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DOI： 10.1128/JVI.00037-14

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DOI： 10.1016/j.molcel.2013.01.039

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DOI： 10.1128/JVI.06872-11

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DOI： 10.1128/JVI.00679-09

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DOI： 10.1128/JVI.00649-07

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DOI： 10.1128/JVI.79.5.2847-2858.2005

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Hepatitis B virus (HBV) infection is a major global health burden worldwide despite the availability of an effective vaccine and effective anti-HBV drugs. The currently approved anti-HBV drugs-i.e., nucleos(t)ide analogues and pegylated interferon α-can effectively suppress HBV replication, but rarely achieve a functional cure. Accordingly, new anti-HBV agents targeting different aspects of the HBV life cycle are needed. In this study, we screened for anti-HBV agents using the recombinant HBV expressing NanoLuc (NL) reporter gene (HBV/NL) and our original synthetic heterocyclic compound library. As a result, we identified a synthetic bile acid derivative, SO-145, as a potential novel anti-HBV agent, and investigated its effects in several cellular models of HBV. Treatment of HepG2-NTCP-C4 cells with SO-145 suppressed their NL activity following infection with HBV/NL. SO-145 suppressed HBV replication in PXB-cells infected with HBV genotype D, but did not show any inhibitory effect on HBV replication in Hep38.7-Tet cells. These results suggest that SO-145 specifically inhibits the early phase of the HBV life cycle. In other experiments, SO-145 was also shown to inhibit hepatitis D virus infection. Immunofluorescence analysis using fluorescent-labeled preS1 peptide revealed that SO-145 does not inhibit the preS1 attachment to the NTCP, but does markedly inhibit the HBV/preS1 internalization. Moreover, SO-145 does not inhibit the bile acid uptake facilitated by NTCP. Further mechanistic analysis suggested that SO-145 interferes with the NTCP oligomerization. Taken together, these results suggest that SO-145 inhibits HBV entry into hepatocytes by interfering with the NTCP oligomerization.

DOI： 10.1016/j.antiviral.2025.106267

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Hepatitis C virus (HCV) infection induces chaperone-mediated autophagy (CMA), where the HCV NS5A protein promotes the binding of the molecular chaperone HSC70 to substrate proteins containing a KFERQ motif. HSC70 recognizes this pentapeptide motif and transports substrates to lysosomes for degradation. In this study, we identified a KFERQ motif (324ELLRQ328) in the YAP1 protein, a key regulator of the Hippo pathway, and examined its interaction with HSC70 during HCV infection. To determine whether HSC70 directly binds to this motif, we generated four YAP1 mutants with specific alterations in the KFERQ motif and assessed their binding to HSC70. Among these, the R327A/Q328A mutant showed the greatest reduction in HSC70 binding, indicating that the sequence 324ELLRQ328 functions as the KFERQ motif in YAP1. Further analysis revealed that YAP1 binds to the substrate-binding domain of HSC70. Moreover, shRNA-mediated knockdown of LAMP2A, a critical receptor for CMA, led to increased levels of YAP1, confirming that YAP1 is indeed a CMA substrate. Notably, HSC70 was also found to interact with phosphorylated YAP1 at serine 127 (S127). Although NS5A did not bind directly to YAP1, NS5A expression reduced the binding between YAP1 and HSC70. This suggests that under normal conditions, YAP1 is recognized by HSC70 and degraded via CMA. However, during HCV infection, NS5A interferes with YAP1-HSC70 interaction, preventing YAP1 from being degraded. As a result, YAP1 accumulates in the cytoplasm and subsequently translocates to the nucleus, where YAP1 may activate genes involved in cell proliferation and survival. This mechanism may contribute to HCV-induced pathogenesis.

DOI： 10.24546/0100497746

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We previously demonstrated that interferon-stimulated gene 15 protein (ISG15) plays a role in enhancing hepatitis B virus (HBV) and hepatitis C virus (HCV) infections through the ISGylation of the HBV X protein (HBx) and the HCV NS5A protein. ISGylation is a post-translational modification where ISG15 is covalently attached to target proteins. These findings suggest that targeting ISGylation could be a potential therapeutic strategy for HBV and HCV infections. In this study, we evaluated the antiviral activity of HZ-6d, a quinoline derivative that inhibits HERC5-mediated ISGylation. Our results showed that HZ-6d did not inhibit HBx ISGylation and only modestly suppressed HBV replication in HBV-infected HepG2-NTCP cells and in HBV-replicating cells. Interestingly, HZ-6d also did not affect NS5A-ISGylation, however, it significantly suppressed HCV replication. These observations suggest that HZ-6d exerts its antiviral effects in HCV-replicating cells through mechanisms independent of HERC5-mediated NS5A-ISGylation. Furthermore, HZ-6d strongly activated the p53-mediated apoptosis signaling pathway, as evidenced by increased levels of phosphorylated p53, cleaved caspase-8, and cleaved caspase-3. Notably, activation of caspase-3 has been implicated in the proteolysis of HCV NS5A, indicating that apoptosis-related mechanisms may contribute to HCV suppression. Collectively, our findings suggest that HZ-6d induces antiviral activity against HCV through the p53-mediated apoptosis pathway, rather than by interfering with HERC5-mediated NS5A ISGylation.

