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  1. Article ; Online: Deep Mutational Scanning to Predict Escape from Bebtelovimab in SARS-CoV-2 Omicron Subvariants

    Mellissa C. Alcantara / Yusuke Higuchi / Yuhei Kirita / Satoaki Matoba / Atsushi Hoshino

    Vaccines, Vol 11, Iss 711, p

    2023  Volume 711

    Abstract: The major concern with COVID-19 therapeutic monoclonal antibodies is the loss of efficacy against continuously emerging variants of SARS-CoV-2. To predict antibody efficacy against future Omicron subvariants, we conducted deep mutational scanning (DMS) ... ...

    Abstract The major concern with COVID-19 therapeutic monoclonal antibodies is the loss of efficacy against continuously emerging variants of SARS-CoV-2. To predict antibody efficacy against future Omicron subvariants, we conducted deep mutational scanning (DMS) encompassing all single mutations of the receptor-binding domain of the BA.2 strain utilizing an inverted infection assay with an ACE2-harboring virus and library spike-expressing cells. In the case of bebtelovimab, which preserves neutralization activity against BA.2 and BA.5, a broad range of amino acid substitutions at K444, V445, and G446, and some substitutions at P499 and T500, were indicated to achieve the antibody escape. Among subvariants with current rises in case numbers, BA2.75 with G446S partially evaded neutralization by bebtelovimab, while complete evasion was observed in XBB with V445P and BQ.1 with K444T. This is consistent with the DMS results against BA.2, highlighting the potential of DMS as a predictive tool for antibody escape.
    Keywords deep mutational scanning ; escape mutation ; bebtelovimab ; BA.2 ; Medicine ; R
    Language English
    Publishing date 2023-03-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Liver lipophagy ameliorates nonalcoholic steatohepatitis through extracellular lipid secretion

    Yoshito Minami / Atsushi Hoshino / Yusuke Higuchi / Masahide Hamaguchi / Yusaku Kaneko / Yuhei Kirita / Shunta Taminishi / Toshiyuki Nishiji / Akiyuki Taruno / Michiaki Fukui / Zoltan Arany / Satoaki Matoba

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 15

    Abstract: Abstract Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Therapeutic efforts at lipid reduction via increasing cytoplasmic lipolysis unfortunately ... ...

    Abstract Abstract Nonalcoholic steatohepatitis (NASH) is a progressive disorder with aberrant lipid accumulation and subsequent inflammatory and profibrotic response. Therapeutic efforts at lipid reduction via increasing cytoplasmic lipolysis unfortunately worsens hepatitis due to toxicity of liberated fatty acid. An alternative approach could be lipid reduction through autophagic disposal, i.e., lipophagy. We engineered a synthetic adaptor protein to induce lipophagy, combining a lipid droplet-targeting signal with optimized LC3-interacting domain. Activating hepatocyte lipophagy in vivo strongly mitigated both steatosis and hepatitis in a diet-induced mouse NASH model. Mechanistically, activated lipophagy promoted the excretion of lipid from hepatocytes, thereby suppressing harmful intracellular accumulation of nonesterified fatty acid. A high-content compound screen identified alpelisib and digoxin, clinically-approved compounds, as effective activators of lipophagy. Administration of alpelisib or digoxin in vivo strongly inhibited the transition to steatohepatitis. These data thus identify lipophagy as a promising therapeutic approach to prevent NASH progression.
    Keywords Science ; Q
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Activating transcription factor 3 (ATF3) as a perspective biomarker of Crohn’s disease

    Nobuyuki Kobayashi / Seiji Arihiro / Kazuya Shimada / Atsushi Hoshino / Hiroki Saijo / Naomi Oka / Masayuki Saruta / Kazuhiro Kondo

    European Journal of Inflammation, Vol

    2020  Volume 18

    Abstract: Introduction: Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract. Known types are Crohn’s disease (CD) and ulcerative colitis (UC), but their cause remains unclear and there is no convenient biomarker for ... ...

