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| Open AccessA patient-based iPSC-derived hepatocyte model of alcohol-associated cirrhosis reveals bioenergetic insights into disease pathogenesis
Most people affected by Alcohol Use Disorder do not develop cirrhosis. Here, the authors show that induced pluripotent stem cell-derived hepatocytes from patients with Alcohol Cirrhosis, have impaired cell energy production and were more susceptible to oxidative stress, which is partially reversed by treatment with Aramchol.
- Bani Mukhopadhyay
- , Cheryl Marietta
- & David Goldman
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Article
| Open AccessGut microbiome composition and metabolic activity in women with diverticulitis
Here, the authors present a multi-omics examination of stool samples obtained from individuals with diverticulitis and controls, uncovering disruptions in the balance of microbial composition and metabolites, as well as co-occurring microbe-metabolite associations relevant to the disease.
- Wenjie Ma
- , Yiqing Wang
- & Andrew T. Chan
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| Open AccessThe gut commensal Blautia maintains colonic mucus function under low-fiber consumption through secretion of short-chain fatty acids
Here, the authors show that elevating fiber intake in humans alters their gut microbiota, which, upon transplantation into mice, enhances intestinal mucus function, and identify a crucial role played by the commensal bacterium Blautia and its fermentation products.
- Sandra M. Holmberg
- , Rachel H. Feeney
- & Bjoern O. Schroeder
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| Open AccessDiet changes due to urbanization in South Africa are linked to microbiome and metabolome signatures of Westernization and colorectal cancer
Here, the authors present a comparative analysis of the diet, microbiome and metabolome of rural and urban Xhosa people in South Africa, associating urban diets with higher abundances of pro-neoplastic microbial metabolites.
- M. C. Ramaboli
- , S. Ocvirk
- & S. J. D. O’Keefe
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| Open AccessMalnutrition enteropathy in Zambian and Zimbabwean children with severe acute malnutrition: A multi-arm randomized phase II trial
Childhood malnutrition in Africa is a glaring example of global inequality, and mortality remains high. Here, the authors report the results of the TAME randomized phase II clinical trial, in which intestinal healing was the target of four potential interventions in malnourished children in Zambia and Zimbabwe.
- Kanta Chandwe
- , Mutsa Bwakura-Dangarembizi
- & Paul Kelly
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| Open AccessBacterial peptidoglycan acts as a digestive signal mediating host adaptation to diverse food resources in C. elegans
Here, by using a food digestion model in C. elegans, the authors identify a mechanism by which bacterial peptidoglycan (PGN) interacts with Bacterial Colonization Factor-1 (BCF-1) triggering C. elegans to expand its ability to consume a wide range of foods in their natural environment.
- Fanrui Hao
- , Huimin Liu
- & Bin Qi
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Article
| Open Accessp53 promotes revival stem cells in the regenerating intestine after severe radiation injury
The tumor suppressor p53 is the guardian of the genome. Here, the authors use comprehensive approaches to demonstrate that transient p53 activity induces revival stem cells to promote the regeneration of severely irradiated intestinal epithelium in mice.
- Clara Morral
- , Arshad Ayyaz
- & David G. Kirsch
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| Open AccessThe secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation
Microbiome-secreted proteins act as key modulators of host-microbiome crosstalk. Here, the authors show that Amuc_1409 protein, secreted from Akkermansia muciniphila, plays a key role in intestinal homeostasis by regulating intestinal stem cells through interaction with E-cadherin, indicating its potential as a biomolecule for improving gut health.
- Eun-Jung Kang
- , Jae-Hoon Kim
- & Chul-Ho Lee
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Article
| Open AccessTargeting pathogenic CD8+ tissue-resident T cells with chimeric antigen receptor therapy in murine autoimmune cholangitis
CD8 + T cells play an important role in primary biliary cholangitis (PBC). In this study, the authors demonstrate that PD-1-expressing CD8+ liver-resident T cells are pathogenic in murine PBC and that targeting these cells using a chimaeric antigen receptor reduces disease severity.
