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| Open AccessRapid emergence and predominance of a broadly recognizing and fast-evolving norovirus GII.17 variant in late 2014
Norovirus GII.4 has been predominating in viral gastroenteritis for 20 years. Here the authors report the emergence and predominance of a novel fast-evolving GII.17 lineage norovirus causing viral gastroenteritis in Hong Kong, with a shift in age distribution of affected individuals towards an older age as compared to GII.4.
- Martin C. W. Chan
- , Nelson Lee
- & Paul K. S. Chan
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Article
| Open AccessAsparagine requirement in Plasmodium berghei as a target to prevent malaria transmission and liver infections
Malaria parasites obtain amino acids primarily from the host, but possess a gene encoding a putative asparagine synthetase. Here, the authors show that this enzyme is functional and that asparagine is crucial for the development of the parasite’s sexual stages in mosquitoes and liver stages in mice.
- Viswanathan A. Nagaraj
- , Dhanunjay Mukhi
- & Govindarajan Padmanaban
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| Open AccessMaternal bile acid transporter deficiency promotes neonatal demise
The mechanisms underlying perinatal mortality due to intrahepatic cholestasis of pregnancy are not fully understood. Here, the authors show that absence of the nuclear receptor and bile acid regulator Nrli2 and the biliary transporter Abcb11 strongly reduces maternal serum bile acid levels, improving neonatal survival.
- Yuanyuan Zhang
- , Fei Li
- & John D. Schuetz
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| Open AccessInternational genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways
Primary biliary cirrhosis is an autoimmune liver disease with poor therapeutic options. Here Cordell et al. a perform meta-analysis of European genome-wide association studies identifying six novel risk loci and a number of potential therapeutic pathways.
- Heather J. Cordell
- , Younghun Han
- & Katherine A. Siminovitch
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| Open AccessSialic acid catabolism drives intestinal inflammation and microbial dysbiosis in mice
Intestinal inflammation is often associated with a shift in microbiota composition but the mechanisms are unclear. Here the authors show that an increase in caecal sialidase activity occurring during intestinal inflammation promotes the expansion of Enterobacteriaceae, which can lead to exacerbated inflammatory response.
- Yen-Lin Huang
- , Christophe Chassard
- & Thierry Hennet
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| Open AccessExperimental colitis in SIV-uninfected rhesus macaques recapitulates important features of pathogenic SIV infection
HIV-1 infection in humans and SIV infection in rhesus macaques are associated with mucosal damage to the gastrointestinal tract, microbial translocation and chronic immune activation. Here the authors develop a non-human primate DSS colitis model that recapitulates these aspects of the disease in uninfected rhesus macaques.
- Xing Pei Hao
- , Carissa M. Lucero
- & Jacob D. Estes
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| Open AccessDiet and specific microbial exposure trigger features of environmental enteropathy in a novel murine model
Environmental enteropathy is a disorder of the small intestine that contributes to the persistence of childhood malnutrition worldwide. Here, Brownet al. show in mice that early-life malnourishment, in combination with exposure to commensal bacteria, remodels the small intestine to resemble features of the disease.
- Eric M. Brown
- , Marta Wlodarska
- & B. Brett Finlay
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Article
| Open AccessIntestinal CD169+ macrophages initiate mucosal inflammation by secreting CCL8 that recruits inflammatory monocytes
Macrophages and dendritic cells residing in the lamina propria are involved in controlling mucosal immune balance. Here, the authors identify CD169+macrophages as contributors to the inflammation of DSS colitis through their role in mediating the recruitment of monocytes by secreting the cytokine CCL8.
- Kenichi Asano
- , Naomichi Takahashi
- & Masato Tanaka
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| Open AccessStereomicroscopic 3D-pattern profiling of murine and human intestinal inflammation reveals unique structural phenotypes
The gut epithelium is damaged in inflammatory bowel disease, but capturing such lesions by histology can be difficult. Here, the authors use stereomicroscopy to visualize different 3D inflammatory structures and associated microbes in humans and in 16 genetic mouse models relevant to intestinal inflammation.
