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Article ; Online: Glutathione depletion results in S-nitrosylation of protein disulfide isomerase in neuroblastoma cells.

Ono, Shinji / Ogura, Jiro / Sugiura, Hiroki / Yamauchi, Minami / Tanaka, Atsushi / Sato, Toshihiro / Maekawa, Masamitsu / Yamaguchi, Hiroaki / Mano, Nariyasu

Life sciences

2023 Volume 316, Page(s) 121442

Abstract: ... protein folding. PDI is S-nitrosylated in the brains of Alzheimer's disease patients, and S-nitrosylated PDI is ... considered one of main causes of Alzheimer's disease. However, the mechanisms underlying PDI S-nitrosylation ... of Alzheimer's disease, we investigated the effect of GSH depletion on the S-nitrosylation level of PDI.: Main methods ...

Abstract	Aims: Protein disulfide isomerase (PDI) is an essential enzyme involved in oxidative protein folding. PDI is S-nitrosylated in the brains of Alzheimer's disease patients, and S-nitrosylated PDI is considered one of main causes of Alzheimer's disease. However, the mechanisms underlying PDI S-nitrosylation have not yet been elucidated. Because glutathione (GSH) depletion is a pathological feature of Alzheimer's disease, we investigated the effect of GSH depletion on the S-nitrosylation level of PDI. Main methods: SH-SY5Y cells, which is a human derived neuroblastoma cells, were used in this study. Glutamate and buthionine sulfoximine (BSO) were used as GSH depletors. S-nitrosylated PDI was detected by biotin-switch assay. Key findings: GSH depletion by glutamate, a cystine/glutamate antiporter xCT inhibitor, increased S-nitrosylated PDI at C343 in SH-SY5Y cells, and induced IRE1α phosphorylation. BSO, a γ-glutamylcysteine synthetase inhibitor, also increased S-nitrosylated PDI and phosphorylated IRE1α upon GSH depletion. Because S-nitrosylated PDI at C343 is stable in neuro cells, S-nitrosylated PDI by GSH depletion progresses to neurodegeneration by the induction of endoplasmic reticulum stress via phosphorylated IRE1α signaling from the early to late stage. Furthermore, treatment with neohesperidin, but not N-acetylcysteine (NAC), improved PDI S-nitrosylation level in GSH-depleted SH-SY5Y cells because nitrosylated compound of NAC induces PDI S-nitrosylation. Significance: The results of our study provide a new insight into the mechanisms of neurodegeneration, and may be useful for the development of drugs for Alzheimer's diseases.
MeSH term(s)	Humans ; Protein Disulfide-Isomerases/metabolism ; Alzheimer Disease ; Endoribonucleases ; Neuroblastoma/pathology ; Protein Serine-Threonine Kinases ; Glutathione ; Glutamates
Chemical Substances	Protein Disulfide-Isomerases (EC 5.3.4.1) ; Endoribonucleases (EC 3.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Glutathione (GAN16C9B8O) ; Glutamates
Language	English
Publishing date	2023-01-26
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2023.121442
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Article ; Online: Randomized phase II trial of chemoradiotherapy with S-1 versus combination chemotherapy with gemcitabine and S-1 as neoadjuvant treatment for resectable pancreatic cancer (JASPAC 04).

Sugiura, Teiichi / Toyama, Hirochika / Fukutomi, Akira / Asakura, Hirofumi / Takeda, Yuriko / Yamamoto, Kouji / Hirano, Satoshi / Satoi, Sohei / Matsumoto, Ippei / Takahashi, Shinichiro / Morinaga, Soichiro / Yoshida, Makoto / Sakuma, Yasunaru / Iwamoto, Hidetaka / Shimizu, Yasuhiro / Uesaka, Katsuhiko

Journal of hepato-biliary-pancreatic sciences

2023 Volume 30, Issue 11, Page(s) 1249–1260

Abstract: ... chemoradiotherapy (NAC-RT) with S-1 or combination neoadjuvant chemotherapy with gemcitabine and S-1 (NAC-GS), is ... of effectiveness and safety.: Methods: In the NAC-RT with S-1 group, the patients received a total radiation ... dose of 50.4 Gy in 28 fractions with oral S-1. In the NAC-GS group, the patients received intravenous ...