- Hao-Xian Zhu
- , Shu-Han Yang
- & Zhe-Xiong Lian
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Article
| Open AccessDysregulation of Wnt/β-catenin signaling contributes to intestinal inflammation through regulation of group 3 innate lymphoid cells
RORγt+ group 3 innate lymphoid cells are intimately involved in intestinal homeostasis, their dysregulation is linked to inflammatory gut diseases. Here the authors show that dysregulated Wnt/β-catenin signalling contributes to disturbed regulation of group 3 innate cells and intestinal inflammation.
- Jiacheng Hao
- , Chang Liu
- & Xiaohuan Guo
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Article
| Open AccessIdentification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms
The current stratification of Intraductal Papillary Mucinous Neoplasms (IPMN) is based on clinical and histological features rather than molecular ones. Here, the authors use spatial transcriptomics to characterise IPMN patient samples, and identify markers associated with progression to pancreatic cancer.
- Antonio Agostini
- , Geny Piro
- & Carmine Carbone
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Article
| Open AccessDiindoles produced from commensal microbiota metabolites function as endogenous CAR/Nr1i3 ligands
Here, combining metabolomic, proteomic and biophysical analyses, the authors identify and characterize a series of diindole molecules produced from commensal bacteria metabolites that act as specific agonists for the orphan constitutive androstane receptor (CAR), having potential to modulate gut and liver inflammation, metabolic diseases and cancer.
- Jiabao Liu
- , Ainaz Malekoltojari
- & Henry M. Krause
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Article
| Open AccessAutologous cell transplantation for treatment of colorectal aganglionosis in mice
Neurointestinal diseases cause significant morbidity and effective treatments are lacking. Here, authors perform autologous cell transplantation of enteric neural stem cells in a mouse model of colonic aganglionosis and report restoration of colonic contractile activity.
- Weikang Pan
- , Ahmed A. Rahman
- & Ryo Hotta
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| Open AccessHarnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation
Developing clinically predictive model systems for evaluating gene transfer and gene editing technologies has become increasingly important. This study introduces human liver ex situ normothermic perfusion as a model to evaluate gene therapy vectors, paving the way for advanced liver disease treatment.
- Marti Cabanes-Creus
- , Sophia H. Y. Liao
- & Leszek Lisowski
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| Open AccessInhibition of 7-dehydrocholesterol reductase prevents hepatic ferroptosis under an active state of sterol synthesis
Ferroptosis has been connected to liver disease through unclear mechanisms. Here, the authors identify the terminal enzyme of cholesterol synthesis, 7-dehydrocholesterol reductase, as a regulator of ferroptosis in hepatocytes that suppresses ferroptosis through 7-dehydrocholesterol accumulation.
- Naoya Yamada
- , Tadayoshi Karasawa
- & Masafumi Takahashi
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Article
| Open AccessEnabling large-scale screening of Barrett’s esophagus using weakly supervised deep learning in histopathology
Diagnosis of Barrett’s esophagus depends on pathologist assessment of stained slides. Here, the authors utilise a deep learning approach to prioritize potential cases using diagnostic labels in two datasets, with the aim to improve Barrett’s screening capacity.
- Kenza Bouzid
- , Harshita Sharma
- & Javier Alvarez-Valle
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Article
| Open AccessMagnetically driven capsules with multimodal response and multifunctionality for biomedical applications
Untethered capsules exhibit clinical promise for diagnosing and treating gastrointestinal diseases. Here, the authors develop small-scale magnetically driven capsules featuring a distinct magnetic soft valve, integrating multiple functional and motion modalities for biomedical applications.