DOI： 10.24546/0100497747

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Publishing type：Research paper (scientific journal)   Publisher：American Society for Microbiology  

ABSTRACT

Hepatitis C virus (HCV) assembles in close proximity to lipid droplets (LDs), which play important roles in HCV RNA replication. HCV infection often causes the accumulation of large LDs in hepatocytes. However, the molecular mechanism underlying HCV-induced large LD formation is poorly understood. It has been reported that the SPG20/Spartin protein associates with the LD surface and plays a crucial role in LD turnover by recruiting the ubiquitin ligase Itch to promote the ubiquitin-dependent degradation of adipophilin (ADRP), which protects LDs from lipase-mediated degradation. To elucidate the mechanism underlying HCV-induced large LD formation, we investigated the SPG20 protein’s role in LD formation in HCV J6/JFH1-infected Huh-7.5 cells. Immunoblot analysis revealed that HCV infection promoted SPG20 protein cleavage. Transfection of increasing amounts of NS3/4A, but not the inactive NS3/4A mutant, resulted in SPG20 cleavage, implicating the NS3/4A protease in this cleavage. Site-directed mutagenesis suggested that the NS3/4A protease cleaves SPG20 at Cys ⁵⁰⁴ and Cys ⁵⁶² . The SPG20 protein was co-immunoprecipitated with the LD-attached protein TIP47. Increasing amounts of NS3/4A protease, but not inactive NS3/4A, decreased the co-precipitation of SPG20 with TIP47. The siRNA-mediated knockdown of Itch in Huh-7.5 cells restored ADRP levels, suggesting that Itch mediates ubiquitylation-dependent ADRP degradation. Immunofluorescence staining of HCV-infected cells revealed that ADRP was localized mainly around LDs in HCV-infected cells, whereas cytosolic ADRP was decreased. We propose that the HCV NS3/4A protease specifically cleaves SPG20 and inhibits Itch-mediated ubiquitin-dependent degradation of LD-associated ADRP, thereby promoting the formation of large LDs.

IMPORTANCE

HCV infection often promotes the formation of large LDs in HCV-infected cells. However, the molecular mechanism underlying large LD formation is poorly understood. LD turnover is regulated by SPG20, Itch E3 ligase, and ADRP. To elucidate the mechanism underlying the formation of large LDs induced by HCV infection, we investigated the roles of SPG20, Itch, and ADRP in large LD formation. The HCV NS3/4A protease specifically cleaves SPG20 and disrupts Itch recruitment to LD-associated ADRP. Therefore, LD-associated ADRP can escape and protects LDs from lipase-mediated degradation, thereby promoting LD growth. We propose that HCV NS3/4A protease-mediated cleavage of SPG20 contributes to a previously uncharacterized mechanism underlying the formation of large LDs in HCV-infected cells. These findings may lead to a better understanding of how the virus forms large LDs in infected cells.

DOI： 10.1128/jvi.00890-25

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Hepatitis C virus (HCV) is a positive-sense, single-stranded RNA virus that causes chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. The release of infectious HCV particles from infected hepatocytes is a crucial step in viral dissemination and disease progression. While the exact mechanisms of HCV particle release remain poorly understood, emerging evidence suggests that HCV utilizes intracellular membrane trafficking and secretory pathways. These pathways include the Golgi secretory pathway and the endosomal trafficking pathways, such as the recycling endosome pathway and the endosomal sorting complex required for transport (ESCRT)-dependent multivesicular bodies (MVBs) pathway. This review provides an overview of recent advances in understanding the release of infectious HCV particles, with a particular focus on the involvement of the host cell factors that participate in HCV particle release. By summarizing the current knowledge in this area, this review aims to contribute to a better understanding of endosomal pathways involved in the extracellular release of HCV particles and the development of novel antiviral strategies.

