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| Open AccessPredicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment
Predictive methods for gastric cancer to try and differentiate between potential treatment response are required. Here the authors use a multiplexed immunohistochemistry method to propose the proximity of tumour infiltrating immune cells as an indicator of likely therapeutic response.
- Yang Chen
- , Keren Jia
- & Lin Shen
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Article
| Open AccessMannose ameliorates experimental colitis by protecting intestinal barrier integrity
New potential therapies for inflammatory bowel disease are needed as not all patients respond to or maintain a response to conventional therapies. Here the authors report that mannose supplementation ameliorates experimental colitis in male mice, potentially via effects on intestinal epithelium lysosomal integrity.
- Lijun Dong
- , Jingwen Xie
- & Daming Zuo
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Article
| Open AccessMettl3-mediated mRNA m6A modification controls postnatal liver development by modulating the transcription factor Hnf4a
m6A is the most abundant RNA modification of eukaryotic mRNAs and is involved in various physiological and pathological processes. Here the authors show a role for Mettl3-mediated RNA m6A modification in postnatal liver development by regulating the Hnf4a-centered transcriptional network
- Yan Xu
- , Zhuowei Zhou
- & Qi Zhang
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Article
| Open AccessDeficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH)
Ectopic lipid accumulation and inflammation are the essential signs of NASH. Here, the authors show that hepatic WTAP is a key integrative repressor of ectopic lipid accumulation and inflammation during NASH progression, and hepatic deletion of Wtap promotes both of them, leading to NASH
- Xinzhi Li
- , Kaixin Ding
- & Zheng Chen
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Article
| Open AccessIn mouse chronic pancreatitis CD25+FOXP3+ regulatory T cells control pancreatic fibrosis by suppression of the type 2 immune response
The function of T regulatory cells in the tissue fibrosis in chronic pancreatitis is not fully understood. Here the authors use a mouse model of chronic pancreatitis to show that Treg cells reduce IL-4 mediated chronic inflammation in the pancreas associated with M2-like macrophages in vivo.
- Juliane Glaubitz
- , Anika Wilden
- & Matthias Sendler
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Article
| Open AccessCholesterol sulfate alleviates ulcerative colitis by promoting cholesterol biosynthesis in colonic epithelial cells
New treatment strategies are required for ulcerative colitis. Here the authors show in mouse models that cholesterol sulfate, an endogenous active cholesterol derivative, contributes to the healing of the mucosal barrier by promoting cholesterol biosynthesis in colonic epithelial cells and exhibits therapeutic efficacy against ulcerative colitis.
- Dongke Xu
- , Ruijun Ma
- & Xiaobo Li
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Article
| Open AccessLactational delivery of Triclosan promotes non-alcoholic fatty liver disease in newborn mice
Triclosan is an antimicrobial additive in consumer products that has been detected in human breast milk. Here the authors report that exposure of pregnant mice to triclosan leads to lactational exposure to newborns and the development of liver steatosis.
- André A. Weber
- , Xiaojing Yang
- & Robert H. Tukey
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Article
| Open AccessPancreatic tumor eradication via selective Pin1 inhibition in cancer-associated fibroblasts and T lymphocytes engagement
Pharmacological inhibition of the prolyl isomerase PIN1, highly expressed in cancer cells and cancer associated fibroblasts (CAF), has been proposed for cancer therapy. Here the authors report the design of a DNA-barcoded micellular system functionalized with antibodies targeting CAFs and a T cell recruiting aptamer to deliver the PIN1 inhibitor AG17724, showing antitumor response in preclinical models of pancreatic cancer.
- Jiaye Liu
- , Yang Wang
- & Yong Liu
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Article
| Open AccessLoss of immunity-related GTPase GM4951 leads to nonalcoholic fatty liver disease without obesity
Obesity is a major risk factor for fatty liver disease. Here, using a forward genetic screen, the authors identify the gene GM4951 as a GTPase involved in lipid oxidation and development of NAFLD in mice.
- Zhao Zhang
- , Yu Xun
- & Bruce Beutler
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Article
| Open AccessInstant diagnosis of gastroscopic biopsy via deep-learned single-shot femtosecond stimulated Raman histology
Diagnosis of gastric cancer currently requires gastroscopic biopsy, which requires time and expertize to perform. Here, the authors demonstrate a femto-SRS imaging method which showed high accuracy in diagnosing gastric cancer without the need for pathologistbased diagnosis.
