Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Necroptosis, a form of necrosis, and alterations in mitochondrial dynamics, a coordinated process of mitochondrial fission and fusion, have been implicated in the pathogenesis of cardiovascular diseases. This study aimed to determine the role of mitochondrial morphology in canonical necroptosis induced by a combination of TNFα and zVAD (TNF/zVAD) in H9c2 cells, rat cardiomyoblasts. Time-course analyses of mitochondrial morphology showed that mitochondria were initially shortened after the addition of TNF/zVAD and then their length was restored, and the proportion of cells with elongated mitochondria at 12 h was larger in TNF/zVAD-treated cells than in non-treated cells (16.3 ± 0.9% vs. 8.0 ± 1.2%). The knockdown of dynamin-related protein 1 (Drp1) and fission 1, fission promoters, and treatment with Mdivi-1, a Drp-1 inhibitor, had no effect on TNF/zVAD-induced necroptosis. In contrast, TNF/zVAD-induced necroptosis was attenuated by the knockdown of mitofusin 1/2 (Mfn1/2) and optic atrophy-1 (Opa1), proteins that are indispensable for mitochondrial fusion, and the attenuation of necroptosis was not canceled by treatment with Mdivi-1. The expression of TGFβ-activated kinase (TAK1), a negative regulator of RIP1 activity, was upregulated and the TNF/zVAD-induced RIP1-Ser166 phosphorylation, an index of RIP1 activity, was mitigated by the knockdown of Mfn1/2 or Opa1. Pharmacological TAK1 inhibition attenuated the protection afforded by Mfn1/2 and Opa1 knockdown. In conclusion, the inhibition of mitochondrial fusion increases TAK1 expression, leading to the attenuation of canonical necroptosis through the suppression of RIP1 activity.

DOI： 10.3390/ijms25052905

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Language：English   Publisher：(一社)日本循環器学会  

Ichushi

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Other Link： https://link.springer.com/article/10.1007/s11010-024-04951-z/fulltext.html

DOI： 10.1007/s11010-024-04951-z

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

It has been reported that autophagic activity is disturbed in the skeletal muscles of dystrophin-deficient mdx mice and patients with Duchenne muscular dystrophy (DMD). Transcriptional regulations of autophagy by FoxO transcription factors (FoxOs) and transcription factor EB (TFEB) play critical roles in adaptation to cellular stress conditions. Here, we investigated whether autophagic activity is dysregulated at the transcription level in dystrophin-deficient muscles. Expression levels of autophagy-related genes were globally decreased in tibialis anterior and soleus muscles of mdx mice compared with those of wild-type mice. DNA microarray data from the NCBI database also showed that genes related to autophagy were globally downregulated in muscles from patients with DMD. These downregulated genes are known as targets of FoxOs and TFEB. Immunostaining showed that nuclear localization of FoxO1 and FoxO3a was decreased in mdx mice. Western blot analyses demonstrated increases in phosphorylation levels of FoxO1 and FoxO3a in mdx mice. Nuclear localization of TFEB was also reduced in mdx mice, which was associated with elevated phosphorylation levels of TFEB. Collectively, the results suggest that autophagy is disturbed in dystrophin-deficient muscles via transcriptional downregulation due to phosphorylation-mediated suppression of FoxOs and TFEB.

DOI： 10.1038/s41598-024-51746-9

PubMed

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

All eukaryotic cells require a minimal iron threshold to sustain anabolic metabolism. However, the mechanisms by which cells sense iron to regulate anabolic processes are unclear. Here we report a previously undescribed eukaryotic pathway for iron sensing in which molecular iron is required to sustain active histone demethylation and maintain the expression of critical components of the pro-anabolic mTORC1 pathway. Specifically, we identify the iron-binding histone-demethylase KDM3B as an intrinsic iron sensor that regulates mTORC1 activity by demethylating H3K9me2 at enhancers of a high-affinity leucine transporter, LAT3, and RPTOR. By directly suppressing leucine availability and RAPTOR levels, iron deficiency supersedes other nutrient inputs into mTORC1. This process occurs in vivo and is not an indirect effect by canonical iron-utilizing pathways. Because ancestral eukaryotes share homologues of KDMs and mTORC1 core components, this pathway probably pre-dated the emergence of the other kingdom-specific nutrient sensors for mTORC1.

