Featured
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| Open AccessEfficient intracellular delivery of proteins by a multifunctional chimaeric peptide in vitro and in vivo
Protein delivery with cell-penetrating peptides suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting treatment success. Here the authors present an intracellular protein delivery system and demonstrate efficient delivery in vitro and therapeutic efficacy in a liver failure model in vivo.
- Siyuan Yu
- , Han Yang
- & Ningshao Xia
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Article
| Open AccessIntestinal-derived FGF15 protects against deleterious effects of vertical sleeve gastrectomy in mice
The mechanisms that mediate the effects of weight loss surgeries such as vertical sleeve gastrectomy (VSG) are incompletely understood. Here the authors show that intestinal FGF15 is necessary to improve glucose tolerance and to prevent the loss of muscle and bone mass after VSG, potentially via protection against bile acid toxicity.
- Nadejda Bozadjieva-Kramer
- , Jae Hoon Shin
- & Randy J. Seeley
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Article
| Open AccessSuper enhancer regulation of cytokine-induced chemokine production in alcoholic hepatitis
Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.
- Mengfei Liu
- , Sheng Cao
- & Vijay H. Shah
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Article
| Open AccessCD8+ tissue-resident memory T cells promote liver fibrosis resolution by inducing apoptosis of hepatic stellate cells
The cellular and molecular mechanisms underlying the resolution of non-alcoholic steatohepatitis remain incompletely understood. Here the authors report a single cell-based analysis that identified CD8 + tissue-resident memory T cells, which contribute to resolution of liver fibrosis potentially via elimination of hepatic stellate cells through Fas-mediated cytotoxicity.
- Yuzo Koda
- , Toshiaki Teratani
- & Nobuhiro Nakamoto
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Article
| Open AccessMitochondrial transcription factor A in RORγt+ lymphocytes regulate small intestine homeostasis and metabolism
RORγt is known to play critical roles in the regulation of a number of immune cell subsets. Here the authors implicate mitochondrial transcription factor A in the regulation of intestinal RORγt + lymphocyte homeostasis and metabolic control in a murine in vivo model.
- Zheng Fu
- , Joseph W. Dean
- & Liang Zhou
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Article
| Open AccessInsulin protects acinar cells during pancreatitis by preserving glycolytic ATP supply to calcium pumps
Acute pancreatitis is a serious inflammatory disease, which is more severe in diabetic mice. Here the authors use mice lacking pancreatic acinar cell insulin receptors to show that this may be because insulin preserves glycolytic energy supply in acinar cell during pancreatitis, which prevents cytotoxic calcium overload and cell death.
- Jason I. E. Bruce
- , Rosa Sánchez-Alvarez
- & John A. Williams
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Article
| Open AccessArtificial intelligence guided discovery of a barrier-protective therapy in inflammatory bowel disease
Traditional drug discovery process use differential, Bayesian and other network based approaches. We developed a Boolean approach for building disease maps and prioritizing pre-clinical models to discover a first-in-class therapy to restore and protect the leaky gut barrier in inflammatory bowel disease.
- Debashis Sahoo
- , Lee Swanson
- & Pradipta Ghosh
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Article
| Open AccessPredicting disease course in ulcerative colitis using stool proteins identified through an aptamer-based screen
Stool biomarkers hold promise for monitoring disease activity and predicting clinical course in inflammatory bowel disease (IBD) as they originate from the inflamed tissue. Here the authors report an aptamer-based proteomic screen, and discover several stool proteins that predict remission at four weeks.
- Sanam Soomro
- , Suresh Venkateswaran
- & Chandra Mohan
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Article
| Open AccessMETTL3 promotes tumour development by decreasing APC expression mediated by APC mRNA N6-methyladenosine-dependent YTHDF binding
The epitranscriptomic regulation of adenomatous polyposis coli (APC) tumour suppressor gene in cancers is unclear. Here the authors show that N6-methyladenosine methylation writer METTL3 downregulates APC by recruiting YTHDF2 for APC mRNA degradation, and that this promotes glycolysis and tumour growth in oesophageal cancers.
- Wei Wang
- , Fei Shao
- & Zhimin Lu
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Article
| Open AccessMeasurement of lipogenic flux by deuterium resolved mass spectrometry
Fat synthesis is necessary for normal physiology, but its dysregulation contributes to the pathology of many diseases. Here, the authors report a high-resolution mass spectrometry approach that quantifies fat synthesis flux in humans and mice following a brief and low dose of deuterated water.
