Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

This study aimed to reveal the possible mechanisms by which O-linked-N-acetylglucosaminylation (O-GlcNAcylation) regulates osteoblast differentiation using a series of bioinformatics-oriented experiments. To examine the influence of O-GlcNAcylation levels on osteoblast differentiation, osteoblastic MC3T3-E1 cells were treated with O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) inhibitors. Correlations between the levels of O-GlcNAcylation and the expression of osteogenic markers as well as OGT were evaluated by qPCR and western blotting. The O-GlcNAcylated proteins assumed to correlate with Runx2 expression were retrieved from several public databases and used for further bioinformatics analysis. Following the findings of the bioinformatics analysis, intracellular calcium ([Ca2+ ]i ) was monitored in the cells treated with OGT and OGA inhibitors using a confocal laser-scanning microscope (CLS). The interaction effect between O-GlcNAcylation and [Ca2+ ]i on osteogenic marker expression was determined using stable OGT knockdown MC3T3-E1 cells. O-GlcNAcylation was positively associated with osteoblast differentiation. The time-course profile of global O-GlcNAcylated proteins showed a distinctive pattern with different molecular weights during osteoblast differentiation. The expression pattern of several O-GlcNAcylated proteins was significantly similar to that of Runx2 expression. Bioinformatic analysis of the retrieved Runx2-related-O-GlcNAcylated-proteins revealed the importance of [Ca2+ ]i . CLS showed that alteration of O-GlcNAcylation rapidly changed [Ca2+ ]i in MC3T3-E1 cells. O-GlcNAcylation and [Ca2+ ]i showed an interaction effect on the expression of osteogenic markers. OGT knockdown disrupted the [Ca2+ ]i -induced expression changes of osteogenic markers. O-GlcNAcylation interacts with [Ca2+ ]i and elicits osteoblast differentiation by regulating the expression of osteogenic markers.

DOI： 10.1002/biof.1774

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1α is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1a regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1α have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1α/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1α is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing.

DOI： 10.3390/ijms22168992

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>Bone loss due to smoking represents a major risk factor for fractures and bone osteoporosis. Signaling through the aryl hydrocarbon receptor (AhR) and its ligands contributes to both bone homeostasis and inflammatory diseases. It remains unclear whether the same AhR signaling axis affects the temporomandibular joint (TMJ). The aim of this study was to investigate possible mechanisms which mediate bone loss in the TMJ due to smoking. In particular, whether benzo[<italic>a</italic>]pyrene (B[<italic>a</italic>]P), a carcinogen of tobacco smoke, induces expression of the AhR target gene, Cyp1a1, in mandibular condyles. Possible functions of an endogenous ligand of FICZ, were also investigated in a TMJ-osteoarthritis (OA) mouse model. B[<italic>a</italic>]P was administered orally to wild-type and <italic>AhR</italic>^−/− mice and bone metabolism was subsequently examined. TMJ-OA was induced in wild-type mice with forceful opening of the mouth. Therapeutic functions of FICZ were detected with μCT and histology. Exposure to B[<italic>a</italic>]P accelerated bone loss in the mandibular subchondral bone. This bone loss manifested with osteoclastic bone resorption and upregulated expression of Cyp1a1 in an <italic>AhR</italic>-dependent manner. In a mouse model of TMJ-OA, FICZ exhibited a dose-dependent rescue of mandibular subchondral bone loss by repressing osteoclast activity. Meanwhile, in vitro, pre-treatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[<italic>a</italic>]P regulates mandibular subchondral bone metabolism via the Cyp1a1. The AhR ligand, FICZ, can prevent TMJ-OA by regulating osteoclast differentiation.

DOI： 10.1038/s41598-021-94470-4

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Other Link： http://www.nature.com/articles/s41598-021-94470-4

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/cre2.404

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Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PeerJ  

<sec>
<title>Background</title>
In this study, we investigated the effect of the mechanical loading history on the expression of receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG) in MLO-Y4 osteocyte-like cells.


</sec>
<sec>
<title>Methods</title>
Three hours after MLO-Y4 osteocytes were seeded, a continuous compressive force (CCF) of 31 dynes/cm² with or without additional CCF (32 dynes/cm²) was loaded onto the osteocytes. After 36 h, the additional CCF (loading history) was removed for a recovery period of 10 h. The expression of RANKL, OPG, RANKL/OPG ratio, cell numbers, viability and morphology were time-dependently examined at 0, 3, 6 and 10 h. Then, the same additional CCF was applied again for 1 h to all osteocytes with or without the gap junction inhibitor to examine the expression of RANKL, OPG, the RANKL/OPG ratio and other genes that essential to characterize the phenotype of MLO-Y4 cells. Fluorescence recovery after photobleaching technique was also applied to test the differences of gap-junctional intercellular communications (GJIC) among MLO-Y4 cells.