- Zhijie Liu
- , Wei Su
- & Minbiao Ji
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Article
| Open AccessImbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment
Steatohepatitis is a chronic hepatic inflammation associated with increased risk of hepatocellular carcinoma progression. Here the authors show that intestinal dysbiosis in mice lacking the inflammasome sensor molecule NLRP6 aggravates steatohepatitis and accelerates liver cancer progression, a process that can be delayed by antibiotic treatment.
- Kai Markus Schneider
- , Antje Mohs
- & Christian Trautwein
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Article
| Open AccessInherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells
Inherited mutations in MUTYH have been shown to predispose patients to colorectal cancers. Here, the authors show that MUTYH mutations lead to an increased somatic base substitution mutation rate in normal intestinal epithelial cells, which is the likely cause for the increased cancer risk.
- Philip S. Robinson
- , Laura E. Thomas
- & Michael R. Stratton
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Article
| Open AccessHigh-dimensional profiling reveals Tc17 cell enrichment in active Crohn’s disease and identifies a potentially targetable signature
The T cell compartment in patients with Crohn's disease is dysregulated. Here the authors use cytometric profiling to reveal an enrichment of distinct Tc17 cells during active Crohn's disease and may suggest CD6 as a potential target for therapeutic studies.
- A.-M. Globig
- , A. V. Hipp
- & B. Bengsch
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Article
| Open AccessHost control and the evolution of cooperation in host microbiomes
Humans, and many other species, carry a large set of beneficial microbes. Here, the authors present new theory and data to argue that these vital relationships only work when hosts can control their microbiome and suppress wayward symbionts.
- Connor Sharp
- & Kevin R. Foster
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Article
| Open AccessProfiling Fusobacterium infection at high taxonomic resolution reveals lineage-specific correlations in colorectal cancer
Bacteria from the genus Fusobacterium can promote colorectal cancer (CRC) development; however, the exact Fusobacterium species involved in this process remain underexplored. Here, the authors develop a rpoB amplicon sequencing approach to identify Fusobacterium species and subspecies in CRC patient samples.
- Dexi Bi
- , Yin Zhu
- & Huanlong Qin
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Poster
| Open AccessImmune monitoring and treatment in immune-mediated inflammatory diseases
Immune monitoring assists in the diagnosis and clinical management of immune-mediated inflammatory diseases.
- Femke van Wijk
- , Marjolein de Bruin
- & Stefan Nierkens
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Article
| Open AccessMachine learning aided construction of the quorum sensing communication network for human gut microbiota
Microbes communicate with each other by Quorum sensing (QS) languages. Here the authors construct a QS database and the QS communication network to decipher intricate QSbased communications and form one of the key knowledge maps for human gut microbiota.
- Shengbo Wu
- , Jie Feng
- & Jianjun Qiao
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Article
| Open AccessInfluence of NAFLD and bariatric surgery on hepatic and adipose tissue mitochondrial biogenesis and respiration
Impaired mitochondrial function in liver tissue may contribute to the pathogenesis and disease progression of nonalcoholic fatty liver disease (NAFLD). Here the authors report that patients with obesity have lower mitochondrial capacity in adipose tissues but higher capacity in the liver, without overall associations to NAFLD severity, and that bariatric surgery increases hepatic mitochondrial respiration and mitochondrial biogenesis.
- Julie S. Pedersen
- , Marte O. Rygg
- & Flemming Dela
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Article
| Open AccessMutational landscape of normal epithelial cells in Lynch Syndrome patients
It is unclear whether somatic mutation rates are elevated in Lynch Syndrome (LS), which is the most common cause of hereditary colorectal cancer. Here, the authors use whole-genome sequencing and organoid cultures to show that normal tissues in LS patients are genomically stable, while ancestor cells of neoplastic tissues undergo multiple cycles of clonal evolution.
- Bernard C. H. Lee
- , Philip S. Robinson
- & Michael R. Stratton
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Article
| Open AccessSomatic whole genome dynamics of precancer in Barrett’s esophagus reveals features associated with disease progression
Barrett’s esophagus is a pre-malignant condition that can progress to esophageal cancer. Here, the authors carry out whole genome sequencing of samples from patients who did or did not progress to cancer and find that mutations in many genes occur regardless of progression status, but also find features associated with progressive disease.
- Thomas G. Paulson
- , Patricia C. Galipeau
- & Xiaohong Li
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Article
| Open AccessA systems genomics approach to uncover patient-specific pathogenic pathways and proteins in ulcerative colitis
Single Nucleotide Polymorphisms (SNPs) affect cellular regulatory networks, and SNP co-occurrences contribute to disease pathogenesis in ulcerative colitis (UC). Here the authors introduce iSNP, a precision medicine pipeline that combines genomics and network biology approaches to uncover patient specific pathways affected in complex diseases.