Abstract	Objective: The aim of the present study was to investigate which treatment, neoadjuvant chemoradiotherapy (NAC-RT) with S-1 or combination neoadjuvant chemotherapy with gemcitabine and S-1 (NAC-GS), is more promising as neoadjuvant treatment (NAT) for resectable pancreatic cancer in terms of effectiveness and safety. Methods: In the NAC-RT with S-1 group, the patients received a total radiation dose of 50.4 Gy in 28 fractions with oral S-1. In the NAC-GS group, the patients received intravenous gemcitabine at a dose of 1000 mg/m Results: From April 2014 to April 2017, a total of 103 patients were enrolled. After exclusion of one patient because of ineligibility, 51 patients were included in the NAC-RT with S-1 group, and 51 patients were included in the NAC-GS group in the intention-to-treat analysis. The 2-year PFS rate was 45.0% (90% confidence interval [CI]: 33.3%-56.0%) in the NAC-RT with S-1 group and 54.9% (42.8%-65.5%) in the NAC-GS group (p = .350). The 2-year overall survival rate was 66.7% in the NAC-RT with S-1 group and 72.4% in the NAC-GS group (p = .300). Although leukopenia and neutropenia rates were significantly higher in the NAC-GS group than in the NAC-RT with S-1 group (p = .023 and p < .001), other adverse events of NAT and postoperative complications were comparable between the two groups. Conclusion: Both NAC-RT with S-1 and NAC-GS are considered promising treatments for resectable pancreatic cancer.
MeSH term(s)	Humans ; Chemoradiotherapy ; Gemcitabine ; Neoadjuvant Therapy/adverse effects ; Pancreatic Neoplasms
Chemical Substances	Gemcitabine
Language	English
Publishing date	2023-09-25
Publishing country	Japan
Document type	Clinical Trial, Phase II ; Randomized Controlled Trial ; Journal Article
ZDB-ID	2536236-7
ISSN	1868-6982 ; 1868-6974
ISSN (online)	1868-6982
ISSN	1868-6974
DOI	10.1002/jhbp.1353
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Article ; Online: Probing the proton release by Photosystem II in the S

Boussac, Alain / Sugiura, Miwa / Sellés, Julien

Biochimica et biophysica acta. Bioenergetics

2022 Volume 1863, Issue 5, Page(s) 148546

Abstract: ... of the S-state cycle in Photosystem II (PSII) from Thermosynechococcus elongatus containing either a Mn ...

Abstract	The stoichiometry and kinetics of the proton release were investigated during each transition of the S-state cycle in Photosystem II (PSII) from Thermosynechococcus elongatus containing either a Mn
MeSH term(s)	Cyanobacteria/metabolism ; Electron Transport ; Oxidation-Reduction ; Photosystem II Protein Complex/metabolism ; Protons
Chemical Substances	Photosystem II Protein Complex ; Protons
Language	English
Publishing date	2022-03-23
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1879-2650 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1879-2650 ; 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbabio.2022.148546
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Article ; Online: Feasibility of S-1 adjuvant chemotherapy after major hepatectomy for biliary tract cancers: An exploratory subset analysis of JCOG1202.

European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology

2023 Volume 50, Issue 2, Page(s) 107324

Abstract: ... the superiority of adjuvant S-1 chemotherapy for biliary tract cancer (BTC). The aim of this study is to examine ... the influence of MH for BTC on adjuvant S-1.: Materials and methods: Of the total 424 patients, 207 received ... S-1 (S-1 arm) while the remaining 217 were not. We compared MH with non-major hepatectomy (NMH ...

Abstract	Introduction: Major hepatectomy (MH) may produce the impaired liver function and affect the feasibility of adjuvant chemotherapy in terms of early period after the surgery, but there have not been detailed investigations. JCOG1202 (UMIN000011688) is a randomized phase III trial demonstrating the superiority of adjuvant S-1 chemotherapy for biliary tract cancer (BTC). The aim of this study is to examine the influence of MH for BTC on adjuvant S-1. Materials and methods: Of the total 424 patients, 207 received S-1 (S-1 arm) while the remaining 217 were not. We compared MH with non-major hepatectomy (NMH) for BTC. Results: In the S-1 arm, 42 had undergone MH, and 165 had undergone NMH. MH had similar pretreatment features to NMH, including the proportion of biliary reconstruction, to NMH, except for a lower platelet count (17.7 vs. 23.4 × 10 Conclusion: The treatment completion proportion and dose intensity were lower in MH than in NMH. Caution should be exercised against biliary tract infections and gastrointestinal disorders during adjuvant S-1 after MH for BTC.
MeSH term(s)	Humans ; Antineoplastic Combined Chemotherapy Protocols ; Biliary Tract Neoplasms/drug therapy ; Biliary Tract Neoplasms/surgery ; Chemotherapy, Adjuvant ; Feasibility Studies ; Gastrointestinal Diseases/drug therapy ; Gastrointestinal Diseases/surgery ; Hepatectomy ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase III as Topic
Language	English
Publishing date	2023-12-20
Publishing country	England
Document type	Journal Article
ZDB-ID	632519-1
ISSN	1532-2157 ; 0748-7983
ISSN (online)	1532-2157
ISSN	0748-7983
DOI	10.1016/j.ejso.2023.107324
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Article ; Online: Glutathione depletion results in S-nitrosylation of protein disulfide isomerase in neuroblastoma cells