DOI： 10.3390/v15122430

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Hepatitis B virus (HBV) infection promotes reactive oxygen species production while paradoxically inducing the expression of antioxidant enzymes. HBV-induced disorders of redox homeostasis are closely associated with the development of hepatic diseases. However, the molecular mechanisms underlying the HBV-induced antioxidant response are poorly understood. The NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an intrinsic defense mechanism against oxidative stress. We here aim to elucidate the role of the Nrf2/ARE signaling pathway in the HBV life cycle. ARE-driven reporter assays revealed that expression of HBV X protein (HBx), but not HBV core, large HBV surface, or HBV polymerase, strongly enhanced ARE-luciferase activity, suggesting that HBx plays an important role in the HBV-induced antioxidant response. Knockdown of Nrf2 resulted in a marked decrease in HBx-induced ARE-luciferase activity. Immunoblot analysis and immunofluorescence staining suggested that HBx activates Nrf2 by increasing Nrf2 protein levels and enhancing Nrf2 nuclear localization. The oxidative stress sensor Kelch-like ECH-associated protein 1 (Keap1) is required for the ubiquitin-dependent degradation of Nrf2. Coimmunoprecipitation analysis revealed that HBx interacted with Keap1, suggesting that HBx competes with Nrf2 for interaction with Keap1. A cell-based ubiquitylation assay showed that HBx promoted polyubiquitylation of Nrf2 via K6-linked polyubiquitin chains, and that this action may be associated with Nrf2 stabilization. A chromatin immunoprecipitation assay suggested that Nrf2 interacts with the HBV core promoter. Overexpression of Nrf2 strongly suppressed HBV core promoter activity, resulting in a marked reduction in viral replication. Based on the above, we propose that Keap1 recognizes HBx to activate the Nrf2/ARE signaling pathway upon HBV infection, thereby inhibiting HBV replication.IMPORTANCEThe Kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is one of the most important defense mechanisms against oxidative stress. We previously reported that a cellular hydrogen peroxide scavenger protein, peroxiredoxin 1, a target gene of transcription factor Nrf2, acts as a novel HBV X protein (HBx)-interacting protein and negatively regulates hepatitis B virus (HBV) propagation through degradation of HBV RNA. This study further demonstrates that the Nrf2/ARE signaling pathway is activated during HBV infection, eventually leading to the suppression of HBV replication. We provide evidence suggesting that Keap1 interacts with HBx, leading to Nrf2 activation and inhibition of HBV replication via suppression of HBV core promoter activity. This study raises the possibility that activation of the Nrf2/ARE signaling pathway is a potential therapeutic strategy against HBV. Our findings may contribute to an improved understanding of the negative regulation of HBV replication by the antioxidant response.

DOI： 10.1128/jvi.01287-23

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Norovirus (NoV) is a leading cause of epidemic and sporadic gastroenteritis in people of all ages. Humans are the primary source of NoV and household contact is one of the risk factors for NoV transmission. However, the mechanisms underlying person-to-person NoV transmission are poorly understood. Here we conducted a survey to profile the frequency and characteristics of intrafamily NoV transmission. Stool samples were collected every week from three households between 2016 and 2020; the total number of samples was 1105. The detection of NoV and the genotyping were performed by reverse transcription-polymerase chain reaction targeting the capsid region and direct sequencing methods. NoV was detected in 3.4% of all samples. Eight NoV genotypes were identified. The most common genotype was GII.17, followed in order by GII.6, GI.6, GII.4, GI.3, and GI.2/GI.8/GI.9. Most NoV-positive samples were obtained from asymptomatic individuals. The highest number of NoV transmissions was found in household 3 (6 infections), followed by household 2 (2 infections), while household 1 had no NoV transmission, suggesting that asymptomatic NoV carriers play a major role in infection as NoV reservoirs in the households. Further clarification of the mode of infection will contribute to improved understanding and an appropriate prevention.

DOI： 10.1002/jmv.29164

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We previously reported that hepatitis C virus (HCV) infection activates the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) signaling pathway. Activation of JNK contributes to the development of liver diseases, including metabolic disorders, steatosis, liver cirrhosis and hepatocellular carcinoma. JNK is known to have numerous target genes, including JunB, a member of activator protein-1 transcription factor family. However, the roles of JunB in the HCV life cycle and HCV-associated pathogenesis remain unclear. To clarify a physiological role of JunB in HCV infection, we investigated the phosphorylation of JunB in HCV J6/JFH1-infected Huh-7.5 cells. Immunoblot analysis revealed that HCV-induced ROS/JNK activation promoted phosphorylation of JunB. The small interfering RNA (siRNA) knockdown of JunB significantly increased the amount of intracellular HCV RNA as well as the intracellular and extracellular HCV infectivity titers. Conversely, overexpression of JunB significantly reduced the amount of intracellular HCV RNA and the intracellular and extracellular HCV infectivity titers. These results suggest that JunB plays a role in inhibiting HCV propagation. Additionally, HCV-mediated JunB activation promoted hepcidin promoter activity and hepcidin mRNA levels, a key factor in modulating iron homeostasis, suggesting that JunB is involved in HCV-induced transcriptional upregulation of hepcidin. Taken together, we propose that the HCV-induced ROS/JNK/JunB signaling pathway plays roles in inhibiting HCV replication and contributing to HCV-mediated iron metabolism disorder.

