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Gastroenterology

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TRAP-seq identifies cystine/glutamate antiporter as a driver of recovery from liver injury
Amber W. Wang, … , Noam Erez, Klaus H. Kaestner
Amber W. Wang, … , Noam Erez, Klaus H. Kaestner
Published March 8, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI95120.
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TRAP-seq identifies cystine/glutamate antiporter as a driver of recovery from liver injury

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Abstract

Understanding the molecular basis of the regenerative response following hepatic injury holds promise for improved treatments of liver diseases. Here, we report an innovative method to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury. We utilize the Fah–/– mouse, a model of hereditary tyrosinemia, which conditionally undergoes severe liver injury unless fumarylacetoacetate hydrolase (FAH) expression is reconstituted ectopically. We employ translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs specific to repopulating hepatocytes. We uncover novel upstream regulators and important signaling pathways to be highly enriched in genes changed in regenerating hepatocytes. Specifically, we identify glutathione metabolism — particularly the gene Slc7a11 encoding the cystine/glutamate antiporter (xCT) — to be massively upregulated during liver regeneration. Furthermore, we show that Slc7a11 overexpression in hepatocytes enhances, and its suppression inhibits, repopulation following toxic injury. TRAP-seq allows cell type-specific expression profiling in repopulating hepatocytes and suggests xCT as a potential therapeutic target for supporting antioxidant responses during liver regeneration.

Authors

Amber W. Wang, Kirk J. Wangensteen, Yue J. Wang, Adam M. Zahm, Nicholas G. Moss, Noam Erez, Klaus H. Kaestner

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Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease
Liming Mao, … , Ivan J. Fuss, Warren Strober
Liming Mao, … , Ivan J. Fuss, Warren Strober
Published February 6, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI98642.
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Loss-of-function CARD8 mutation causes NLRP3 inflammasome activation and Crohn’s disease

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Abstract

In these studies we evaluated the contribution of the NLRP3 inflammasome to Crohn’s disease (CD) in a kindred containing individuals having a missense mutation in CARD8, a protein known to inhibit this inflammasome. Whole exome sequencing and PCR studies identified that the affected individuals had a V44I mutation in a single allele of the T60 isoform of CARD8. The serum levels of IL-1β in the affected individuals were increased compared with that in healthy controls and their peripheral monocytes produced increased amounts of IL-1β when stimulated by NLRP3 activators. Immunoblot studies probing the basis of these findings showed that mutated T60 CARD8 fails to down-regulate the NLRP3 inflammasome because it does not bind to NLRP3 and inhibit its oligomerization. In addition, these studies showed that mutated T60 CARD8 exerts a dominant negative effect by its capacity to bind to and form oligomers with unmutated T60 or T48 CARD8 that impede their binding to NLRP3. Finally, inflammasome activation studies revealed that intact but not mutated CARD8 prevents NLRP3 deubiquitination and serine dephosphorylation. CD due to a CARD8 mutation was not effectively treated by anti-TNF-α, but did respond to IL-1β inhibitors. Thus, patients with anti-TNF-α-resistant CD may respond to this treatment option.

Authors

Liming Mao, Atsushi Kitani, Morgan Similuk, Andrew J. Oler, Lindsey Albenberg, Judith Kelsen, Atiye Aktay, Martha Quezado, Michael Yao, Kim Montgomery-Recht, Ivan J. Fuss, Warren Strober

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BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease
Evelyn Ullrich, … , Markus F. Neurath, Kai Hildner
Evelyn Ullrich, … , Markus F. Neurath, Kai Hildner
Published January 29, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI89242.
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BATF-dependent IL-7RhiGM-CSF+ T cells control intestinal graft-versus-host disease

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Abstract

Acute graft-versus-host disease (GVHD) represents a severe, T cell–driven inflammatory complication following allogeneic hematopoietic cell transplantation (allo-HCT). GVHD often affects the intestine and is associated with a poor prognosis. Although frequently detectable, proinflammatory mechanisms exerted by intestinal tissue–infiltrating Th cell subsets remain to be fully elucidated. Here, we show that the Th17-defining transcription factor basic leucine zipper transcription factor ATF-like (BATF) was strongly regulated across human and mouse intestinal GVHD tissues. Studies in complete MHC-mismatched and minor histocompatibility–mismatched (miHA-mismatched) GVHD models revealed that BATF-expressing T cells were functionally indispensable for intestinal GVHD manifestation. Mechanistically, BATF controlled the formation of colon-infiltrating, IL-7 receptor–positive (IL-7R+), granulocyte-macrophage colony-stimulating factor–positive (GM-CSF+), donor T effector memory (Tem) cells. This T cell subset was sufficient to promote intestinal GVHD, while its occurrence was largely dependent on T cell–intrinsic BATF expression, required IL-7–IL-7R interaction, and was enhanced by GM-CSF. Thus, this study identifies BATF-dependent pathogenic GM-CSF+ effector T cells as critical promoters of intestinal inflammation in GVHD and hence putatively provides mechanistic insight into inflammatory processes previously assumed to be selectively Th17 driven.