- Johanne Brooks-Warburton
- , Dezso Modos
- & Tamas Korcsmaros
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Article
| Open AccessIntestinal fibroblastic reticular cell niches control innate lymphoid cell homeostasis and function
Fibroblastic reticular cells (FRCs) support localisation of immune cells in secondary lymphoid tissues but less is known about the lamina propria. Here the authors use scRNA-seq and intestinal infection to characterise FRCs in the intestinal lamina propria and show specialised niches that foster innate lymphoid cells during homeostasis and infection.
- Hung-Wei Cheng
- , Urs Mörbe
- & Burkhard Ludewig
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Article
| Open AccessBMP feed-forward loop promotes terminal differentiation in gastric glands and is interrupted by H. pylori-driven inflammation
Helicobacter pylori causes gastric inflammation, gland hyperplasia and is linked to gastric cancer. Here the authors identify a BMP feedback loop between the stomach epithelium and surrounding stroma that controls gland homeostasis and demonstrate its interruption upon infection with H. pylori.
- Marta Kapalczynska
- , Manqiang Lin
- & Michael Sigal
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Article
| Open AccessAutophagy impairment in liver CD11c+ cells promotes non-alcoholic fatty liver disease through production of IL-23
The function of autophagy and how this affects non-alcoholic fatty liver disease is not fully known. Here the authors show that in mice with a targeted disruption of the autophagy pathway in CD11c+ cells, development of NAFLD is accelerated involving IL-23 and blocking of IL-23 reduces disease.
- Lauriane Galle-Treger
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessCharacterisation and induction of tissue-resident gamma delta T-cells to target hepatocellular carcinoma
Many cancer immune therapy approaches depend on an HLA-restricted neoantigen-specific T cell response. AUs show here that Zoledronic acid can expand, and induce tumour recognition by, a population of tissue resident memory gamma-delta T cells associated with an efficient anti-tumour immune response in hepatocellular carcinoma.
- Nekisa Zakeri
- , Andrew Hall
- & Mala K. Maini
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Article
| Open AccessAntibody decay, T cell immunity and breakthrough infections following two SARS-CoV-2 vaccine doses in inflammatory bowel disease patients treated with infliximab and vedolizumab
Vaccination is effective in protecting from COVID-19. Here the authors report immune responses and breakthrough infections in twice-vaccinated patients receiving anti-TNF treatments for inflammatory bowel disease, and find dampened vaccine responses that implicate the need of adapted vaccination schedules for these patients.
- Simeng Lin
- , Nicholas A. Kennedy
- & Jeannie Bishop
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Article
| Open AccessThe aberrant upregulation of exon 10-inclusive SREK1 through SRSF10 acts as an oncogenic driver in human hepatocellular carcinoma
Alternative splicing is dysregulated in hepatocellular carcinoma. Here, the authors investigate the role of the splice variant of Splicing Regulatory Glutamic Acid and Lysine Rich Protein 1 (SREK1) and its upstream regulator, Serine/arginine-rich splicing factor 10 (SRSF10) in sustaining the oncogenic signal.
- Cunjie Chang
- , Muthukumar Rajasekaran
- & Jianxiang Chen
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Article
| Open AccessDeep proteomic profiling unveils arylsulfatase A as a non-alcoholic steatohepatitis inducible hepatokine and regulator of glycemic control
Non-alcoholic steatohepatitis (NASH) and type 2 diabetes are closely linked, but the connecting pathophysiological mechanisms are incompletely understood. Here the authors identify arylsulfatase A as a NASH-induced hepatokine that inhibits hepatic lysophosphatidylcholine and lysophosphatidic acid secretion, and improves muscle insulin action and systemic glucose homeostasis.
- Magdalene K. Montgomery
- , Jacqueline Bayliss
- & Matthew J. Watt
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Article
| Open AccessSIRT1 selectively exerts the metabolic protective effects of hepatocyte nicotinamide phosphoribosyltransferase
NAD + metabolism is potential target to treat metabolic disorders, in part due to the effects of the NAD + dependent enzyme Sirt1. Here the authors report that hepatic nicotinamide phosphoribosyltransferase, a rate-limiting step in the NAD + salvage pathway, regulates dark-cycle thermogenesis in a Sirt1-dependent but light-cycle thermogenesis and glucose homeostasis in a Sirt1-independent manner.
- Cassandra B. Higgins
- , Allyson L. Mayer
- & Brian J. DeBosch
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Article
| Open AccessThe E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease with complex disease mechanisms. Here the authors report that the E3 ubiquitin-protein ligase Trim31 mitigates development of NASH via inhibition of rhomboid 5 homolog 2 (Rhbdf2) in mice.