</sec>
<sec>
<title>Results</title>
The expression of RANKL and OPG by MLO-Y4 osteocytes without a loading history was dramatically decreased and increased, respectively, in response to the 1-h loading of additional weight. However, the expression of RANKL, OPG and the RANKL/OPG ratio were maintained at the same level as in the control group in the MLO-Y4 osteocytes with a loading history but without gap junction inhibitor treatment. Treatment of loading history significantly changed the capacity of GJIC and protein expression of connexin 43 (Cx43) but not the mRNA expression of Cx43. No significant difference was observed in the cell number or viability between the MLO-Y4 osteocyte-like cells with and without a loading history or among different time checkpoints during the recovery period. The cell morphology showed significant changes and was correlated with the expression of OPG, Gja1 and Dmp1 during the recovery period.


</sec>
<sec>
<title>Conclusion</title>
Our findings indicated that the compressive force-induced changes in the RANKL/OPG expression could be habituated within at least 11 h by 36-h CCF exposure. GJIC and cell morphology may play roles in response to loading history in MLO-Y4 osteocyte-like cells.


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DOI： 10.7717/peerj.10244

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DOI： 10.1186/s13005-019-0187-7.

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jdsr.2018.09.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Saudi Arabian Armed Forces Hospital  

Objectives: To evaluate the effectiveness of pre-surgical nasoalveolar molding (PNAM) in patients with unilateral cleft lip nasal deformities. Methods: This was a retrospective study involving 29 patients with unilateral cleft lip and palate defects, of whom 13 were treated with palatal devices with nasal stents (PNAM group) and 16 were treated with palatal devices without nasal stents or surgical tapes (control group). Submental oblique photographs and orthodontic models were longitudinally obtained at the initial visit (T1) and immediately before (T2) and after cheiloplasty (T3). Asymmetry of the external nose, degree of columellar shifting, nasal tip/ala nose ratio, nasal base angle, interalveolar gap, and the sagittal difference in the alveolar gap were measured. The study was conducted in the Orthodontic Clinic at Tokushima University Hospital, Tokushima, Japan between 1997 and 2012. Results: At T1, there were no significant intergroup differences in the first 4 asymmetry parameters. At T2, the PNAM group showed a significant improvement in all values compared to the control group. At T3, the PNAM group showed significant improvement in nasal asymmetry and columellar shifting. Model analysis showed significantly greater changes in the inter-alveolar gap and the sagittal difference of the alveolar cleft gap from T1 to T2 in the PNAM group. Conclusion: The use of PNAM is indispensable for pre-surgical orthodontic treatment at the early postnatal age.

DOI： 10.15537/smj.2018.2.21020

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Bentham Science Publishers B.V.  

Background: Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease that involves changes in subchondral bone and progressive degradation of cartilage. Currently, rebamipide, a gastroprotective drug, is administered to protect gastric mucosa and accelerate ulcer healing. Objectives: Recent studies have shown that rebamipide also attenuates cartilage degeneration by suppressing oxidative damage and inducing homeostasis of the extracellular matrix of articular chondrocytes. Regarding the latter, reduced expression of cathepsin K, NFATc1, c-Src, and integrin β3, and increased expression of nuclear factor-kappa B, have been found to be mediated by the transcription factor, receptor activator of nuclear factor kappa-B ligand (RANKL). Methods: Treatment with rebamipide was also found to activate, mitogen-activated protein kinases such as p38, ERK, and JNK to reduce osteoclast differentiation. Taken together, these results strongly indicate that rebamipide mediates inhibitory effects on cartilage degradation and osteoclastogenesis in TMJ-OA. Results and Conclusion: Here, we highlight recent evidence regarding the potential for rebamipide to affect osteoclast differentiation and TMJ-OA pathogenesis. We also discuss the potential role of rebamipide to serve as a new strategy for the treatment of TMJ-OA.

DOI： 10.2174/1573397113666171017113441

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DOI： 10.4103/jos.JOS_63_17

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Enhanced turnover of subchondral trabecular bone is a hallmark of rheumatoid arthritis (RA) and it results from an imbalance between bone resorption and bone formation activities. To investigate the formation and activation of osteoclasts which mediate bone resorption, a Fas-deficient MRL/Ipr mouse model which spontaneously develops autoimmune arthritis and exhibits decreased bone mass was studied. Various assays were performed on subchondral trabecular bone of the temporomandibular joint (TMJ) from MRL/lpr mice and MRL+/+ mice. Initially, greater osteoclast production was observed in vitro from bone marrow macrophages obtained from MRL/lpr mice due to enhanced phosphorylation of NF-kappa B, as well as Akt and MAPK, to receptor activator of nuclear factor-kappa B ligand (RANKL). Expression of sphingosine 1-phosphate receptor 1 (SIP1) was also significantly upregulated in the condylar cartilage. S1P(1) was found to be required for S1P-induced migration of osteoclast precursor cells and downstream signaling via Rac1. When SN50, a synthetic NF-kappa B-inhibitory peptide, was applied to the MRL/Ipr mice, subchondral trabecular bone loss was reduced and both production of osteoclastogenesis markers and sphingosine kinase (Sphk) 1/S1P(1) signaling were reduced. Thus, the present results suggest that Fas/S1P(1) signaling via activation of NF-kappa B in osteoclast precursor cells is a key factor in the pathogenesis of RA in the TMJ. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2017.07.006

