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論文 - 末松　誠

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Xanthine oxidase inhibitor ameliorates postischemic renal injury in mice by promoting resynthesis of adenine nucleotides

Fujii K., Kubo A., Miyashita K., Sato M., Hagiwara A., Inoue H., Ryuzaki M., Tamaki M., Hishiki T., Hayakawa N., Kabe Y., Itoh H., Suematsu M.

JCI Insight （JCI Insight） 4 （ 22 ） 2019年11月

© 2019, American Society for Clinical Investigation. Although oxidative stress plays central roles in postischemic renal injury, region-specific alterations in energy and redox metabolism caused by short-duration ischemia remain unknown. Imaging mass spectrometry enabled us to reveal spatial heterogeneity of energy and redox metabolites in the postischemic murine kidney. After 10-minute ischemia and 24-hour reperfusion (10mIR), in the cortex and outer stripes of the outer medulla, ATP substantially decreased, but not in the inner stripes of the outer medulla and inner medulla. 10mIR caused renal injury with elevation of fractional excretion of sodium, although histological damage by oxidative stress was limited. Ischemia-induced NADH elevation in the cortex indicated prolonged production of reactive oxygen species by xanthine oxidase (XOD). However, consumption of reduced glutathione after reperfusion suggested the amelioration of oxidative stress. An XOD inhibitor, febuxostat, which blocks the degradation pathway of adenine nucleotides, promoted ATP recovery and exerted renoprotective effects in the postischemic kidney. Because effects of febuxostat were canceled by silencing of the hypoxanthine phosphoribosyl transferase 1 gene in cultured tubular cells, mechanisms for the renoprotective effects appear to involve the purine salvage pathway, which uses hypoxanthine to resynthesize adenine nucleotides, including ATP. These findings suggest a novel therapeutic approach for acute ischemia/reperfusion renal injury with febuxostat through salvaging high-energy adenine nucleotides.

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Mutant ASXL1 Promotes Expansion of the Phenotypic Hematopoietic Stem Cell Compartment

Fujino Takeshi, Goyama Susumu, Sugiura Yuki, Inoue Daichi, Yamasaki Satoshi, Matsumoto Akiko, Sato Naru, Morinaga Hironobu, Shikata Shiori, Fukuyama Tomofusa, Tanaka Yosuke, Asada Shuhei, Fukushima Tsuyoshi, Honda Hiroaki, Nishimura Emi K., Shibata Tatsuhiro, Suematsu Makoto, Kitamura Toshio

BLOOD 134 2019年11月

ISSN 0006-4971

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Hydrogen sulfide bypasses the rate-limiting oxygen activation of heme oxygenase

Matsui T., Sugiyama R., Sakanashi K., Tamura Y., Iida M., Nambu Y., Higuchi T., Suematsu M., Ikeda-Saito M.

Journal of Biological Chemistry （Journal of Biological Chemistry） 293 （ 43 ） 16931 - 16939 2019年10月

ISSN 00219258

© 2018 Matsui et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. Discovery of unidentified protein functions is of biological importance because it often provides new paradigms for many research areas. Mammalian heme oxygenase (HO) enzyme catalyzes the O2-dependent degradation of heme into carbon monoxide (CO), iron, and biliverdin through numerous reaction intermediates. Here, we report that H2S, a gaseous signaling molecule, is part of a novel reaction pathway that drastically alters HO's products, reaction mechanism, and catalytic properties. Our prediction of this interplay is based on the unique reactivity of H2S with one of the HO intermediates. We found that in the presence of H2S, HO produces new linear tetrapyr-roles, which we identified as isomers of sulfur-containing biliverdin (SBV), and that only H2S, but not GSH, cysteine, and polysulfides, induces SBV formation. As BV is converted to bilirubin (BR), SBV is enzymatically reduced to sulfur-containing bilirubin (SBR), which shares similar properties such as antioxidative effects with normal BR. SBR was detected in culture media of mouse macrophages, confirming the existence of this H2S-induced reaction in mammalian cells. H2S reacted specifically with a ferric verdoheme intermediate of HO, and verdoheme cleavage proceeded through an O2-independent hydrolysis-like mechanism. This change in activation mode diminished O2 dependence of the overall HO activity, circumventing the rate-limiting O2 activation of HO. We propose that H2S could largely affect O2 sensing by mammalian HO, which is supposed to relay hypoxic signals by decreasing CO output to regulate cellular functions. Moreover, the novel H2S-induced reaction identified here helps sustain HO's heme-degrading and antioxidant-generating capacity under highly hypoxic conditions.