- Alex Rodriguez-Palacios
- , Tomohiro Kodani
- & Fabio Cominelli
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| Open AccessDiscovery of intramolecular trans-sialidases in human gut microbiota suggests novel mechanisms of mucosal adaptation
Mucosal sialoglycans contribute to host–microbe interactions at mucosal surfaces and impact bacterial colonization of the digestive system. Here the authors identify and characterize an intramolecular trans-sialidase produced by the gut bacterium R. gnavusATCC 29149 that may contribute to adaptation to the mucosal environment.
- Louise E. Tailford
- , C. David Owen
- & Nathalie Juge
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A metabolic stress-inducible miR-34a-HNF4α pathway regulates lipid and lipoprotein metabolism
The nuclear hormone receptor HNF4α is important for liver function. Here, Xu et al.show that miR-34a regulates expression of HNF4α and is increased under conditions of metabolic stress, suggesting miR-34a promotes the development of non-alcoholic fatty liver disease.
- Yang Xu
- , Munaf Zalzala
- & Yanqiao Zhang
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The oncogenic microRNA miR-21 promotes regulated necrosis in mice
The microRNA miR-21 is overexpressed in cancer and is thought to function through anti-apoptotic activity. Here, Ma et al. show that deleting or blocking miR-21 in mice protects against acute pancreatitis and TNF-α-induced tissue damage by inhibiting RIP3-dependent regulated necrosis (necroptosis).
- Xiaodong Ma
- , Daniel J. Conklin
- & Yong Li
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Article
| Open AccessC8orf4 negatively regulates self-renewal of liver cancer stem cells via suppression of NOTCH2 signalling
Cancer stem cells are a small proportion of tumours that often confer resistance to chemotherapy but how these cells are maintained is unclear. Here, Zhu et al. study hepatocellular carcinoma stem cells and identify C8orf4 as a negative regulator of Notch2, which is required for the self-renewal of the cells.
- Pingping Zhu
- , Yanying Wang
- & Zusen Fan
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Alternatively activated macrophages promote pancreatic fibrosis in chronic pancreatitis
Chronic pancreatitis is an inflammatory disease accompanied by fibrosis. Here the authors show that pancreatic stellate cells produce IL-4 and IL-13 that trigger alternative activation of macrophages, and that genetic or pharmacological inhibition of IL-4/IL-13 signaling ameliorates the disease.
- Jing Xue
- , Vishal Sharma
- & Aida Habtezion
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The non-muscle-myosin-II heavy chain Myh9 mediates colitis-induced epithelium injury by restricting Lgr5+ stem cells
Colitis is a common human disorder but the clinical interventions are limited as the pathological mechanisms are not very clear. Here the authors find an elevated expression of non-muscle-myosin-II heavy chain Myh9 in a colitis mouse model, and show that Myh9 expression reduction or activity inhibition ameliorates epithelial injuries.
- Bing Zhao
- , Zhen Qi
- & Ye-Guang Chen
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Interplay between enterobactin, myeloperoxidase and lipocalin 2 regulates E. coli survival in the inflamed gut
Gut inflammation triggers a bloom of certain resident bacteria such as E. coli that can contribute to disease. Here, Singh et al. show that a siderophore produced by E. coliinhibits the antibacterial activity of host myeloperoxidase and enhances bacterial survival in the gut of lab mice.
- Vishal Singh
- , Beng San Yeoh
- & Matam Vijay-Kumar
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| Open AccessEnterohemorrhagic Escherichia coli senses low biotin status in the large intestine for colonization and infection
Enterohaemorrhagic Escherichia coli(EHEC) is an important foodborne pathogen that colonizes the large intestine. Here, the authors identify a signalling pathway that controls EHEC adherence to host cells in response to variations in biotin levels, ensuring selective colonization of the large intestine.
- Bin Yang
- , Lu Feng
- & Lei Wang
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Immunotoxin targeting glypican-3 regresses liver cancer via dual inhibition of Wnt signalling and protein synthesis
Tumour-targeted antibodies can kill cancer cells by blocking pro-survival signalling or by delivering a toxin. Here the authors show that glypican-3 antibody fused to a bacterial toxin suppresses tumour growth more efficiently if designed to block Wnt signalling downstream of glypican-3.