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4172/2155-9899.1000512

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4172/2572-4916.100017

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.4172/2576-3881.1000114

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MOSBY-ELSEVIER  

We successfully treated a patient with achondroplasia with conventional orthodontic techniques. It was followed by long-term retention. The patient, a 12-year-old boy, had chief complaints of occlusal disturbance and mandibular protrusion. He had been diagnosed with achondroplasia and had growth hormone treatment in his early teenage years. His facial profile was concave with a bulging forehead and a retrognathic maxilla. It was characterized by a skeletal Class III jaw-base relationship with a retropositioned maxilla. At the age of 12 years 9 months, maxillary protraction was initiated with a reverse headgear; for 2 years 6 months, the maxillomandibular growth was controlled. After the growth spurt, at the age of 15 years 6 months, leveling and alignment of both dental arches were started with preadjusted edgewise appliances. After 83 months of multibracket treatment, an acceptable occlusion with a Class I molar relationship and an adequate interincisal relationship was achieved, despite the simultaneous marked vertical growth of the mandible. The resultant occlusion was stable during a 6-year retention period, although considerable forward-downward mandibular growth was observed. Conclusively, our results indicated the necessity of long-term observation in this patient with achondroplasia, especially because of the persistent mandibular growth.

DOI： 10.1016/j.ajodo.2016.03.034

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Objective: Temporomandibular joint osteoarthritis (TMJ-OA) is a degenerative disease characterized by permanent cartilage loss. Articular cartilage is maintained in a low-oxygen environment. The chondrocyte response to hypoxic conditions involves expression of hypoxia inducible factor 1 alpha (HIF-1 alpha), which induces chondrocytes to increase expression of vascular endothelial growth factor (VEGF). Here, we investigated the role of HIF-1 alpha in mechanical load effects on condylar cartilage and subchondral bone in heterozygous HIF-1 alpha-deficient mice (HIF-1 alpha(+/-)).
Design: Mechanical stress was applied to the TMJ of C57BL/6NCr wild-type (WT) and HIF-1 alpha(+/-) mice with a sliding plate for 10 days. Histological analysis was performed by HE staining, Safranin-O/Fast green staining, and immunostaining specific for articular cartilage homeostasis.
Results: HIF-1 alpha+/- mice had thinner cartilage and smaller areas of proteoglycan than WT controls, without and with mechanical stress. Mechanical stress resulted in prominent degenerative changes with increased expression of HIF-1 alpha, VEGF, and the apoptosis factor cleaved Caspase-3 in condylar cartilage.
Conclusion: Our results indicate that HIF-1 alpha may be important for articular cartilage homeostasis and protective against articular cartilage degradation in the TMJ under mechanical stress condition, therefore HIF-1 alpha could be an important new therapeutic target in TMJ-OA. (C) 2016 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.archoralbio.2016.10.028

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This study aimed to examine hyaluronan (HA) metabolism in relation to the onset and progression of temporomandibular joint osteoarthritis (TMJ-OA) induced by mechanical overloading. Two-month-old and 6-month-old C57BL/6N mice were divided into experimental and untreated control groups (n = 5/group). A sliding plate was attached to the maxillary incisors of the experimental mice for 10 days to overload the condylar cartilage in TMJ. In experimental group, profound cartilage degradation was detected in haematoxylin-eosin, Safranin-O-Fast Green-stained sections. It was also shown that the cartilage degradation was greater in older mice in both the control and the experimental groups. The number of HABP-positive cells was decreased by mechanical overloading and with age. The reduction of HA expression was correlated with the progression of cartilage degradation induced by mechanical overloading. The absolute quantification of the mRNA expression related to HA synthesis and HA degradation was also performed in each group. The mRNA expression levels of HA synthase (HAS) 2 and 3 were lower in the experimental group compared with the control group in the younger mice. In contrast, the mRNA expression levels of the HA degradation gene, HYAL2 and KIAA1199, were higher in the experimental group compared with the control group in the older mice. Thus, mechanical overload differently affected the balance of HA degradation and HA synthesis in the older and younger mice, respectively. In conclusion, mechanical overloading affects HA metabolism and it might initiate or amplify the condylar cartilage degradation.