- Minxuan Xu
- , Jun Tan
- & Bochu Wang
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Article
| Open AccessKindlin-2 haploinsufficiency protects against fatty liver by targeting Foxo1 in mice
Here, the authors show that expression of kindlin-2 is increased in patients with nonalcoholic fatty liver disease (NAFLD). In mouse models, specific deletion of kindlin-2 in liver ameliorates, while its overexpression exacerbates, NAFLD by modulating Foxo1 in hepatocytes.
- Huanqing Gao
- , Liang Zhou
- & Guozhi Xiao
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Article
| Open AccessHypoxia-induced macropinocytosis represents a metabolic route for liver cancer
Cancer cells rely on macropinocytosis to scavenge extracellular proteins for growth. Here the authors show that macropinocytosis supports the survival of hypoxic hepatocellular carcinoma cells and this is dependent on HIF-1, which in turns activates the transcription of a membrane ruffling protein, EH domain-containing protein 2.
- Misty Shuo Zhang
- , Jane Di Cui
- & Carmen Chak-Lui Wong
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Article
| Open AccessAn efficient urine peptidomics workflow identifies chemically defined dietary gluten peptides from patients with celiac disease
Gluten peptides from wheat enter the bloodstream and are excreted in urine but are yet to be chemically characterised. Here, the authors show by mass spectrometry that quantitative and qualitative differences in urinary peptides can be detected between healthy people and patients with celiac disease.
- Brad A. Palanski
- , Nielson Weng
- & Joshua E. Elias
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Article
| Open AccessThe spatial transcriptomic landscape of the healing mouse intestine following damage
The colon is comprised of specialized cells that interact with each other to function, however, the molecular regionalization of the colon is incompletely understood. Here, the authors use spatial transcriptomics to generate a publicly available resource defining the transcriptomic regionalization of the colon during steady state and mucosal healing.
- Sara M. Parigi
- , Ludvig Larsson
- & Eduardo J. Villablanca
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Article
| Open AccessFormyl peptide receptor 2 determines sex-specific differences in the progression of nonalcoholic fatty liver disease and steatohepatitis
Prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) higher in men than premenopausal women. Here the authors report that formyl peptide receptor 2 (FPR2) levels are regulated by estrogen, and that FPR2 contributes to NAFLD resistance in female mice.
- Chanbin Lee
- , Jieun Kim
- & Youngmi Jung
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Article
| Open AccessDepletion of mitochondrial methionine adenosyltransferase α1 triggers mitochondrial dysfunction in alcohol-associated liver disease
Lower activity of MATα1, which catalyzes the synthesis of the methyl donor S-adenosylmethionine, and mitochondrial dysfunction occur in alcohol-associated liver disease (ALD). Here the authors report that the peptidyl-prolyl cis/trans isomerase PIN1 mediates a selective depletion of MATα1 in the mitochondria, which contributes to mitochondrial dysfunction and fat accumulation, in mouse models of ALD.
- Lucía Barbier-Torres
- , Ben Murray
- & Shelly C. Lu
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Article
| Open AccessTransglutaminase 3 crosslinks the secreted gel-forming mucus component Mucin-2 and stabilizes the colonic mucus layer
The colonic mucus layer is an organized system providing a physical barrier against pathogens and simultaneously harbouring the commensal flora. Here the authors report that transglutaminase 3 activity contributes to homeostasis of the colonic mucus layer and the lack of this enzymatic activity leads to increased susceptibility against DSS-induced colitis in mice.
- Jack D. A. Sharpen
- , Brendan Dolan
- & Christian V. Recktenwald
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Article
| Open AccessReduced infant rhesus macaque growth rates due to environmental enteric dysfunction and association with histopathology in the large intestine
Environmental enteric dysfunction (EED), a subclinical disorder of intestinal function, is associated with malnutrition, infant growth stunting and pathologies in the small intestine. Here the authors report that infant rhesus macaques that are naturally exposed to enteric pathogens commonly linked to human growth stunting present with EED and growth faltering that associates with large intestine pathologies.
- Sara M. Hendrickson
- , Archana Thomas
- & Mark K. Slifka
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Article
| Open AccessGut microbiota promotes cholesterol gallstone formation by modulating bile acid composition and biliary cholesterol secretion
Metabolic conditions associated with alterations of the gut microbiome, such as obesity and diabetes, predispose to gallstone disease. Here the authors demonstrate that the gut microbiome, in particular the genus Desulfovibrionale, contribute to gallstone formation in mice.