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Detection of a High-Turnover Serotonin Circuit in the Mouse Brain Using Mass Spectrometry Imaging

Sugiyama E., Guerrini M.M., Honda K., Hattori Y., Abe M., Källback P., Andrén P.E., Tanaka K.F., Setou M., Fagarasan S., Suematsu M., Sugiura Y.

iScience （iScience） 20 359 - 372 2019年10月

© 2019 The Author(s) Monoamine neurotransmitters are released by specialized neurons regulating behavioral, motor, and cognitive functions. Although the localization of monoaminergic neurons in the brain is well known, the distribution and kinetics of monoamines remain unclear. Here, we generated a murine brain atlas of serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels using mass spectrometry imaging (MSI). We found several nuclei rich in both 5-HT and a catecholamine (DA or NE) and identified the paraventricular nucleus of the thalamus (PVT), where 5-HT and NE are co-localized. The analysis of 5-HT fluctuations in response to acute tryptophan depletion and infusion of isotope-labeled tryptophan in vivo revealed a close kinetic association between the raphe nuclei, PVT, and amygdala but not the other nuclei. Our findings imply the existence of a highly dynamic 5-HT-mediated raphe to PVT pathway that likely plays a role in the brain monoamine system.

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Mechanical allodynia induced by optogenetic sensory nerve excitation activates dopamine signaling and metabolism in medial nucleus accumbens

Sugiyama E., Kondo T., Kuzumaki N., Honda K., Yamanaka A., Narita M., Suematsu M., Sugiura Y.

Neurochemistry International （Neurochemistry International） 129 104494 2019年10月

ISSN 01970186

© 2019 The Authors The mesolimbic dopaminergic signaling, such as that originating from the ventral tegmental area (VTA) neurons in the medial part of the nucleus accumbens (mNAc), plays a role in complex sensory and affective components of pain. To date, we have demonstrated that optogenetic sensory nerve stimulation rapidly alters the dopamine (DA) content within the mNAc. However, the physiological role and biochemical processes underlying such rapid and regional dynamics of DA remain unclear. In this study, using imaging mass spectrometry (IMS), we observed that sensitized pain stimulation by optogenetic sensory nerve activation increased DA and 3-Methoxytyramine (3-MT; a post-synaptic metabolite obtained following DA degradation) in the mNAc of the experimental mice. To delineate the mechanism associated with elevation of DA and 3-MT, the de novo synthesized DA in the VTA/substantia nigra terminal areas was evaluated using IMS by visualizing the metabolic conversion of stable isotope-labeled tyrosine (13C15N-Tyr) to DA. Our approach revealed that at steady state, the de novo synthesized DA occupied >10% of the non-labeled DA pool in the NAc within 1.5 h of isotope-labeled Tyr administration, despite no significant increase following pain stimulation. These results suggested that sensitized pain triggered an increase in the release and postsynaptic intake of DA in the mNAc, followed by its degradation, and likely delayed de novo DA synthesis. In conclusion, we demonstrated that short, peripheral nerve excitation with mechanical stimulation accelerates the mNAc-specific DA signaling and metabolism which might be associated with the development of mechanical allodynia.

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Molecular characterization of the gastric commensal bacteria progressing gastric carcinogenesis in H. pylori-infected gastric mucosa

TsugaWa H., Matsuzaki J., Mori H., Suematsu M., Suzuki H.

HELICOBACTER 24 2019年09月

ISSN 1083-4389

IMP dehydrogenase-2 drives aberrant nucleolar activity and promotes tumorigenesis in glioblastoma

Kofuji S., Hirayama A., Eberhardt A.O., Kawaguchi R., Sugiura Y., Sampetrean O., Ikeda Y., Warren M., Sakamoto N., Kitahara S., Yoshino H., Yamashita D., Sumita K., Wolfe K., Lange L., Ikeda S., Shimada H., Minami N., Malhotra A., Morioka S., Ban Y., Asano M., Flanary V.L., Ramkissoon A., Chow L.M.L., Kiyokawa J., Mashimo T., Lucey G., Mareninov S., Ozawa T., Onishi N., Okumura K., Terakawa J., Daikoku T., Wise-Draper T., Majd N., Kofuji K., Sasaki M., Mori M., Kanemura Y., Smith E.P., Anastasiou D., Wakimoto H., Holland E.C., Yong W.H., Horbinski C., Nakano I., DeBerardinis R.J., Bachoo R.M., Mischel P.S., Yasui W., Suematsu M., Saya H., Soga T., Grummt I., Bierhoff H., Sasaki A.T.