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Rotavirus A (RVA) is a major viral cause of acute gastroenteritis worldwide. G12 RVA strains have emerged globally since 2007. There has been no report of the whole genome sequences of G12 RVAs in Indonesia. We performed the complete genome analysis by the next-generation sequencing of five G12 strains from hospitalized children with acute gastroenteritis in Surabaya from 2017-2018. All five G12 strains were Wa-like strains (G12-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1) and were clustered into lineage-III of VP7 gene phylogenetic tree. STM430 sample was observed as a mixed-infection between G12 and G1 strains: G12/G1-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. A phylogenetic tree analysis revealed that all five Indonesian G12 strains (SOEP379, STM371, STM413, STM430, and STM433) were genetically close to each other in all 11 genome segments with 98.0-100% nucleotide identities, except VP3 and NSP4 of STM430, suggesting that these strains have originated from a similar ancestral G12 RVA. The VP3 and NSP4 genome segments of STM430-G12P[8] were separated phylogenetically from those of the other four G12 strains, probably due to intra-genotype reassortment between the G12 and G1 Wa-like strains. The change from G12P[6] lineage-II in 2007 to G12P[8] lineage-III 2017-2018 suggests the evolution and diversity of G12 RVAs in Indonesia over the past approximately 10 years. This article is protected by copyright. All rights reserved.

DOI： 10.1002/jmv.28485

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Publishing type：Research paper (scientific journal)   Publisher：Informa UK Limited  

DOI： 10.1080/27694127.2022.2095591

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We previously reported that hepatitis C virus (HCV) infection activates the reactive oxygen species (ROS)/c-Jun N-terminal kinase (JNK) signaling pathway. However, the roles of ROS/JNK activation in the HCV life cycle remain unclear. We sought to identify a novel role of the ROS/JNK signaling pathway in the HCV life cycle. Immunoblot analysis revealed that HCV-induced ROS/JNK activation promoted phosphorylation of Itch, a HECT-type E3 ubiquitin ligase, leading to activation of Itch. The small interfering RNA (siRNA) knockdown of Itch significantly reduced the extracellular HCV infectivity titers, HCV RNA, and HCV core protein without affecting intracellular HCV infectivity titers, HCV RNA, and HCV proteins, suggesting that Itch is involved in the release of HCV particles. HCV-mediated JNK/Itch activation specifically promoted polyubiquitylation of an AAA-type ATPase, VPS4A, but not VPS4B, required to form multivesicular bodies. Site-directed mutagenesis revealed that two lysine residues (K23 and K121) on VPS4A were important for VPS4A polyubiquitylation. The siRNA knockdown of VPS4A, but not VPS4B, significantly reduced extracellular HCV infectivity titers. Coimmunoprecipitation analysis revealed that HCV infection specifically enhanced the interaction between CHMP1B, a subunit of endosomal sorting complexes required for transport (ESCRT)-III complex, and VPS4A, but not VPS4B, whereas VPS4A K23R/K121R greatly reduced the interaction with CHMP1B. HCV infection significantly increased ATPase activity of VPS4A, but not VPS4A K23R/K121R or VPS4B, suggesting that HCV-mediated polyubiquitylation of VPS4A contributes to activation of VPS4A. Taken together, we propose that the HCV-induced ROS/JNK/Itch signaling pathway promotes VPS4A polyubiquitylation, leading to enhanced VPS4A-CHMP1B interaction and promotion of VPS4A ATPase activity, thereby promoting the release of HCV particles. IMPORTANCE The ROS/JNK signaling pathway contributes to liver diseases, including steatosis, metabolic disorders, and hepatocellular carcinoma. We previously reported that HCV activates the ROS/JNK signaling pathway, leading to the enhancement of hepatic gluconeogenesis and apoptosis induction. This study further demonstrates that the HCV-induced ROS/JNK signaling pathway activates the E3 ubiquitin ligase Itch to promote release of HCV particles via polyubiquitylation of VPS4A. We provide evidence suggesting that HCV infection promotes the ROS/JNK/Itch signaling pathway and ESCRT/VPS4A machinery to release infectious HCV particles. Our results may lead to a better understanding of the mechanistic details of HCV particle release.

DOI： 10.1128/JVI.01811-21

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Ubiquitin and ubiquitin-like protein modification play important roles in modulating the functions of viral proteins in many viruses. Here we demonstrate that hepatitis B virus (HBV) X protein (HBx) is modified by ISG15, which is a type I IFN-inducible, ubiquitin-like protein; this modification is called ISGylation. Immunoblot analyses revealed that HBx proteins derived from four different HBV genotypes accepted ISGylation in cultured cells. Site-directed mutagenesis revealed that three lysine residues (K91, K95 and K140) on the HBx protein, which are well conserved among all the HBV genotypes, are involved in acceptance of ISGylation. Using expression plasmids encoding three known E3 ligases involved in the ISGylation to different substrates, we found that HERC5 functions as an E3 ligase for HBx-ISGylation. Treatment with type I and type III IFNs resulted in the limited suppression of HBV replication in Hep38.7-Tet cells. When cells were treated with IFN-α, silencing of ISG15 resulted in a marked reduction of HBV replication in Hep38.7-Tet cells, suggesting a role of ISG15 in the resistance to IFN-α. In contrast, the silencing of USP18 (an ISG15 de-conjugating enzyme) increased the HBV replication in Hep38.7-Tet cells. Taken together, these results suggest that the HERC5-mediated ISGylation of HBx protein confers pro-viral functions on HBV replication and participates in the resistance to IFN-α-mediated antiviral activity.