- Wei Gao
- , Zhewei Tang
- & Mitchell Ho
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| Open AccessInterferon-λ rs12979860 genotype and liver fibrosis in viral and non-viral chronic liver disease
Tissue fibrosis is a major contributor to mortality in the developed world. Here, the authors identify a genetic variant in the intronic region of interferon-λ4 that is a strong predictor of hepatic inflammation and fibrosis, independent of liver disease aetiology
- Mohammed Eslam
- , Ahmed M. Hashem
- & Rosanna Santaro
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IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis
The pro-inflammatory cytokine IL-1ß promotes the accumulation of pathologic Th17 lymphocytes that contribute to colitis. Here the authors show that the critical role of IL-10 in colitis suppression can be explained by its inhibition of IL-1ß production in macrophages.
- Bofeng Li
- , Prajwal Gurung
- & Terrence L. Geiger
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Mutational landscape of intrahepatic cholangiocarcinoma
Intrahepatic cholangiocarcinoma (ICC) is a fatal primary liver cancer with a known genetic component. Here the authors sequence the exomes of matched tumour and normal tissue from 103 ICC patients in China, and identify an ICC mutational profile associated with liver inflammation, fibrosis and cirrhosis.
- Shanshan Zou
- , Jiarui Li
- & Heping Hu
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| Open AccessA nairovirus isolated from African bats causes haemorrhagic gastroenteritis and severe hepatic disease in mice
Bats carry viruses that can cause disease in other animals and in humans. Here, Ishii et al.identify new nairoviruses from African bats and show that some of them can produce a severe haemorrhagic disease in laboratory mice that is similar to Crimean–Congo haemorrhagic fever in humans.
- Akihiro Ishii
- , Keisuke Ueno
- & Hirofumi Sawa
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GWAS identifies four novel eosinophilic esophagitis loci
Eosinophilic oesophagitis (EoE) is an allergic, inflammatory disorder of the oesophagus. Here the authors carry out a genome-wide association study in over 5,000 individuals and identify four genetic loci that affect the onset of EoE.
- Patrick M. A. Sleiman
- , Mei-Lun Wang
- & Hakon Hakonarson
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Article
| Open AccessGermline variants in the SEMA4A gene predispose to familial colorectal cancer type X
It is known that hereditary factors contribute to familial colorectal cancer type X. Here, the authors uncover the SEMA4A p.Val78Met germline mutation and show that the protein product is associated with changes in cell cycle progression in colorectal cancer cells.
- Eduard Schulz
- , Petra Klampfl
- & Heinz Sill
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| Open AccessPPARα-UGT axis activation represses intestinal FXR-FGF15 feedback signalling and exacerbates experimental colitis
Bile acids have been linked to the development of inflammatory bowel diseases, such as colitis. Here the authors show that bile acid levels in mice are controlled by a circular feedback system involving the nuclear receptors PPARα and FXR, and that this system is dysregulated in colitis.
- Xueyan Zhou
- , Lijuan Cao
- & Haiping Hao
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High susceptibility to fatty liver disease in two-pore channel 2-deficient mice
Two-pore channel 2 has been implicated in coupling changes in cellular energy status with endolysosomal function. Grimm et al.show that mice lacking this channel display defects in endolysosomal trafficking of LDL-cholesterol and are susceptible to hepatic cholesterol overload and fatty liver disease.
- Christian Grimm
- , Lesca M. Holdt
- & Christian Wahl-Schott
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| Open AccessIndividual diet has sex-dependent effects on vertebrate gut microbiota
Diet variations can alter gut microbial composition, but the potential influence of host genetic factors on these effects is unclear. Here, the authors show, in humans and in natural and laboratory fish populations, that such effects are dependent on the host’s sex, a genetically determined factor.
- Daniel I. Bolnick
- , Lisa K. Snowberg
- & Richard Svanbäck
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GIV/Girdin is a central hub for profibrogenic signalling networks during liver fibrosis
Liver fibrosis involves the activation of hepatic stellate cells (HSCs). Here the authors show that the guanine exchange factor GIV is specifically upregulated in HSCs, and that it serves as an integrator of multi-receptor driven pro-fibrotic signalling in the liver via its ability to activate G proteins.
