than in males during PD20-60, although the mRNA levels of Cyp19a1 and Ar did not differ between sexes. Additionally, we revealed that orchiectomy at PD20 induced a failure of normal formation of the male BNSTp and testosterone replacement in the prepubertal period rescued the effect of orchiectomy at PD20. Taken together, it is suggested that pubertal testosterone transported to the AVPV is not converted to estradiol there and does not act via ESR1 and ESR2. By contrast, the formation of the male BNSTp may be affected by testicular testosterone during puberty via AR and/or via ESR1 after conversion to estradiol by CYP19A1.

DOI： 10.3389/fendo.2018.00213

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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）  

We recently reported a female-biased sexually dimorphic area in the mouse brain in the boundary region between the preoptic area and the bed nucleus of the stria terminalis (BNST). We reexamined this area and found that it is a ventral part of the principal nucleus of the BNST (BNSTp). The BNSTp is a male-biased sexually dimorphic nucleus, but the ventral part of the BNSTp (BNSTpv) exhibits female-biased sex differences in volume and neuron number. The volume and neuron number of the BNSTpv were increased in males by neonatal orchiectomy and decreased in females by treatment with testosterone, dihydrotestosterone, or estradiol within 5 days after birth. Sex differences in the volume and neuron number of the BNSTpv emerged before puberty. These sex differences became prominent in adulthood with increasing volume in females and loss of neurons in males during the pubertal/adolescent period. Prepubertal orchiectomy did not affect the BNSTpv, although prepubertal ovariectomy reduced the volume increase and induced loss of neurons in the female BNSTpv. In contrast, the volume and neuron number of male-biased sexually dimorphic nuclei that are composed of mainly calbindin neurons and are located in the preoptic area and BNST were decreased by prepubertal orchiectomy but not affected by prepubertal ovariectomy. Testicular testosterone during the postnatal period may defeminize the BNSTpv via binding directly to the androgen receptor and indirectly to the estrogen receptor after aromatization, although defeminization may proceed independently of testicular hormones in the pubertal/adolescent period. Ovarian hormones may act to feminize the BNSTpv during the pubertal/adolescent period.

DOI： 10.1210/en.2017-00240

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The medial preoptic nucleus (MPN) and the bed nucleus of the stria terminalis (BNST) of mice contain sexually dimorphic nuclei (SDNs) that are larger and have more neurons expressing calbindin D-28K (CB), a calcium-binding protein, in males than females. However, it is largely unknown whether such SDNs exist in species other than rodents. In this study, we performed an immunohistochemical study of CB in the MPN and BNST of musk shrews and Japanese quails to examine the existence of homologs of SDNs in mice. Like mice, musk shrews had a SDN exhibiting male-biased sex differences in volume and CB-immunoreactive (ir) cell number in the MPN. The BNST of musk shrews also contained a male-biased SDN, but consisted of non-CB neurons. The paratenial thalamic nucleus of musk shrews, but not mice, had more CB-ir cells in males than females. In Japanese quails of both sexes, CB-ir cells in the MPN and BNST were extremely small in number and did not cluster. These results suggest that the distribution of CB neurons differs among these species. Musk shrews may have a homolog of the SDN composed of CB neurons in the MPN of mice.

DOI： 10.1016/j.neulet.2016.08.018

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Testosterone plays a central role in the facilitation of male-type social behaviors, such as sexual and aggressive behaviors, and the development of their neural bases in male mice. The action of testosterone via estrogen receptor (ER) α, after being aromatized to estradiol, has been suggested to be crucial for the full expression of these behaviors. We previously reported that silencing of ERα in adult male mice with the use of a virally mediated RNAi method in the medial preoptic area (MPOA) greatly reduced sexual behaviors without affecting aggressive behaviors whereas that in the medial amygdala (MeA) had no effect on either behavior. It is well accepted that testosterone stimulation during the pubertal period is necessary for the full expression of male-type social behaviors. However, it is still not known whether, and in which brain region, ERα is involved in this developmental effect of testosterone. In this study, we knocked down ERα in the MeA or MPOA in gonadally intact male mice at the age of 21 d and examined its effects on the sexual and aggressive behaviors later in adulthood. We found that the prepubertal knockdown of ERα in the MeA reduced both sexual and aggressive behaviors whereas that in the MPOA reduced only sexual, but not aggressive, behavior. Furthermore, the number of MeA neurons was reduced by prepubertal knockdown of ERα. These results indicate that ERα activation in the MeA during the pubertal period is crucial for male mice to fully express their male-type social behaviors in adulthood.

DOI： 10.1073/pnas.1524907113

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：英語   出版者・発行元：(一社)日本生理学会  

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記述言語：英語   出版者・発行元：(一社)日本生理学会  

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記述言語：英語   出版者・発行元：(一社)日本生理学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：英語   出版者・発行元：(一社)日本生理学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本比較内分泌学会  

DOI： 10.5983/nl2008jsce.43.88

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J05140&link_issn=&doc_id=20170609420004&doc_link_id=10.5983%2Fnl2008jsce.43.88&url=https%3A%2F%2Fdoi.org%2F10.5983%2Fnl2008jsce.43.88&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

記述言語：英語   出版者・発行元：(一社)日本生理学会  

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記述言語：英語   出版者・発行元：(一社)日本生理学会  

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(一社)日本内分泌学会  

J-GLOBAL

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記述言語：日本語   出版者・発行元：環境ホルモン学会(日本内分泌撹乱化学物質学会)  

J-GLOBAL

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開催年月日： 2023年9月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2023年8月 - 2023年9月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2021年7月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2020年9月

記述言語：日本語   会議種別：口頭発表（一般）  

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開催年月日： 2020年3月

記述言語：日本語  

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開催年月日： 2019年7月

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2019年3月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2019年3月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2018年7月

記述言語：英語   会議種別：ポスター発表  

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開催年月日： 2016年11月

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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