Ono, Shinji / Ogura, Jiro / Sugiura, Hiroki / Yamauchi, Minami / Tanaka, Atsushi / Sato, Toshihiro / Maekawa, Masamitsu / Yamaguchi, Hiroaki / Mano, Nariyasu

Life Sciences. 2023 Mar., v. 316 p.121442-

2023

Abstract: ... is S-nitrosylated in the brains of Alzheimer's disease patients, and S-nitrosylated PDI is considered ... one of main causes of Alzheimer's disease. However, the mechanisms underlying PDI S-nitrosylation have ... of Alzheimer's disease, we investigated the effect of GSH depletion on the S-nitrosylation level of PDI. SH-SY5Y cells ...

Abstract	Protein disulfide isomerase (PDI) is an essential enzyme involved in oxidative protein folding. PDI is S-nitrosylated in the brains of Alzheimer's disease patients, and S-nitrosylated PDI is considered one of main causes of Alzheimer's disease. However, the mechanisms underlying PDI S-nitrosylation have not yet been elucidated. Because glutathione (GSH) depletion is a pathological feature of Alzheimer's disease, we investigated the effect of GSH depletion on the S-nitrosylation level of PDI. SH-SY5Y cells, which is a human derived neuroblastoma cells, were used in this study. Glutamate and buthionine sulfoximine (BSO) were used as GSH depletors. S-nitrosylated PDI was detected by biotin-switch assay. GSH depletion by glutamate, a cystine/glutamate antiporter xCT inhibitor, increased S-nitrosylated PDI at C343 in SH-SY5Y cells, and induced IRE1α phosphorylation. BSO, a γ-glutamylcysteine synthetase inhibitor, also increased S-nitrosylated PDI and phosphorylated IRE1α upon GSH depletion. Because S-nitrosylated PDI at C343 is stable in neuro cells, S-nitrosylated PDI by GSH depletion progresses to neurodegeneration by the induction of endoplasmic reticulum stress via phosphorylated IRE1α signaling from the early to late stage. Furthermore, treatment with neohesperidin, but not N-acetylcysteine (NAC), improved PDI S-nitrosylation level in GSH-depleted SH-SY5Y cells because nitrosylated compound of NAC induces PDI S-nitrosylation. The results of our study provide a new insight into the mechanisms of neurodegeneration, and may be useful for the development of drugs for Alzheimer's diseases.
Keywords	Alzheimer disease ; S-nitrosylation ; acetylcysteine ; antiporters ; cystine ; endoplasmic reticulum stress ; glutamic acid ; glutathione ; humans ; neohesperidin ; neurodegenerative diseases ; phosphorylation ; protein disulfide-isomerase ; Oxidative stress ; Protein disulfide isomerase ; Alzheimer's disease
Language	English
Dates of publication	2023-03
Publishing place	Elsevier Inc.
Document type	Article ; Online
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2023.121442
Database	NAL-Catalogue (AGRICOLA)

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Article: Thrombosis-related characteristics of pregnant women with antithrombin deficiency, protein C deficiency and protein S deficiency in Japan.

Kobayashi, Takao / Sugiura, Kazuko / Ojima, Toshiyuki / Serizawa, Mariko / Hirai, Kyuya / Morishita, Eriko

Thrombosis journal

2024 Volume 22, Issue 1, Page(s) 18

Abstract: ... characteristics. Antithrombin (AT) deficiency, protein C (PC) deficiency and protein S (PS) deficiency are ...