- Hai Hu
- , Wentao Shao
- & Aihua Gu
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Article
| Open AccessMaternal regulation of biliary disease in neonates via gut microbial metabolites
The pathogenesis of biliary atresia remains poorly understood. Here, the authors report that maternal butyrate treatment alters the gut microbiome and glutamine/hypoxanthine metabolites similar to human subjects, and suppresses biliary atresia in newborn mice.
- Jai Junbae Jee
- , Li Yang
- & Jorge A. Bezerra
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Article
| Open AccessMicrobial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract
Triclosan (TCS), an antimicrobial agent commonly found in consumer products, has been reported to exacerbates colitis in animal models. Here, using in vitro and in vivo approaches, the authors show that gut bacterial enzymes can drive the metabolic activation and gut toxicity of TCS, highlighting an important role of intestinal microbial factors in the complex etiology of colitis.
- Jianan Zhang
- , Morgan E. Walker
- & Guodong Zhang
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Article
| Open AccessIntraperitoneal microbial contamination drives post-surgical peritoneal adhesions by mesothelial EGFR-signaling
Abdominal surgery can often lead to complications including the formation of peritoneal adhesions and the molecular mechanisms underlying this process are still unknown. Here, the authors suggest that bacterial contamination drives adhesion formation through mesothelial EGFR signalling.
- Joel Zindel
- , Jonas Mittner
- & Daniel Candinas
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Article
| Open AccessDirectly recruited GATA6 + peritoneal cavity macrophages contribute to the repair of intestinal serosal injury
Upon intestinal injury, bone marrow derived monocytes are recruited to the damaged site through the bloodstream. Authors here show that peritoneal cavity macrophages directly migrate to the damaged intestine in an ATP and hyaluronan dependent manner, and participate in the restoration of tissue integrity.
- Masaki Honda
- , Masashi Kadohisa
- & Taizo Hibi
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Article
| Open AccessThe methyltransferase METTL3 negatively regulates nonalcoholic steatohepatitis (NASH) progression
Mechanisms that underlie the progression of non-alcoholic fatty liver disease to the more severe non-alcoholic steatohepatitis are incompletely understood. Here the authors show that METTL3, a RNA methyltransferase that catalyzes mRNA m6 modifications, negatively regulates NASH progression via inhibiting the transcription of Cd36 and Ccl2.
- Xinzhi Li
- , Bingchuan Yuan
- & Zheng Chen
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Article
| Open AccessSpatial Transcriptomics to define transcriptional patterns of zonation and structural components in the mouse liver
Global transcriptional differences across lobular units in the liver remain unknown. Here the authors perform spatial transcriptomics of liver tissue to delineate transcriptional differences in physical space, confirm lobular zonation along transcriptional gradients and suggest the presence of previously uncharacterized structures within liver tissue.
- Franziska Hildebrandt
- , Alma Andersson
- & Johan Ankarklev
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Article
| Open AccessDietary excess regulates absorption and surface of gut epithelium through intestinal PPARα
Intestinal surface changes in size and function, but what propels these alterations is unknown. Here, the authors show that food excess increases the gut absorptive capacity, and that in presence of dietary lipids, intestinal PPARα is indispensable for the adaptive increase in villi length and function.
- Ozren Stojanović
- , Jordi Altirriba
- & Mirko Trajkovski
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Article
| Open AccessDesmoplakin and periplakin genetically and functionally contribute to eosinophilic esophagitis
Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease with a complex underlying genetic etiology. Here, the authors identify a series of rare variants in DSP and PPL in multiplex families with EoE and uncover a pathogenic role for desmosomal dysfunction in EoE.
- Tetsuo Shoda
- , Kenneth M. Kaufman
- & Marc E. Rothenberg
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Article
| Open AccessDysbiosis of human gut microbiome in young-onset colorectal cancer
The incidence of young-onset sporadic colorectal cancer (yCRC) is rapidly rising and frequently associated with an aggressive disease. Here the authors show that gut microbial diversity is increased in patients with yCRC compared to old-onset CRC and that fecal microbial markers could be used to detect individuals with yCRC.
- Yongzhi Yang
- , Lutao Du
- & Yanlei Ma
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Article
| Open AccessPsychological stress impairs IL22-driven protective gut mucosal immunity against colonising pathobionts
Altered gut microbiome and exacerbation of symptoms at times of psychological stress are feature characteristics of Crohn’s disease. Here authors show in a mouse model that psychological stress impairs IL-22-dependent protective immunity of the ileal mucosa, which allows invasive bacteria to colonise the gut.
- Christopher R. Shaler
- , Alexandra A. Parco
- & Brian K. Coombes