- Inmaculada Lopez-Sanchez
- , Ying Dunkel
- & Pradipta Ghosh
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| Open AccessGlucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR
Patients with cystic fibrosis harbour mutations in the CFTR chloride channel and often develop diabetes for reasons that are poorly understood. Here Guo et al.show that CFTR is involved in the regulation of glucose-stimulated insulin secretion from pancreatic β-cells.
- Jing Hui Guo
- , Hui Chen
- & Hsiao Chang Chan
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Article
| Open AccessThe Opisthorchis viverrini genome provides insights into life in the bile duct
The Asian liver fluke is a parasitic worm that is linked to an increased risk of malignant cancer. Here, the authors sequence the draft genome and transcriptome of this fluke and provide insight into how the species has adapted to be able to survive in the bile duct.
- Neil D. Young
- , Niranjan Nagarajan
- & Robin B. Gasser
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| Open AccessTM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is characterized by increased hepatic triglyceride content (HTGC) in the absence of high alcohol consumption. Here the authors show that a genetic variant in TM6SF2, which is known to be associated with HTGC, is a clinically relevant modifier of hepatic fibrogenesis and increases the risk of progressive NAFLD.
- Yang-Lin Liu
- , Helen L. Reeves
- & Quentin M. Anstee
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NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity
Autophagosome biogenesis depends on the lipid kinase Vps34 and its binding proteins Beclin 1 and Atg14L. Lu et al.identify nuclear receptor binding factor 2 (NRBF2) as a regulator of this complex, and show that loss of NRBF2 impairs autophagy, enhances cell vulnerability to endoplasmic reticulum stress and promotes necrosis in the liver.
- Jiahong Lu
- , Liqiang He
- & Zhenyu Yue
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High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model
The influence of diet on the establishment of gut microbiota early in life is poorly understood. Here the authors show, in a primate model, that maternal diet during pregnancy affects the offspring’s microbiome, and that dietary intervention after weaning only partially reverses this effect.
- Jun Ma
- , Amanda L. Prince
- & Kjersti M. Aagaard
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| Open AccessBlockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome
Ionizing radiation damages small intestinal crypt cells, including epithelial stem cells and their progeny. Here the authors show that radiation-induced crypt cell death is amplified by the release of cellular RNA from apoptotic epithelial cells, which then triggers pro-apoptotic TLR3 signalling on neighbouring cells.
- Naoki Takemura
- , Takumi Kawasaki
- & Satoshi Uematsu
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Ionizing irradiation induces acute haematopoietic syndrome and gastrointestinal syndrome independently in mice
Ionizing radiation damages the gastrointestinal system, but the cell types involved in intestinal damage and repair are controversial. Here the authors use bone marrow transplantation models and various irradiation regimes to rule out a role of bone marrow-derived cells in acute gastrointestinal injury and recovery in mice.
- Brian J. Leibowitz
- , Liang Wei
- & Jian Yu
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Autotransporters but not pAA are critical for rabbit colonization by Shiga toxin-producing Escherichia coli O104:H4
An outbreak of diarrhoea and haemolytic uraemic syndrome in Germany in 2011 was caused by a Shiga toxin-producing enteroaggregative E. coli, which carried the aggregative adherence plasmid pAA. Here, the authors show that autotransporters, but not pAA, are required for intestinal colonization in an infant rabbit model.
- Diana Munera
- , Jennifer M. Ritchie
- & Matthew K. Waldor
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Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease
Alterations in hepatocyte metabolism can lead to disorders such as non-alcoholic steatohepatitis (NASH). Here the authors create a comprehensive model of hepatocyte metabolism and use it to identify metabolic pathways altered in disease, revealing that serine levels are reduced in patients with NASH.
- Adil Mardinoglu
- , Rasmus Agren
- & Jens Nielsen
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Article
| Open AccessMicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice
The micro-RNA miR-33 is encoded by an intron of the gene encoding sterol regulatory-binding protein 2 (SREBP-2) and controls cholesterol homoeostasis. Here, Horie et al.identify SREBP-1 as a target of miR-33 and show that deletion of miR-33 promotes diet-induced obesity and liver steatosis in mice.