DOI： 10.1111/joor.12443

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC IMMUNOLOGISTS  

The aryl hydrocarbon receptor (AhR) pathway plays a key role in receptor activator of NF-kappa B ligand (RANKL)-mediated osteoclastogenesis. However, the mechanism underlying the regulation of AhR expression in osteoclasts and the signaling pathway through which AhR controls osteoclastogenesis remain unclear. We found that the expression of AhR in bone marrow-derived osteoclasts was upregulated by RANKL at an earlier stage than was the expression of signature osteoclast genes such as those encoding cathepsin K and NFAT, cytoplasmic, calcineurin-dependent 1. In response to RANKL, bone marrow macrophages isolated from AhR(-/-) mice exhibited impaired phosphorylation of Akt and MAPK as well as NF-kappa B, whereas their response to M-CSF remained unchanged. Osteoclast differentiation mediated by the AhR signaling pathway was also regulated in an RANKL/c-Fos-dependent manner. Furthermore, ligand activation of AhR by the smoke toxin benzo[a] pyrene accelerated osteoclast differentiation in a receptor-dependent manner, and AhR-dependent regulation of mitochondrial biogenesis in osteoclasts was observed. Moreover, AhR(-/-) mice exhibited impaired bone healing with delayed endochondral ossification. Taken together, the present results suggest that the RANKL/AhR/c-Fos signaling axis plays a critical role in osteoclastogenesis, thereby identifying the potential of AhR in treating pathological, inflammatory, or metabolic disorders of the bone.

DOI： 10.4049/jimmunol.1600822

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

Amelotin (AMTN) is expressed and secreted by ameloblasts in the maturation stage of amelogenesis and persist with low levels in the junctional epithelium (JE) of erupted teeth. The purpose of this study is to investigate the transcriptional regulation of the AMTN gene by transforming growth factor beta1 (TGF beta 1) in gingival epithelial (GE1) cells in the apoptosis phase. Apoptosis was evaluated by the fragmentation of chromosomal DNA and TUNEL staining. A real-time PCR was carried out to examine the AMTN mRNA levels induced by TGF beta 1 and Smad3 overexpression. Transient transfection analyses were completed using the various lengths of mouse AMTN gene promoter constructs with or without TGF beta 1. Chromatin immunoprecipitation (ChIP) assays were performed to investigate the Smad3 bindings to the AMTN gene promoter by TGF beta 1. TGF beta 1-induced apoptosis in GE1 cells were detected at 24 and 48 h by DNA fragmentation and TUNEL staining. AMTN mRNA levels increased at 6 h and reached maximum at 24 h in GE1 cells. Luciferase activities of the mouse AMTN gene promoter constructs were induced by TGF beta 1. The results of the ChIP assays showed that there was an increase in Smad3 binding to Smad-binding element (SBE)#1 and SBE#2 after stimulation by TGF beta 1. Immunohistochemical localization of AMTN was detected in the JE, and the AMTN protein levels in Smad3-deficient mice were decreased compared with wild-type mice. AMTN mRNA levels were induced at the initiation of apoptosis by TGF beta 1, which mediated through the Smad3 bindings to SBEs in the mouse AMTN gene promoter.

DOI： 10.1007/s10495-016-1279-5

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

DOI： 10.1371/journal.pone.0162032

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PUBLIC LIBRARY SCIENCE  

Temporomandibular joint osteoarthritis (TMJ-OA) is characterized by progressive degradation of cartilage and changes in subchondral bone. It is also one of the most serious subgroups of temporomandibular disorders. Rebamipide is a gastroprotective agent that is currently used for the treatment of gastritis and gastric ulcers. It scavenges reactive oxygen radicals and has exhibited anti-inflammatory potential. The aim of this study was to investigate the impact of rebamipide both in vivo and in vitro on the development of cartilage degeneration and osteoclast activity in an experimental murine model of TMJ-OA, and to explore its mode of action. Oral administration of rebamipide (0.6 mg/kg and 6 mg/kg) was initiated 24 h after TMJ-OA was induced, and was maintained daily for four weeks. Rebamipide treatment was found to attenuate cartilage degeneration, to reduce the number of apoptotic cells, and to decrease the expression levels of matrix metalloproteinase-13 (MMP-13) and inducible nitric oxide synthase (iNOS) in TMJ-OA cartilage in a dose-dependent manner. Rebamipide also suppressed the activation of transcription factors (e.g., NF-kappa B, NFATc1) and mitogen-activated protein kinases (MAPK) by receptor activator of nuclear factor kappa-B ligand (RANKL) to inhibit the differentiation of osteoclastic precursors, and disrupted the formation of actin rings in mature osteoclasts. Together, these results demonstrate the inhibitory effects of rebamipide on cartilage degradation in experimentally induced TMJ-OA. Furthermore, suppression of oxidative damage, restoration of extracellular matrix homeostasis of articular chondrocytes, and reduced subchondral bone loss as a result of blocked osteoclast activation suggest that rebamipide is a potential therapeutic strategy for TMJ-OA.

