3,658 results on '"Research Institute for Microbial Diseases"'
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2. Experimental cerebral malaria progresses independently of the Nlrp3 inflammasome
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Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA, Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA ; Paul H. Dekruif Professor of Pathology, University of Michigan Medical School, 1500 E. Medical Center Dr, 4215 CCGC, Ann Arbor, MI 48109, USA Fax: +1-734-647-9654, Laboratory of Host Defense, Immunology Frontier Research Center, World Premier Immunology Institute, Osaka University, Osaka, Japan, Laboratory of Host Defense, Immunology Frontier Research Center, World Premier Immunology Institute, Osaka University, Osaka, Japan ; Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan, Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan, Department of Medical Parasitology, New York University School of Medicine, New York, NY, USA, Reimer, Thornik, Shaw, Michael H., Franchi, Luigi, Coban, Cevayir, Ishii, Ken J., Akira, Shizuo, Horii, Toshihiro, Rodriguez, Ana, N????ez, Gabriel, Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA, Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI, USA ; Paul H. Dekruif Professor of Pathology, University of Michigan Medical School, 1500 E. Medical Center Dr, 4215 CCGC, Ann Arbor, MI 48109, USA Fax: +1-734-647-9654, Laboratory of Host Defense, Immunology Frontier Research Center, World Premier Immunology Institute, Osaka University, Osaka, Japan, Laboratory of Host Defense, Immunology Frontier Research Center, World Premier Immunology Institute, Osaka University, Osaka, Japan ; Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan, Department of Molecular Protozoology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan, Department of Medical Parasitology, New York University School of Medicine, New York, NY, USA, Reimer, Thornik, Shaw, Michael H., Franchi, Luigi, Coban, Cevayir, Ishii, Ken J., Akira, Shizuo, Horii, Toshihiro, Rodriguez, Ana, and N????ez, Gabriel
- Abstract
Cerebral malaria is the most severe complication of Plasmodium falciparum infection in humans and the pathogenesis is still unclear. Using the P. berghei ANKA infection model of mice, we investigated a potential involvement of Nlrp3 and the inflammasome in the pathogenesis of cerebral malaria. Nlrp3 mRNA expression was upregulated in brain endothelial cells after exposure to P. berghei ANKA. Although ??-hematin, a synthetic compound of the parasites heme polymer hemozoin, induced the release of IL-1?? in macrophages through Nlrp3, we did not obtain evidence for a role of IL-1?? in vivo . Nlrp3 knock-out mice displayed a delayed onset of cerebral malaria; however, mice deficient in caspase-1, the adaptor protein ASC or the IL-1 receptor succumbed as WT mice. These results indicate that the role of Nlrp3 in experimental cerebral malaria is independent of the inflammasome and the IL-1 receptor pathway.
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- 2010
3. Regulation of the Epstein−Barr Virus LMP1-mediated NF-kappaB Signaling Pathway by a Novel Adaptor Protein STAP-2
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Ikeda, Osamu, Sekine, Yuichi, Yasui, Teruhito, Sugiyma, Suita Kenji, Oritani, Kenji, Yoshimura, Suita Akihiko, and Matsuda, Tadashi
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- 2007
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4. Cellular Senescence: Defining a Path Forward
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John M. Sedivy, Paul D. Robbins, Cleo L. Bishop, Vassilis G. Gorgoulis, Konstantinos Vougas, Konstantinos Evangelou, Valery Krizhanovsky, Dorothy C. Bennett, Eiji Hara, Diana Jurk, Gerardo Ferbeyre, Judith Campisi, Masashi Narita, Laura J. Niedernhofer, Manuel Serrano, Clemens A. Schmitt, Peter D. Adams, Oliver Bischof, Andrea Alimonti, Marco Demaria, Jesús Gil, Daohong Zhou, Manuel Collado, Thomas von Zglinicki, Andrea B. Maier, João F. Passos, Institut Pasteur [Paris], National and Kapodistrian University of Athens (NKUA), University of Manchester [Manchester], Biomedical Research Foundation of the Academy of Athens (BRFAA), Institute of Cancer Sciences [Glasgow, UK] (CR-UK Beatson Institute), University of Glasgow, Sanford Burnham Prebys Medical Discovery Institute, Oncology Institute of Southern Switzerland (IOSI), Università della Svizzera italiana = University of Italian Switzerland (USI), Universita degli Studi di Padova, Veneto Institute of Molecular Medicine [Padova, Italy] (VIMM), University of London [London], Organisation Nucléaire et Oncogenèse / Nuclear Organization and Oncogenesis, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Bart's and The London School of Medicine and Dentistry, Queen Mary University of London (QMUL), Buck Institute for Research on Aging, Universidade de Santiago de Compostela [Spain] (USC ), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Université de Montréal (UdeM), MRC London Institute of Medical Sciences (LMC), Imperial College London, Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), Osaka University [Osaka], Department of Molecular Cell Biology [Rehovot], Weizmann Institute of Science [Rehovot, Israël], Robert and Arlene Kogod Center on Aging [Rochester, MN, USA], Mayo Clinic, Vrije Universiteit Amsterdam [Amsterdam] (VU), University of Melbourne, University of Cambridge [UK] (CAM), University of Minnesota [Twin Cities] (UMN), University of Minnesota System, Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Kepler University Hospital, Brown University, Newcastle University [Newcastle], University of Florida [Gainesville] (UF), Institute for Research in Biomedicine [Barcelona, Spain] (IRB), University of Barcelona-Barcelona Institute of Science and Technology (BIST), Institució Catalana de Recerca i Estudis Avançats (ICREA), University of Groningen [Groningen], European Research Institute for the Biology of Ageing [Groningen] (ERIBA), University Medical Center Groningen [Groningen] (UMCG), M.D. is funded by the Dutch Cancer Foundation, Netherlands (grant ID 10989). V.G., K.E., and K.V. were financially supported by the European Union’s Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grants agreement no. 722729 (SYNTRAIN), the Welfare Foundation for Social & Cultural Sciences (KIKPE), Greece, the KIKPE Foundation, Athens, Greece, Pentagon Biotechnology, UK, DeepMed IO, UK, grant no. 775 from the Hellenic Foundation for Research and Innovation (HFRI), and NKUA-SARG grants 70/3/9816, 70/3/12128, and 70/3/15603. M.S.: is funded by the IRB and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2013-48256-R), the European Research Council (ERC-2014-AdG/669622), and 'laCaixa' Foundation., We would like to thank Nikolaos Kastrinakis, Panagiotis V.S. Vasileiou, Gkikas Magiorkinis, Eleni Fitsiou, and Michela Borghesan for their valuable support to this work. We apologize in advance that, for reason of space, we have omitted the citations of relevant papers and reviews., National and Kapodistrian University of Athens = University of Athens (NKUA | UoA), Organisation Nucléaire et Oncogenèse - Nuclear Organization and Oncogenesis, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], University of Santiago de Compostela [Spain] (USC), Centre de recherche du Chum [Montréal] (CRCHUM), Université de Montréal [Montréal], Research Institute for Microbial Diseases, Weizmann Institute of Science, University of Minnesota [Twin Cities], Max Delbrück Center for Molecular Medicine [Berlin], Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, University of Florida [Gainesville], University of Barcelona, Università degli Studi di Padova = University of Padua (Unipd), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Narita, Masashi [0000-0001-7764-577X], and Apollo - University of Cambridge Repository
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Senescence ,EXPRESSION ,Aging ,Cell cycle checkpoint ,[SDV]Life Sciences [q-bio] ,Cell ,DNA-DAMAGE RESPONSE ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Computational biology ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Mitochondrion ,Biology ,General Biochemistry, Genetics and Molecular Biology ,CHROMATIN LANDSCAPE ,03 medical and health sciences ,0302 clinical medicine ,MITOCHONDRIA ,ONCOGENE-INDUCED SENESCENCE ,medicine ,Humans ,OXIDATIVE STRESS ,Senolytic ,Cellular Senescence ,11 Medical and Health Sciences ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,P53 ,[SDV.MHEP.GEG]Life Sciences [q-bio]/Human health and pathology/Geriatry and gerontology ,Genetic Diseases, Inborn ,DARK SIDE ,Cell Cycle Checkpoints ,06 Biological Sciences ,CANCER ,Chromatin ,medicine.anatomical_structure ,Gene Expression Regulation ,CELLS ,Developmental biology ,030217 neurology & neurosurgery ,Biomarkers ,Developmental Biology - Abstract
International audience; Cellular senescence is a cell state implicated in various physiological processes and a wide spectrum of age-related diseases. Recently, interest in therapeutically targeting senescence to improve healthy aging and age-related disease, otherwise known as senotherapy, has been growing rapidly. Thus, the accurate detection of senescent cells, especially in vivo, is essential. Here, we present a consensus from the International Cell Senescence Association (ICSA), defining and discussing key cellular and molecular features of senescence and offering recommendations on how to use them as biomarkers. We also present a resource tool to facilitate the identification of genes linked with senescence, SeneQuest (available at http://Senequest.net). Lastly, we propose an algorithm to accurately assess and quantify senescence, both in cultured cells and in vivo.
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- 2019
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5. Worldwide sequence conservation of transmission-blocking vaccine candidate Pvs230 in Plasmodium vivax
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Kazuyuki Tanabe, Jetsumon Sattabongkot, Shin-Ichiro Tachibana, Masanori Yagi, Meiko Hamai, Marcelo U. Ferreira, Takafumi Tsuboi, Hiroshi Ohmae, Toshihiro Horii, Masanori Doi, Yaming Cao, Milijaona Randrianarivelojosia, Akira Kaneko, Toshihiro Mita, Motomi Torii, Mayumi Tachibana, Fadile Yildiz Zeyrek, Cell-free Science and Technology Research Center, Ehime University [Matsuyama], Laboratory of Malariology, Research Institute for Microbial Diseases, Osaka University [Osaka], Department of Molecular Parasitology, Ehime University Graduate School of Medicine, Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University (TWMU), Department of Molecular Protozoology, Research Institute for Microbial Diseases, Department of Microbiology, Harran University Medical Faculty, Department of Parasitology [São Paulo] (IBS), Institute of Biomedical Sciences (ICB/USP), Universidade de São Paulo (USP)-Universidade de São Paulo (USP), Department of Parasitology, National Institute of Infectious Diseases, Karolinska Institutet [Stockholm], Global COE, Nagasaki University, Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), Department of Immunology, College of Basic Medical Sciences, China Medical University, Ehime Proteo-Medicine Research Center, Venture Business Laboratory, and This research was supported by the Ministry of Education, Culture, Sports, Science and Technology (18073013, 18GS03140013, 20390120, 19406009, 21022034, 22406012), and by the Ministry of Health, Labour, and Welfare, Japan (H20-Shinkou-ippan-013, H21-Chikyukibo-ippan-005) and by Japan Society for the Promotion of Science Fellowship Program (to FYZ). Field work in Brazil was funded by the National Institutes of Health of USA (RO1 AI 075416-01), the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, 470570/2006-7), and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP, 05/51988-0 and 07/51199-0). This work was also supported by grant from the National Natural Science Foundation of China (30972774)
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MESH: Sequence Analysis, DNA ,[SDV]Life Sciences [q-bio] ,Plasmodium vivax ,Protozoan Proteins ,MESH: Amino Acid Sequence ,Nucleotide diversity ,Conserved sequence ,0302 clinical medicine ,MESH: Animals ,MESH: Phylogeny ,MESH: Protozoan Proteins ,Conserved Sequence ,Phylogeny ,Genetics ,0303 health sciences ,education.field_of_study ,MESH: Conserved Sequence ,biology ,MESH: Malaria Vaccines ,MESH: Plasmodium vivax ,3. Good health ,Infectious Diseases ,Molecular Medicine ,Sequence analysis ,Molecular Sequence Data ,030231 tropical medicine ,Population ,MESH: Sequence Alignment ,MESH: DNA, Protozoan ,Antigens, Protozoan ,Article ,03 medical and health sciences ,Malaria Vaccines ,parasitic diseases ,Malaria, Vivax ,medicine ,Gametocyte ,Animals ,Humans ,Amino Acid Sequence ,education ,030304 developmental biology ,MESH: Humans ,MESH: Molecular Sequence Data ,General Veterinary ,General Immunology and Microbiology ,Public Health, Environmental and Occupational Health ,MESH: Malaria, Vivax ,Plasmodium falciparum ,Sequence Analysis, DNA ,DNA, Protozoan ,biology.organism_classification ,medicine.disease ,Virology ,Sequence Alignment ,Malaria ,MESH: Antigens, Protozoan - Abstract
International audience; Pfs230, surface protein of gametocyte/gamete of the human malaria parasite, Plasmodium falciparum, is a prime candidate of malaria transmission-blocking vaccine. Plasmodium vivax has an ortholog of Pfs230 (Pvs230), however, there has been no study in any aspects on Pvs230 to date. To investigate whether Pvs230 can be a vivax malaria transmission-blocking vaccine, we performed evolutionary and population genetic analysis of the Pvs230 gene (pvs230: PVX_003905). Our analysis of Pvs230 and its orthologs in eight Plasmodium species revealed two distinctive parts: an interspecies variable part (IVP) containing species-specific oligopeptide repeats at the N-terminus and a 7.5kb interspecies conserved part (ICP) containing 14 cysteine-rich domains. Pvs230 was closely related to its orthologs, Pks230 and Pcys230, in monkey malaria parasites. Analysis of 113 pvs230 sequences obtained from worldwide, showed that nucleotide diversity is remarkably low in the non-repeat 8-kb region of pvs230 (θπ=0.00118) with 77 polymorphic nucleotide sites, 40 of which results in amino acid replacements. A signature of purifying selection but not of balancing selection was seen on pvs230. Functional and/or structural constraints may limit the level of polymorphism in pvs230. The observed limited polymorphism in pvs230 should ground for utilization of Pvs230 as an effective transmission-blocking vaccine.