- Yuxuan Sun
- , Wang Zhang
- & Liang Li
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Article
| Open AccessBTLA contributes to acute-on-chronic liver failure infection and mortality through CD4+ T-cell exhaustion
Acute-on-chronic liver failure (ACLF) is characterized by rapid deterioration of liver function in patients with chronic liver disease. Here, the authors show that BTLA expression in CD4+ T cells is associated with disease severity and inflammation in hepatitis B virus-related ACLF.
- Xueping Yu
- , Feifei Yang
- & Jiming Zhang
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| Open AccessTargeted delivery of Fc-fused PD-L1 for effective management of acute and chronic colitis
Triggering the PD-1/PD-L1 immune checkpoint is an attractive therapeutic approach in inflammatory bowel disease, and PD-L1, conjugated to the Fc part of an immunoglobulin (PD-L1-Fc) has been shown to be effective in mouse models. Here authors show that fusing to reactive oxygen species (ROS)-responsive nanoparticles improves effect of PD-L1-Fc due to targeting to inflammation sites, while systemic toxicity is reduced.
- Xudong Tang
- , Yangyang Shang
- & Lei Chen
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| Open AccessThe gut ileal mucosal virome is disturbed in patients with Crohn’s disease and exacerbates intestinal inflammation in mice
Gut bacteriome dysbiosis has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Here, they authors characterize the small bowel (terminal ileum) virome and bacteriome of patients with Crohn´s Disease (CD), and show that ileal virions from CD patients causally exacerbate intestinal inflammation in IBD mouse models.
- Zhirui Cao
- , Dejun Fan
- & Tao Zuo
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Article
| Open AccessIntestinal IL-22RA1 signaling regulates intrinsic and systemic lipid and glucose metabolism to alleviate obesity-associated disorders
Interleukin (IL)-22 is critical in ameliorating obesity-induced metabolic disorders; however, it is unclear where IL-22 acts to mediate these outcomes. Here, the authors show in tissue-specific IL-22 receptor knockout mice a key role of intestinal epithelium-specific IL-22RA1 signaling in regulating intestinal metabolism and alleviating obesity-associated disorders.
- Stephen J. Gaudino
- , Ankita Singh
- & Pawan Kumar
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| Open AccessMucosal host-microbe interactions associate with clinical phenotypes in inflammatory bowel disease
Here, through parallel profiling of the mucosal transcriptome and microbiome of intestinal biopsies derived from patients with IBD and from non-IBD controls, the authors characterize interactions between gene expression and microbiota composition associated with traits of patients with inflammatory bowel diseases. Peer Review Information: Nature Communications thanks Robert Häsler, and the other, anonymous, reviewers for their contribution to the peer review of this work. A peer review file is available.
- Shixian Hu
- , Arno R. Bourgonje
- & Rinse K. Weersma
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| Open AccessDubosiella newyorkensis modulates immune tolerance in colitis via the L-lysine-activated AhR-IDO1-Kyn pathway
Here, Zhang et al. identify a metabolic axis by which Lys-producing commensal bacterium Dubosiella newyorkensis mediates a Treg-mediated immunosuppressive microenvironment by activating AhR-IDO1-Kyn metabolic circuitry in dendritic cells.
- Yanan Zhang
- , Shuyu Tu
- & Shu Jeffrey Zhu
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Article
| Open AccessEFHD2 suppresses intestinal inflammation by blocking intestinal epithelial cell TNFR1 internalization and cell death
Physiologically, the host suppresses intestinal epithelial cell death to prevent intestinal inflammation. Here, the authors show that EF-hand domain-containing protein D2 (EFHD2) endogenously suppresses intestinal epithelial cell death by blocking TNFR1 internalization and protects the intestine from excessive inflammation.
- Jiacheng Wu
- , Xiaoqing Xu
- & Xuetao Cao
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Article
| Open AccessSonic hedgehog-heat shock protein 90β axis promotes the development of nonalcoholic steatohepatitis in mice
The mechanistic involvement of sonic hedgehog signaling in nonalcoholic steatohepatitis is not clear. Here, the authors show that sonic hedgehog protein regulates the stability of HSP90β, enabling hepatocytes to secrete exosomes containing miR-28-5-p to promote NASH development.