Nature Cell Biology （Nature Cell Biology） 21 （ 8 ） 1003 - 1014 2019年08月

ISSN 14657392

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. In many cancers, high proliferation rates correlate with elevation of rRNA and tRNA levels, and nucleolar hypertrophy. However, the underlying mechanisms linking increased nucleolar transcription and tumorigenesis are only minimally understood. Here we show that IMP dehydrogenase-2 (IMPDH2), the rate-limiting enzyme for de novo guanine nucleotide biosynthesis, is overexpressed in the highly lethal brain cancer glioblastoma. This leads to increased rRNA and tRNA synthesis, stabilization of the nucleolar GTP-binding protein nucleostemin, and enlarged, malformed nucleoli. Pharmacological or genetic inactivation of IMPDH2 in glioblastoma reverses these effects and inhibits cell proliferation, whereas untransformed glia cells are unaffected by similar IMPDH2 perturbations. Impairment of IMPDH2 activity triggers nucleolar stress and growth arrest of glioblastoma cells even in the absence of functional p53. Our results reveal that upregulation of IMPDH2 is a prerequisite for the occurance of aberrant nucleolar function and increased anabolic processes in glioblastoma, which constitutes a primary event in gliomagenesis.

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Tandem Mass Spectrometry Imaging Reveals Distinct Accumulation Patterns of Steroid Structural Isomers in Human Adrenal Glands

Takeo E., Sugiura Y., Uemura T., Nishimoto K., Yasuda M., Sugiyama E., Ohtsuki S., Higashi T., Nishikawa T., Suematsu M., Fukusaki E., Shimma S.

Analytical Chemistry （Analytical Chemistry） 91 （ 14 ） 8918 - 8925 2019年07月

ISSN 00032700

© 2019 American Chemical Society. Visualizing tissue distribution of steroid hormones is a promising application of MALDI mass spectrometry imaging (MSI). On-tissue chemical derivatization using Girard's T reagent has enhanced the ionization efficiency of steroids. However, discriminating between structural isomers with distinct bioactivities remains a challenge. Herein, we used ion trap MS/tandem MS (MS3) to distinguish a mineralcorticoid aldosterone (Aldo) and a glucocorticoid cortisol (F), from their structural isomers. Our method is also useful to detect hybrid steroids (18-hydroxycortisol [18-OHF] and 18-oxocortisol) with sufficient signal-to-noise ratio. The clinical applicability of the tandem MS method was evaluated by analyzing F, Aldo, and 18-OHF distributions in human adrenal glands. In such clinical specimens, small Aldo-producing cell clusters (APCCs) were identified and were first found to produce a high level of Aldo and not to contain F. Moreover, a part of APCCs produced 18-OHF, presumably converted from F by APCC-specific CYP11B2 activity. Catecholamine species were also visualized with another derivatization reagent (TAHS), and those profiling successfully discriminated pheochromocytoma species. These tandem MSI-methods, coupled with on-tissue chemical derivatization has proven to be useful for detecting low-abundance steroids, including Aldo and hybrid steroids and thus identifying steroid hormone-producing lesions.

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Environmental Optimization Enables Maintenance of Quiescent Hematopoietic Stem Cells Ex Vivo

Kobayashi H., Morikawa T., Okinaga A., Hamano F., Hashidate-Yoshida T., Watanuki S., Hishikawa D., Shindou H., Arai F., Kabe Y., Suematsu M., Shimizu T., Takubo K.

Cell Reports （Cell Reports） 28 （ 1 ） 145 - 158.e9 2019年07月

ISSN 2211-1247

© 2019 The Authors Hematopoietic stem cells (HSCs) maintain lifelong hematopoiesis by remaining quiescent in the bone marrow niche. Recapitulation of a quiescent state in culture has not been achieved, as cells rapidly proliferate and differentiate in vitro. After exhaustive analysis of different environmental factor combinations and concentrations as a way to mimic physiological conditions, we were able to maintain engraftable quiescent HSCs for 1 month in culture under very low cytokine concentrations, hypoxia, and very high fatty acid levels. Exogenous fatty acids were required likely due to suppression of intrinsic fatty acid synthesis by hypoxia and low cytokine conditions. By contrast, high cytokine concentrations or normoxia induced HSC proliferation and differentiation. Our culture system provides a means to evaluate properties of steady-state HSCs and test effects of defined factors in vitro under near-physiological conditions. Maintaining quiescent HSCs under physiological conditions facilitates evaluation of the properties of steady-state HSCs. Kobayashi et al. report that low cytokine concentrations, hypoxia, and high fatty acid levels mimicking the bone marrow microenvironment enable maintenance of engraftable quiescent HSCs for 1 month in culture.