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- 2011
6. Spontaneous mutations in the Plasmodium falciparum sarcoplasmic/ endoplasmic reticulum Ca2+-ATPase (PfATP6) gene among geographically widespread parasite populations unexposed to artemisinin-based combination therapies
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Tanabe, Kazuyuki, Zakeri, Sedigheh, Palacpac, Nirianne Marie Q, Afsharpad, Manada, Randrianarivelojosia, Milijaona, Kaneko, Akira, Marma, Aung Swi Prue, Horii, Toshihiro, Mita, Toshihiro, Laboratory of Malariology, Research Institute for Microbial Diseases, Biotechnology Research Center, Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Department of Molecular Protozoology, Osaka University [Osaka]-Research Institute for Microbial Diseases, Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Karolinska Institutet [Stockholm], Emerging and Re-emerging Diseases, Communicable Disease Control, Directorate General of Health Services, Department of International Affairs and Tropical Medicine, Tokyo Women's Medical University (TWMU), and This work was supported by Grant-in-Aids for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (18073013), from the Japan Society for Promotion of Sciences (18GS03140013, 20390120, 22406012), and from the Ministry of Health, Labor and Welfare (H20-Shinkou-ippan-013).
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MESH: Mutation ,MESH: Polymorphism, Single Nucleotide ,[SDV]Life Sciences [q-bio] ,MESH: Anti-Infective Agents ,Plasmodium falciparum ,Protozoan Proteins ,MESH: Haplotypes ,Polymorphism, Single Nucleotide ,Artemisinins ,Sarcoplasmic Reticulum Calcium-Transporting ATPases ,MESH: Sarcoplasmic Reticulum Calcium-Transporting ATPases ,Anti-Infective Agents ,Gene Frequency ,Haplotypes ,Mechanisms of Resistance ,MESH: Artemisinins ,parasitic diseases ,Mutation ,MESH: Gene Frequency ,Animals ,MESH: Animals ,MESH: Protozoan Proteins ,MESH: Plasmodium falciparum - Abstract
International audience; Recent reports on the decline of the efficacy of artemisinin-based combination therapies (ACTs) indicate a serious threat to malaria control. The endoplasmic/sarcoplasmic reticulum Ca(2+)-ATPase ortholog of Plasmodium falciparum (PfSERCA) has been suggested to be the target of artemisinin and its derivatives. It is assumed that continuous artemisinin pressure will affect polymorphism of the PfSERCA gene (serca) if the protein is the target. Here, we investigated the polymorphism of serca in parasite populations unexposed to ACTs to obtain baseline information for the study of potential artemisinin-driven selection of resistant parasites. Analysis of 656 full-length sequences from 13 parasite populations in Africa, Asia, Oceania, and South America revealed 64 single nucleotide polymorphisms (SNPs), of which 43 were newly identified and 38 resulted in amino acid substitutions. No isolates showed L263E and S769N substitutions, which were reportedly associated with artemisinin resistance. Among the four continents, the number of SNPs was highest in Africa. In Africa, Asia, and Oceania, common SNPs, or those with a minor allele frequency of ≥0.05, were less prevalent, with most SNPs noted to be continent specific, whereas in South America, common SNPs were highly prevalent and often shared with those in Africa. Of 50 amino acid haplotypes observed, only one haplotype (3D7 sequence) was seen in all four continents (64%). Forty-eight haplotypes had frequencies of less than 5%, and 40 haplotypes were continent specific. The geographical difference in the diversity and distribution of serca SNPs and haplotypes lays the groundwork for assessing whether some artemisinin resistance-associated mutations and haplotypes are selected by ACTs.
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- 2010
7. The late endosome/lysosome-anchored p18-mTORC1 pathway controls terminal maturation of lysosomes
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Okada, Masato [Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)]
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- 2012
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8. PSF3 marks malignant colon cancer and has a role in cancer cell proliferation
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Takakura, Nobuyuki [Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871 (Japan)]
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- 2010
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9. Broad neutralizing human monoclonal antibodies against influenza virus from vaccinated healthy donors
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Ikuta, Kazuyoshi [Department of Virology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871 (Japan)]
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- 2009
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10. Putative sperm fusion protein IZUMO and the role of N-glycosylation
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Okabe, Masaru [Research Institute for Microbial Diseases, Osaka University, Yamadaoka 3-1, Suita, Osaka 565-0871 (Japan)]
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- 2008
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11. Retro-transduction by virus pseudotyped with glycoprotein of vesicular stomatitis virus
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Sakuragi, Jun-ichi [Department of Viral Infections, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita City, Osaka 565-0871 (Japan)]
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- 2007
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12. Crystallization and preliminary crystallographic studies of the Pasteurella multocida toxin catalytic domain
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Horiguchi, Yasuhiko [Research Institute for Microbial Diseases, Osaka University, 3-1 Yamada-oka, Suita-shi, Osaka 565-0871 (Japan)]
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- 2006
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13. A FRET-based probe for epidermal growth factor receptor bound non-covalently to a pair of synthetic amphipathic helixes
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Matsuda, Michiyuki [Department of Tumor Virology, Research Institute for Microbial Diseases, Osaka University, Yamadaoka, Suita-shi, Osaka 565-0871 (Japan)]
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- 2005
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14. IFN-γ extends the immune functions of Guanylate Binding Proteins to inflammasome-independent antibacterial activities during Francisella novicida infection
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Sacha Benaoudia, Sophia Djebali, Pierre Wallet, Angelina Provost, Pauline Basso, Igor Golovliov, Anders Sjöstedt, Etienne Meunier, Eric Faudry, Bénédicte F. Py, Fanny Michal, Omran Allatif, Brice Lagrange, Helena Lindgren, Amandine Mosnier, Amandine Martin, Petr Broz, Thomas Henry, Masahiro Yamamoto, Inflammasome, Infections bactériennes et autoinflammation, Inflammasome, Bacterial Infections and Autoinflammation (I2BA), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Immunologie de l'allergie cutanée et vaccination – Immunology of skin allergy and vaccination, Laboratory for Molecular Infection Medicine Sweden and Department of Clinical Microbiology, Pathogénie bactérienne et réponses cellulaires, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Immunité et lymphocytes cytotoxiques – Immunity and cytotoxic lymphocytes, Focal Area Infection Biology, Biozentrum, University of Basel (Unibas), Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), Osaka University [Osaka], Inflammasome NLRP3 – NLRP3 Inflammasome, Pathogenèse bactérienne et réponses cellulaires (PBRC), Biologie du Cancer et de l'Infection (BCI ), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Male ,Inflammasomes ,Fluorescent Antibody Technique ,Apoptosis ,medicine.disease_cause ,Pathology and Laboratory Medicine ,Inbred C57BL ,Biochemistry ,White Blood Cells ,Mice ,0302 clinical medicine ,Animal Cells ,Medicine and Health Sciences ,Biology (General) ,Francisella ,Francisella tularensis ,Tularemia ,Mice, Knockout ,Immune System Proteins ,Cell Death ,Effector ,Antimicrobials ,Biochemistry and Molecular Biology ,Drugs ,Inflammasome ,Flow Cytometry ,3. Good health ,Cell biology ,Bacterial Pathogens ,Chemistry ,Intracellular Pathogens ,Cell Processes ,Medical Microbiology ,Gene Knockdown Techniques ,Physical Sciences ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Cellular Types ,Pathogens ,medicine.drug ,Research Article ,QH301-705.5 ,Immune Cells ,Knockout ,Immunology ,Immunoblotting ,Enzyme-Linked Immunosorbent Assay ,Biology ,Microbiology ,03 medical and health sciences ,AIM2 ,Interferon-gamma ,Immune system ,GTP-Binding Proteins ,Virology ,Microbial Control ,Genetics ,medicine ,Animals ,Francisella novicida ,Molecular Biology ,Microbial Pathogens ,Pharmacology ,Blood Cells ,Bacteria ,Animal ,Intracellular parasite ,Macrophages ,Chemical Compounds ,Organisms ,Biology and Life Sciences ,Proteins ,Cell Biology ,RC581-607 ,Iodides ,biology.organism_classification ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Disease Models ,Antibacterials ,Parasitology ,Immunologic diseases. Allergy ,Gram-Negative Bacterial Infections ,Inflammasome complex ,Biokemi och molekylärbiologi ,030215 immunology - Abstract
Guanylate binding proteins (GBPs) are interferon-inducible proteins involved in the cell-intrinsic immunity against numerous intracellular pathogens. The molecular mechanisms underlying the potent antibacterial activity of GBPs are still unclear. GBPs have been functionally linked to the NLRP3, the AIM2 and the caspase-11 inflammasomes. Two opposing models are currently proposed to explain the GBPs-inflammasome link: i) GBPs would target intracellular bacteria or bacteria-containing vacuoles to increase cytosolic PAMPs release ii) GBPs would directly facilitate inflammasome complex assembly. Using Francisella novicida infection, we investigated the functional interactions between GBPs and the inflammasome. GBPs, induced in a type I IFN-dependent manner, are required for the F. novicida-mediated AIM2-inflammasome pathway. Here, we demonstrate that GBPs action is not restricted to the AIM2 inflammasome, but controls in a hierarchical manner the activation of different inflammasomes complexes and apoptotic caspases. IFN-γ induces a quantitative switch in GBPs levels and redirects pyroptotic and apoptotic pathways under the control of GBPs. Furthermore, upon IFN-γ priming, F. novicida-infected macrophages restrict cytosolic bacterial replication in a GBP-dependent and inflammasome-independent manner. Finally, in a mouse model of tularemia, we demonstrate that the inflammasome and the GBPs are two key immune pathways functioning largely independently to control F. novicida infection. Altogether, our results indicate that GBPs are the master effectors of IFN-γ-mediated responses against F. novicida to control antibacterial immune responses in inflammasome-dependent and independent manners., Author summary The cell-intrinsic immunity is defined as the mechanisms allowing a host cell infected by an intracellular pathogen to mount effective immune mechanisms to detect and eliminate pathogens without any help from other immune cells. In infected macrophages, the Guanylate Binding Proteins (GBPs) are immune proteins, induced at low levels in a cell autonomous manner by endogenous type I IFN or at high levels following IFN-γ production by innate and adaptive lymphocytes. The antibacterial activity of GBPs has been recently tightly linked to the inflammasomes. Inflammasomes are innate immune complexes leading to inflammatory caspases activation and death of the infected cell. Francisella novicida, a bacterium replicating in the macrophage cytosol, is closely related to F. tularensis, the agent of tularemia and is used as a model to study cytosolic immunity. GBPs contribute to F. novicida lysis within the host cytosol leading to DNA release and AIM2 inflammasome activation. In addition to their regulation of the AIM2 inflammasome, we identified that GBPs also control several other pyroptotic and apoptotic pathways activated in a hierarchical manner. Furthermore, we demonstrate that IFN-γ priming extends GBPs anti-microbial responses from the inflammasome-dependent control of cell death to an inflammasome-independent control of cytosolic bacterial replication. Our results, validated in a mouse model of tularemia, thus segregate the antimicrobial activities of inflammasomes and GBPs as well as highlight GBPs as the master effectors of IFN-γ-mediated cytosolic immunity.