    Abstract Introduction: Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestinal tract. Known types are Crohn’s disease (CD) and ulcerative colitis (UC), but their cause remains unclear and there is no convenient biomarker for IBD. The present study aimed to demonstrate an association between the onset of CD and activating transcription factor 3 (ATF3); as a new biomarker, measurement of blood ATF3 mRNA would be useful for distinguishing between CD and UC. Methods: First, in a mouse model of IBD in which damage to the intestinal mucosa was chemically induced with dextran sulfate sodium (DSS), intestinal ATF3 mRNA was evaluated. Next, in human subjects, CD and UC patients, blood ATF3 mRNA and intestinal ATF3 protein production were evaluated. Results: In the mouse model of IBD, intestinal ATF3 mRNA was elevated compared with the control ( P < 0.0001). In CD patients, blood ATF3 mRNA was elevated as compared with normal controls (NCs) and UC patients ( P < 0.05). In addition, we observed an increase in ATF3 production in the intestinal tract specific to CD. Conclusion: ATF3 is involved in the onset of CD, and blood ATF3 mRNA measurements would be useful for distinguishing it from UC.
    Keywords Medicine ; R
    Subject code 610
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher SAGE Publishing
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Therapeutic efficacy of an elemental diet for patients with crohn's disease and its association with amino acid metabolism

    Masakazu Nakano / Keiichi Tominaga / Atsushi Hoshino / Takeshi Sugaya / Kazunari Kanke / Hideyuki Hiraishi

    Saudi Journal of Gastroenterology, Vol 23, Iss 1, Pp 20-

    2017  Volume 27

    Abstract: Background/Aim: We investigated the association between blood amino acid concentration changes caused by elemental diet (ED) and their relationship to its therapeutic effect. Patients and Methods: Patients with active Crohn's disease (CD) followed ED for ...

    Abstract Background/Aim: We investigated the association between blood amino acid concentration changes caused by elemental diet (ED) and their relationship to its therapeutic effect. Patients and Methods: Patients with active Crohn's disease (CD) followed ED for 12 weeks. Patients not previously treated with ED were defined as new ED, and those with previous ED therapy (≥900 kcal/day) were defined as previous ED. Disease activity markers [Crohn's disease activity index (CDAI) and C-reactive protein (CRP) level], blood biochemistry test results, and plasma amino acid concentrations were measured before and after the treatment. Results: Histidine (His), tryptophan (Trp), valine (Val), and methionine (Met) increased after the treatment in the 17 patients with clinical remission, however, no increase occurred in plasma amino acid concentrations in the 8 patients without remission. The multivariate index using AminoIndex™technology (MIAI) was correlated with the CDAI (r = 0.475,P < 0.001), and it decreased as patients' conditions improved during the treatment. All patients in the new ED group (n = 11) exhibited increases in the nutritional indices, albumin level, and body mass index after treatment, as well as increased levels of His, Trp, Val, and phenylalanine. None of these changes were observed in the previous ED group (n = 14). Conclusions: Plasma amino acid concentrations and MIAI may provide useful noninvasive markers for evaluating disease activity and response to treatment. ED was effective in improving disease activity, nutritional status, and plasma amino acid levels, and thus it may be particularly effective for poorly nourished patients with CD who have not previously undergone this treatment.
    Keywords Crohn's disease ; elemental diet ; multivariate index using AminoIndex™ technology ; histidine ; tryptophan ; Diseases of the digestive system. Gastroenterology ; RC799-869 ; Specialties of internal medicine ; RC581-951 ; Internal medicine ; RC31-1245 ; Medicine ; R
    Subject code 610
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Medknow Publications
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Structural delineation and computational design of SARS-CoV-2-neutralizing antibodies against Omicron subvariants