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Maintenance of tissue stiffness via metabolism in Presbyopia

Hayano Motoshi, Nagashima Hayato, Amano Sachie, Sakuma Atsushi, Hishiki Takako, Suematsu Makoto, Tsubota Kazuo

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 60 （ 9 ） 2019年07月

ISSN 0146-0404

Research on decrease of lens elasticity in mice and rats during aging

Nagashima Hayato, Hayano Motoshi, Amano Sachie, Sakuma Atsushi, Hishiki Takako, Suematsu Makoto, Tsubota Kazuo

INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE 60 （ 9 ） 2019年07月

ISSN 0146-0404

The Fundamental Characteristics of a Translational Scientist.

Gilliland CT, White J, Gee B, Kreeftmeijer-Vegter R, Bietrix F, Ussi AE, Hajduch M, Kocis P, Chiba N, Hirasawa R, Suematsu M, Bryans J, Newman S, Hall MD, Austin CP

ACS pharmacology & translational science 2 （ 3 ） 213 - 216 2019年06月

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Application of high-performance magnetic nanobeads to biological sensing devices

Kabe Y., Sakamoto S., Hatakeyama M., Yamaguchi Y., Suematsu M., Itonaga M., Handa H.

Analytical and Bioanalytical Chemistry （Analytical and Bioanalytical Chemistry） 411 （ 9 ） 1825 - 1837 2019年03月

ISSN 16182642

© 2019, The Author(s). Nanomaterials have extensive applications in the life sciences and in clinical diagnosis. We have developed magnetic nanoparticles with high dispersibility and extremely low nonspecific binding to biomolecules and have demonstrated their application in chemical biology (e.g., for the screening of drug receptor proteins). Recently, the excellent properties of nanobeads have made possible the development of novel rapid immunoassay systems and high-precision technologies for exosome detection. For immunoassays, we developed a technology to encapsulate a fluorescent substance in magnetic nanobeads. The fluorescent nanobeads allow the rapid detection of a specific antigen in solution or in tissue specimens. Exosomes, which are released into the blood, are expected to become markers for several diseases, including cancer, but techniques for measuring the absolute quantity of exosomes in biological fluids are lacking. By integrating magnetic nanobead technology with an optical disc system, we developed a novel method for precisely quantifying exosomes in human serum with high sensitivity and high linearity without requiring enrichment procedures. This review focuses on the properties of our magnetic nanobeads, the development of novel biosensors using these nanobeads, and their broad practical applications. [Figure not available: see fulltext.].

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Increased cytotoxicity of herpes simplex virus thymidine kinase expression in human induced pluripotent stem cells

Iwasawa C., Tamura R., Sugiura Y., Suzuki S., Kuzumaki N., Narita M., Suematsu M., Nakamura M., Yoshida K., Toda M., Okano H., Miyoshi H.

International Journal of Molecular Sciences （International Journal of Molecular Sciences） 20 （ 4 ） 2019年02月

ISSN 16616596

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Human induced pluripotent stem cells (iPSCs) hold enormous promise for regenerative medicine. The major safety concern is the tumorigenicity of transplanted cells derived from iPSCs. A potential solution would be to introduce a suicide gene into iPSCs as a safety switch. The herpes simplex virus type 1 thymidine kinase (HSV-TK) gene, in combination with ganciclovir, is the most widely used enzyme/prodrug suicide system from basic research to clinical applications. In the present study, we attempted to establish human iPSCs that stably expressed HSV-TK with either lentiviral vectors or CRISPR/Cas9-mediated genome editing. However, this task was difficult to achieve, because high-level and/or constitutive expression of HSV-TK resulted in the induction of cell death or silencing of HSV-TK expression. A nucleotide metabolism analysis suggested that excessive accumulation of thymidine triphosphate, caused by HSV-TK expression, resulted in an imbalance in the dNTP pools. This unbalanced state led to DNA synthesis inhibition and cell death in a process similar to a “thymidine block”, but more severe. We also demonstrated that the Tet-inducible system was a feasible solution for overcoming the cytotoxicity of HSV-TK expression. Our results provided a warning against using the HSV-TK gene in human iPSCs, particularly in clinical applications.