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- 2017
15. Caspase-1 Activation of IL-1β and IL-18 Are Essential for Shigella flexneri–Induced Inflammation
- Author
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Josette Arondel, Philippe J. Sansonetti, Kiyoshi Takeda, Subhashis Banerjee, Kavitha Thirumalai, Arturo Zychlinsky, Armelle Phalipon, Shizuo Akira, Pathogénie Microbienne Moléculaire, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Skirball Institute of Biomolecular Medicine, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), BASF Bioresearch Corporation, BASF SE, Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), Osaka University [Osaka], This work was supported by a collaborative NATO grant (CLG.976285) shared by the P. J. S. and A. Z. laboratories, by a grant from the Biotechnology Program of the French Ministére de l'Education Nationale de la Recherche et la Technologie to P. J. S. and by a National Institutes of Health grant (AI37720) to A. Z., We wish to thank Michel Huerre and his group (laboratoire d'histopathologie, Institut Pasteur) for excellent assistance in histopathology and Lionel Lafitte (Service Photographie, Institut Pasteur) for assistance in image analysis., and Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)
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Proteases ,Immunology ,Caspase 1 ,Inflammation ,Shigella flexneri ,Substrate Specificity ,Microbiology ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Immunology and Allergy ,Caspase ,Dysentery, Bacillary ,0303 health sciences ,biology ,030306 microbiology ,Interleukin-18 ,Interleukin ,biology.organism_classification ,Immunohistochemistry ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,humanities ,3. Good health ,Infectious Diseases ,Apoptosis ,biology.protein ,medicine.symptom ,Interleukin-1 ,030215 immunology - Abstract
International audience; Caspases are intracellular proteases that mediate mammalian cell apoptosis. Caspase-1 (Casp-1) is a unique caspase because it activates the proinflammatory cytokines interleukin (IL)-1beta and IL-18. Shigella flexneri, the etiological agent of bacillary dysentery, induces macrophage apoptosis, which requires Casp-1 and results in the release of mature IL-1beta and IL-18. Here we show that casp-1(-/-) mice infected with S. flexneri do not develop the acute inflammation characteristic of shigellosis and are unable to resolve the bacterial infection. Using casp-1(-/-) mice supplemented with recombinant cytokines and experiments with IL-1beta(-/-) and IL-18(-/-) mice, we show that IL-1beta and IL-18 are both required to mediate inflammation in S. flexneri infections. Together, these data demonstrate the importance of Casp-1 in acute inflammation and show the different roles of its substrates, IL-1beta and IL-18, in this response.
- Published
- 2000
- Full Text
- View/download PDF
16. The Origins of African Plasmodium vivax; Insights from Mitochondrial Genome Sequencing
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Shigeyuki Kano, Richard Carter, Anna Färnert, Milijaona Randrianarivelojosia, Voahangy Andrianaranjaka, Cevayir Coban, Paul M. Sharp, Richard Culleton, Pedro Cravo, Fadile Yildiz Zeyrek, Kazuyuki Tanabe, Akira Kaneko, Ana Paula Arez, Instituto de Higiene e Medicina Tropical (IHMT), Centro de Malária e outras Doenças Tropicais (CMDT), Laboratory of Malariology, International Research Centre of Infectious Diseases, Osaka University [Osaka]-Research Institute of Microbial Diseases, Malaria Unit, Nagasaki University-Institute of Tropical Medicine [Antwerp] (ITM), Laboratory of Malaria Immunology, Immunology Frontier Research Center, Osaka University [Osaka]-World Premier Institute for Immunology, Department of Microbiology, School of Medicine, Harran University, Centro de Malaria e outras Doenças Tropicais, Unidade de Parasitologia, Instituto de Higiene e Medicina Tropical, Instituto de Patologia Tropical e Saúde Pública (IPTSP), Universidade Federal de Goiás [Goiânia] (UFG), Department of medicine [Stockholm], Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), Research Institute, International Medical Centre of Japan, Centre for Immunity, Infection and Evolution, University of Edinburgh, and This study was supported by Grant-in-Aid for Scientific Research on Priority Areas from The Japanese Ministry of Education, Culture, Sports, Science and Technology (18073013) and Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (17-05495, 18390131, 18GS03140013). CC and FYZ were supported by a JSPS bilateral research grant
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MESH: Sequence Analysis, DNA ,Turkey ,[SDV]Life Sciences [q-bio] ,Plasmodium vivax ,Population genetics ,Protozoology ,MESH: Africa ,MESH: Base Sequence ,Genome ,MESH: Madagascar ,0302 clinical medicine ,MESH: Turkey ,Plasmodium Vivax ,MESH: Genetic Variation ,MESH: Phylogeny ,Genome Evolution ,Phylogeny ,Genetics ,Medicine(all) ,0303 health sciences ,education.field_of_study ,Multidisciplinary ,biology ,Agricultural and Biological Sciences(all) ,Nucleotides ,MESH: Polymorphism, Single Nucleotide ,Genomics ,MESH: Plasmodium vivax ,3. Good health ,Phylogenetics ,Infectious Diseases ,Veterinary Diseases ,Medicine ,MESH: Genome, Mitochondrial ,Research Article ,Mitochondrial DNA ,Science ,Molecular Sequence Data ,030231 tropical medicine ,Population ,Microbiology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,SDG 3 - Good Health and Well-being ,parasitic diseases ,Parasitic Diseases ,Madagascar ,medicine ,Humans ,Evolutionary Systematics ,Parasite Evolution ,education ,Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Evolutionary Biology ,MESH: Humans ,MESH: Molecular Sequence Data ,Base Sequence ,Biochemistry, Genetics and Molecular Biology(all) ,Haplotype ,Computational Biology ,Tropical Diseases (Non-Neglected) ,Genetic Variation ,Genomic Evolution ,Sequence Analysis, DNA ,MESH: Haplotypes ,World population ,Veterinary Parasitology ,medicine.disease ,biology.organism_classification ,Malaria ,MESH: Nucleotides ,Haplotypes ,Evolutionary biology ,Africa ,Genome, Mitochondrial ,Parastic Protozoans ,Veterinary Science ,Parasitology - Abstract
Plasmodium vivax, the second most prevalent of the human malaria parasites, is estimated to affect 75 million people annually. It is very rare, however, in west and central Africa, due to the high prevalence of the Duffy negative phenotype in the human population. Due to its rarity in Africa, previous studies on the phylogeny of world-wide P. vivax have suffered from insufficient samples of African parasites. Here we compare the mitochondrial sequence diversity of parasites from Africa with those from other areas of the world, in order to investigate the origin of present-day African P. vivax. Mitochondrial genome sequencing revealed relatively little polymorphism within the African population compared to parasites from the rest of the world. This, combined with sequence similarity with parasites from India, suggests that the present day African P. vivax population in humans may have been introduced relatively recently from the Indian subcontinent. Haplotype network analysis also raises the possibility that parasites currently found in Africa and South America may be the closest extant relatives of the ancestors of the current world population. Lines of evidence are adduced that this ancestral population may be from an ancient stock of P. vivax in Africa., PLoS One, 6(12), e29137; 2011
- Published
- 2011
17. Involvement of Toll-like Receptor 3 in the Immune Response of Lung Epithelial Cells to Double-stranded RNA and Influenza A Virus
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Michel Chignard, Ronan Le Goffic, Sarah Bloch, Mustapha Si-Tahar, Shizuo Akira, Loïc Guillot, Nicolas Escriou, Le Goffic, Ronan, Défense Innée et Inflammation Pulmonaire, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique Moléculaire des Virus Respiratoires, Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), Osaka University [Osaka], Association Vaincre la Mucoviscidose, Pasteur Institute through 'Programme Transversal de Recherche' Grant PTR94, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut Pasteur [Paris]
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Lipopolysaccharides ,viruses ,medicine.disease_cause ,Biochemistry ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,[SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Influenza A virus ,Receptors, Immunologic ,Extracellular Signal-Regulated MAP Kinases ,Lung ,[SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,0303 health sciences ,Toll-like receptor ,Membrane Glycoproteins ,biology ,Toll-Like Receptors ,NF-kappa B ,Up-Regulation ,3. Good health ,Protein Transport ,medicine.anatomical_structure ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,[SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Cytokines ,Tetradecanoylphorbol Acetate ,Signal transduction ,Signal Transduction ,T cell ,Receptors, Cell Surface ,Protein Serine-Threonine Kinases ,Response Elements ,03 medical and health sciences ,Immune system ,Proto-Oncogene Proteins ,medicine ,Humans ,Molecular Biology ,[SDV.IMM.II] Life Sciences [q-bio]/Immunology/Innate immunity ,Adaptor Proteins, Signal Transducing ,RNA, Double-Stranded ,030304 developmental biology ,Innate immune system ,Tumor Necrosis Factor-alpha ,Epithelial Cells ,RNA virus ,Cell Biology ,biology.organism_classification ,Antigens, Differentiation ,Molecular biology ,Toll-Like Receptor 3 ,Poly I-C ,Gene Expression Regulation ,Myeloid Differentiation Factor 88 ,TLR3 ,[SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract ,Interferons ,Proto-Oncogene Proteins c-akt ,Interleukin-1 ,030215 immunology - Abstract
Loïc Guillot: Supported by the Delegation General pour l’Armement Ronan Le Goffic: Supported by “Vaincre la Mucoviscidose” (Paris, France); International audience; Influenza A is a highly contagious single-stranded RNA virus that infects both the upper and lower respiratory tracts of humans. The host innate immune Tolllike receptor (TLR) 3 was shown previously in cells of myeloid origin to recognize the viral replicative, intermediate double-stranded RNA (dsRNA). Thus, dsRNA may be critical for the outcome of the infection. Here we first compared the activation triggered by either influenza A virus or dsRNA in pulmonary epithelial cells. We established that TLR3 is constitutively expressed in human alveolar and bronchial epithelial cells, and we describe its intracellular localization. Expression of TLR3 was positively regulated by the influenza A virus and by dsRNA but not by other inflammatory mediators, including bacterial lipopolysaccharide, the cytokines tumor necrosis factor-␣ and interleukin (IL)-1, and the protein kinase C activator phorbol 12-myristate 13-acetate. We also demonstrated that TLR3 contributes directly to the immune response of respiratory epithelial cells to influenza A virus and dsRNA, and we propose a molecular mechanism by which these stimuli induce epithelial cell activation. This model involves mitogen-activated protein kinases, phosphatidylinositol 3-kinase/ Akt signaling, and the TLR3-associated adaptor molecule TRIF but not MyD88-dependent activation of the transcription factors NF-B or interferon regulatory factor/interferon-sensitive response-element pathways. Ultimately, this signal transduction elicits an epithelial response that includes the secretion of the cytokines IL-8, IL-6, RANTES (regulated on activation normal T cell expressed and secreted), and interferon- and the up-regulation of the major adhesion molecule ICAM-1.