Authors

Evelyn Ullrich, Benjamin Abendroth, Johanna Rothamer, Carina Huber, Maike Büttner-Herold, Vera Buchele, Tina Vogler, Thomas Longerich, Sebastian Zundler, Simon Völkl, Andreas Beilhack, Stefan Rose-John, Stefan Wirtz, Georg F. Weber, Sakhila Ghimire, Marina Kreutz, Ernst Holler, Andreas Mackensen, Markus F. Neurath, Kai Hildner

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The deubiquitinase USP9X regulates FBW7 stability and suppresses colorectal cancer
Omar M. Khan, … , Stephen A. Wood, Axel Behrens
Omar M. Khan, … , Stephen A. Wood, Axel Behrens
Published January 18, 2018
Citation Information: J Clin Invest. 2018. https://doi.org/10.1172/JCI97325.
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The deubiquitinase USP9X regulates FBW7 stability and suppresses colorectal cancer

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Abstract

The tumor suppressor FBW7 targets oncoproteins such as c-MYC for ubiquitylation and is mutated in several human cancers. We noted that in a significant percentage of colon cancers, FBW7 protein is undetectable despite the presence of FBW7 mRNA. To understand the molecular mechanism of FBW7 regulation in these cancers, we employed proteomics and identified the deubiquitinase USP9X as an FBW7 interactor. USP9X antagonised FBW7 ubiquitylation, and Usp9x deletion caused Fbw7 destabilization. Mice lacking Usp9x in the gut showed reduced secretory cell differentiation and increased progenitor proliferation, phenocopying Fbw7 loss. In addition, Usp9x inactivation impaired intestinal regeneration and increased tumor burden in colitis-associated intestinal cancer. c-Myc heterozygosity abrogated increased progenitor proliferation and tumor burden in Usp9x-deficient mice, suggesting that Usp9x suppresses tumor formation by regulating Fbw7 protein stability and thereby reducing c-Myc. Thus, we identify a novel tumor suppressor mechanism in the mammalian intestine that arises from the posttranslational regulation of FBW7 by USP9X independent of somatic FBW7 mutations.

Authors

Omar M. Khan, Joana Carvalho, Bradley Spencer-Dene, Richard Mitter, David Frith, Ambrosius P. Snijders, Stephen A. Wood, Axel Behrens

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Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway
Saara Ollila, … , Kari Vaahtomeri, Tomi P. Mäkelä
Saara Ollila, … , Kari Vaahtomeri, Tomi P. Mäkelä
Published December 4, 2017
Citation Information: J Clin Invest. 2017. https://doi.org/10.1172/JCI93597.
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Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11–JAK/STAT3 pathway

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Abstract

Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast–specific deletion of Lkb1 results in fully penetrant polyposis in mice. Lineage tracing and immunohistochemical analyses revealed clonal expansion of Lkb1-deficient myofibroblast-like cell foci in the tumor stroma. Loss of Lkb1 in stromal cells was associated with induction of an inflammatory program including IL-11 production and activation of the JAK/STAT3 pathway in tumor epithelia concomitant with proliferation. Importantly, treatment of LKB1-defcient mice with the JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis. These data indicate that IL-11–mediated induction of JAK/STAT3 is critical in gastrointestinal tumorigenesis following Lkb1 mutations and suggest that targeting this pathway has therapeutic potential in Peutz-Jeghers syndrome.

Authors

Saara Ollila, Eva Domènech-Moreno, Kaisa Laajanen, Iris P.L. Wong, Sushil Tripathi, Nalle Pentinmikko, Yajing Gao, Yan Yan, Elina H. Niemelä, Timothy C. Wang, Benoit Viollet, Gustavo Leone, Pekka Katajisto, Kari Vaahtomeri, Tomi P. Mäkelä

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Discovery, characterization, and clinical development of the glucagon-like peptides
Daniel J. Drucker, … , Joel F. Habener, Jens Juul Holst
Daniel J. Drucker, … , Joel F. Habener, Jens Juul Holst
Published December 1, 2017
Citation Information: J Clin Invest. 2017;127(12):4217-4227. https://doi.org/10.1172/JCI97233.
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Discovery, characterization, and clinical development of the glucagon-like peptides

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Abstract

The discovery, characterization, and clinical development of glucagon-like-peptide-1 (GLP-1) spans more than 30 years and includes contributions from multiple investigators, science recognized by the 2017 Harrington Award Prize for Innovation in Medicine. Herein, we provide perspectives on the historical events and key experimental findings establishing the biology of GLP-1 as an insulin-stimulating glucoregulatory hormone. Important attributes of GLP-1 action and enteroendocrine science are reviewed, with emphasis on mechanistic advances and clinical proof-of-concept studies. The discovery that GLP-2 promotes mucosal growth in the intestine is described, and key findings from both preclinical studies and the GLP-2 clinical development program for short bowel syndrome (SBS) are reviewed. Finally, we summarize recent progress in GLP biology, highlighting emerging concepts and scientific insights with translational relevance.