DOI： 10.1099/jgv.0.001668

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We previously reported that hepatitis C virus (HCV) NS5A (1b, Con1) protein accepts covalent ISG15 conjugation at specific lysine (Lys) residues (K44, K68, K166, K215 and K308), exhibiting proviral effects on HCV RNA replication. Here we investigated a role of NS5A-ISGylation via Lys residues in HCV propagation using HCV infectious clone. The alignment of amino acid sequences revealed that 5 Lys residues (K20, K26, K44, K139, and K166) of the 13 Lys residues within NS5A (genotype 2a, JFH1 strain) were conserved compared to those of HCV (genotype 1b, Con1 strain). The cell-based ISGylation assay revealed that the K26 residue in the amphipathic helix (AH) domain and the K139 residue in domain I of NS5A (2a, JFH1) had the potential to accept ISGylation. Use of the HCV replicon carrying luciferase gene revealed that the K26 residue but not K139 residue of NS5A (2a, JFH1) was important for HCV RNA replication. Furthermore, cell culture HCV revealed that the mutation with the K26 residue in combination with K139 or K166 on NS5A (2a, JFH1) resulted in complete abolishment of viral propagation, suggesting that the K26 residue collaborates with either the K139 residue or K166 residue for efficient HCV propagation. Taken together, these results suggest that HCV NS5A protein has the potential to accept ISGylation via specific Lys residues, involving efficient viral propagation in a genotype-specific manner.

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Noroviruses are recognized as a leading cause of outbreaks and sporadic cases of acute gastroenteritis (AGE) among individuals of all ages worldwide, especially in children <5 years old. We investigated the epidemiology of noroviruses among hospitalized children at two hospitals in East Java, Indonesia. Stool samples were collected from 966 children with AGE during September 2015-July 2019. All samples were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) for the amplification of both the RNA-dependent RNA polymerase (RdRp) and the capsid genes of noroviruses. The genotypes were determined by phylogenetic analyses. In 2015-2019, noroviruses were detected in 12.3% (119/966) of the samples. Children <2 years old showed a significantly higher prevalence than those ≥2 years old (P = 0.01). NoV infections were observed throughout the year, with the highest prevalence in December. Based on our genetic analyses of RdRp, GII.[P31] (43.7%, 31/71) was the most prevalent RdRp genotype, followed by GII.[P16] (36.6%, 26/71). GII.[P31] was a dominant genotype in 2016 and 2018, whereas GII.[P16] was a dominant genotype in 2015 and 2017. Among the capsid genotypes, the most predominant norovirus genotype from 2015 to 2018 was GII.4 Sydney_2012 (33.6%, 40/119). The most prevalent genotype in each year was GII.13 in 2015, GII.4 Sydney_2012 in 2016 and 2018, and GII.3 in 2017. Based on the genetic analyses of RdRp and capsid sequences, the strains were clustered into 13 RdRp/capsid genotypes; 12 of them were discordant, e.g., GII.4 Sydney[P31], GII.3[P16], and GII.13[P16]. The predominant genotype in each year was GII.13[P16] in 2015, GII.4 Sydney[P31] in 2016, GII.3[P16] in 2017, and GII.4 Sydney[P31] in 2018. Our results demonstrate high detection rates and genetic diversity of norovirus GII genotypes in pediatric AGE samples from Indonesia. These findings strengthen the importance of the continuous molecular surveillance of emerging norovirus strains.

DOI： 10.1016/j.meegid.2020.104703

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Lysosome incorporate and degrade proteins in a process known as autophagy. There are three types of autophagy; macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA). Although autophagy is considered a nonselective degradation process, CMA is known as a selective degradation pathway. All proteins internalized in the lysosome via CMA contain a pentapeptide KFERQ-motif, also known as a CMA-targeting motif, which is necessary for selectivity. CMA directly delivers a substrate protein into the lysosome lumen using the cytosolic chaperone HSC70 and the lysosomal receptor LAMP-2A for degradation. Hepatitis C virus (HCV) NS5A protein interacts with hepatocyte-nuclear factor 1α (HNF-1α) together with HSC70 and promotes the lysosomal degradation of HNF-1α via CMA, resulting in HCV-induced pathogenesis. HCV NS5A promotes recruitment of HSC70 to the substrate protein HNF-1α. HCV NS5A plays a crucial role in HCV-induced CMA. Further investigations of HCV NS5A-interacting proteins containing CMA-targeting motifs may help to elucidate HCV-induced pathogenesis.