- Xiaorong Fu
- , Stanisław Deja
- & Shawn C. Burgess
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Article
| Open AccessRationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis
Fecal microbiota transplantation and probiotics have been tested/used as potential therapeutics against inflammatory bowel diseases (IBD). Here the authors use a bottom-up rational consortium design approach that combines well-characterized strains isolated from healthy human stool samples to produce two consortia of metabolically interdependent strains for the treatment of IBD.
- Daniel van der Lelie
- , Akihiko Oka
- & R. Balfour Sartor
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Article
| Open AccessEpigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption
While coffee and tea consumption has been associated with risk of diseases, their mechanisms of action remain elusive. Here the authors present a large EWAS on coffee and tea consumption in cohorts of European and African-American ancestries, finding that coffee consumption is associated with differential DNA methylation levels at multiple CpGs.
- Irma Karabegović
- , Eliana Portilla-Fernandez
- & Mohsen Ghanbari
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Article
| Open AccessA stem cell population at the anorectal junction maintains homeostasis and participates in tissue regeneration
Transition zones connect distinct epithelia, contain cells expressing stem cell markers, and contribute to cancer development. Here, the authors examine the mouse anorectal junction, identifying a population of Krt17-positive basal cells that contribute to squamous and glandular epithelia during homeostasis and repair.
- Louciné Mitoyan
- , Véronique Chevrier
- & Géraldine Guasch
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Article
| Open AccessEtiological, epidemiological, and clinical features of acute diarrhea in China
Diarrhoea is a major cause of morbidity and mortality in China. Here, the authors present results from a large sentinel surveillance scheme from 217 hospitals in all 31 provinces in mainland China, including ~150,000 patients with acute diarrhoea and covering years 2009-2018.
- Li-Ping Wang
- , Shi-Xia Zhou
- & Jun Wang
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Article
| Open AccessPrimary and secondary clarithromycin resistance in Helicobacter pylori and mathematical modeling of the role of macrolides
Clarithromycin is a macrolide antibiotic widely used for eradication of Helicobacter pylori infection. Here, Kocsmár et al. study clarithromycin resistance and previous macrolide consumption in 4,744 H. pylori-infected patients, shedding light into the sources of primary resistant cases and the role played by prior consumption of macrolides for non-eradication purposes.
- Éva Kocsmár
- , György Miklós Buzás
- & Gábor Lotz
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Article
| Open AccessNonlinear machine learning pattern recognition and bacteria-metabolite multilayer network analysis of perturbed gastric microbiome
Drug use or bacterial infection can cause significant alterations of gastric microbiome. Here, the authors show how advanced pattern recognition by nonlinear machine intelligence can help disclose a bacteria-metabolite network which enlightens mechanisms behind such perturbations.
- Claudio Durán
- , Sara Ciucci
- & Carlo Vittorio Cannistraci
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Article
| Open AccessSingle-cell analyses of Crohn’s disease tissues reveal intestinal intraepithelial T cells heterogeneity and altered subset distributions
Crohn’s disease results from transmural inflammation in the gut, but analyses of local immune populations are still lacking. Here, the authors show, by combining multiple single-cell approaches, that intraepithelial and lamina propria T cells are heterogenous, show unique phenotypes, and exhibit altered subsets upon inflammation.
- Natalia Jaeger
- , Ramya Gamini
- & Marco Colonna
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Article
| Open AccessTrans-illumination intestine projection imaging of intestinal motility in mice
Current preclinical imaging of intestine in animal models cannot reveal intestinal dynamics in awake condition. Here the authors report a Transillumination Intestine Projection (TIP) imaging system for free-moving mice, and showed the intestine dynamics in conscious animal in natural physiological states.
- Depeng Wang
- , Huijuan Zhang
- & Jun Xia
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Article
| Open AccessEnsembled deep learning model outperforms human experts in diagnosing biliary atresia from sonographic gallbladder images
It is still challenging to make accurate diagnosis of biliary atresia (BA) with sonographic gallbladder images particularly in rural areas without relevant expertise. Here, the authors develop a diagnostic deep learning model which favourable performance in comparison with human experts in multi-center external validation.