DOI： 10.1038/s41556-023-01225-6

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

Sirtuins (SIRT) exhibit deacetylation or ADP-ribosyltransferase activity and regulate a wide range of cellular processes in the nucleus, mitochondria and cytoplasm. The role of the only sirtuin that resides in the cytoplasm, SIRT2, in the development of ischemic injury and cardiac hypertrophy is not known. In this paper, we show that the hearts of mice with deletion of Sirt2 (Sirt2-/-) display improved cardiac function after ischemia-reperfusion (I/R) and pressure overload (PO), suggesting that SIRT2 exerts maladaptive effects in the heart in response to stress. Similar results were obtained in mice with cardiomyocyte-specific Sirt2 deletion. Mechanistic studies suggest that SIRT2 modulates cellular levels and activity of nuclear factor (erythroid-derived 2)-like 2 (NRF2), which results in reduced expression of antioxidant proteins. Deletion of Nrf2 in the hearts of Sirt2-/- mice reversed protection after PO. Finally, treatment of mouse hearts with a specific SIRT2 inhibitor reduced cardiac size and attenuates cardiac hypertrophy in response to PO. These data indicate that SIRT2 has detrimental effects in the heart and plays a role in cardiac response to injury and the progression of cardiac hypertrophy, which makes this protein a unique member of the SIRT family. Additionally, our studies provide a novel approach for treatment of cardiac hypertrophy and injury by targeting SIRT2 pharmacologically, providing a novel avenue for the treatment of these disorders.

DOI： 10.7554/eLife.85571

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

BACKGROUND: Proper nuclear organization is critical for cardiomyocyte function, because global structural remodeling of nuclear morphology and chromatin structure underpins the development and progression of cardiovascular disease. Previous reports have implicated a role for DNA damage in cardiac hypertrophy; however, the mechanism for this process is not well delineated. AMPK (AMP-activated protein kinase) family of proteins regulates metabolism and DNA damage response (DDR). Here, we examine whether a member of this family, SNRK (SNF1-related kinase), which plays a role in cardiac metabolism, is also involved in hypertrophic remodeling through changes in DDR and structural properties of the nucleus. METHODS: We subjected cardiac-specific Snrk-/- mice to transaortic banding to assess the effect on cardiac function and DDR. In parallel, we modulated SNRK in vitro and assessed its effects on DDR and nuclear parameters. We also used phosphoproteomics to identify novel proteins that are phosphorylated by SNRK. Last, coimmunoprecipitation was used to verify Destrin (DSTN) as the binding partner of SNRK that modulates its effects on the nucleus and DDR. RESULTS: Cardiac-specific Snrk-/- mice display worse cardiac function and cardiac hypertrophy in response to transaortic banding, and an increase in DDR marker pH2AX (phospho-histone 2AX) in their hearts. In addition, in vitro Snrk knockdown results in increased DNA damage and chromatin compaction, along with alterations in nuclear flatness and 3-dimensional volume. Phosphoproteomic studies identified a novel SNRK target, DSTN, a member of F-actin depolymerizing factor proteins that directly bind to and depolymerize F-actin. SNRK binds to DSTN, and DSTN downregulation reverses excess DNA damage and changes in nuclear parameters, in addition to cellular hypertrophy, with SNRK knockdown. We also demonstrate that SNRK knockdown promotes excessive actin depolymerization, measured by the increased ratio of G-actin to F-actin. Last, jasplakinolide, a pharmacological stabilizer of F-actin, rescues the increased DNA damage and aberrant nuclear morphology in SNRK-downregulated cells. CONCLUSIONS: These results indicate that SNRK is a key player in cardiac hypertrophy and DNA damage through its interaction with DSTN. This interaction fine-tunes actin polymerization to reduce DDR and maintain proper cardiomyocyte nuclear shape and morphology.