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- 2005
18. 32nd annual meeting of European Environmental Mutagen Society. DNA damage and repair fundamental aspects and contribution to human disorders
- Author
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Tudek, Barbara, Ciesla, Zygmunt, Janion, Celina, Boiteux, Serge, Bebenek, Katarzyna, Shinagawa, Hideo, Bartsch, Helmut, Laval, Jacques, van Zeeland, Albert A, Mullenders, Leon F H, Szyfter, Krzysztof, Collins, Andrew, Kruszewski, Marcin, Institute of Biochemistry and Biophysics, Polska Akademia Nauk = Polish Academy of Sciences (PAN), Radiobiologie moléculaire et cellulaire (RMC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences [Durham] (NIEHS-NIH), National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), Osaka University [Osaka], Division of Toxicology and Cancer Risk Factors, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Laboratoire de Biologie et de Pharmacologie Appliquée (LBPA), École normale supérieure - Cachan (ENS Cachan)-Centre National de la Recherche Scientifique (CNRS), Department of Radiation Genetics and Chemical Mutagenesis, Leiden University Medical Center (LUMC), Institute of Human Genetics, Department of Nutrition [Oslo], Institute of Basic Medical Sciences [Oslo], Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO)-Faculty of Medicine [Oslo], University of Oslo (UiO)-University of Oslo (UiO), Department of Radiobiology and Health Protection, Institute of Nuclear Chemistry and Technology, and Universiteit Leiden-Universiteit Leiden
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MESH: Oxidation-Reduction ,DNA Replication ,DNA Repair ,MESH: Mitochondria ,MESH: DNA Replication ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Genomic Instability ,DNA Glycosylases ,Neoplasms ,Humans ,MESH: Neoplasms ,Genetic Predisposition to Disease ,MESH: DNA Glycosylases ,ComputingMilieux_MISCELLANEOUS ,MESH: Mutagenesis ,MESH: DNA Damage ,MESH: DNA Repair ,Recombination, Genetic ,MESH: Werner Syndrome ,MESH: Humans ,MESH: Genomic Instability ,MESH: Genetic Predisposition to Disease ,Congresses as Topic ,Mitochondria ,MESH: Poland ,Mutagenesis ,MESH: Recombination, Genetic ,Poland ,Werner Syndrome ,Oxidation-Reduction ,MESH: Congresses as Topic ,DNA Damage - Abstract
International audience
- Published
- 2003
19. Genetic Characterization of DNA Region Containing the trh and ure Genes of Vibrio parahaemolyticus
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Takeshi Honda, Yoshiharu Yamaichi, Tetsuya Iida, Kwon-Sam Park, Tomohito Oyagi, Koichiro Yamamoto, Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), and Osaka University [Osaka]
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DNA, Bacterial ,Operon ,Molecular Sequence Data ,Immunology ,Mutant ,Biology ,medicine.disease_cause ,Microbiology ,Hemolysin Proteins ,03 medical and health sciences ,Bacterial Proteins ,Ileum ,Nickel ,Gene cluster ,medicine ,Animals ,Humans ,Cloning, Molecular ,Insertion sequence ,Escherichia coli ,Gene ,030304 developmental biology ,Genetics ,0303 health sciences ,Mutation ,030306 microbiology ,Vibrio parahaemolyticus ,Sequence Analysis, DNA ,biology.organism_classification ,Urease ,Molecular biology ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Infectious Diseases ,Genes, Bacterial ,Multigene Family ,Vibrio Infections ,Molecular and Cellular Pathogenesis ,Trans-Activators ,ATP-Binding Cassette Transporters ,Parasitology ,Rabbits - Abstract
We have demonstrated that possession of the gene for thermostable direct hemolysin-related hemolysin ( trh ) coincides with the presence of the urease gene among clinical Vibrio parahaemolyticus strains and that the location of the two genes are in close proximity on the chromosome. Here, we cloned and sequenced the 15,754-bp DNA region containing the trh gene and the gene cluster for urease production from the chromosome of clinical V. parahaemolyticus (TH3996). We found 16 open reading frames (ORFs) and a lower G+C content (41%) compared with the total genome of this bacterium (46 to 47%). The ure cluster consisted of eight genes, namely, ureDABCEFG and ureR. ureR was located 5.2 kb upstream of the other seven genes in the opposite direction. The genetic organization and sequences of the ure genes resembled those found in Proteus mirabilis . Between ureR and the other ure genes, there were five ORFs, which are homologous with the nickel transport operon ( nik ) of Escherichia coli . We disrupted each of the ureR , ureC , and nikD genes in TH3996 by homologous recombination and analyzed the phenotype of the mutants. In the presence of urea these mutant strains had dramatically less urease activity than the strain they were derived from. Disruption of ureR , nikD , or ureC , however, had no effect on TRH production. The DNA region containing the trh , nik , and ure genes was found in only trh -positive strains and not in Kanagawa phenomenon-positive and environmental V. parahaemolyticus strains. At the end of the region, an insertion sequence-like element existed. These results suggest that the DNA region was introduced into V. parahaemolyticus in the past through a mechanism mediated by insertion sequences. This is the first reported case that the genes for an ATP-binding cassette-type nickel transport system, which may play a role in nickel transport through bacterial cytoplasmic membrane, are located adjacent to the ure cluster on the genome of an organism.
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- 2000
20. Physical and genetic map of the genome of Vibrio parahaemolyticus: presence of two chromosomes in Vibrio species
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Kwon-Sam Park, Koichiro Yamamoto, Yoshiharu Yamaichi, Tetsuya Iida, Takeshi Honda, Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), and Osaka University [Osaka]
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Biovar ,Restriction Mapping ,Microbiology ,Genome ,03 medical and health sciences ,Restriction map ,Pulsed-field gel electrophoresis ,Deoxyribonucleases, Type II Site-Specific ,Molecular Biology ,030304 developmental biology ,Southern blot ,Vibrio ,Genetics ,0303 health sciences ,biology ,Models, Genetic ,030306 microbiology ,Vibrio parahaemolyticus ,Chromosome Mapping ,DNA Restriction Enzymes ,biochemical phenomena, metabolism, and nutrition ,Chromosomes, Bacterial ,biology.organism_classification ,Physical Chromosome Mapping ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Electrophoresis, Gel, Pulsed-Field ,genomic DNA ,Digoxigenin ,Genome, Bacterial - Abstract
International audience; We constructed a physical map of the genomic DNA (5.1 Mb) for Vibrio parahaemolyticus strain AQ4673 by combining 17 adjacent NotI fragments. This map shows two circular replicons of 3.2 and 1.9 Mb. Pulsed-field gel electrophoresis (PFGE) of undigested genomic DNA revealed two bands of corresponding sizes. Analysis both by NotI digestion and by Southern blot of the two isolated bands confirmed the existence of two replicons. The presence of genes for 16S rRNA on both the replicons indicates that the replicons are chromosomes rather than megaplasmids. The two bands were also seen after PFGE of undigested genomic DNA of V. parahaemolyticus strains other than AQ4673, and of strains belonging to other Vibrio species, such as V. vulnificus, V. fluvialis and various serovars and biovars of V. cholerae. It is noteworthy that V. cholerae O1 strain 569B, a classical biovar, was also shown to have two replicons of 2.9 and 1.2 Mb, which does not agree with a physical map proposed in a previous study. Our results suggest that a two-replicon structure is common throughout Vibrio species.
- Published
- 1999
21. Close proximity of the tdh, trh and ure genes on the chromosome of Vibrio parahaemolyticus
- Author
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Iida, T, Park, K.-S., Suthienkul, O., Kozawa, J., Yamaichi, Yoshiharu, Yamamoto, K., Honda, T., lida, T., Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), and Osaka University [Osaka]
- Subjects
DNA, Bacterial ,Bacterial Toxins ,Biology ,Microbiology ,Polymerase Chain Reaction ,03 medical and health sciences ,Hemolysin Proteins ,Bacterial Proteins ,Humans ,Gene ,030304 developmental biology ,Southern blot ,DNA Primers ,Genetics ,Gel electrophoresis ,0303 health sciences ,Base Sequence ,Virulence ,030306 microbiology ,Vibrio parahaemolyticus ,Structural gene ,Chromosome ,Chromosome Mapping ,food and beverages ,Hemolysin ,Chromosomes, Bacterial ,biology.organism_classification ,Molecular biology ,Urease ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,3. Good health ,Gastroenteritis ,genomic DNA ,Genes, Bacterial ,Vibrio Infections - Abstract
The distribution and location of the virulence-factor genes of Vibrio parahaemolyticus, tdh and trh, and the structural gene of urease, ureC, were examined on the genomic DNAs of 115 clinical isolates of V. parahaemolyticus. The majority of strains (81%) had two copies of tdh on the chromosome, and no copies of trh or ure. Southern hybridization with a tdh probe, after pulsed-field gel electrophoresis of Noti-digested genomic DNA of each strain revealed only single bands, suggesting that the two copies of tdh exist on single Notl fragments in each strain. Of the 115 strains, 7% had the tdh, trh and ure genes on chromosomal DNA. The three genes were also detected on single Notl fragments in these strains. More detailed analysis revealed that the three genes were localized within 40 kb. By long and accurate polymerase chain reactions (LA-PCR), the distance between trh and ure was shown to be less than 8.5 kb. These results reveal a close proximity of the tdh, trh and ure genes on the chromosome of pathogenic V. parahaemolyticus strains.
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- 1998
22. Complete Nucleotide Sequences of 93-kb and 3.3-kb Plasmids of an Enterohemorrhagic Escherichia coli O157:H7 Derived from Sakai Outbreak
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Koichiro Yamamoto, Kazuo Ishii, Chang Gyun Han, Satoru Kuhara, Yoshiharu Yamaichi, Tetsuya Hayashi, Hideo Shinagawa, Takeshi Honda, Teruo Yasunaga, Masahira Hattori, Yoshino Kubota, Chikako H. Yutsudo, Eiichi Ohtsubo, Masaaki Kasamatsu, Katsushi Yokoyama, Tetsuya Iida, Kozo Makino, Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), and Osaka University [Osaka]
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Transposable element ,DNA, Bacterial ,Biology ,medicine.disease_cause ,Escherichia coli O157 ,DNA sequencing ,Microbiology ,Disease Outbreaks ,03 medical and health sciences ,chemistry.chemical_compound ,Open Reading Frames ,Plasmid ,Japan ,Genetics ,medicine ,Molecular Biology ,Gene ,Escherichia coli ,Escherichia coli Infections ,030304 developmental biology ,0303 health sciences ,030306 microbiology ,DNA replication ,Nucleic acid sequence ,General Medicine ,Sequence Analysis, DNA ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,3. Good health ,chemistry ,bacteria ,DNA ,Plasmids - Abstract
International audience; Enterohemorrhagic Escherichia coli (EHEC) O157:H7, derived from an outbreak in Sakai city, Japan in 1996, possesses two kinds of plasmids: a 93-kb plasmid termed pO157, found in clinical EHEC isolates world-wide and a 3.3-kb plasmid termed pOSAK1, prevalent in EHEC strains isolated in Japan. Complete nucleotide sequences of both plasmids have been determined, and the putative functions of the encoded proteins and the cis-acting DNA sequences have been analyzed. pO157 shares strikingly similar genes and DNA sequences with F-factor and the transmissible drug-resistant plasmid R100 for DNA replication, copy number control, plasmid segregation, conjugative functions and stable maintenance in the host, although it is defective in DNA transfer by conjugation due to the truncation and deletion of the required genes and DNA sequences. In addition, it encodes several proteins implicated in EHEC pathogenicity such as an EHEC hemolysin (HlyA), a catalase-peroxidase (KatP), a serine protease (EspP) and type II secretion system. pOSAK1 possesses a ColE1-like replication system, and the DNA sequence is extremely similar to that of a drug-resistant plasmid, NTP16, derived from Salmonella typhimurium except that it lacks drug resistance transposons.