DOI： 10.3389/fcimb.2021.796664

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DOI： 10.1128/JVI.02203-18

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Group A rotavirus (RVA) is the most important cause of severe gastroenteritis among children worldwide, and effective RVA vaccines have been introduced in many countries. Here we performed a molecular epidemiological analysis of RVA infection among pediatric patients in East Java, Indonesia, during 2015-2018. A total of 432 stool samples were collected from hospitalized pediatric patients with acute gastroenteritis. None of the patients in this cohort had been immunized with an RVA vaccine. The overall prevalence of RVA infection was 31.7% (137/432), and RVA infection was significantly more prevalent in the 6- to 11-month age group than in the other age groups (P < 0.05). Multiplex reverse transcription-PCR (RT-PCR) revealed that the most common G-P combination was equine-like G3P[8] (70.8%), followed by equine-like G3P[6] (12.4%), human G1P[8] (8.8%), G3P[6] (1.5%), and G1P[6] (0.7%). Interestingly, the equine-like strains were exclusively detected until May 2017, but in July 2017 they were completely replaced by a typical human genotype (G1 and G3), suggesting that the dynamic changes in RVA genotypes from equine-like G3 to typical human G1/G3 in Indonesia can occur even in the country with low RVA vaccine coverage rate. The mechanism of the dynamic changes in RVA genotypes needs to be explored. Infants and children with RVA-associated gastroenteritis presented more frequently with some dehydration, vomiting, and watery diarrhea, indicating a greater severity of RVA infection compared to those with non-RVA gastroenteritis. In conclusion, a dynamic change was found in the RVA genotype from equine-like G3 to a typical human genotype. Since severe cases of RVA infection were prevalent, especially in children aged 6 to 11 months or more generally in those less than 2 years old, RVA vaccination should be included in Indonesia's national immunization program.

DOI： 10.3389/fmicb.2019.00940

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DOI： 10.1016/bs.ircmb.2018.09.002

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DOI： 10.3390/v10090510

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Rotavirus A (RVA) is a major cause of acute gastroenteritis in humans and animals worldwide. As a result of the segmented nature of the rotavirus genome, genetic reassortment commonly occurs. This study aims to clarify the genetic characteristics of RVAs circulating in Indonesia. From June 2015 through August 2016, stool samples were collected from 134 children aged <5 years (71 male and 63 female) with acute gastroenteritis who were inpatients at a private hospital in Surabaya, Indonesia. All stool samples were screened for RVA antigen using immunochromatography. Forty-two samples (31.3%, 42/134) were RVA antigen-positive. All RVA positive samples tested showed the unusual combinations of G3P[8] (n = 36) and G3P[6] (n = 3) with a short RNA pattern by G/P typing and polyacrylamide gel electrophoresis (PAGE). Whole genome analysis by next-generation sequencing (NGS) was performed for 11 strains to determine the RVA genotypes. Eleven rotavirus strains were found to carry a DS-like genetic backbone; nine strains showed a G3-P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2 genome constellation, which was recently reported in Australia, Hungary, Spain and Brazil; as well, two strains showed a G3-P[6]-I2-R2-C2-M2-A2-N2-T2-E2-H2 genome constellation. The phylogenetic tree based on the VP7 gene showed that all 11 strains were classified as equine-like G3, which is genetically distinct and different in origin from typical human G3 strains. The phylogenetic tree based on the NSP4 gene showed that six strains were classified as bovine-like strain and the remaining five were classified as human strain. In conclusion, we identified the strains which are intergenogroup reassortants containing an equine-like G3 VP7, a P[8])/P[6] VP4, with a DS-1-like genetic backbone. These findings suggest that equine-like G3P[8] and P[6] RVA strains have been circulating in the Indonesian population for at least 1 year and probably longer, indicating a diversity of RVAs in this area.

DOI： 10.1016/j.meegid.2018.03.027

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Hepatitis C virus (HCV) infection is closely associated with type 2 diabetes. We reported that HCV infection induces the lysosomal degradation of hepatocyte nuclear factor 1 alpha (HNF-1α) via interaction with HCV nonstructural protein 5A (NS5A) protein, thereby suppressing GLUT2 gene expression. The molecular mechanisms of selective degradation of HNF-1α caused by NS5A are largely unknown. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway. Here, we investigated whether CMA is involved in the selective degradation of HNF-1α in HCV-infected cells and observed that the pentapeptide spanning from amino acid (aa) 130 to aa 134 of HNF-1α matches the rule for the CMA-targeting motif, also known as KFERQ motif. A cytosolic chaperone protein, heat shock cognate protein of 70 kDa (HSC70), and a lysosomal membrane protein, lysosome-associated membrane protein type 2A (LAMP-2A), are key components of CMA. Immunoprecipitation analysis revealed that HNF-1α was coimmunoprecipitated with HSC70, whereas the Q130A mutation (mutation of Q to A at position 130) of HNF-1α disrupted the interaction with HSC70, indicating that the CMA-targeting motif of HNF-1α is important for the association with HSC70. Immunoprecipitation analysis revealed that increasing amounts of NS5A enhanced the association of HNF-1α with HSC70. To determine whether LAMP-2A plays a role in the degradation of HNF-1α protein, we knocked down LAMP-2A mRNA by RNA interference; this knockdown by small interfering RNA (siRNA) recovered the level of HNF-1α protein in HCV J6/JFH1-infected cells. This result suggests that LAMP-2A is required for the degradation of HNF-1α. Immunofluorescence study revealed colocalization of NS5A and HNF-1α in the lysosome. Based on our findings, we propose that HCV NS5A interacts with HSC70 and recruits HSC70 to HNF-1α, thereby promoting the lysosomal degradation of HNF-1α via CMA.IMPORTANCE Many viruses use a protein degradation system, such as the ubiquitin-proteasome pathway or the autophagy pathway, for facilitating viral propagation and viral pathogenesis. We investigated the mechanistic details of the selective lysosomal degradation of hepatocyte nuclear factor 1 alpha (HNF-1α) induced by hepatitis C virus (HCV) NS5A protein. Using site-directed mutagenesis, we demonstrated that HNF-1α contains a pentapeptide chaperone-mediated autophagy (CMA)-targeting motif within the POU-specific domain of HNF-1α. The CMA-targeting motif is important for the association with HSC70. LAMP-2A is required for degradation of HNF-1α caused by NS5A. We propose that HCV NS5A interacts with HSC70, a key component of the CMA machinery, and recruits HSC70 to HNF-1α to target HNF-1α for CMA-mediated lysosomal degradation, thereby facilitating HCV pathogenesis. We discovered a role of HCV NS5A in CMA-dependent degradation of HNF-1α. Our results may lead to a better understanding of the role of CMA in the pathogenesis of HCV.