DOI： 10.1161/CIRCULATIONAHA.123.066002

PubMed

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Language：English   Publisher：(一社)日本循環器学会  

Ichushi

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

Systemic branched-chain amino acid (BCAA) metabolism is dysregulated in cardiometabolic diseases. We previously demonstrated that upregulated AMP deaminase 3 (AMPD3) impairs cardiac energetics in a rat model of obese type 2 diabetes, Otsuka Long-Evans-Tokushima fatty (OLETF). Here, we hypothesized that the cardiac BCAA levels and the activity of branched-chain α-keto acid dehydrogenase (BCKDH), a rate-limiting enzyme in BCAA metabolism, are altered by type 2 diabetes (T2DM), and that upregulated AMPD3 expression is involved in the alteration. Performing proteomic analysis combined with immunoblotting, we discovered that BCKDH localizes not only to mitochondria but also to the endoplasmic reticulum (ER), where it interacts with AMPD3. Knocking down AMPD3 in neonatal rat cardiomyocytes (NRCMs) increased BCKDH activity, suggesting that AMPD3 negatively regulates BCKDH. Compared with control rats (Long-Evans Tokushima Otsuka [LETO] rats), OLETF rats exhibited 49% higher cardiac BCAA levels and 49% lower BCKDH activity. In the cardiac ER of the OLETF rats, BCKDH-E1α subunit expression was downregulated, while AMPD3 expression was upregulated, resulting in an 80% lower AMPD3-E1α interaction compared to LETO rats. Knocking down E1α expression in NRCMs upregulated AMPD3 expression and recapitulated the imbalanced AMPD3-BCKDH expressions observed in OLETF rat hearts. E1α knockdown in NRCMs inhibited glucose oxidation in response to insulin, palmitate oxidation, and lipid droplet biogenesis under oleate loading. Collectively, these data revealed previously unrecognized extramitochondrial localization of BCKDH in the heart and its reciprocal regulation with AMPD3 and imbalanced AMPD3-BCKDH interactions in OLETF. Downregulation of BCKDH in cardiomyocytes induced profound metabolic changes that are observed in OLETF hearts, providing insight into mechanisms contributing to the development of diabetic cardiomyopathy.

DOI： 10.14814/phy2.15608

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：American Society for Clinical Investigation  

DOI： 10.1172/JCI154491

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier {BV}  

DOI： 10.1016/j.yjmcc.2018.05.003

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

Diabetes mellitus is a major risk factor for acute kidney injury (AKI). Here, we hypothesized that suppression of autophagic response underlies aggravation of renal ischemia/reperfusion (I/R) injury by type 2 diabetes mellitus (T2DM). In OLETF, a rat model of T2DM, and its non-diabetic control, LETO, AKI was induced by unilateral nephrectomy and 30-min occlusion and 24-h reperfusion of the renal artery in the contralateral kidney. Levels of serum creatinine and blood urea nitrogen and tubular injury score after I/R were significantly higher in OLETF than in LETO. Administration of chloroquine, a widely used autophagy inhibitor, aggravated I/R-induced renal injury in LETO, but not in OLETF. In contrast to LETO, OLETF exhibited no increase in autophagosomes in the proximal tubules after I/R. Immunoblotting showed that I/R activated the AMPK/ULK1 pathway in LETO but not in OLETF, and mTORC1 activation after I/R was enhanced in OLETF. Treatment of OLETF with rapamycin, an mTORC1 inhibitor, partially restored autophagic activation in response to I/R and significantly attenuated I/R-induced renal injury. Collectively, these findings indicate that suppressed autophagic activation in proximal tubules by impaired AMPK/ULK1 signaling and upregulated mTORC1 activation underlies T2DM-induced worsening of renal I/R injury.