DOI： 10.1371/journal.pone.0154107

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Temporomandibular joint osteoarthritis is a degenerative disease that is characterized by permanent cartilage destruction. Transforming growth factor (TGF)-beta is one of the most abundant cytokines in the bone matrix and is shown to regulate the migration of osteoprogenitor cells. It is hypothesized that TGF-beta/Smad3 signaling affects cartilage homeostasis by influencing sphingosine 1-phosphate (S1P)/S1P receptor signaling and chondrocyte migration. We therefore investigated the molecular mechanisms by which crosstalk may occur between TGF-beta/Smad3 and S1P/S1P receptor signaling to maintain condylar cartilage and to prevent temporomandibular joint osteoarthritis. Abnormalities in the condylar subchondral bone, including dynamic changes in bone mineral density and microstructure, were observed in Smad3(-/-) mice by microcomputed tomography. Cell-free regions and proteoglycan Loss characterized the cartilage degradation present, and increased numbers of apoptotic chondrocytes and matrix metalloproteinase 13 chondrocytes were also detected. Furthermore, expression of SIP receptor 3 (S1P(3)), but not S1P(1) or S1P(2), was significantly down-regulated in the condylar cartilage of Smad3(-/-) mice. By using RNA interference technology and pharmacologic tools, S1P was found to transactivate Smad3 in an S1P(3)/TGF-beta type II receptor-dependent manner, and S1P(3) was found to be required for TGF-beta-induced migration of chondrocyte cells and downstream signal transduction via Rac1, RhoA, and Cdc42. Taken together, these results indicate that the Smad3/S1P(3) signaling pathway plays an important role in the pathogenesis of temporomandibular joint osteoarthritis.

DOI： 10.1016/j.ajpath.2015.06.015

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

ASXL2 is an ETP family protein that interacts with PPAR gamma. We find that ASXL2-/- mice are insulin resistant, lipodystrophic, and fail to respond to a high-fat diet. Consistent with genetic variation at the ASXL2 locus and human bone mineral density, ASXL2-/- mice are also severely osteopetrotic because of failed osteoclast differentiation attended by normal bone formation. ASXL2 regulates the osteoclast via two distinct signaling pathways. It induces osteoclast formation in a PPAR gamma/c-Fos-dependent manner and is required for RANK ligand-and thiazolidinedione-induced bone resorption independent of PGC-1 beta. ASXL2 also promotes osteoclast mitochondrial biogenesis in a process mediated by PGC-1 beta but independent of c-Fos. Thus, ASXL2 is a master regulator of skeletal, lipid, and glucose homeostasis.

DOI： 10.1016/j.celrep.2015.05.019

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DOI： 10.1038/nrendo.2015.102

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DOI： 10.1128/MCB.00790-12

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Background: Although autoimmunity in MRL/lpr mice occurs due to a defect in Fas-mediated cell death of T cells, the role of Fas-independent apoptosis in pathogenesis has rarely been investigated. We have recently reported that receptor activator of nuclear factor (NF)-kappa B ligand (RANKL)-activated dendritic cells (DCs) play a key role in the pathogenesis of rheumatoid arthritis (RA) in MRL/lpr mice. We here attempted to establish a new therapeutic strategy with RANKL-activated DCs in RA by controlling apoptosis of peripheral T cells. Repeated transfer of RANKL-activated DCs into MRL/lpr mice was tested to determine whether this had a therapeutic effect on autoimmunity.
Methods and Finding: Cellular and molecular mechanisms of Fas-independent apoptosis of T cells induced by the DCs were investigated by in vitro and in vivo analyses. We demonstrated that repeated transfers of RANKL-activated DCs into MRL/lpr mice resulted in therapeutic effects on RA lesions and lymphoproliferation due to declines of CD4(+) T, B, and CD4(-)CD8(-) double negative (DN) T cells. We also found that the Fas-independent T-cell apoptosis was induced by a direct interaction between tumor necrosis factor (TNF)-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) on T cells and TRAIL on Fas-deficient DCs in MRL/lpr mice.
Conclusion: These results strongly suggest that a novel Fas-independent apoptosis pathway in T cells maintains peripheral tolerance and thus controls autoimmunity in MRL/lpr mice.