- Takahiro Horie
- , Tomohiro Nishino
- & Koh Ono
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Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology
Myofibroblasts drive fibrogenesis in the liver but their cellular origins remain unclear. Here Mederacke et al. use the Lratgene to label hepatic stellate cells (HSCs) in transgenic mice and reveal HSCs as the major source of myofibroblasts in models of toxic, biliary and fatty liver fibrosis.
- Ingmar Mederacke
- , Christine C. Hsu
- & Robert F. Schwabe
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Persistent infection with Crohn’s disease-associated adherent-invasive Escherichia coli leads to chronic inflammation and intestinal fibrosis
Intestinal infection with adherent-invasive Escherichia coliis associated with Crohn’s disease in humans; however, its functional role remains unclear, in part due to a lack of animal models, which sustain chronic disease. Here the authors establish such a model in mice and show that it shares features with human Crohn’s disease.
- Cherrie-Lee N. Small
- , Sarah A. Reid-Yu
- & Brian K. Coombes
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R-Spondin 2 signalling mediates susceptibility to fatal infectious diarrhoea
Citrobacter rodentiumis an intestinal pathogen of mice widely used to model enteropathogenicE. coli infection in humans. Using a forward genetic approach, Papapietro and colleagues identify R-Spondin 2 expression and resulting Wnt signalling activation as a major regulator of C. rodentium-induced colitis.
- Olivier Papapietro
- , Sarah Teatero
- & Samantha Gruenheid
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Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity
Interstitial cells of Cajal generate rhythmic pacemaker currents, which result in rhythmic bowel contractions. Klein and colleagues use knock-in mutations to inactivate these cells in mice and find that they modulate bowel contractions by integrating excitatory and inhibitory neurotransmission in the gut.
- Sabine Klein
- , Barbara Seidler
- & Dieter Saur
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MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice
Mice lacking the anti-inflammatory cytokine IL-10 can develop colitis, which depends on inappropriate responses to commensal bacteria. Hoshiet al. now show that these responses are driven by colonic mononuclear phagocytes, providing insight to the initiating events, which may underlie inflammatory bowel disease.
- Namiko Hoshi
- , Dominik Schenten
- & Ruslan Medzhitov
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| Open AccessExtracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors
Mast cells are mediators of type I allergic disease and inflammation. Here, Kurashimaet al. show that mast cells are increased in the colons of mice with colitis, and that activation of the cells and subsequent inflammation can be blocked by inhibition of the purinoceptor, P2X7.
- Yosuke Kurashima
- , Takeaki Amiya
- & Hiroshi Kiyono
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Article
| Open AccessPPARγ contributes to PKM2 and HK2 expression in fatty liver
Molecular factors, regulating the expression of specific glycolytic enzymes that favour biosynthetic processes, have remained unknown. Panasyuket al. identify PPARγ as a novel transcription factor turning on pyruvate kinase M2 and hexokinase 2, which are frequently upregulated in pathophysiological growth.
- Ganna Panasyuk
- , Catherine Espeillac
- & Mario Pende
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| Open AccessProstaglandin E2 and SOCS1 have a role in intestinal immune tolerance
The gut is populated by a myriad of microorganisms and how the immune system tolerates their presence is of great interest. Here, by studying colon morphology in multiple knockout mice, the authors demonstrate a potential role for prostaglandin E2 and SOCS1 in mediating immune tolerance.
- Takatoshi Chinen
- , Kyoko Komai
- & Akihiko Yoshimura
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Article
| Open AccessConformational rearrangement of gastric H+,K+-ATPase induced by an acid suppressant
The gastric proton pump, H+,K+-ATPase, contributes to stomach acidification and is a target of acid suppressants. Here, the three-dimensional structure of the pump is determined using electron crystallography, providing the first structural information about the binding of a new class of acid suppressants.
- Kazuhiro Abe
- , Kazutoshi Tani
- & Yoshinori Fujiyoshi
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