- Wenying Zhou
- , Yang Yang
- & Luyao Zhou
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Article
| Open AccessGWAS of peptic ulcer disease implicates Helicobacter pylori infection, other gastrointestinal disorders and depression
Genetic factors contribute to peptic ulcer disease (PUD). Here, the authors perform a genome-wide association analysis on PUD in the UK Biobank, highlighting shared architecture with other gastrointestinal disorders and possible causal links with depression.
- Yeda Wu
- , Graham K. Murray
- & Naomi R. Wray
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Article
| Open AccessInflammation status modulates the effect of host genetic variation on intestinal gene expression in inflammatory bowel disease
Inflammatory bowel diseases are heterogeneous, and little is known about how underlying genetic variation can affect their development. Here, the authors report that intestinal inflammation modulates the effect of host genetics on the gut mucosal expression of 190 genes in the context of inflammatory bowel diseases.
- Shixian Hu
- , Werna T. Uniken Venema
- & Rinse K. Weersma
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Article
| Open AccessMaternal aryl hydrocarbon receptor activation protects newborns against necrotizing enterocolitis
Necrotizing enterocolitis (NEC) is a disease of prematurity requiring Toll-like receptor 4 (TLR4) activation on the gut epithelium. Here the authors show that the aryl hydrocarbon receptor (AHR) mediates NEC pathogenesis via effects on TLR4, and that supplementing the diet with AHR ligands during pregnancy or postnatally prevents NEC.
- Peng Lu
- , Yukihiro Yamaguchi
- & David J. Hackam
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Matters Arising
| Open AccessHypothermic machine perfusion before viability testing of previously discarded human livers
- Otto B. van Leeuwen
- , Yvonne de Vries
- & Robert J. Porte
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Matters Arising
| Open AccessReply to ‘Hypothermic machine perfusion before viability testing of previously discarded human livers’
- Hynek Mergental
- , Richard W. Laing
- & Darius F. Mirza
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Article
| Open AccessSprouty2 limits intestinal tuft and goblet cell numbers through GSK3β-mediated restriction of epithelial IL-33
Dynamic regulation of colonic secretory cell numbers is a critical component of the response to intestinal injury and inflammation. Here, the authors show that loss of the intracellular signalling regulator Sprouty2 in the intestinal epithelial cells is a protective response to injury that leads to increased secretory cell numbers, thus limiting colitis severity.
- Michael A. Schumacher
- , Jonathan J. Hsieh
- & Mark R. Frey
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Article
| Open AccessGenome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology
Serum liver enzymes are used as markers of liver disease, their concentration influenced in part by genetic factors. Here the authors meta-analyse genome-wide association studies on the UK Biobank and BioBank Japan to evaluate the association of three liver enzymes with liver and other metabolic diseases.
- Vincent L. Chen
- , Xiaomeng Du
- & Elizabeth K. Speliotes
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Article
| Open AccessCD4 derived double negative T cells prevent the development and progression of nonalcoholic steatohepatitis
Hepatic inflammation contributes to the development of nonalcoholic steatohepatitis (NASH). Here, the authors show that a transfer of ex vivo generated CD4 derived double negative T cells can prevent the development and progression of NASH by suppression of inflammatory Th17 cells and M1 macrophages in mouse models.
- Guangyong Sun
- , Xinyan Zhao
- & Dong Zhang
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Article
| Open AccessMurine liver repair via transient activation of regenerative pathways in hepatocytes using lipid nanoparticle-complexed nucleoside-modified mRNA
When severely or chronically injured, the liver loses ability to regenerate. Here, the authors utilize transient lipid nanoparticle-enclosed HGF and EGF-encoding mRNA delivery to induce hepatocyte proliferation and harness recovery of liver function in murine acute and chronic liver injury models.
- Fatima Rizvi
- , Elissa Everton
- & Valerie Gouon-Evans
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Article
| Open AccessClostridioides difficile exploits toxin-mediated inflammation to alter the host nutritional landscape and exclude competitors from the gut microbiota
The effects of antibiotics on the gut microbiota can lead to enhanced colonization of Clostridioides difficile (C. difficile) and toxin-mediated pathogenesis. Here, using defined toxin-mutant strains and a murine model, the authors provide insights into how toxin-induced inflammation alters C. difficile metabolism, host tissue gene expression and gut microbiota, together influencing a beneficial niche for infection.