- Published
- 1998
23. A filamentous phage associated with recent pandemic Vibrio parahaemolyticus O3:K6 strains
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Tetsuya Iida, Hatsumi Nasu, Yoshiharu Yamaichi, Kozo Makino, Takeshi Honda, Tomomi Sugahara, Hideo Shinagawa, Kwon-Sam Park, Katsushi Yokoyama, Research Institute for Microbial Diseases [Osaka, Japan] (RIMD), and Osaka University [Osaka]
- Subjects
Microbiology (medical) ,Diarrhea ,Molecular Sequence Data ,Restriction Mapping ,Genome ,DNA sequencing ,Microbiology ,Disease Outbreaks ,Bacteriophage ,03 medical and health sciences ,Open Reading Frames ,Plasmid ,Japan ,ORFS ,Gene ,030304 developmental biology ,0303 health sciences ,Travel ,biology ,030306 microbiology ,Vibrio parahaemolyticus ,Inoviridae ,Bacteriology ,Sequence Analysis, DNA ,biology.organism_classification ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,Virology ,3. Good health ,Genetic marker ,Vibrio Infections ,Plasmids - Abstract
A specific serotype, O3:K6, of Vibrio parahaemolyticus has recently been causing epidemics of gastroenteritis in Southeast Asia, Japan, and North America. To examine whether the new O3:K6 strains possess characteristics that may exacerbate outbreaks, we compared V. parahaemolyticus O3:K6 strains with non-O3:K6 strains using strains isolated from individuals with traveler's diarrhea at Kansai Airport Quarantine Station, Osaka, Japan. All 24 O3:K6 strains possessed a common plasmid, pO3K6 (DNA size, 8,782 bp, with 10 open reading frames [ORFs]). The gene organization of pO3K6 was similar to that of Vf33, a filamentous phage previously described in V. parahaemolyticus . We isolated a phage (phage f237) from the culture supernatant of V. parahaemolyticus O3:K6 strain KXV237, which formed a turbid plaque on an indicator strain. The genome of f237 was single-stranded DNA, and the double-stranded DNA obtained by treatment of the genome with DNA polymerase was identical to that of pO3K6 when analyzed by agarose gel electrophoresis after Hin dIII digestion. Furthermore, the N-terminal amino acid sequence of the f237 major coat protein was found in ORF4 of pO3K6. Our results showed that pO3K6 is a replicative form of f237. Among the ORFs found in the f237 genome, the sequence of ORF8 had no significant homology to those of any proteins in databases. ORF8 was located on a region corresponding to the distinctive region of Vf33, and its G+C content was apparently lower than that of the remaining DNA sequence of f237. By colony hybridization, ORF8 was detected only in O3:K6 strains isolated since 1996 and was not found in O3:K6 strains isolated before 1996 and clinical V. parahaemolyticus strains other than those of serotype O3:K6. Thus, this study shows that f237 is exclusively associated with recent V. parahaemolyticus O3:K6 strains. The ORF8 gene can be a useful genetic marker for the identification of the recently widespread O3:K6 strains of V. parahaemolyticus .
24. The pyruvate-GPR31 axis promotes transepithelial dendrite formation in human intestinal dendritic cells.
- Author
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Oguro-Igashira E, Murakami M, Mori R, Kuwahara R, Kihara T, Kohara M, Fujiwara M, Motooka D, Okuzaki D, Arase M, Toyota H, Peng S, Ogino T, Kitabatake Y, Morii E, Hirota S, Ikeuchi H, Umemoto E, Kumanogoh A, and Takeda K
- Subjects
- Humans, Intestinal Mucosa metabolism, Intestinal Mucosa cytology, Dendrites metabolism, Gastrointestinal Microbiome, Signal Transduction, Induced Pluripotent Stem Cells metabolism, Induced Pluripotent Stem Cells cytology, Organoids metabolism, Intestines cytology, Receptors, G-Protein-Coupled metabolism, Dendritic Cells metabolism, Pyruvic Acid metabolism
- Abstract
The intestinal lumen is rich in gut microbial metabolites that serve as signaling molecules for gut immune cells. G-protein-coupled receptors (GPCRs) sense metabolites and can act as key mediators that translate gut luminal signals into host immune responses. However, the impacts of gut microbe-GPCR interactions on human physiology have not been fully elucidated. Here, we show that GPR31, which is activated by the gut bacterial metabolite pyruvate, is specifically expressed on type 1 conventional dendritic cells (cDC1s) in the lamina propria of the human intestine. Using human induced pluripotent stem cell-derived cDC1s and a monolayer human gut organoid coculture system, we show that cDC1s extend their dendrites toward pyruvate on the luminal side, forming transepithelial dendrites (TED). Accordingly, GPR31 activation via pyruvate enhances the fundamental function of cDC1 by allowing efficient uptake of gut luminal antigens, such as dietary compounds and bacterial particles through TED formation. Our results highlight the role of GPCRs in tuning the human gut immune system according to local metabolic cues., Competing Interests: Competing interests statement:The authors declare no competing interest.
- Published
- 2024
- Full Text
- View/download PDF
25. Pneumolysin contributes to dysfunction of nasal epithelial barrier for promotion of pneumococcal dissemination into brain tissue.
- Author
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Takahara Y, Sumitomo T, Kono M, Takemura M, Akamatsu Y, Hirose Y, Yamaguchi M, Nakata M, Hotomi M, and Kawabata S
- Subjects
- Animals, Mice, Disease Models, Animal, Nasal Mucosa microbiology, Female, Humans, Streptolysins genetics, Streptolysins metabolism, Streptococcus pneumoniae genetics, Streptococcus pneumoniae pathogenicity, Bacterial Proteins genetics, Bacterial Proteins metabolism, Pneumococcal Infections microbiology, Brain microbiology
- Abstract
Streptococcus pneumoniae is one of the major pathogens responsible for bacterial meningitis and neurological sequelae. The present study was conducted to identify a non-hematogenous route used by S. pneumoniae to gain access to brain tissue without causing bacteremia or pneumonia, as well as bacterial and host factors involved in this process. To investigate the molecular mechanisms and dissemination pathways of pneumococcal infection in brain tissue, mice were intranasally inoculated with S. pneumoniae strain EF3030, a clinical isolate from a patient with otitis media. Pneumococci were isolated from the frontal olfactory bulb, caudal cerebrum, and cerebellum, with neither bacteremia nor pneumonia observed in the present model. Immunostaining imaging revealed the presence of S. pneumoniae organisms in olfactory nerve fibers. Knockout of the ply gene encoding pneumolysin (PLY) markedly compromised the ability of the bacterial organisms to disseminate into brain tissue, whereas the dissemination efficiency of the complemented strain was restored to nearly the same level as the wild type. Notably, distinct upregulation of Gli1 and Snail1, which are involved in the transcriptional repression of junctional proteins, along with downregulation of E-cadherin, was detected in nasal lavage samples from mice infected with the wild-type or complemented strain, but not in those from mice infected with the ply mutant. Taken together, the present findings indicate that PLY induces Gli1-Snail1-dependent dysfunction of the nasal epithelial barrier, thus allowing pneumococcal dissemination to brain tissue that occurs in a non-hematogenous manner.IMPORTANCEBacterial meningitis, considered to be caused by bacteremia, can lead to blood-brain barrier disruption and bacterial dissemination into the central nervous system. Despite the availability of intravenously administered antibiotics with cerebrospinal fluid transferability, bacterial meningitis remains associated with high rates of morbidity and mortality. Here, we utilized Streptococcus pneumoniae strain EF3030, clinically isolated from otitis media, for the construction of a murine infection model to investigate the molecular mechanisms by which nasally colonized pneumococci disseminate into brain tissue. The obtained findings indicate that pneumolysin (PLY) induces Gli1-Snail1-dependent dysfunction of the nasal epithelial barrier, which facilitates pneumococcal dissemination to brain tissue in a non-hematogenous manner. Our results support the existence of an alternative route by which S. pneumoniae can reach the central nervous system and indicate the need for the development of novel therapeutic strategies, which would be an important contribution to the clinical management of bacterial meningitis., Competing Interests: The authors declare no conflict of interest.
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- 2024
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26. Development of a high-throughput screening system targeting the protein-protein interactions between PRL and CNNM.
- Author
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Funato Y, Mimura M, Nunomura K, Lin B, Fujii S, Haruta J, and Miki H
- Subjects
- Humans, Animals, Protein Binding, Magnesium metabolism, HEK293 Cells, Neoplasm Proteins metabolism, Neoplasm Proteins antagonists & inhibitors, High-Throughput Screening Assays methods, Protein Tyrosine Phosphatases antagonists & inhibitors, Protein Tyrosine Phosphatases metabolism, Fluorescence Resonance Energy Transfer methods
- Abstract
Phosphatase of regenerating liver (PRL) is an oncogenic protein that promotes tumor progression by directly binding to cyclin M (CNNM) membrane proteins and inhibiting their Mg
2+ efflux activity. In this study, we have developed a high-throughput screening system to detect the interactions between PRL and CNNM proteins based on homogenous time-resolved fluorescence resonance energy transfer (HTR-FRET, HTRF). We optimized the tag sequences attached to the recombinant proteins of the CNNM4 CBS domains and PRL3 lacking the carboxyl terminal CAAX motif, and successfully detected the interaction by observing the FRET signal in the mixture of the tagged proteins and fluorophore-conjugated antibodies. Moreover, we performed compound library screening using this system and discovered several compounds that could efficiently inhibit the PRL-CNNM interaction. Characterization of one candidate compound revealed that it was relatively stable compared with thienopyridone, a known inhibitor of the PRL-CNNM interaction. The candidate compound can also inhibit PRL function in cells: suppression of CNNM-dependent Mg2+ efflux, and has sufficient in vitro drug metabolism and pharmacokinetic properties. Overall, these results demonstrate the effectiveness of this screening system for identifying novel inhibitors of the PRL-CNNM interaction, which could contribute to the development of novel anti-cancer drugs., (© 2024. The Author(s).)- Published
- 2024
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27. Understanding the immunogenicity of RTS,S in infants.
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Palacpac NMQ and Horii T
- Abstract
Competing Interests: We declare no competing interests.
- Published
- 2024
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28. Recessive Variants in PIGG Cause a Motor Neuropathy with Variable Conduction Block, Childhood Tremor, and Febrile Seizures: Expanding the Phenotype.
- Author
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Record CJ, O'Connor A, Verbeek NE, van Rheenen W, Zamba Papanicolaou E, Peric S, Ligthart PC, Skorupinska M, van Binsbergen E, Campeau PM, Ivanovic V, Hennigan B, McHugh JC, Blake JC, Murakami Y, Laura M, Murphy SM, and Reilly MM
- Abstract
Biallelic variants in phosphatidylinositol glycan anchor biosynthesis, class G (PIGG) cause hypotonia, intellectual disability, seizures, and cerebellar features. We present 8 patients from 6 families with a childhood-onset motor neuropathy and neurophysiology demonstrating variable motor conduction block and temporal dispersion. All individuals had a childhood onset tremor, 5 of 8 had cerebellar involvement, and 6 of 8 had childhood febrile seizures. All individuals have biallelic PIGG variants, including the previously reported pathogenic variant Trp505*, plus 6 novel variants. Null enzyme activity is demonstrated via PIGO/PIGG double knockout system for Val339Gly and Gly19Glu, and residual activity for Trp505* due to read-through. Emm negative blood group status was confirmed in 1 family. PIGG should be considered in unsolved motor neuropathy. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)
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- 2024
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29. Author Correction: A newly identified gene Ahed plays essential roles in murine haematopoiesis.
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Nakai R, Yokota T, Tokunaga M, Takaishi M, Yokomizo T, Sudo T, Shi H, Yasumizu Y, Okuzaki D, Kokubu C, Tanaka S, Takaoka K, Yamanishi A, Yoshida J, Watanabe H, Kondoh G, Horie K, Hosen N, Sano S, and Takeda J
- Published
- 2024
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30. High prevalence of ESBL-producing E. coli phylogroup B2 clinical isolates in northeastern Thailand.
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Chaisaeng S, Chopjitt P, Kasemsiri P, Putthanachote N, Boueroy P, Takeuchi D, Akeda Y, Hamada S, and Kerdsin A
- Subjects
- Thailand epidemiology, Humans, Prevalence, Tertiary Care Centers statistics & numerical data, Drug Resistance, Multiple, Bacterial genetics, beta-Lactamases genetics, Escherichia coli genetics, Escherichia coli isolation & purification, Escherichia coli drug effects, Escherichia coli classification, Escherichia coli enzymology, Phylogeny, Anti-Bacterial Agents pharmacology, Microbial Sensitivity Tests, Escherichia coli Infections microbiology, Escherichia coli Infections epidemiology
- Abstract
Background: Production of extended-spectrum β-lactamases (ESBLs) is a common resistance mechanism in Enterobacteriaceae, leading to serious hospital-acquired infections. This study aimed to assess phenotypic, phylogenetic, and antibiotic resistance patterns among ESBL-producing Escherichia coli isolates recovered from two rural tertiary hospitals in Thailand., Results: Among 467 Enterobacteriaceae isolates, E. coli was the most prevalent 356 (76.2%) followed by K. pneumoniae 88 (18.8%), K. aerogenes 8 (1.7%), K. variicola 3 (0.6%), K. quasipneumoniae 1 (0.2%%), K. oxytoca 1 (0.2%), and unidentified 9 (1.9%). Of the 202 cephalosporin-resistant E. coli isolates, 195 (96.5%) were ESBL-producing and 7 (3.5%) were non-ESBL-producing. Clermont typing revealed that phylogroup B2 was predominant (43.3%), followed by phylogroups F (11.3%), D (10.3%), C (9.7%), and A (8.7%). Among the beta-lactamase-encoding genes, bla
CTX-M (83.6%) and blaTEM (81.0%) were widely found among the isolates, and blaCTX-M-1 (60.7%) was the most common among the five blaCTX-M subgroups detected. The predominant ESBL was blaCTX-M-15 (58.3%). All isolates were resistant to cefotaxime (100%) and ampicillin (100%), followed by ciprofloxacin (91.3 %), ceftazidime (72.8 %), and tetracycline (64.1%)., Conclusion: Our findings show that phylogroup B2 was the most prevalent phylogroup among ESBL-producing E. coli isolates in northeastern Thailand. Notably, the isolates mostly carried the blaCTX-M gene(s)., (© 2024. The Author(s).)- Published
- 2024
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31. Development of Ribityllumazine Analogue as Mucosal-Associated Invariant T Cell Ligands.