DOI： 10.1128/JVI.00639-18

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

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DOI： 10.1016/j.meegid.2017.08.020

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DOI： 10.1111/1348-0421.12493

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DOI： 10.1038/srep21638

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DOI： 10.1128/JVI.03055-13

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DOI： 10.1021/pr3011217

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DOI： 10.1021/pr300121a

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DOI： 10.1128/JVI.06704-11

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DOI： 10.1128/JVI.00846-11

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DOI： 10.1016/j.micinf.2011.01.005

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DOI： 10.1016/j.virol.2011.01.011

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DOI： 10.1371/journal.pone.0015967

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DOI： 10.1016/j.immuni.2010.10.013

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DOI： 10.1053/j.gastro.2010.07.058

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DOI： 10.1111/j.1348-0421.2010.00209.x

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DOI： 10.1128/JVI.02519-09

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DOI： 10.1128/JVI.02499-09

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DOI： 10.1128/JVI.01035-09

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DOI： 10.1128/JVI.00889-09

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DOI： 10.1002/jgm.1299

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

DOI： 10.1038/gt.2008.29

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DOI： 10.1128/JVI.02253-07

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DOI： 10.1128/JVI.02153-07

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DOI： 10.1038/sj.mt.6300364

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Language：English  

DOI： 10.2217/17460794.3.1.35

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

DOI： 10.1128/JVI.00477-07

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

DOI： 10.1073/pnas.0607312104

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

DOI： 10.1128/JVI.01203-06

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

DOI： 10.1016/j.bbrc.2006.08.184

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

Japanese encephalitis virus (JEV) core protein is detected not only in the cytoplasm but also in the nucleoli of infected cells. We previously showed that a mutant JEV lacking the nucleolar localization of the core protein impaired viral replication in mammalian cells. In this study, we identified a nucleolar phosphoprotein B23 as a protein binding with the core protein of JEV but not with that of dengue virus. The region binding with JEV core protein was mapped to amino acid residues 38 to 77 of B23. Upon JEV infection, some fraction of B23 was translocated from the nucleoli to the cytoplasm, and cytoplasmic B23 was colocalized with the core protein of wild-type JEV but not with that of the mutant JEV. Furthermore, overexpression of dominant negatives of B23 reduced JEV replication. These results suggest that B23 plays an important role in the intracellular localization of the core protein and replication of JEV.

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

DOI： 10.1128/JVI.79.21.13473-13482.2005

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

DOI： 10.1016/S0014-5793(04)00073-0

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

DOI： 10.2222/jsv.53.185

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/nass/3.1.323

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

We have shown previously that the 5′-capped short phosphodiester RNA fragments, Cap decoy, (Gm 12 nt) are potent inhibitors of influenza virus RNA polymerase gene expression. Here we investigate the modified capped RNA derivative containing phosphorothioate oligonucleotides (Cap decoy) as a potential influenza virus RNA polymerase inhibitor. The modified 5′-capped short phosphorothioate RNA fragments (Gms 12–15 nt) with the 5′-capped structure (m7GpppGm) were synthesized by T7 RNA polymerase. The 5′-capped short RNA fragments (Gms 12–15 nt) were encapsulated in liposome particulates and tested for their inhibitory effects on influenza virus RNA polymerase gene expression in the clone 76 cells. The 12–15 nt long Gms RNA fragments showed highly inhibitory effects. By contrast, the inhibitory effects of the 13 nt long short RNA fragments (Gm 13 nt) were considerably less in comparison with the 5′-capped short phosphorothioate RNA fragments (Gms 12–15 nt). In particular, the various Gms RNA chain lengths showed no significant differences in the inhibition of influenza virus RNA polymerase gene expression. Furthermore, the capped RNA with a phosphorothioate backbone was resistant to nuclease activity. These phosphorothioate RNA fragments exhibited higher inhibitory activity than the 5′-capped short RNA fragments (Gm 12 nt). These decoys may prove to be useful in anti-influenza virus therapeutics.