DOI： 10.1371/journal.pone.0048798

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RANK ligand (RANKL), by mechanisms unknown, directly activates osteoclasts to resorb bone. Because c-Src is key to organizing the cell's cytoskeleton, we asked if the tyrosine kinase also mediates RANKL-stimulated osteoclast activity. RANKL induces c-Src to associate with RANK(369-373) in an alpha v beta 3-dependent manner. Furthermore, RANK(369-373) is the only one of six putative TRAF binding motifs sufficient to generate actin rings and activate the same cytoskeleton-organizing proteins as the integrin. While c-Src organizes the cell's cytoskeleton in response to the cytokine, it does not participate in RANKL-stimulated osteoclast formation. Attesting to their collaboration, alpha v beta 3 and activated RANK coprecipitate, but only in the presence of c-Src. c-Src binds activated RANK via its Src homology 2 (SH2) domain and alpha v beta 3 via its SH3 domain, suggesting the kinase links the two receptors. Supporting this hypothesis, deletion or inactivating point mutation of either the c-Src SH2 or SH3 domain obviates the RANK/alpha v beta 3 association. Thus, activated RANK prompts two distinct signaling pathways; one promotes osteoclast formation, and the other, in collaboration with c-Src-mediated linkage to alpha v beta 3, organizes the cell's cytoskeleton.

DOI： 10.1128/MCB.00077-12

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The human masticatory system consists of a mandible which is able to move with respect to the skull at its bilateral temporomandibular joint (TMJ) through contractions of the masticatory muscles. Like other synovial joints, the TMJ is loaded mechanically during function. The articular surface of the mandibular condyle is covered with cartilage that is composed mainly of collagen fibers and proteoglycans. This construction results in a viscoelastic response to loading and enables the cartilage to play an important role as a stress absorber during function. To understand its mechanical functions properly, and to assess its limitations, detailed information about the viscoelastic behavior of the mandibular condylar cartilage is required. The purpose of this paper is to review the fundamental concepts of the biomechanical behavior of the mandibular condylar cartilage. This review consists of four parts. Part 1 is a brief introduction of the structure and function of the mandibular condylar cartilage. In Part 2, the biochemical composition of the mandibular condylar cartilage is summarized. Part 3 explores the biomechanical properties of the mandibular condylar cartilage. Finally, Part 4 relates this behavior to the breakdown mechanism of the mandibular condylar cartilage which is associated with the progression of osteoarthritis in the TMJ. (C) 2009 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.joca.2009.04.025

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Periodontal ligament (PDL) cells appear to play important functional roles in response to mechanical stress. We hypothesized that hypoxia caused by a deformation of blood vessels and the following ischaemia may play a crucial role in differential gene expression in PDL cells affected by mechanical stress. Gene induction in cultured human PDL cells by hypoxia was analyzed using cDNA array, followed by RT-PCR analysis. Eleven hypoxia-responsive genes were found differentially expressed under low-oxygen conditions in PDL cells. Among them, CCR2, CC chemokine ligand 2 (CCL2) receptor was studied in more detail since little information is available on the role of chemokines in adaptive responses of PDL cells under hypoxia. Here we investigate whether CCR2 mediates the signalling to maintain the homeostasis of PDL cells. We found that cell death of PDL cells was induced under hypoxia with down-regulation of CCL2 mRNA expression. However, the exogenous CCL2 prevented PDL cell death under oxygen shortage with the increment of cellular inhibitor of apoptosis (cIAP) mRNA expression. The present study demonstrated substantial effects of hypoxia on gene expression of CCL2 and CCR2 in PDL cells, indicating that mechanical loading accompanied with mild hypoxia allows PDL cells to elicit adaptive responses with up-regulation of CCR2. (C) 2009 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.archoralbio.2009.03.010

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

The behavioral differences in muscle use are related to the fiber type composition of the muscles among other variables. The aim of this study was to examine the degree of heterogeneity in the fiber type composition in the rat temporalis muscle. The temporalis muscle was taken from 10-week-old Wistar strain male rats (n = 5). Fiber types were classified by immunohistochemical staining according to their myosin heavy chain content. The anterior temporalis revealed an obvious regional difference of the fiber type distribution, whereas the posterior temporalis was homogeneous. The deep anterior temporalis showed a predominant proportion of type IIA fibers and was the only muscle portion displaying slow type fibers (&lt; 10%). The other two muscle portions, the superficial anterior and posterior temporalis, did not differ significantly from each other and contained mainly type IIB fibers. Moreover, the deep anterior temporalis was the only muscle portion showing slow type fibers (&lt; 10%). In the deep portion, type IIX fibers revealed the largest cross-sectional area (1943.1 +/- 613.7 mu m(2)), which was significantly (P &lt; 0.01) larger than those of type IIA and I + IIA fibers. The cross-sectional area of type IIB fibers was the largest in the remaining two muscle portions and was significantly (P &lt; 0.01) larger than that of type IIX fibers. In conclusion, temporalis muscle in rats showed an obvious heterogeneity of fiber type composition and fiber cross-sectional area, which suggests multiple functions of this muscle.