- Weitao Zhang
- , Junfeng Lu
- & Xiaojun Xu
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| Open AccessHeterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage
Hepatocytes regenerate the liver after injury, however, the tissue repair mechanisms have been little explored. Here, the authors show that midlobular and pericentral hepatocytes increase their number and size in response to chemical, physical, and viral insults facilitating liver regeneration.
- Inmaculada Ruz-Maldonado
- , John T. Gonzalez
- & Carlos Fernández-Hernando
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| Open AccessA multicenter clinical AI system study for detection and diagnosis of focal liver lesions
Early detection and accurate diagnosis of focal liver lesions are crucial for effective treatment and prognosis. Here, the authors present a fully automated diagnostic system that leverages multi-phase CT scans and clinical features, for diagnosing liver lesions.
- Hanning Ying
- , Xiaoqing Liu
- & Xiujun Cai
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Article
| Open AccessIdentification of myeloid-derived growth factor as a mechanically-induced, growth-promoting angiocrine signal for human hepatocytes
After partial liver resection, the remaining liver blood vessels receive more blood flow and get mechanically stretched. Here the authors show that MYDGF is released from the stretched cells of these liver vessels, and that it is required and sufficient to promote liver regeneration and cell proliferation.
- Linda Große-Segerath
- , Paula Follert
- & Eckhard Lammert
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Article
| Open AccessEtrolizumab-s fails to control E-Cadherin-dependent co-stimulation of highly activated cytotoxic T cells
The clinical success of anti- αEβ7 antibody Etrolizumab for Crohn’s disease is less than what is expected based on proof-of-concept studies. Here authors show, by characterization of T cells from Etrolizumab-treated patients, in vitro functional assays and reanalysis of public single cell datasets on Etrolizumab-treated patients, that at high level of T cell activation, which characterises T cells in Crohn’s disease, E-Cadherin-αEβ7 interactions become resistant to Etrolizumab inhibition.
- Maximilian Wiendl
- , Mark Dedden
- & Sebastian Zundler
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| Open AccessIntraocular liver spheroids for non-invasive high-resolution in vivo monitoring of liver cell function
Longitudinal monitoring of liver function in vivo is hindered by the lack of high-resolution non-invasive imaging techniques. Here, the authors show a crucial and unique tool for longitudinal in vivo imaging of liver spheroids at cellular resolution to study liver physiology and disease.
- Francesca Lazzeri-Barcelo
- , Nuria Oliva-Vilarnau
- & Per-Olof Berggren
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Article
| Open AccessEngineering tumor-colonizing E. coli Nissle 1917 for detection and treatment of colorectal neoplasia
There is an unmet medical need for the detection and treatment of early adenomas to prevent their progression to malignant disease. Here the authors show that orally administered E. coli Nissle 1917 can selectively colonize adenomas in mouse models and in patients as a detection tool, as well as deliver immunotherapeutics for colorectal neoplasia treatment.
- Candice R. Gurbatri
- , Georgette A. Radford
- & Tal Danino
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| Open AccessMacro CD5L+ deteriorates CD8+T cells exhaustion and impairs combination of Gemcitabine-Oxaliplatin-Lenvatinib-anti-PD1 therapy in intrahepatic cholangiocarcinoma
The role of the tumor microenvironment in immunotherapy response in intrahepatic cholangiocarcinoma remains unclear. Here, single cell RNA and TCR sequencing of samples before and after immunotherapy highlights the role of CD8 T-cell status conversion and exhaustion induced by Macro CD5L+ in treatment response.