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CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy

Tsugawa H., Mori H., Matsuzaki J., Sato A., Saito Y., Imoto M., Suematsu M., Suzuki H.

Autophagy （Autophagy） 15 （ 2 ） 242 - 258 2019年02月

ISSN 15548627

© 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Helicobacter pylori-derived CagA, a type IV secretion system effector, plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by macroautophagy/autophagy. Hence, the induction of autophagy in H. pylori-infected epithelial cells is an important host-protective ability against gastric carcinogenesis. However, the mechanisms by which autophagosome-lysosome fusion is regulated, are unknown. Here, we report that enhancement of LAMP1 (lysosomal associated membrane protein 1) expression is necessary for autolysosome formation. LAMP1 expression is induced by nuclear translocated LRP1 (LDL receptor related protein 1) intracellular domain (LRP1-ICD) binding to the proximal LAMP1 promoter region. Nuclear translocation of LRP1-ICD is enhanced by H. pylori infection. In contrast, CAPZA1 (capping actin protein of muscle Z-line alpha subunit 1) inhibits LAMP1 expression via binding to LRP1-ICD in the nuclei. The binding of CAPZA1 to LRP1-ICD prevents LRP1-ICD binding to the LAMP1 proximal promoter. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autolysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis. Abbreviations: CagA: cytotoxin-associated gene A; CAPZA1: capping actin protein of muscle Z-line alpha subunit 1; ChIP: chromatin immunoprecipitation; GTF2I: general transcription factor IIi; HDAC: histone deacetylase; LAMP1: lysosomal associated membrane protein 1; LRP1: LDL receptor related protein 1; LRP1-ICD: CagA intracellular domain; qPCR: quantitative polymerase chain reaction; VacA: vacuolating cytotoxin.

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A defined commensal consortium elicits CD8 T cells and anti-cancer immunity

Tanoue T., Morita S., Plichta D.R., Skelly A.N., Suda W., Sugiura Y., Narushima S., Vlamakis H., Motoo I., Sugita K., Shiota A., Takeshita K., Yasuma-Mitobe K., Riethmacher D., Kaisho T., Norman J.M., Mucida D., Suematsu M., Yaguchi T., Bucci V., Inoue T., Kawakami Y., Olle B., Roberts B., Hattori M., Xavier R.J., Atarashi K., Honda K.

Nature （Nature） 565 （ 7741 ） 600 - 605 2019年01月

ISSN 00280836

© 2019, Springer Nature Limited. There is a growing appreciation for the importance of the gut microbiota as a therapeutic target in various diseases. However, there are only a handful of known commensal strains that can potentially be used to manipulate host physiological functions. Here we isolate a consortium of 11 bacterial strains from healthy human donor faeces that is capable of robustly inducing interferon-γ-producing CD8 T cells in the intestine. These 11 strains act together to mediate the induction without causing inflammation in a manner that is dependent on CD103 + dendritic cells and major histocompatibility (MHC) class Ia molecules. Colonization of mice with the 11-strain mixture enhances both host resistance against Listeria monocytogenes infection and the therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumour models. The 11 strains primarily represent rare, low-abundance components of the human microbiome, and thus have great potential as broadly effective biotherapeutics.

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Fatty acid β-oxidation-dependent and -independent responses and tumor aggressiveness acquired under mild hypoxia

Wakui M., Kawai K., Mizushima T., Nishime C., Serizawa A., Suemizu H., Asakura K., Yamauchi Y., Hayashida T., Suematsu M., Murata M.

Anticancer Research （Anticancer Research） 39 （ 1 ） 191 - 200 2019年01月

ISSN 02507005

© 2019 International Institute of Anticancer Research. All Rights Reserved. Background/Aim: The present study assessed whether and how tumor cells undergoing hypoxia contribute to disease progression after moving to areas with different oxygen conditions. Materials and Methods: Human colorectal carcinoma HCT116 cells cultured under mild hypoxia were subjected to in vivo experiments using transfer to immunodeficient murine recipients and to in vitro experiments using pharmacological inhibition of fatty acid β-oxidation (FAO). Results: Bone involvement and hepatic metastases were accelerated in transfer models of hypoxically cultured HCT116 cells. Hypoxic HCT116 cells exhibited FAO-dependent glycogen synthesis. FAO-dependent and -independent induction of gene expression also occurred under hypoxia. The distribution of glucose transporter 1 expression compared with heme oxygenase 1 expression in HCT116 cell spheroids seemed consistent with differential dependence of hypoxic expression of these molecules on FAO. Conclusion: These results provide insights into the contribution of hypoxia to tumor progression and the relevance of FAO.