DOI： 10.1111/j.1469-7580.2008.00990.x

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Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.11246/gakukansetsu1989.20.134

CiNii Article

CiNii Books

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Language：Japanese  

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Language：Japanese  

DOI： 10.11246/gakukansetsu1989.20.134

CiNii Article

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Language：English   Publisher：AMER SOC BONE & MINERAL RES  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC HEMATOLOGY  

Although receptor activator of nuclear factor (NF)-kappa B ligand (RANKL) signaling has been shown to prolong the survival of mature dendritic cells (DCs), the association of RANKL pathway with Fas-mediated apoptosis is obscure. Here, we found that bone marrow-derived DCs (BMDCs) from the Fas-deficient strain MRL/lpr mice, could survive much longer than normal DCs. The expressions of Bcl-x and Bcl-2 and the nuclear transport of NF-kappa B of RANKL-stimulated BMDCs from MRL/lpr mice were significantly upregulated. By contrast, Fas expression of BMDCs from normal C57BL/6 and MRL+/+ mice was increased by RANKL stimulation, and an enhanced DC apoptosis was found when stimulated with both RANKL and anti-Fas mAb, which was associated with activation of caspase-3 and caspase-9. Furthermore, the expression of FLIPL, an inhibitory molecule against Fas-mediated apoptosis, in normal DCs was significantly decreased by RANKL and anti-Fas mAb. Indeed, the adoptive transfer of RANKL-stimulated DCs resulted in rapid acceleration of autoimmunity in MRL/lpr recipients. These findings indicate that the crosstalk between RANKL and Fas signaling in DCs might control immune tolerance.

DOI： 10.1182/blood-2006-11-059980

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Language：English   Publisher：(一社)日本顎関節学会  

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Language：English   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Language：Japanese   Publisher：(一社)日本顎関節学会  

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Language：Japanese   Publisher：(NPO)日本免疫学会  

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Language：Japanese   Publisher：(NPO)日本口腔科学会  

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Language：Japanese  

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Language：Japanese   Publisher：(一社)日本顎関節学会  

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Language：English   Publisher：(公社)日本矯正歯科学会  

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ENDOCRINE SOC  

The aims of this study were to evaluate the in vivo effects of estrogen deficiency in MRL/lpr mice as a model for rheumatoid arthritis and to analyze the possible relationship between immune dysregulation and receptor activator of nuclear factor-kappaB ligand (RANKL)-mediated osteoclastogenesis. Experimental studies were performed in ovariectomized (Ovx)-MRL/lpr, Ovx-MRL +/+, sham-operated-MRL/ lpr, and sham-operated- MRL +/+ mice. Severe autoimmune arthritis developed in younger Ovx-MRL/lpr mice until 24 wk of age, whereas these lesions were entirely recovered by pharmacological levels of estrogen administration. A significant elevation in serum rheumatoid factor, anti-double-stranded DNA, and anti-type II collagen was found in Ovx-MRL/lpr mice and recovered in mice that underwent estrogen administration. A high proportion of CD4(+) T cells bearing RANKL was found, and an enhanced expression of RANKL mRNA and an impaired osteoprotegerin mRNA was detected in the synovium. An increase in both osteoclast formation and bone resorption pits was found. These results indicate that estrogen deficiency may play a crucial role in acceleration of autoimmune arthritis associated with RANKL-mediated osteoclastogenesis in a murine model for rheumatoid arthritis.

DOI： 10.1210/en.2003-1536

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PubMed

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Language：Japanese   Publishing type：Rapid communication, short report, research note, etc. (bulletin of university, research institution)  

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Language：Japanese   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

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Language：Japanese   Publishing type：Rapid communication, short report, research note, etc. (bulletin of university, research institution)  

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (bulletin of university, research institution)  

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Language：Japanese   Publishing type：Rapid communication, short report, research note, etc. (bulletin of university, research institution)  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY  

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Language：English   Publisher：生命科学系学会合同年次大会運営事務局  

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Language：Japanese   Publisher：(一社)日本骨代謝学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：WILEY-BLACKWELL  

Web of Science

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

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Language：Japanese   Publisher：(公社)日本矯正歯科学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本骨代謝学会  

J-GLOBAL

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

CiNii Article

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Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

CiNii Article

CiNii Books

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC BONE & MINERAL RES  

Web of Science

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Language：Japanese   Publisher：(一社)日本病理学会  

J-GLOBAL

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Language：Japanese   Publisher：(一社)日本病理学会  

J-GLOBAL

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：AMER SOC BONE & MINERAL RES  

Web of Science

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Event date： 2023.10.13 - 2023.10.16

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Event date： 2023.10.13 - 2023.10.16

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Event date： 2023.9.16 - 2023.9.18

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Event date： 2023.7.27 - 2023.7.29

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Event date： 2023.7.27 - 2023.7.29

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Event date： 2023.7.1 - 2023.7.2

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Event date： 2023.7.1 - 2023.7.2

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Event date： 2023.6.29 - 2023.7.1

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Event date： 2023.6.29 - 2023.7.1

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Event date： 2023.6.29 - 2023.7.1

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Event date： 2023.6.25 - 2023.6.27

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Event date： 2022.10.7

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Event date： 2022.10.5 - 2022.10.7