    Saya Moriyama / Yuki Anraku / Shunta Taminishi / Yu Adachi / Daisuke Kuroda / Shunsuke Kita / Yusuke Higuchi / Yuhei Kirita / Ryutaro Kotaki / Keisuke Tonouchi / Kohei Yumoto / Tateki Suzuki / Taiyou Someya / Hideo Fukuhara / Yudai Kuroda / Tsukasa Yamamoto / Taishi Onodera / Shuetsu Fukushi / Ken Maeda /
    Fukumi Nakamura-Uchiyama / Takao Hashiguchi / Atsushi Hoshino / Katsumi Maenaka / Yoshimasa Takahashi

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 17

    Abstract: Abstract SARS-CoV-2 Omicron subvariants have evolved to evade receptor-binding site (RBS) antibodies that exist in diverse individuals as public antibody clones. We rationally selected RBS antibodies resilient to mutations in emerging Omicron subvariants. ...

    Abstract Abstract SARS-CoV-2 Omicron subvariants have evolved to evade receptor-binding site (RBS) antibodies that exist in diverse individuals as public antibody clones. We rationally selected RBS antibodies resilient to mutations in emerging Omicron subvariants. Y489 was identified as a site of virus vulnerability and a common footprint of broadly neutralizing antibodies against the subvariants. Multiple Y489-binding antibodies were encoded by public clonotypes and additionally recognized F486, potentially accounting for the emergence of Omicron subvariants harboring the F486V mutation. However, a subclass of antibodies broadly neutralized BA.4/BA.5 variants via hydrophobic binding sites of rare clonotypes along with high mutation-resilience under escape mutation screening. A computationally designed antibody based on one of the Y489-binding antibodies, NIV-10/FD03, was able to bind XBB with any 486 mutation and neutralized XBB.1.5. The structural basis for the mutation-resilience of this Y489-binding antibody group may provide important insights into the design of therapeutics resistant to viral escape.
    Keywords Science ; Q
    Language English
    Publishing date 2023-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Engineered ACE2 receptor therapy overcomes mutational escape of SARS-CoV-2

    Yusuke Higuchi / Tatsuya Suzuki / Takao Arimori / Nariko Ikemura / Emiko Mihara / Yuhei Kirita / Eriko Ohgitani / Osam Mazda / Daisuke Motooka / Shota Nakamura / Yusuke Sakai / Yumi Itoh / Fuminori Sugihara / Yoshiharu Matsuura / Satoaki Matoba / Toru Okamoto / Junichi Takagi / Atsushi Hoshino

    Nature Communications, Vol 12, Iss 1, Pp 1-

    2021  Volume 13

    Abstract: Hoshino et al., engineer a human virus receptor, hACE2, and demonstrate its potential for overcoming SARS-CoV-2 mutations that otherwise hinder therapeutic interventions. Overall, the data provide insights in to the therapeutic potential of engineered ... ...

    Abstract Hoshino et al., engineer a human virus receptor, hACE2, and demonstrate its potential for overcoming SARS-CoV-2 mutations that otherwise hinder therapeutic interventions. Overall, the data provide insights in to the therapeutic potential of engineered receptors.
    Keywords Science ; Q
    Language English
    Publishing date 2021-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: A conserved strategy of chalcone isomerase-like protein to rectify promiscuous chalcone synthase specificity

    Toshiyuki Waki / Ryo Mameda / Takuya Nakano / Sayumi Yamada / Miho Terashita / Keisuke Ito / Natsuki Tenma / Yanbing Li / Naoto Fujino / Kaichi Uno / Satoshi Yamashita / Yuichi Aoki / Konstantin Denessiouk / Yosuke Kawai / Satoko Sugawara / Kazuki Saito / Keiko Yonekura-Sakakibara / Yasumasa Morita / Atsushi Hoshino /
    Seiji Takahashi / Toru Nakayama

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 14

    Abstract: Chalcone synthase is the first committed enzyme in the plant flavonoid biosynthesis pathway, yet shows low product specificity in vitro. Here Waki et al. show that chalcone isomerase-like proteins bind to and reduce the catalytic promiscuity of chalcone ... ...