DOI： 10.1038/s41598-017-05667-5

PubMed

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

BACKGROUND: The role of necroptosis in myocardial injury has not been fully characterized. Here we examined roles of mitochondrial permeability transition pore (mPTP) and autophagy in necroptosis of cardiomyocytes. METHODS AND RESULTS: In H9c2 cells, necroptosis was induced by treatment with TNF-α (TNF) and z-VAD-fmk (zVAD) for 24h, and necroptotic death was determined by LDH release (as % of total). TNF/zVAD increased LDH release from 16.6±4.3% to 60.6±2.7%, and the LDH release was suppressed by necrostatin-1 (29.4±4.0%), a RIP1 inhibitor, and by siRNA-mediated knockdown of RIP3 (27.7±2.0%), confirming RIP1-RIP3-dependent necroptosis. TNF/zVAD-induced necroptosis was not attenuated by mPTP inhibitors or GSK-3β inhibitors. TNF/zVAD increased LC3-II level, but the change was not further enhanced by bafilomycin A1. The increase of LC3-II by TNF/zVAD was associated with suppression of both autophagic flux and LC3-LAMP1 co-localization. TNF/zVAD did not modify phosphorylation of Akt, p70s6K, AMPK, ULK1 or VASP but significantly increased RIP1-p62 binding and conversely reduced p62-LC3 binding. Rapamycin inhibited RIP1-p62 and RIP1-RIP3 interactions induced by TNF/zVAD and partly restored autophagic flux and suppressed LDH release in TNF/zVAD-treated cells. The effect of rapamycin on LDH release was reduced by knockdown of Atg5 expression. Knockdown of p62 by siRNA augmented LDH release by TNF/zVAD. CONCLUSION: Suppression of autophagic flux contributes to RIP1-RIP3 interaction and necroptosis of cardiomyocytes, and sequestration of p62 from its interaction with LC3-II by p62-RIP1 interaction possibly underlies the suppressed autophagy. The mPTP is unlikely to play a major role in execution of necroptosis in cardiomyocytes.

DOI： 10.1016/j.yjmcc.2017.06.008

PubMed

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

BACKGROUND: Sleep-disordered breathing (SDB) is highly prevalent in patients with diabetes mellitus (DM) and heart failure (HF) and contributes to poor cardiovascular outcomes. Enlarged glycemic variability (GV) is a risk factor of cardiac events independently of average blood glucose level, but the influence of SDB on GV is uncertain. In this study, we examined whether the impact of SDB on GV is modified by the presence of DM with or without HF. METHODS AND RESULTS: Two hundred three patients (67.5±14.1 [SD] years old, 132 males) who were admitted to our institute for examination or treatment of DM and/or HF underwent continuous glucose monitoring and polysomnography. Both HbA1c (8.0±2.0 vs. 5.7±0.4%) and mean amplitude of glycemic excursion (MAGE, median: 95.5 vs. 63.5 mg/dl) were significantly higher in a DM group (n = 100) than in a non-DM group (n = 103), but apnea-hypopnea index (AHI: 29.0±22.7 vs. 29.3±21.5) was similar in the two groups. AHI was correlated with log MAGE in the non-DM group but not in the DM group, and multivariate regression analysis revealed that AHI was an independent variable for log MAGE in the non-DM group but not in the DM group. We then divided the non-DM patients into two subgroups according to BNP level (100 pg/ml). AHI was positively correlated with log MAGE (r = 0.74, p<0.001) in the non-DM low-BNP subgroup, but such a correlation was not found in the non-DM high-BNP subgroup. Continuous positive airway pressure (CPAP) reduced MAGE from 75.3 to 53.0 mg/dl in the non-DM group but did not reduce MAGE in the DM group. CONCLUSION: Severity of SDB was associated with higher GV, but DM as well as HF diminished the contribution of SDB to GV. Treatment with CPAP was effective for reduction of GV only in patients without DM.