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Takasaki R, Ito E, Nagae M, Takahashi Y, Matsuoka T, Yasue W, Arichi N, Ohno H, Yamasaki S, and Inuki S
- Abstract
Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells abundant in human tissues that play a significant role in defense against bacterial and viral infections and in tissue repair. MAIT cells are activated by recognizing microbial-derived small-molecule ligands presented by the MHC class I related-1 protein. Although several MAIT cell modulators have been identified in the past decade, potent and chemically stable ligands remain limited. Herein, we carried out a structure-activity relationship study of ribityllumazine derivatives and found a chemically stable MAIT cell ligand with a pteridine core and a 2-oxopropyl group as the Lys-reactive group. The ligand showed high potency in a cocultivation assay using model cell lines of antigen-presenting cells and MAIT cells. The X-ray crystallographic analysis revealed the binding mode of the ligand to MR1 and the T cell receptor, indicating that it forms a covalent bond with MR1 via Schiff base formation. Furthermore, we found that the ligand stimulated proliferation of human MAIT cells in human peripheral blood mononuclear cells and showed an adjuvant effect in mice. Our developed ligand is one of the most potent among chemically stable MAIT cell ligands, contributing to accelerating therapeutic applications of MAIT cells.
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- 2024
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32. Neoself-antigens are the primary target for autoreactive T cells in human lupus.
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Mori S, Kohyama M, Yasumizu Y, Tada A, Tanzawa K, Shishido T, Kishida K, Jin H, Nishide M, Kawada S, Motooka D, Okuzaki D, Naito R, Nakai W, Kanda T, Murata T, Terao C, Ohmura K, Arase N, Kurosaki T, Fujimoto M, Suenaga T, Kumanogoh A, Sakaguchi S, Ogawa Y, and Arase H
- Subjects
- Humans, Animals, Mice, CD4-Positive T-Lymphocytes immunology, Female, Antigens, Differentiation, B-Lymphocyte metabolism, Antigens, Differentiation, B-Lymphocyte immunology, Herpesvirus 4, Human immunology, Adult, T-Lymphocytes immunology, Mice, Inbred C57BL, Lupus Erythematosus, Systemic immunology, Autoantigens immunology, Histocompatibility Antigens Class II immunology, Histocompatibility Antigens Class II metabolism, Antigen Presentation
- Abstract
Major histocompatibility complex class II (MHC-II) is the most significant genetic risk factor for systemic lupus erythematosus (SLE), but the nature of the self-antigens that trigger autoimmunity remains unclear. Unusual self-antigens, termed neoself-antigens, are presented on MHC-II in the absence of the invariant chain essential for peptide presentation. Here, we demonstrate that neoself-antigens are the primary target for autoreactive T cells clonally expanded in SLE. When neoself-antigen presentation was induced by deleting the invariant chain in adult mice, neoself-reactive T cells were clonally expanded, leading to the development of lupus-like disease. Furthermore, we found that neoself-reactive CD4
+ T cells were significantly expanded in SLE patients. A high frequency of Epstein-Barr virus reactivation is a risk factor for SLE. Neoself-reactive lupus T cells were activated by Epstein-Barr-virus-reactivated cells through downregulation of the invariant chain. Together, our findings imply that neoself-antigen presentation by MHC-II plays a crucial role in the pathogenesis of SLE., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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33. A plasmid-mediated type III secretion system associated with invasiveness and diarrheagenicity of Providencia rustigianii .
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Hassan J, Hinenoya A, Hatanaka N, Awasthi SP, Manjunath GB, Rahman N, Yamate J, Nakamura S, Motooka D, Nagita A, Faruque SM, and Yamasaki S
- Subjects
- Humans, Animals, HeLa Cells, Rabbits, Diarrhea microbiology, Genome, Bacterial, Whole Genome Sequencing, Virulence Factors genetics, Virulence genetics, Conjugation, Genetic, Gene Transfer, Horizontal, Providencia genetics, Providencia metabolism, Providencia pathogenicity, Plasmids genetics, Type III Secretion Systems genetics, Type III Secretion Systems metabolism, Bacterial Toxins genetics, Bacterial Toxins metabolism, Enterobacteriaceae Infections microbiology
- Abstract
We have recently described a clinical isolate of Providencia rustigianii strain JH-1 carrying the genes for cytolethal distending toxin (CDT) in a conjugative plasmid. A cdtB mutant of strain JH-1, which lost CDT activity, was still found to retain invasiveness and diarrheagenicity. The strain was subjected to phenotypic and genetic analyses including whole genome sequencing (WGS) to explore the genetic determinants of the observed invasiveness and diarrheagenic properties. Analysis and annotation of WGS data revealed the presence of two distinct type III secretion systems (T3SS) in strain JH-1, one of which was located on the chromosome designated as cT3SS (3,992,833 bp) and the other on a mega-plasmid designated as pT3SS (168,819 bp). Comparative genomic analysis revealed that cT3SS is generally conserved in Providencia spp. but pT3SS was limited to a subset of Providencia spp., carrying cdt genes. Strain JH-1 was found to invade HeLa cells and induce fluid accumulation with characteristic pathological lesions in rabbit ileal loops. Remarkably, these phenomena were associated with the pT3SS but not cT3SS. The plasmid could be transferred by conjugation from strain JH-1 to other strains of P. rustigianii , Providencia rettgeri , and Escherichia coli with concomitant transfer of these virulence properties. This is the first report of a functional and mobile T3SS in P. rustigianii and its association with invasiveness and diarrheagenicity of this bacterium. These data suggest that P. rustigianii and other CDT-producing Providencia strains might carry T3SS and exert their diarrheagenic effect by exploiting the T3SS nano-machinery.IMPORTANCEThe precise mechanism of virulence of Providencia rustigianii is unclear, although some strains produce cytolethal distending toxin as a putative virulence factor. We have detected the presence of a type III secretion system (T3SS) for the first time on a plasmid in a P. rustigianii strain. Plasmid-mediated T3SS seems to be directly involved in virulence of P. rustigianii and may serve as a means of horizontal transfer of T3SS genes. Our results may have implication in understanding the mechanism of emergence of new pathogenic strains of P. rustigianii ., Competing Interests: The authors declare no conflict of interest.
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- 2024
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34. Polyploidy mitigates the impact of DNA damage while simultaneously bearing its burden.
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Hayashi K, Horisaka K, Harada Y, Ogawa Y, Yamashita T, Kitano T, Wakita M, Fukusumi T, Inohara H, Hara E, and Matsumoto T
- Abstract
Polyploidy is frequently enhanced under pathological conditions, such as tissue injury and cancer in humans. Polyploidization is critically involved in cancer evolution, including cancer initiation and the acquisition of drug resistance. However, the effect of polyploidy on cell fate remains unclear. In this study, we explored the effects of polyploidization on cellular responses to DNA damage and cell cycle progression. Through various comparisons based on ploidy stratifications of cultured cells, we found that polyploidization and the accumulation of genomic DNA damage mutually induce each other, resulting in polyploid cells consistently containing more genomic DNA damage than diploid cells under both physiological and stress conditions. Notably, despite substantial DNA damage, polyploid cells demonstrated a higher tolerance to its impact, exhibiting delayed cell cycle arrest and reduced secretion of inflammatory cytokines associated with DNA damage-induced senescence. Consistently, in mice with ploidy tracing, hepatocytes with high ploidy appeared to potentially persist in the damaged liver, while being susceptible to DNA damage. Polyploidy acts as a reservoir of genomic damage by mitigating the impact of DNA damage, while simultaneously enhancing its accumulation., (© 2024. The Author(s).)
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- 2024
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35. Recombinant RSV G protein vaccine induces enhanced respiratory disease via IL-13 and mucin overproduction.
- Author
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Kawahara E, Senpuku K, Kawaguchi Y, Yamamoto S, Yasuda K, Kuroda E, Ouji-Sageshima N, Ito T, Hirai T, Shibata T, and Yoshioka Y
- Abstract
The G protein expressed on the surface of respiratory syncytial virus (RSV) is important for adhesion to host cells and as a vaccine target antigen. The corresponding vaccines can effectively eliminate RSV. However, they exacerbate pulmonary immunopathology including eosinophilic infiltration in the lungs after an RSV challenge in animal models, raising concerns about enhanced respiratory disease (ERD); thus, approaches that mitigate these effects are urgently needed. Herein, we aimed to examine the mechanisms of G protein vaccine-induced ERD in mice, using recombinant G protein as a vaccine antigen. After the RSV challenge, G protein-vaccinated mice exhibited lung weight gain, lung tissue damage, and increased infiltration of eosinophils, neutrophils, and CD4
+ T cells into the lungs. We set lung weight gain as the endpoint for ERD and examined the impact of each infiltrating cell on lung weight gain. We observed that CD4+ T cells, but not eosinophils or neutrophils, that infiltrate the lungs are responsible for lung weight gain. In addition, T helper 2 cell-mediated IL-13 induced mucin hypersecretion and lung weight gain. Mucin hypersecretion may contribute to weight gain in the lungs. In conclusion, our results indicate a novel mechanism of G protein vaccine-induced ERD via IL-13 and mucin hypersecretion, which could lead to the development of safe G protein vaccines and the elucidation of the causes of ERD associated with other vaccines., (© 2024. The Author(s).)- Published
- 2024
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36. miR-147-3p in pathogenic CD4 T cells controls chemokine receptor expression for the development of experimental autoimmune diseases.
- Author
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Iijima N, Yamaguchi M, Hayashi T, Rui Y, Ohira Y, Miyamoto Y, Niino M, Okuno T, Suzuki O, Oka M, and Ishii KJ
- Abstract
Incomplete Freund's adjuvant (IFA) has long been used to trigger autoimmune diseases in animal models, such as experimental autoimmune encephalitis and collagen-induced arthritis. However, the molecular mechanisms that control CD4 T cell effector functions and lead to the development of autoimmune diseases are not well understood. A self-antigen and heat-killed Mycobacterium tuberculosis emulsified in IFA augmented the activation of CD4 T cells, leading to the differentiation of pathogenic CD4 T cells in the draining lymph nodes. In contrast, IFA emulsification did not elicit Foxp3
+ regulatory T cell expansion. We found that pathogenic Th1 cells expressed miR-147-3p, which targets multiple genes to affect T cell function. Finally, miR-147-3p expressed in CXCR6+ SLAMF6- Th1 cells was required for the onset of neurological symptoms through the control of CXCR3 expression. Our findings demonstrate that miR-147-3p expressed in pathogenic CD4 T cells regulates the migratory potential in peripheral tissues and impacts the development of autoimmune diseases., Competing Interests: Declaration of competing interest The authors declare no competing financial interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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37. A conserved fertilization complex bridges sperm and egg in vertebrates.