Abstract	Background: We previously conducted a primary survey of pregnant women with hereditary thrombophilia based on national surveillance in Japan, but did not examine their thrombosis-related characteristics. Antithrombin (AT) deficiency, protein C (PC) deficiency and protein S (PS) deficiency are the major types of hereditary thrombophilia in Japan. Methods: We examined their detailed information related to thrombosis, and evaluated peripartum outcomes in comparison with control data obtained from the Japan Society of Obstetrics and Gynecology. Results: Definite or probable AT deficiency, PC deficiency and PS deficiency were observed in 80, 50, and 317 pregnancies, respectively, from 2014 to 2018 in Japan, with prevalence rates among total deliveries of 0.011%, 0.007%, 0.044%. The number of pregnancies with AT, PC and PS deficiency might have been as many as 27, 17 and 108 every year if complete answers had been provided. In the peripartum period of current pregnancies, 27.5% of women with AT deficiency, 28.0% with PC deficiency and 13.2% with PS deficiency developed thrombosis (p < 0.001 vs. control). Pregnant women with AT and PC deficiency were more susceptible to thrombosis than those with PS deficiency (P < 0.01). Of the thromboses, 92.3% occurred during pregnancy, 62.8% at less than 15 gestational weeks. The earliest onset of thrombosis was 5 gestational weeks. Prophylactic anticoagulation significantly prevented the onset of both antepartum and postpartum thrombosis (p < 0.0001). The rate of recurrent pregnancy loss in women with low PC or PS activities was significantly higher than in controls (p < 0.0001); however, it is unknown whether recurrent pregnancy loss is related to hereditary PS deficiency. There seem to have been few serious maternal or fetal/neonatal complications due to placental insufficiency related to a hypercoagulable state other than growth restriction. Conclusions: This survey revealed the thrombosis-related characteristics of pregnant women with hereditary thrombophilia in Japan. We suggest prophylactic anticoagulation to prevent maternal or fetal/neonatal complications.
Language	English
Publishing date	2024-02-08
Publishing country	England
Document type	Journal Article
ZDB-ID	2118392-2
ISSN	1477-9560
ISSN	1477-9560
DOI	10.1186/s12959-024-00581-z
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Article: Retroperitoneal Castleman’s Disease

Shimokihara, Kota / Kawahara, Takashi / Kasahara, Ryo / Kasuga, Jun / Sugiura, Shinpei / Tajiri, Ryosuke / Uemura, Hiroji / Chiba, Kimio

Case Reports in Oncology

2019 Volume 12, Issue 3, Page(s) 885–889

Abstract: Castleman’s disease was first reported in 1954 by Castleman et al. and identified as an uncommon ... lymphoproliferative disorder. In most cases, Castleman’s diseases are detected in the chest, head, and neck. A 71-year-old man ... diseases. Laparoscopic tumorectomy was performed, and the pathological diagnosis was Castleman’s ...

Institution	Department of Urology, Fujisawa Municipal Hospital, Kanagawa, Japan Departments of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Japan Department of Pathology, Fujisawa Municipal Hospital, Kanagawa, Japan
Abstract	Castleman’s disease was first reported in 1954 by Castleman et al. and identified as an uncommon lymphoproliferative disorder. In most cases, Castleman’s diseases are detected in the chest, head, and neck. A 71-year-old man was referred to our hospital due to a retroperitoneal tumor in the para-aortic area by computed tomography (CT). Positron emission tomography-CT revealed an uptake in this tumor, suggesting malignant diseases. Laparoscopic tumorectomy was performed, and the pathological diagnosis was Castleman’s disease, hyaline vascular type. No evidence of recurrence was observed 20 months after surgery. We herein report a rare case of retroperitoneal Castleman’s disease.
Keywords	Retroperitoneal tumor ; Castleman’s disease ; Hyaline vascular type
Language	English
Publishing date	2019-11-27
Publisher	S. Karger AG
Publishing place	Basel, Switzerland
Document type	Article
Note	Case Report ; This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC).
ZDB-ID	2458961-5
ISSN	1662-6575 ; 1662-6575
ISSN (online)	1662-6575
ISSN	1662-6575
DOI	10.1159/000504700
Database	Karger publisher's database

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Article ; Online: Diagnosis of carpal tunnel syndrome using a 10-s grip-and-release test with video and machine learning analysis.

Tsukamoto, Kazuya / Matsui, Ryota / Sugiura, Yuta / Fujita, Koji

The Journal of hand surgery, European volume

2023 Volume 49, Issue 5, Page(s) 634–636

Abstract: We developed a finger motion-based diagnostic system for carpal tunnel syndrome by analysing 10 second grip-and-release test videos. Using machine learning, it estimated presence of carpal tunnel syndrome (89% sensitivity and 83% specificity) and ... ...