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Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori–Infected CAPZA1-Overexpressing Cells

Tsugawa H., Kato C., Mori H., Matsuzaki J., Kameyama K., Saya H., Hatakeyama M., Suematsu M., Suzuki H.

Cellular and Molecular Gastroenterology and Hepatology （Cellular and Molecular Gastroenterology and Hepatology） 8 （ 3 ） 319 - 334 2019年

ISSN 2352-345X

© 2019 The Authors Background & Aims: CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. Methods: CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. Results: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori–infected gastric mucosa. Conclusions: CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.

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Brief exposure of skin to near-infrared laser modulates mast cell function and augments the immune response

Kimizuka Y., Katagiri W., Locascio J., Shigeta A., Sasaki Y., Shibata M., Morse K., Sirbulescu R., Miyatake M., Reeves P., Suematsu M., Gelfand J., Brauns T., Poznansky M., Tsukada K., Kashiwagi S.

Journal of Immunology （Journal of Immunology） 201 （ 12 ） 3587 - 3603 2018年12月

ISSN 00221767

©2018 by The American Association of Immunologists,Inc. The treatment of skin with a low-power continuous-wave (CW) near-infrared (NIR) laser prior to vaccination is an emerging strategy to augment the immune response to intradermal vaccine, potentially substituting for chemical adjuvant, which has been linked to adverse effects of vaccines. This approach proved to be low cost, simple, small, and readily translatable compared with the previously explored pulsed-wave medical lasers. However, little is known on the mode of laser-tissue interaction eliciting the adjuvant effect. In this study, we sought to identify the pathways leading to the immunological events by examining the alteration of responses resulting from genetic ablation of innate subsets including mast cells and specific dendritic cell populations in an established model of intradermal vaccination and analyzing functional changes of skin microcirculation upon the CW NIR laser treatment in mice. We found that a CW NIR laser transiently stimulates mast cells via generation of reactive oxygen species, establishes an immunostimulatory milieu in the exposed tissue, and provides migration cues for dermal CD103+ dendritic cells without inducing prolonged inflammation, ultimately augmenting the adaptive immune response. These results indicate that use of an NIR laser with distinct wavelength and power is a safe and effective tool to reproducibly modulate innate programs in skin. These mechanistic findings would accelerate the clinical translation of this technology and warrant further explorations into the broader application of NIR lasers to the treatment of immune-related skin diseases. The Journ Al of Immunology, 2018, 201: 3587-3603.

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Deep whole-genome sequencing reveals recent selection signatures linked to evolution and disease risk of Japanese

Okada Y., Momozawa Y., Sakaue S., Kanai M., Ishigaki K., Akiyama M., Kishikawa T., Arai Y., Sasaki T., Kosaki K., Suematsu M., Matsuda K., Yamamoto K., Kubo M., Hirose N., Kamatani Y.

Nature Communications （Nature Communications） 9 （ 1 ） 1631 2018年12月

ISSN 2041-1723

© 2018 The Author(s). Understanding natural selection is crucial to unveiling evolution of modern humans. Here, we report natural selection signatures in the Japanese population using 2234 high-depth whole-genome sequence (WGS) data (25.9×). Using rare singletons, we identify signals of very recent selection for the past 2000-3000 years in multiple loci (ADH cluster, MHC region, BRAP-ALDH2, SERHL2). In large-scale genome-wide association study (GWAS) dataset (n = 171,176), variants with selection signatures show enrichment in heterogeneity of derived allele frequency spectra among the geographic regions of Japan, highlighted by two major regional clusters (Hondo and Ryukyu). While the selection signatures do not show enrichment in archaic hominin-derived genome sequences, they overlap with the SNPs associated with the modern human traits. The strongest overlaps are observed for the alcohol or nutrition metabolism-related traits. Our study illustrates the value of high-depth WGS to understand evolution and their relationship with disease risk.

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