- Author
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Deneke VE, Blaha A, Lu Y, Suwita JP, Draper JM, Phan CS, Panser K, Schleiffer A, Jacob L, Humer T, Stejskal K, Krssakova G, Roitinger E, Handler D, Kamoshita M, Vance TDR, Wang X, Surm JM, Moran Y, Lee JE, Ikawa M, and Pauli A
- Abstract
Fertilization, the basis for sexual reproduction, culminates in the binding and fusion of sperm and egg. Although several proteins are known to be crucial for this process in vertebrates, the molecular mechanisms remain poorly understood. Using an AlphaFold-Multimer screen, we identified the protein Tmem81 as part of a conserved trimeric sperm complex with the essential fertilization factors Izumo1 and Spaca6. We demonstrate that Tmem81 is essential for male fertility in zebrafish and mice. In line with trimer formation, we show that Izumo1, Spaca6, and Tmem81 interact in zebrafish sperm and that the human orthologs interact in vitro. Notably, complex formation creates the binding site for the egg fertilization factor Bouncer in zebrafish. Together, our work presents a comprehensive model for fertilization across vertebrates, where a conserved sperm complex binds to divergent egg proteins-Bouncer in fish and JUNO in mammals-to mediate sperm-egg interaction., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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38. Cases of endophthalmitis caused by Candida albicans and Candida dubliniensis identified via internal transcribed spacer deep sequencing.
- Author
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Asao K, Hashida N, Maruyama K, Motooka D, Nakamura S, and Nishida K
- Subjects
- Humans, Middle Aged, Female, Male, DNA, Fungal genetics, Vitrectomy, Antifungal Agents therapeutic use, Vitreous Body microbiology, Endophthalmitis microbiology, Endophthalmitis diagnosis, Eye Infections, Fungal microbiology, Eye Infections, Fungal diagnosis, Candidiasis microbiology, Candidiasis diagnosis, Candidiasis drug therapy, High-Throughput Nucleotide Sequencing, Candida albicans isolation & purification, Candida albicans genetics, Candida genetics, Candida isolation & purification
- Abstract
Background: We report two cases of fungal endophthalmitis induced by Candida species identified based on internal transcribed spacer 1 (ITS1) sequencing., Case Presentation: In two cases, endophthalmitis was suspected, and the patients underwent pars plana vitrectomy. Case 1 was a 64-year-old woman with a history of cataract surgery 10 days prior. She had a history of anal primary melanoma, which metastasized throughout the body and subsequently relapsed. Vitreous culture and ITS-1 deep sequencing revealed the presence of the rare fungus, Candida dubliniensis. Case 2 was a 54-year-old man with a history of liver cancer and kidney failure. Culture methods and ITS1 deep sequencing both revealed the presence of Candida albicans. Both patients exhibited good visual prognoses after treatment with topical and systemic antibiotics., Conclusions: We present two cases of fungal endophthalmitis caused by two Candida species identified by both the culture method and ITS1 deep sequencing. The fungal pathogen was identified by ITS deep sequencing three days after sample submission; the culture method yielded results after 1 week. These findings support the applicability of ITS1 sequencing for timely pathogen identification for cases of fungal endophthalmitis and provide detailed taxonomic information at the species level., (© 2024. The Author(s).)
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- 2024
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39. Variability of macrolide-resistant profile in Mycobacterium avium complex pulmonary disease.
- Author
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Fukushima K, Matsumoto Y, Abe Y, Hashimoto K, Motooka D, Kitada S, Saito H, Komukai S, Fukui E, Niitsu T, Nabeshima H, Nagahama Y, Yamauchi J, Nitta T, Nii T, Matsuki T, Tsujino K, Miki K, Shintani Y, Kumanogoh A, Akira S, Nakamura S, and Kida H
- Abstract
This single-center retrospective study aimed to analyze the variability of macrolide resistance (MR) in 68 patients with Mycobacterium avium complex pulmonary disease. Among 25 patients treated without macrolides, 13 (52%) reverted to macrolide-susceptible (MS) profiles. Only one (2%) of 43 patients who continued macrolide treatment showed this change. We compared 30 MR isolates with recent specimens. Among them, seven shifted to MS (five attributed to clonally related strains; two resulting from reinfection or polyclonal infection).
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- 2024
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40. Synthesis of Low-Molecular-Weight Fucoidan Analogue and Its Inhibitory Activities against Heparanase and SARS-CoV-2 Infection.
- Author
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Sugimoto A, Koike T, Kuboki Y, Komaba S, Kosono S, Aswathy M, Anzai I, Watanabe T, Toshima K, and Takahashi D
- Abstract
Heparan sulfate (HS) is ubiquitous on cell surfaces and is used as a receptor by many viruses including SARS-CoV-2. However, increased activity of the inflammatory enzyme heparanase (HPSE), which hydrolyses HS, in patients with COVID-19 not only increases the severity of symptoms but also may facilitate the spread of the virus by degrading HS on the cell surface. Therefore, synthetic HPSE blockades, which can bind to SARS-CoV-2 spike protein (SARS-CoV-2-S) and inhibit viral entry, have attracted much attention. This study investigated the development of a new dual-targeting antiviral agent against HPSE and SARS-CoV-2-S using fucoidan as a structural motif. It was found that all-sulfated fucoidan derivative 10, which exhibited the highest binding affinity to SARS-CoV-2-S among 13 derivatives, also showed the highest inhibitory activity against HPSE. Based on this, a newly designed and synthesized fucoidan analogue 16, in which the octyl group of 10 was changed to a cholestanyl group, was found to show higher activity than 10 but did not inhibit factor Xa associated with undesired anticoagulant effects. The binding affinity of 16 to SARS-CoV-2-S was significantly increased approximately 400-fold over that of 10. Furthermore, 16 effectively inhibited infection by the SARS-CoV-2 Wuhan strain and two Omicron subvariants., (© 2024 Wiley‐VCH GmbH.)
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- 2024
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41. Pravastatin prevents colitis-associated carcinogenesis by reducing CX3CR1 high M2-like fibrocyte counts in the inflamed colon.
- Author
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Hachiya K, Masuya M, Kuroda N, Yoneda M, Nishimura K, Shiotani T, Tawara I, and Katayama N
- Subjects
- Animals, Mice, Macrophages metabolism, Macrophages drug effects, Colon pathology, Colon drug effects, Colon metabolism, Mice, Inbred C57BL, Colitis-Associated Neoplasms pathology, Colitis-Associated Neoplasms prevention & control, Colitis-Associated Neoplasms metabolism, Colitis-Associated Neoplasms drug therapy, Carcinogenesis drug effects, Carcinogenesis pathology, Disease Models, Animal, Dextran Sulfate, Male, Humans, CX3C Chemokine Receptor 1 metabolism, CX3C Chemokine Receptor 1 genetics, Colitis complications, Colitis metabolism, Colitis pathology, Colitis drug therapy, Pravastatin pharmacology, Pravastatin therapeutic use
- Abstract
Colorectal cancer (CRC) resulting from chronic inflammation is a crucial issue in patients with inflammatory bowel disease (IBD). Although many reports established that intestinal resident CX3CR1
high macrophages play an essential role in suppressing intestinal inflammation, their function in colitis-related CRC remains unclear. In this study, we found that colonic CX3CR1high macrophages, which were positive for MHC-II, F4/80 and CD319, promoted colitis-associated CRC. They highly expressed Col1a1, Tgfb, II10, and II4, and were considered to be fibrocytes with an immunosuppressive M2-like phenotype. CX3CR1 deficiency led to reductions in the absolute numbers of CX3CR1high fibrocytes through increased apoptosis, thereby preventing the development of colitis-associated CRC. We next focused statins as drugs targeting CX3CR1high fibrocytes. Statins have been actively discussed for patients with IBD and reported to suppress the CX3CL1/CX3CR1 axis. Statin treatment after azoxymethane/dextran sulfate sodium-induced inflammation reduced CX3CR1high fibrocyte counts and suppressed colitis-associated CRC. Therefore, CX3CR1high fibrocytes represent a potential target for carcinogenesis-preventing therapy, and statins could be safe therapeutic candidates for IBD., (© 2024. The Author(s).)- Published
- 2024
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42. Regulation of human GnT-IV family activity by the lectin domain.
- Author
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Osada N, Nagae M, Yamasaki T, Harduin-Lepers A, and Kizuka Y
- Abstract
N-Glycan branching critically regulates glycoprotein functions and is involved in various diseases. Among the glycosyltransferases involved in N-glycan branching is the human N-acetylglucosaminyltransferase-IV (GnT-IV) family, which has four members: GnT-IVa, GnT-IVb, GnT-IVc, and GnT-IVd. GnT-IVa and GnT-IVb have glycosyltransferase activity that generates the type-2 diabetes-related β1,4-GlcNAc branch on the α1,3-Man arm of N-glycans, whereas GnT-IVc and GnT-IVd do not. Recently, this enzyme family was found to have a unique lectin domain in the C-terminal region, which is essential for enzyme activity toward glycoprotein substrates but not toward free N-glycans. Furthermore, interaction between the lectin domain of GnT-IV and N-glycan attached to GnT-IV enables self-regulation of GnT-IV activity, indicating that the lectin domain plays a unique and pivotal role in the regulation of GnT-IV activity. In this review, we summarize the GnT-IV family's biological functions, selectivity for glycoprotein substrates, and regulation of enzymatic activity, with a focus on its unique C-terminal lectin domain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
- Published
- 2024
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43. Efficient lipidomic approach for the discovery of lipid ligands for immune receptors by combining LC-HRMS/MS analysis with fractionation and reporter cell assay.
- Author
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Tomiyasu N, Takahashi M, Toyonaga K, Yamasaki S, Bamba T, and Izumi Y
- Subjects
- Ligands, Humans, Animals, Mice, Chromatography, Liquid methods, Receptors, Immunologic metabolism, Lectins, C-Type metabolism, Tandem Mass Spectrometry methods, Lipids analysis, Lipids chemistry, Lipidomics methods
- Abstract
C-type lectin receptors (CLRs), which are pattern recognition receptors responsible for triggering innate immune responses, recognize damaged self-components and immunostimulatory lipids from pathogenic bacteria; however, several of their ligands remain unknown. Here, we propose a new analytical platform combining liquid chromatography-high-resolution tandem mass spectrometry with microfractionation capability (LC-FRC-HRMS/MS) and a reporter cell assay for sensitive activity measurements to develop an efficient methodology for searching for lipid ligands of CLR from microbial trace samples (crude cell extracts of approximately 5 mg dry cell/mL). We also developed an in-house lipidomic library containing accurate mass and fragmentation patterns of more than 10,000 lipid molecules predicted in silico for 90 lipid subclasses and 35 acyl side chain fatty acids. Using the developed LC-FRC-HRMS/MS system, the lipid extracts of Helicobacter pylori were separated and fractionated, and HRMS and HRMS/MS spectra were obtained simultaneously. The fractionated lipid extract samples in 96-well plates were thereafter subjected to reporter cell assays using nuclear factor of activated T cells (NFAT)-green fluorescent protein (GFP) reporter cells expressing mouse or human macrophage-inducible C-type lectin (Mincle). A total of 102 lipid molecules from all fractions were annotated using an in-house lipidomic library. Furthermore, a fraction that exhibited significant activity in the NFAT-GFP reporter cell assay contained α-cholesteryl glucoside, a type of glycolipid, which was successfully identified as a lipid ligand molecule for Mincle. Our analytical platform has the potential to be a useful tool for efficient discovery of lipid ligands for immunoreceptors., (© 2023. The Author(s).)
- Published
- 2024
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44. Kdm4d mutant mice show impaired sperm motility and subfertility.
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Xu Z, Fujimoto Y, Sakamoto M, Ito D, Ikawa M, and Ishiuchi T
- Subjects
- Animals, Male, Mice, Histones metabolism, Mice, Knockout, Mutation, Spermatids metabolism, Spermatogenesis genetics, Spermatozoa metabolism, Testis metabolism, Infertility, Male genetics, Infertility, Male metabolism, Jumonji Domain-Containing Histone Demethylases metabolism, Jumonji Domain-Containing Histone Demethylases genetics, Sperm Motility
- Abstract
Regulation of gene expression through histone modifications underlies cell homeostasis and differentiation. Kdm4d and Kdm4dl exhibit a high degree of similarity and demethylate H3K9me3. However, the physiological functions of these proteins remain unclear. In this study, we generated Kdm4dl mutant mice and found that Kdm4dl was dispensable for mouse development. However, through the generation of Kdm4d mutant mice, we unexpectedly found that Kdm4d mutant male mice were subfertile because of impaired sperm motility. The absence of Kdm4d was associated with an altered distribution of H3K9me3 in round spermatids, suggesting that the Kdm4d-mediated adjustment of H3K9me3 levels is required to generate motile sperm. Further analysis revealed that the absence of Kdm4d did not affect the functionality of sperm nuclei in generating offspring. As KDM4D is specifically expressed in the human testes, our results suggest that changes in KDM4D expression or its activity may be a risk factor for human infertility.