- Jia-Cheng Lu
- , Lei-Lei Wu
- & Jia Fan
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| Open AccessEfficacy of Bifidobacterium animalis subsp. lactis BL-99 in the treatment of functional dyspepsia: a randomized placebo-controlled clinical trial
Functional dyspepsia (FD) is a common chronic gastrointestinal disorder. Here, in a randomized, parallel-group, positive-drug, and placebo-controlled clinical trial, the authors show that supplementation with the probiotic Bifidobacterium animalis subsp. lactis BL-99 (BL-99) improves FD clinical response rate and promotes accumulation of SCFA-producing microbiota.
- Qi Zhang
- , Guang Li
- & Fazheng Ren
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Article
| Open AccessFatty acid synthesis suppresses dietary polyunsaturated fatty acid use
Polyunsaturated Fatty Acids (PUFA), such as omega-3 fatty acids, are recognized for their lipid lowering and anti-inflammatory properties. Here, the authors show that endogenous lipid synthesis controls the use of PUFA and thus determine the therapeutic benefit of omega-3 fatty acid supplementation.
- Anna Worthmann
- , Julius Ridder
- & Christian Schlein
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Article
| Open AccessBinge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease
Deaths from alcohol-related liver disease have sharply increased following the Covid-19 pandemic. Here, the authors show that binge-pattern alcohol consumption, genetic factors and the presence of diabetes mellitus confer the greatest risk, allowing targeted interventions for high-risk individuals.
- Chengyi Ding
- , Linda Ng Fat
- & Gautam Mehta
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Article
| Open AccessSenescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity
Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signalling molecules in metabolic processes. Here, the author show 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes age-related steatosis.
- Jinjie Duan
- , Wenhui Dong
- & Chunjiong Wang
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Article
| Open AccessIgG and IgM cooperate in coating of intestinal bacteria in IgA deficiency
IgA protects mucosal barriers by coating microorganisms, yet infection related complications are rare in human IgA deficiency. Authors here show that in humans lacking IgA, IgG assists IgM in coating of most bacterial families, thus contributing to gut mucosal defence.
- Carsten Eriksen
- , Janne Marie Moll
- & Susanne Brix
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Article
| Open AccessHealth-related quality of life is linked to the gut microbiome in kidney transplant recipients
Here, Swarte et al. use metagenomics to investigate the association between the gut microbiome and Health-Related Quality of Life (HRQoL) in kidney transplant recipients, showing evidence for the association of multiple taxonomic, metabolic and neuroactive pathways (gut brain modules) with lower HRQoL, together suggesting potential modifiable gut microbial factors to improve HRQoL.
- J. Casper Swarte
- , Tim J. Knobbe
- & Rinse K. Weersma
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Article
| Open AccessBile proteome reveals biliary regeneration during normothermic preservation of human donor livers
Normothermic machine perfusion (NMP) is increasingly used for preserving and evaluating donor livers before transplantation. Here, the authors demonstrate increased regenerative protein profiles in the bile of perfused livers considered suitable for transplantation, providing insight into the mechanisms linked to recovery of the biliary tree following ischemia-reperfusion injury.
- Adam M. Thorne
- , Justina C. Wolters
- & Vincent E. de Meijer
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Article
| Open AccessMapping and modeling human colorectal carcinoma interactions with the tumor microenvironment
Tumour-microenvironment interactions, pivotal in cancer progression, are challenging to replicate in vitro. Here, the authors use single-cell RNA-seq to analyse these interactions in colorectal cancer within organoid models, and aim to emulate and understand these crucial interactions by introducing specific microenvironmental components.
- Ning Li
- , Qin Zhu
- & Christopher J. Lengner
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Article
| Open AccessMulti-omics analysis of hospital-acquired diarrhoeal patients reveals biomarkers of enterococcal proliferation and Clostridioides difficile infection
Antibiotics can cause hospital-acquired diarrhoea, resulting in gut microbiota and metabolome changes. Here, the authors study the faecal microbiota and metabolome of 169 patients, offering insights into these changes, and identified biomarkers for diagnostics.