- Joshua R. Fletcher
- , Colleen M. Pike
- & Casey M. Theriot
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Article
| Open AccessLysosomal SLC46A3 modulates hepatic cytosolic copper homeostasis
The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function.
- Jung-Hwan Kim
- , Tsutomu Matsubara
- & Frank J. Gonzalez
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Article
| Open AccessInduced organoids derived from patients with ulcerative colitis recapitulate colitic reactivity
Although ulcerative colitis (UC) is a major type of inflammatory bowel disease, attempts to model it fully have fallen short. Here the authors use patient-derived iPS cells to develop a UC organoid model that recapitulates disease histological and functional features, and confirm the role of CXCL8/CXCR1 in pathogenesis.
- Samaneh K. Sarvestani
- , Steven Signs
- & Emina H. Huang
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Article
| Open AccessHigh-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance
High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells.
- Anil Kumar
- , Kumaran Sundaram
- & Huang-Ge Zhang
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Article
| Open AccessGut microbiota impact on the peripheral immune response in non-alcoholic fatty liver disease related hepatocellular carcinoma
Disease-specific gut microbiome signatures have been previously defined for patients with liver cirrhosis or hepatocellular carcinoma (HCC). Here the authors examine the composition of the gut microbiota in cirrhotic patients with non-alcoholic fatty liver disease with or without HCC and evaluate how dysbiosis influences peripheral immune responses.
- Jason Behary
- , Nadia Amorim
- & Amany Zekry
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Article
| Open AccessBariatric surgery induces a new gastric mucosa phenotype with increased functional glucagon-like peptide-1 expressing cells
GLP-1 is a gastrointestinal peptide that regulates gastric acid secretion and emptying, and due to the rapid degradation of intestinally secreted GLP-1 local gastric production has been suggested. Here the authors report the presence of GLP-1 expressing cells in the rat and human stomach, which contribute to the circulating GLP-1 levels and are affected by weight loss surgeries.
- Lara Ribeiro-Parenti
- , Anne-Charlotte Jarry
- & André Bado
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Article
| Open AccessHepatitis B virus rigs the cellular metabolome to avoid innate immune recognition
RIG-I is a cytosolic antiviral nucleic acid sensor that signals via MAVS to produce type 1 interferons. Here the authors show that hepatits B virus can repress this pathway by activating glycolysis and lactate production, enabling accumulated lactate to bind MAVS and prevent its mitochondrial localization.
- Li Zhou
- , Rui He
- & Shi Liu
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Article
| Open AccessHepatocyte-specific IL11 cis-signaling drives lipotoxicity and underlies the transition from NAFLD to NASH
IL11 contributes to the development of non-alcoholic steatohepatitis (NASH) through incompletely understood mechanisms. Here, the authors report that lipotoxicity-driven autocrine IL11 activity underlies hepatocyte metabolic dysfunction and death via a NOX4/ERK-mediated mechanism while paracrine IL11 activity stimulates hepatic stellate cells contributing to fibrosis and inflammation in the context of NASH.
- Jinrui Dong
- , Sivakumar Viswanathan
- & Anissa A. Widjaja
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Article
| Open AccessAn immune checkpoint score system for prognostic evaluation and adjuvant chemotherapy selection in gastric cancer
Expression patterns of immune checkpoints in patients with gastric cancer remain poorly characterized. Here the authors propose an immune scoring system based on the expression of six immunosuppressive ligands to improve the prognostic accuracy in gastric cancer patients and drive the selection of candidates for adjuvant chemotherapy.
- Jia-Bin Wang
- , Ping Li
- & Chao-Hui Zheng
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Perspective
| Open AccessA bioengineering perspective on modelling the intestinal epithelial physiology in vitro
Maria Antfolk and Kim Jensen discuss how to model intestinal epithelial cell function in the dish and how various physiologically important environmental conditions, for example, extracellular matrix, pressure and flow, can be modelled and how this is applicable to clinical work.
- Maria Antfolk
- & Kim B. Jensen
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Article
| Open AccessNeoadjuvant FLOT versus SOX phase II randomized clinical trial for patients with locally advanced gastric cancer
Neoadjuvant FLOT regimen has shown promising results for the treatment of locally advanced gastric cancer, however SOX regimen remains the preferred chemotherapy in Eastern countries. Here the authors report that the two therapies result in similar outcomes, measured as clinical downstaging and pathological response, in a phase II randomized clinical trial.