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- 2024
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45. Rhesus rotavirus NSP1 mediates extra-intestinal infection and is a contributing factor for biliary obstruction.
- Author
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Li E, Feng N, Zeng Q, Sanchez-Tacuba L, Kawagishi T, Branham G, Hou G, Wang Z, Greenberg HB, and Ding S
- Subjects
- Animals, Mice, Biliary Atresia virology, Biliary Atresia genetics, Macaca mulatta, Virus Replication, Humans, Viral Nonstructural Proteins genetics, Viral Nonstructural Proteins metabolism, Rotavirus Infections virology, Rotavirus pathogenicity
- Abstract
We previously demonstrated that in Ifnar1-/-Ifngr1-/- or Stat1-/- suckling mice lacking intact type I and type II interferon (IFN) signaling, rhesus rotavirus (RRV) infection causes a lethal disease with clinical manifestations similar to biliary atresia, including acholic stools, oily fur, growth retardation, and excess mortality. Elevated levels of viral RNA are detected in the bile ducts and liver of diseased pups together with severe inflammatory responses in these tissues. However, the viral determinants and the molecular mechanisms driving this process remain incompletely understood. Using an optimized rotavirus (RV) reverse genetics system, we generated a panel of recombinant RVs that encode non-structural protein 1 (NSP1) derived from different RV strains. We found that compared to the parental simian SA11 strain that is less biliary pathogenic, SA11 containing an RRV-derived NSP1 resulted in severe biliary obstructive disease comparable to that associated with RRV infection, reflected by high levels of viral RNA and inflammation in the biliary tract, liver, and pancreas. In contrast, RRV containing an SA11-originated NSP1 showed only mild biliary obstruction comparable to what was observed during SA11 infection. Infection with a monoreassortant RRV virus carrying NSP1 from the bovine RV UK strain also showed substantially reduced viral replication in extra-intestinal organs and did not develop clinical biliary diseases. Mechanistically, RRV NSP1 seemed to promote active viral replication in hepatocytes and this expanded tropism led to enhanced infiltration of CD4 and CD8 T cells, causing immunopathology and damage in the hepatobiliary system. These results highlight an unexpectedly important role of RV NSP1 in viral replication and disease progression in extra-intestinal tissues., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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46. Towards a thorough understanding of mammalian glycosylphosphatidylinositol-anchored protein biosynthesis.
- Author
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Kinoshita T
- Subjects
- Humans, Animals, Protein Biosynthesis, Glycosylphosphatidylinositols metabolism, Glycosylphosphatidylinositols biosynthesis, Glycosylphosphatidylinositols chemistry
- Abstract
Glycosylphosphatidylinositols (GPIs) are glycolipids found ubiquitously in eukaryotes. They consist of a glycan and an inositol phospholipid, and act as membrane anchors of many cell-surface proteins by covalently linking to their C-termini. GPIs also exist as unlinked, free glycolipids on the cell surface. In human cells, at least 160 proteins with various functions are GPI-anchored proteins. Because the attachment of GPI is required for the cell-surface expression of GPI-anchored proteins, a thorough knowledge of the molecular basis of mammalian GPI-anchored protein biosynthesis is important for understanding the basic biochemistry and biology of GPI-anchored proteins and their medical significance. In this paper, I review our previous knowledge of the biosynthesis of mammalian GPI-anchored proteins and then examine new findings made since 2020., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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47. Intrahepatic Exhausted Antiviral Immunity in an Immunocompetent Mouse Model of Chronic Hepatitis B.
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Shigeno S, Kodama T, Murai K, Motooka D, Fukushima A, Nishio A, Hikita H, Tatsumi T, Okamoto T, Kanto T, and Takehara T
- Abstract
Background & Aims: Targeting exhausted immune systems would be a promising therapeutic strategy to achieve a functional cure for HBV infection in patients with chronic hepatitis B (CHB). However, animal models recapitulating the immunokinetics of CHB are very limited. We aimed to develop an immunocompetent mouse model of CHB for intrahepatic immune profiling., Methods: CHB mice were created by intrahepatic delivery of the Sleeping Beauty transposon vector tandemly expressing the hepatitis B virus (HBV) genome and fumarylacetoacetate hydrolase (FAH) cDNA into C57BL/6J congenic FAH knockout mice via hydrodynamic tail vein injection. We profiled the viral and intrahepatic immune kinetics in CHB mice with or without treatment with recombinant IFNα or the hepatotropic Toll-like receptor 7 agonist SA-5 using single-cell RNA-seq., Results: CHB mice exhibited sustained HBV viremia and persistent hepatitis. They showed intrahepatic expansion of exhausted CD8+ T (Tex) cells, the frequency of which was positively associated with viral load. Recruited macrophages increased in number but impaired inflammatory responses in the liver. The cytotoxicity of mature natural killer (NK) cells also increased in CHB mice. IFNα and SA-5 treatment both resulted in viral suppression with mild hepatic flares in CHB mice. Although both treatments activated NK cells, SA-5 had the capacity to revitalize the impaired function of Tex cells and liver-recruited macrophages., Conclusion: Our novel CHB mouse model recapitulated the intrahepatic exhausted antiviral immunity in patients with CHB, which might be able to be reinvigorated by a hepatotropic TLR7 agonist., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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48. Full-length nanopore sequencing of circular RNA landscape in peripheral blood cells following sequential BNT162b2 mRNA vaccination.
- Author
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Liu YC, Ishikawa M, Sakakibara S, Kadi MA, Motooka D, Naito Y, Ito S, Imamura Y, Matsumoto H, Sugihara F, Hirata H, Ogura H, and Okuzaki D
- Abstract
Circular RNAs (circRNA) lack 5' or 3' ends; their unique covalently closed structures prevent RNA degradation by exonucleases. These characteristics provide circRNAs with high pharmaceutical stability and biostability relative to current standard-of-care linear mRNAs. CircRNA levels are reportedly associated with certain human diseases, making them novel disease biomarkers and a noncanonical class of therapeutic targets. In this study, the endogenous circRNAs underlying the response to BNT162b2 mRNA vaccination were evaluated. To this end, peripheral blood samples were subjected to full-length sequencing of circRNAs via nanopore sequencing and transcriptome sequencing. Fifteen samples, comprising pre-, first, and second vaccination cohorts, were obtained from five healthcare workers with no history of SARS-CoV-2 infection or previous vaccination. A total of 4706 circRNAs were detected; following full-length sequencing, 4217 novel circRNAs were identified as being specifically expressed during vaccination. These circRNAs were enriched in the binding motifs of stress granule assemblies and SARS-CoV-2 RNA binding proteins, namely poly(A) binding protein cytoplasmic 1 (PABPC1), pumilio RNA binding family member 1 (PUM1), and Y box binding protein 1 (YBX1). Moreover, 489 circRNAs were identified as previously reported miRNA sponges. The differentially expressed circRNAs putatively originated from plasma B cells compared to circRNAs reported in human blood single-cell RNA sequencing datasets. The pre- and post-vaccination differences observed in the circRNA expression landscape in response to the SARS-CoV-2 BNT162b2 mRNA vaccine., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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49. USF2 and TFEB compete in regulating lysosomal and autophagy genes.
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Kim J, Yu YS, Choi Y, Lee DH, Han S, Kwon J, Noda T, Ikawa M, Kim D, Kim H, Ballabio A, Kim KI, and Baek SH
- Subjects
- Humans, Phosphorylation, Histone Deacetylase 1 metabolism, Histone Deacetylase 1 genetics, Glycogen Synthase Kinase 3 beta metabolism, Glycogen Synthase Kinase 3 beta genetics, Gene Expression Regulation, Promoter Regions, Genetic, HEK293 Cells, Animals, Histones metabolism, HeLa Cells, Mice, Acetylation, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors metabolism, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors genetics, Lysosomes metabolism, Autophagy genetics, Upstream Stimulatory Factors metabolism, Upstream Stimulatory Factors genetics
- Abstract
Autophagy, a highly conserved self-digestion process crucial for cellular homeostasis, is triggered by various environmental signals, including nutrient scarcity. The regulation of lysosomal and autophagy-related processes is pivotal to maintaining cellular homeostasis and basal metabolism. The consequences of disrupting or diminishing lysosomal and autophagy systems have been investigated; however, information on the implications of hyperactivating lysosomal and autophagy genes on homeostasis is limited. Here, we present a mechanism of transcriptional repression involving upstream stimulatory factor 2 (USF2), which inhibits lysosomal and autophagy genes under nutrient-rich conditions. We find that USF2, together with HDAC1, binds to the CLEAR motif within lysosomal genes, thereby diminishing histone H3K27 acetylation, restricting chromatin accessibility, and downregulating lysosomal gene expression. Under starvation, USF2 competes with transcription factor EB (TFEB), a master transcriptional activator of lysosomal and autophagy genes, to bind to target gene promoters in a phosphorylation-dependent manner. The GSK3β-mediated phosphorylation of the USF2 S155 site governs USF2 DNA-binding activity, which is involved in lysosomal gene repression. These findings have potential applications in the treatment of protein aggregation-associated diseases, including α1-antitrypsin deficiency. Notably, USF2 repression is a promising therapeutic strategy for lysosomal and autophagy-related diseases., (© 2024. The Author(s).)
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- 2024
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50. HCV infection activates the proteasome via PA28γ acetylation and heptamerization to facilitate the degradation of RNF2, a catalytic component of polycomb repressive complex 1.
- Author
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Kasai H, Yamashita A, Akaike Y, Tanaka T, Matsuura Y, and Moriishi K
- Abstract
We previously reported that hepatitis C virus (HCV) infection or HCV core protein expression induces HOX gene expression by impairing histone H2A monoubiquitination via a proteasome-dependent reduction in the level of RNF2, a key catalytic component of polycomb repressive complex 1 (H. Kasai, K. Mochizuki, T. Tanaka, A. Yamashita, et al., J Virol 95:e01784-20, 2021, https://doi.org/10.1128/jvi.01784-20). In this study, we aimed to investigate the mechanism by which HCV infection accelerates RNF2 degradation. Yeast two-hybrid screening and an immunoprecipitation assay revealed that RNF2 is a PA28γ-binding protein. The proteasome activator PA28γ destabilized the RNF2 protein in a proteasome-dependent manner, since RNF2 degradation was impaired by PA28γ knockout or MG132 treatment. HCV infection or core protein expression reduced the levels of RNF2 and histone H2A K119 monoubiquitination and induced the expression of HOX genes in the presence of PA28γ, while PA28γ knockout reversed these changes. Treatment with a lysine acetyltransferase inhibitor inhibited the acetylation of PA28γ at K195 and the degradation of the RNF2 protein, while treatment with a lysine deacetylase inhibitor accelerated these events in a PA28γ-dependent manner. RNF2 protein degradation was increased by expression of the acetylation mimetic PA28γ mutant but not by expression of the acetylation-defective mutant or the proteasome activation-defective mutant. Furthermore, HCV infection or core protein expression facilitated the interaction between PA28γ and the lysine acetyltransferase CBP/p300 and then accelerated PA28γ acetylation and heptazmerization to promote RNF2 degradation. These data suggest that HCV infection accelerates the acetylation-dependent heptamerization of PA28γ to increase the proteasomal targeting of RNF2.IMPORTANCEHCV is a causative agent of HCV-related liver diseases, including hepatic steatosis, cirrhosis, and hepatocellular carcinoma. PA28γ, which, in heptameric form, activates the 20S core proteasome for the degradation of PA28γ-binding proteins, is responsible for HCV-related liver diseases. HCV core protein expression or HCV infection accelerates RNF2 degradation, leading to the induction of HOX gene expression via a decrease in the level of H2Aub on HOX gene promoters. However, the mechanism of RNF2 degradation in HCV-infected cells has not been clarified. The data presented in this study suggest that PA28γ acetylation and heptamerization are promoted by HCV infection or by core protein expression to activate the proteasome for the degradation of RNF2 and are responsible for HCV propagation. This study provides novel insights valuable for the development of therapies targeting both HCV propagation and HCV-related diseases.
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- 2024
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