    Abstract Chalcone synthase is the first committed enzyme in the plant flavonoid biosynthesis pathway, yet shows low product specificity in vitro. Here Waki et al. show that chalcone isomerase-like proteins bind to and reduce the catalytic promiscuity of chalcone synthase, ensuring efficient flavonoid production in planta.
    Keywords Science ; Q
    Language English
    Publishing date 2020-02-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Hyperacidification of Vacuoles by the Combined Action of Two Different P-ATPases in the Tonoplast Determines Flower Color

    Marianna Faraco / Cornelis Spelt / Mattijs Bliek / Walter Verweij / Atsushi Hoshino / Luca Espen / Bhakti Prinsi / Rinse Jaarsma / Eray Tarhan / Albertus H. de Boer / Gian-Pietro Di Sansebastiano / Ronald Koes / Francesca M. Quattrocchio

    Cell Reports, Vol 6, Iss 1, Pp 32-

    2014  Volume 43

    Abstract: The acidification of endomembrane compartments is essential for enzyme activities, sorting, trafficking, and trans-membrane transport of various compounds. Vacuoles are mildly acidic in most plant cells because of the action of V-ATPase and/or ... ...

    Abstract The acidification of endomembrane compartments is essential for enzyme activities, sorting, trafficking, and trans-membrane transport of various compounds. Vacuoles are mildly acidic in most plant cells because of the action of V-ATPase and/or pyrophosphatase proton pumps but are hyperacidified in specific cells by mechanisms that remained unclear. Here, we show that the blue petal color of petunia ph mutants is due to a failure to hyperacidify vacuoles. We report that PH1 encodes a P3B-ATPase, hitherto known as Mg2+ transporters in bacteria only, that resides in the vacuolar membrane (tonoplast). In vivo nuclear magnetic resonance and genetic data show that PH1 is required and, together with the tonoplast H+ P3A-ATPase PH5, sufficient to hyperacidify vacuoles. PH1 has no H+ transport activity on its own but can physically interact with PH5 and boost PH5 H+ transport activity. Hence, the hyperacidification of vacuoles in petals, and possibly other tissues, relies on a heteromeric P-ATPase pump.
    Keywords Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2014-01-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Genome sequence and analysis of the Japanese morning glory Ipomoea nil

    Atsushi Hoshino / Vasanthan Jayakumar / Eiji Nitasaka / Atsushi Toyoda / Hideki Noguchi / Takehiko Itoh / Tadasu Shin-I / Yohei Minakuchi / Yuki Koda / Atsushi J. Nagano / Masaki Yasugi / Mie N. Honjo / Hiroshi Kudoh / Motoaki Seki / Asako Kamiya / Toshiyuki Shiraki / Piero Carninci / Erika Asamizu / Hiroyo Nishide /
    Sachiko Tanaka / Kyeung-Il Park / Yasumasa Morita / Kohei Yokoyama / Ikuo Uchiyama / Yoshikazu Tanaka / Satoshi Tabata / Kazuo Shinozaki / Yoshihide Hayashizaki / Yuji Kohara / Yutaka Suzuki / Sumio Sugano / Asao Fujiyama / Shigeru Iida / Yasubumi Sakakibara

    Nature Communications, Vol 7, Iss 1, Pp 1-

    2016  Volume 10

    Abstract: Japanese morning glory (Ipomoea nil) has diverse flowering traits. Here, the authors describe the reference genome sequence of I. nil, annotations of genes and transposons, and compare evolution of the I. nilgenome to other Convolvulaceae and Solanales ... ...

    Abstract Japanese morning glory (Ipomoea nil) has diverse flowering traits. Here, the authors describe the reference genome sequence of I. nil, annotations of genes and transposons, and compare evolution of the I. nilgenome to other Convolvulaceae and Solanales genomes.
    Keywords Science ; Q
    Language English
    Publishing date 2016-11-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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