- Marijana Bosnjak
- , Avinash V. Karpe
- & Dena Lyras
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| Open AccessParabacteroides distasonis ameliorates insulin resistance via activation of intestinal GPR109a
Here, the authors show that the gut commensal Parabacteroides distasonis alleviates insulin resistance via nicotinic acid-intestinal GPR109a axis activation, a process promoted by Dendrobium officinale polysaccharide.
- Yonggan Sun
- , Qixing Nie
- & Shaoping Nie
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Article
| Open AccessIntestinal Atp8b1 dysfunction causes hepatic choline deficiency and steatohepatitis
Choline is an essential nutrient derived primarily from dietary phosphatidylcholine, and its deficiency causes steatohepatitis. Here, the authors show that intestinal Atp8b1 contributes to choline metabolism through lysoPC absorption and that its dysfunction causes choline deficiency and steatohepatitis.
- Ryutaro Tamura
- , Yusuke Sabu
- & Hisamitsu Hayashi
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Article
| Open AccessZHX2 emerges as a negative regulator of mitochondrial oxidative phosphorylation during acute liver injury
Mitochondria dysfunction contributes to acute liver injuries. Zhang et al. find that Zhx2 deletion enhances mitochondrial function by promoting electron transport chain gene expression via PGC-1α dependent and independent manner.
- Yankun Zhang
- , Yuchen Fan
- & Chunhong Ma
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Article
| Open AccessIndocyanine green fluorescence imaging-guided versus conventional laparoscopic lymphadenectomy for gastric cancer: long-term outcomes of a phase 3 randomised clinical trial
Due to high rate of metastasis, lymphadenectomy is a cornerstone of the surgical treatment of gastric cancer however the accurate dissection of lymph nodes (LN) can be challenging. Here, the authors present the long-term outcomes of a randomised control trial investigating indocyanine green fluorescence image-guided LN retrieval in gastric cancer patients undergoing laparoscopic gastrectomy.
- Qi-Yue Chen
- , Qing Zhong
- & Chang-Ming Huang
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Article
| Open AccessMicrobiome and metabolome features in inflammatory bowel disease via multi-omics integration analyses across cohorts
Gut microbiota play pivotal roles in IBD. Here, Ning et al. use a multi-omics approach to characterize gut microbiota and metabolites alterations, and potential pathogenic bacteria associated with IBD, with the aim to help develop more precise biomarkers for IBD diagnosis and drug targets
- Lijun Ning
- , Yi-Lu Zhou
- & Jie Hong
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Article
| Open AccessA randomised Phase IIa trial of amine oxidase copper-containing 3 (AOC3) inhibitor BI 1467335 in adults with non-alcoholic steatohepatitis
The authors report data from a Phase IIa randomised, double-blind trial in patients with NASH showing that BI 1467335 strongly and dose-dependently inhibited AOC3 activity (involved in hepatic inflammation) and was well tolerated at all tested doses.
- Philip N. Newsome
- , Arun J. Sanyal
- & Eric Lawitz
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Article
| Open AccessFarnesoid X receptor activation by bile acids suppresses lipid peroxidation and ferroptosis
Ferroptosis is a regulated form of cell death occurring upon lipid peroxidation. Here, the authors discovered that activation of the Farnesoid X receptor by bile acids suppresses ferroptosis through upregulation of anti-ferroptotic genes.
- Juliane Tschuck
- , Lea Theilacker
- & Kamyar Hadian
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Article
| Open AccessFood amyloid fibrils are safe nutrition ingredients based on in-vitro and in-vivo assessment
Food protein amyloid fibrils have superior properties but due to safety concerns, have not yet been used in foods. In-vitro and in-vivo studies here show that upon digestion they are safe and can be used as potential ingredients for human nutrition.
- Dan Xu
- , Jiangtao Zhou
- & Raffaele Mezzenga