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Event date： 2022.10.5 - 2022.10.7

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Event date： 2022.10.5 - 2022.10.7

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Event date： 2022.10.5 - 2022.10.7

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Event date： 2022.9.17 - 2022.9.18

Language：Japanese   Presentation type：Poster presentation  

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Event date： 2022.7.3

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Event date： 2022.7.2 - 2022.7.3

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2022.6.30 - 2022.7.2

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2022.5.26 - 2022.5.27

Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Kagoshima  

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Event date： 2021.11.3 - 2021.11.5

Language：Japanese   Presentation type：Poster presentation  

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Event date： 2021.11.3 - 2021.11.5

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Event date： 2021.10.8 - 2021.10.10

Language：English   Presentation type：Oral presentation (general)  

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Event date： 2021.7.1 - 2021.7.3

Language：Japanese   Presentation type：Oral presentation (general)  

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Event date： 2020.10.9 - 2020.10.11

Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

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Event date： 2020.10.4 - 2020.10.7

Language：English   Presentation type：Poster presentation  

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Event date： 2019.11

Language：English   Presentation type：Poster presentation  

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Event date： 2019.10

Language：Japanese   Presentation type：Poster presentation  

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Event date： 2019.9

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：English   Presentation type：Poster presentation  

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：Tokyo  

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Language：Japanese   Presentation type：Oral presentation (general)  

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Language：Japanese   Presentation type：Public lecture, seminar, tutorial, course, or other speech  

Venue：Obu, Aichi  

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Language：Japanese   Presentation type：Symposium, workshop panel (nominated)  

Venue：Tokushima, Japan  

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Language：English   Presentation type：Poster presentation  

Venue：Hkata, Fukuoka, Japan  

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Language：English   Presentation type：Poster presentation  

Venue：Yokohama, Japan  

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Language：English   Presentation type：Poster presentation  

Venue：Hkkaido University, Hokkaido, Japan  

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Language：English   Presentation type：Poster presentation  

Venue：Yokohama  

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Language：English   Presentation type：Poster presentation  

Venue：Montreal, Quebec, Canada  

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Language：Japanese   Presentation type：Poster presentation  

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Language：Japanese   Presentation type：Poster presentation  

Venue：Nagasaki  

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Language：English   Presentation type：Poster presentation  

Venue：London Convention Center London, England  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Keio Plaza Hotel, Tokyo  

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Language：Japanese   Presentation type：Poster presentation  

Venue：OKINAWA  

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Language：English   Presentation type：Poster presentation  

Venue：Austin Convention Center Austin, TX, USA  

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Language：English   Presentation type：Poster presentation  

Venue：Houston TX, USA  

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Language：English   Presentation type：Poster presentation  

Venue：Houston, TX, USA  

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Language：English   Presentation type：Oral presentation (general)  

Venue：Sendai, Miyagi, Japan  

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Language：Japanese   Presentation type：Poster presentation  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Kurashiki  

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Language：English   Presentation type：Poster presentation  

Venue：Sapporo, Hokkaido  

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Language：English   Presentation type：Poster presentation  

Venue：Denver, CO, USA  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Hakata, Fukuoka  

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Language：English   Presentation type：Poster presentation  

Venue：San Francisco, USA  

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Language：English   Presentation type：Poster presentation  

Venue：San Francisco, USA  

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Language：English   Presentation type：Poster presentation  

Venue：Tokushima, Japan  

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Language：English   Presentation type：Poster presentation  

Venue：Makuhari  

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Language：Japanese   Presentation type：Oral presentation (general)  

Venue：Okayama  

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Language：English   Presentation type：Poster presentation  

Venue：Seoul  

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Language：English   Presentation type：Poster presentation  

Venue：Seattle, USA  

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Language：English   Presentation type：Poster presentation  

Venue：Houston, TX, USA  

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Language：Japanese   Presentation type：Oral presentation (invited, special)  

Venue：Miyazaki, Japan  

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Language：English   Presentation type：Poster presentation  

Venue：Minneapolis, USA  

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Language：English   Presentation type：Oral presentation (general)  

Venue：Minneapolis, USA  

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Language：English   Presentation type：Oral presentation (keynote)  

Venue：St. Louis, MO, USA  

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Language：English   Presentation type：Poster presentation  

Venue：San Diego, CA, USA  

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Language：English   Presentation type：Poster presentation  

Venue：Boston, USA  

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Language：English   Presentation type：Poster presentation  

Venue：Honolulu  

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Language：English   Presentation type：Poster presentation  

Venue：Minneapolis, USA  

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Language：English   Presentation type：Poster presentation  

Venue：San Antonio, USA  

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Award type：Award from international society, conference, symposium, etc.  Country：Singapore

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http://jsbmr.umin.jp/prize/

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Award type：Award from publisher, newspaper, foundation, etc. 

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Country：Japan

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