DOI： 10.1371/journal.pone.0188689

PubMed

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

A 65-year-old male developed acute myocardial infarction due to coronary artery dissection and tricuspid valve injury after blunt chest trauma. Acute myocardial infarction was treated by coronary artery intervention; however, refractory heart failure with pleural effusion remained. The first transthoracic echocardiography (TTE) on admission failed to clearly visualize the tricuspid valve and right ventricle due to poor image quality. A follow-up TTE with contrast ultrasonography revealed pericardial rupture in addition to tricuspid regurgitation. Ruptures of the tricuspid papillary muscle and pericardium were confirmed during surgery and were repaired successfully. Blunt chest trauma results in various cardiac injuries including cardiac rupture, intramural hematoma, valvular injury, coronary artery injury, and electrical disturbances, leading to critical conditions and high mortality. Of such blunt trauma-induced injuries, coronary artery dissection, tricuspid valve injury, and pericardial rupture caused by blunt chest trauma are rare, and simultaneous occurrence of the three types of injuries that were successfully repaired has not been reported. In addition, this case indicates the utility of contrast ultrasonography for diagnosis of pericardial rupture caused by blunt chest trauma.

DOI： 10.1007/s10396-015-0663-z

PubMed

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Authorship：Lead author   Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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

Web of Science

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Authorship：Lead author   Publishing type：Research paper, summary (international conference)  

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Authorship：Lead author   Language：English   Publishing type：Research paper, summary (international conference)  

DOI： 10.1161/res.131.suppl_1.P3014

Web of Science

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Language：English   Publisher：(一社)日本循環器学会  

Ichushi

J-GLOBAL

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Authorship：Lead author   Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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Authorship：Lead author   Language：English   Publishing type：Research paper, summary (international conference)  

DOI： 10.1161/res.127.suppl_1.263

Web of Science

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Language：English   Publisher：(一社)日本循環器学会  

Ichushi

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Language：English   Publisher：(一社)日本循環器学会  

Ichushi

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

DOI： 10.11281/shinzo.50.1289

CiNii Research

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Authorship：Lead author   Publishing type：Research paper, summary (national, other academic conference)  

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Authorship：Lead author   Language：English   Publishing type：Research paper, summary (international conference)  

Web of Science

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Authorship：Lead author   Publishing type：Research paper, summary (national, other academic conference)  

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Authorship：Lead author   Language：Japanese   Publisher：医歯薬出版(株)  

Other Link:： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J00060&link_issn=&doc_id=20170719010009&doc_link_id=issn%3D0039-2359%26volume%3D262%26issue%3D3%26spage%3D243&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D262%26issue%3D3%26spage%3D243&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Ichushi

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Language：English   Publisher：(一社)日本循環器学会  

Ichushi

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Language：Japanese   Publisher：(一社)日本内分泌学会  

Ichushi

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

Web of Science

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

DOI： 10.1016/j.cardfail.2016.07.055

Web of Science

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

Web of Science

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

Web of Science

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Language：Japanese   Publisher：(一社)日本腎臓学会  

Ichushi

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Authorship：Lead author   Publishing type：Research paper, summary (international conference)  

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Language：English   Publisher：(一社)日本循環器学会  

Ichushi

J-GLOBAL

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Language：Japanese   Publisher：科学評論社  

Other Link:： https://search.jamas.or.jp/link/ui/2016075832

CiNii Research

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J-GLOBAL

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Language：Japanese   Publisher：(一社)日本腎臓学会  

Ichushi

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Authorship：Lead author   Publishing type：Research paper, summary (international conference)  

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)   Publisher：(公社)日本超音波医学会  

Ichushi

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper, summary (national, other academic conference)   Publisher：(公社)日本超音波医学会  

Ichushi

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Event date： 2022.9 - 2022.10

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Event date： 2014.5

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Event date： 2013.10

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

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

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Language：English   Presentation type：Poster presentation  

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

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

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

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

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

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Type：Competition, symposium, etc. 

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