- Birendra Kumar Sah
- , Benyan Zhang
- & Zhenggang Zhu
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Article
| Open AccessFAM3D is essential for colon homeostasis and host defense against inflammation associated carcinogenesis
The cytokine like protein FAM3D (Fam3D in mice) is highly expressed in the digestive tract with unknown role in colon pathophysiology. Here, by using gene deficient mice, the authors show that Fam3D is critically involved in colon homeostasis, host defense against colitis-associated carcinogenesis, and the balance of microbiota.
- Weiwei Liang
- , Xinjian Peng
- & Ying Wang
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Article
| Open AccessAdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis
Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. Here the authors report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models.
- Hongjiao Xu
- , Qian Zhao
- & Xianxing Jiang
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Article
| Open AccessIRF3 prevents colorectal tumorigenesis via inhibiting the nuclear translocation of β-catenin
The alternative mechanisms of innate immunity in tumorigenesis of colorectal cancers are unclear. Here, the authors report a non-canonical function of IRF3, a mediator of innate immune signalling, in the suppression of colorectal tumorigenesis and this is via the inhibition of Wnt/β-catenin pathway.
- Miao Tian
- , Xiumei Wang
- & Xiaojian Wang
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Article
| Open AccessInhibition of aquaporin-3 in macrophages by a monoclonal antibody as potential therapy for liver injury
Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide, and hydrogen peroxide mediated oxidative stress has been implicated in liver injury. Here, the authors report the development of an anti-AQP3 monoclonal antibody, which alleviates liver injury in multiple mouse models.
- Mariko Hara-Chikuma
- , Manami Tanaka
- & Masato Yasui
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Article
| Open Access5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation
The relative enrichment of cancer stem cells after treatment results in tumour recurrence. Here, the authors show a mechanism where p53 induces WNT3, which increases the number of colorectal cancer stem cells following treatment of 5-fluorouracil.
- Yong-Hee Cho
- , Eun Ji Ro
- & Kang-Yell Choi
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Article
| Open AccessThe ALPK1/TIFA/NF-κB axis links a bacterial carcinogen to R-loop-induced replication stress
The bacterial pathogen Helicobacter pylori is known for its ability to induce DNA double-strand breaks in the genome of its target cells. Here, we show that H. pylori-induced DNA damage and replication stress occurs in S-phase cells as a result of R-loop-mediated transcription/replication conflicts that are triggered by activation of the ALPK1/TIFA/NF-κB signaling axis.
- Michael Bauer
- , Zuzana Nascakova
- & Anne Müller
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Article
| Open AccessRemote ischemic conditioning counteracts the intestinal damage of necrotizing enterocolitis by improving intestinal microcirculation
Necrotizing enterocolitis (NEC) is one of the most lethal gastrointestinal emergencies in neonates needing precision treatment. Here the authors show that remote ischemic conditioning is a non-invasive therapeutic method that enhances blood flow in the intestine, reduces damage, and improves NEC outcome.
- Yuhki Koike
- , Bo Li
- & Agostino Pierro
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Article
| Open AccessPhase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer
All-trans retinoic acid - ATRA- is known to remodulate the stroma of pancreatic cancer in mice. Here, the authors carried out a Phase Ib trial in pancreatic patients and show that ATRA in combination with chemotherapy is a safe potential treatment for patients with advanced pancreatic cancer, and demonstrate a stromal modulatory effect.
- Hemant M. Kocher
- , Bristi Basu
- & David J. Propper
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Article
| Open AccessEnteroendocrine cells couple nutrient sensing to nutrient absorption by regulating ion transport
Enteroendocrine cells (EECs) are specialized gastrointestinal cells that have a role in nutrient sensing and hormone secretion. Here the authors show that peptide YY from EECs regulates nutrient absorption in intestinal organoids.
- Heather A. McCauley
- , Andrea L. Matthis
- & James M. Wells
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Article
| Open AccessTelomere dysfunction activates YAP1 to drive tissue inflammation
How telomere dysfunction is directly linked to inflammation in humans is currently unclear. Here the authors reveal that telomere dysfunction drives activation of the YAP1 transcription factor, up-regulating the pro inflammatory factor, pro-IL-18 thus revealing a link between telomere dysfunction and initiation of intestinal inflammation.
- Deepavali Chakravarti
- , Baoli Hu
- & Ronald A. DePinho