DOI： 10.1177/095632020101200605

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

DOI： 10.1006/bbrc.2000.3924

CiNii Article

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Publishing type：Research paper (international conference proceedings)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/nass/44.1.287

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

DOI： 10.1006/bbrc.2000.2542

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Publishing type：Research paper (international conference proceedings)   Publisher：Oxford University Press (OUP)  

DOI： 10.1093/nass/42.1.225

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Informa UK Limited  

DOI： 10.1080/07328319908044823

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

DOI： 10.1038/9893

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Other Link： http://www.nature.com/articles/nbt0699_583

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

DOI： 10.1016/s0968-0896(98)00060-1

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

We have demonstrated that antisense phosphorothioate oligonucleotides (S-ODNs) inhibit influenza A virus replication in MDCK cells. Liposomally encapsulated and free antisense S-ODNs with four target sites (PB1, PB2, PA and NP genes) were tested for their abilities to inhibit virus-induced cytopathogenic effects in a MTT assay using MDCK cells. The liposomally encapsulated S-ODN complementary to the site around the PB2 AUG initiation codon showed highly inhibitory effects. In contrast, the inhibitory effect of the liposomally encapsulated S-ODN targeted to PB1 was considerably decreased in comparison with that directed to the PB2 target site. The liposomally encapsulated antisense S-ODNs exhibited higher inhibitory activities than the free oligonucleotides, and showed sequence-specific inhibition, whereas free antisense S-ODNs were observed to inhibit viral adsorption to MDCK cells. Liposomal preparations of oligonucleotides facilitated their release from endocytic vesicles, and thus cytoplasmic and nuclear localization was observed. The activities of the antisense S-ODNs were effectively enhanced by using the liposomal carrier. Interestingly, the liposomally encapsulated FITC-S-ODN-PB2–as accumulated in the nuclear region of MDCK cells. However, weak fluorescence was observed within the endosomes and the cytoplasm of MDCK cells treated with the free antisense S-ODNs. The cationic lipid particles may thus be a potentially useful delivery vehicle for oligonucleotide-based therapeutics and transgenes, appropriate for use in vitro or in vivo.

DOI： 10.1177/095632029800900306

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

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

We have demonstrated that antisense phosphorothioate oligonucleotides (S-ODNs) inhibit influenza virus A replication in MDCK cells. Phosphorothioate and liposomally encapsulated oligonucleotides with two target sites (PB1 and PB2) were synthesized and tested for virus-induced cytopathogenicity effects by a MTT assay using MDCK cells. The liposomally encapsulated S-ODNs complementary to the sites of the PB2-AUG initiation codon showed highly inhibitory effects. On the other hand, the inhibitory effect of the liposomally encapsulated S-ODNs targeted to PB1 was considerably decreased in comparison with the PB2 target sites. The liposomally encapsulated oligonucleotides exhibited higher inhibitory activity than the free oligonucleotides. The activities of the modified oligonucleotides are effectively enhanced by using the liposomal carrier.

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Language：English   Publishing type：Research paper (international conference proceedings)   Publisher：Marcel Dekker Inc.  

DOI： 10.1080/07328319708006261

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

We have designed a new type of antisense oligonucleotide, containing two hairpin loop structures with RNA/DNA base pairs (sense (RNA) and antisense (DNA)) in the double helical stem (nicked and circular dumbbell DNA/RNA chimeric oligonucleotides). The reaction of the nicked and circular dumbbell DNA/RNA chimeric oligonucleotides with RNase H gave the corresponding anti-DNA together with the sense RNA cleavage products. These oligonucleotides were more resistant to exonuclease attack. We also describe the anti-Fluv activities of circular dumbbell DNA/RNA chimeric oligonucleotides.

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Language：Japanese Book type：Scholarly book

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J-GLOBAL

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J-GLOBAL

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Language：Japanese  

CiNii Article

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Other Link： http://search.jamas.or.jp/link/ui/2014065914

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

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Language：Japanese   Publisher：日本癌学会  

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Language：Japanese   Publisher：(有)科学評論社  

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Language：Japanese   Publisher：日本ウイルス学会  

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Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (other)  

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：(公社)日本薬学会  

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Language：Japanese   Publisher：(株)日本臨床社  

J-GLOBAL

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Event date： 2022.11

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Event date： 2017.9

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Venue：Massachusetts, USA  

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Venue：京都  

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Venue：大阪  

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Venue：大阪  

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Venue：大阪  

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Venue：大阪  

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Venue：大阪  

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Venue：Washington DC, USA  

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Venue：Cape Cod, USA  

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Venue：Washington DC, USA  

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Venue：Surabaya, Indonesia  

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Venue：大阪  

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