Abstract	We developed a finger motion-based diagnostic system for carpal tunnel syndrome by analysing 10 second grip-and-release test videos. Using machine learning, it estimated presence of carpal tunnel syndrome (89% sensitivity and 83% specificity) and correlated with severity on nerve conduction studies (coefficient 0.68). Level of evidence: III.
MeSH term(s)	Carpal Tunnel Syndrome/diagnosis ; Carpal Tunnel Syndrome/physiopathology ; Humans ; Machine Learning ; Middle Aged ; Male ; Female ; Video Recording ; Hand Strength/physiology ; Adult ; Aged ; Sensitivity and Specificity ; Neural Conduction/physiology
Language	English
Publishing date	2023-11-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2272801-6
ISSN	2043-6289 ; 1753-1934
ISSN (online)	2043-6289
ISSN	1753-1934
DOI	10.1177/17531934231214661
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Article ; Online: Proton Release Process during the S

Takemoto, Hiroshi / Sugiura, Miwa / Noguchi, Takumi

Biochemistry

2019 Volume 58, Issue 42, Page(s) 4276–4283

Abstract: Photosynthetic water oxidation takes place at the ... ...

Abstract	Photosynthetic water oxidation takes place at the Mn
MeSH term(s)	Catalytic Domain ; Cyanobacteria/chemistry ; Electron Transport ; Hydrogen Bonding ; Hydrogen-Ion Concentration ; Kinetics ; Oxidation-Reduction/radiation effects ; Photosystem II Protein Complex/chemistry ; Photosystem II Protein Complex/isolation & purification ; Protons ; Spectrophotometry, Infrared/methods ; Water/chemistry
Chemical Substances	Photosystem II Protein Complex ; Protons ; Water (059QF0KO0R)
Language	English
Publishing date	2019-10-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.9b00680
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Article ; Online: Glucose-induced oxidative stress leads to in S-nitrosylation of protein disulfide isomerase in neuroblastoma cells.

Ogura, Jiro / Sugiura, Hiroki / Tanaka, Atsushi / Ono, Shinji / Sato, Toshiyuki / Sato, Toshihiro / Maekawa, Masamitsu / Yamaguchi, Hiroaki / Mano, Nariyasu

Biochimica et biophysica acta. General subjects

2021 Volume 1865, Issue 11, Page(s) 129998

Abstract: ... cognitive disorders. Protein disulfide isomerase (PDI) is an enzyme for oxidative protein folding. PDI S-nitrosylation ... the relationship between PDI S-nitrosylation and diabetes.: Methods: We used SH-SY5Y cells cultured in high ... glucose media.: Results: S-nitrosylated PDI level increased at 7 days and remained high till 28 days ...

Abstract	Background: Dementia places a significant burden on both patients and caregivers. Since diabetes is a risk factor for dementia, it is imperative to identify the relationship between diabetes and cognitive disorders. Protein disulfide isomerase (PDI) is an enzyme for oxidative protein folding. PDI S-nitrosylation is observed in the brain tissues of Alzheimer's disease patients. The aim of this study is to clarify the relationship between PDI S-nitrosylation and diabetes. Methods: We used SH-SY5Y cells cultured in high-glucose media. Results: S-nitrosylated PDI level increased at 7 days and remained high till 28 days in SH-SY5Y cells cultured in high-glucose media. Using PDI wild-type- or PDI C343S-expressing SH-SY5Y cells, PDI C343 was identified as the site of glucose-induced S-nitrosylation. IRE1α and PERK were phosphorylated at day 14 in the SH-SY5Y cells cultured in high-glucose media, and the phosphorylated status was maintained to day 28. To determine the effect of S-nitrosylated PDI on endoplasmic reticulum stress signaling, SH-SY5Y cells were treated with S-nitrosocystein (SNOC) for 30 min, following which the medium was replaced with SNOC-free media and the cells were cultured for 24 h. Only phosphorylated IRE1α treated with SNOC was associated with PDI S-nitrosylation. Neohesperidin, a flavonoid in citrus fruits, is a natural antioxidant. The treatment with neohesperidin in the final 7 days of glucose loading reversed PDI S-nitrosylation and improved cell proliferation. Conclusion: Glucose loading leads to S-nitrosylation of PDI C343 and induces neurodegeneration via IRE1α phosphorylation. General significance: The results may be useful for designing curative treatment strategies for dementia.
MeSH term(s)	Glucose/metabolism ; Humans ; Neuroblastoma/metabolism ; Oxidative Stress ; Protein Disulfide-Isomerases/metabolism ; Tumor Cells, Cultured
Chemical Substances	Protein Disulfide-Isomerases (EC 5.3.4.1) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-08-30
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	60-7
ISSN	1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
ISSN (online)	1872-8006 ; 1879-2596 ; 1879-260X ; 1879-2642 ; 1879-2618 ; 1879-2650
ISSN	0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
DOI	10.1016/j.bbagen.2021.129998
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