Authors

Daniel J. Drucker, Joel F. Habener, Jens Juul Holst

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FODMAP diet modulates visceral nociception by lipopolysaccharide-mediated intestinal inflammation and barrier dysfunction
Shi-Yi Zhou, … , Yuanxu Lu, Chung Owyang
Shi-Yi Zhou, … , Yuanxu Lu, Chung Owyang
Published November 27, 2017
Citation Information: J Clin Invest. 2017. https://doi.org/10.1172/JCI92390.
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FODMAP diet modulates visceral nociception by lipopolysaccharide-mediated intestinal inflammation and barrier dysfunction

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Abstract

Foods high in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) exacerbate symptoms of irritable bowel syndrome (IBS); however, their mechanism of action is unknown. We hypothesized that a high-FODMAP (HFM) diet increases visceral nociception by inducing dysbiosis and that the FODMAP-altered gut microbial community leads to intestinal pathology. We fed rats an HFM and showed that HFM increases rat fecal Gram-negative bacteria, elevates lipopolysaccharides (LPS), and induces intestinal pathology, as indicated by inflammation, barrier dysfunction, and visceral hypersensitivity (VH). These manifestations were prevented by antibiotics and reversed by low-FODMAP (LFM) diet. Additionally, intracolonic administration of LPS or fecal supernatant (FS) from HFM-fed rats caused intestinal barrier dysfunction and VH, which were blocked by the LPS antagonist LPS-RS or by TLR4 knockdown. Fecal LPS was higher in IBS patients than in healthy subjects (HS), and IBS patients on a 4-week LFM diet had improved IBS symptoms and reduced fecal LPS levels. Intracolonic administration of FS from IBS patients, but not FS from HS or LFM-treated IBS patients, induced VH in rats, which was ameliorated by LPS-RS. Our findings indicate that HFM-associated gut dysbiosis and elevated fecal LPS levels induce intestinal pathology, thereby modulating visceral nociception and IBS symptomatology, and might provide an explanation for the success of LFM diet in IBS patients.

Authors

Shi-Yi Zhou, Merritt Gillilland III, Xiaoyin Wu, Pornchai Leelasinjaroen, Guanpo Zhang, Hui Zhou, Bo Ye, Yuanxu Lu, Chung Owyang

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Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis
Cyrielle Caussy, … , Rohit Loomba, the Familial NAFLD Cirrhosis Research Consortium
Cyrielle Caussy, … , Rohit Loomba, the Familial NAFLD Cirrhosis Research Consortium
Published June 19, 2017
Citation Information: J Clin Invest. 2017. https://doi.org/10.1172/JCI93465.
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Nonalcoholic fatty liver disease with cirrhosis increases familial risk for advanced fibrosis

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Abstract

BACKGROUND. The risk of advanced fibrosis in first-degree relatives of patients with nonalcoholic fatty liver disease and cirrhosis (NAFLD-cirrhosis) is unknown and needs to be systematically quantified. We aimed to prospectively assess the risk of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis. METHODS. This is a cross-sectional analysis of a prospective cohort of 26 probands with NAFLD-cirrhosis and 39 first-degree relatives. The control population included 69 community-dwelling twin, sib-sib, or parent-offspring pairs (n = 138), comprising 69 individuals randomly ascertained to be without evidence of NAFLD and 69 of their first-degree relatives. The primary outcome was presence of advanced fibrosis (stage 3 or 4 fibrosis). NAFLD was assessed clinically and quantified by MRI proton density fat fraction (MRI-PDFF). Advanced fibrosis was diagnosed by liver stiffness greater than 3.63 kPa using magnetic resonance elastography (MRE). RESULTS. The prevalence of advanced fibrosis in first-degree relatives of probands with NAFLD-cirrhosis was significantly higher than that in the control population (17.9% vs. 1.4%, P = 0.0032). Compared with controls, the odds of advanced fibrosis among the first-degree relatives of probands with NAFLD-cirrhosis were odds ratio 14.9 (95% CI, 1.8–126.0, P = 0.0133). Even after multivariable adjustment by age, sex, Hispanic ethnicity, BMI, and diabetes status, the risk of advanced fibrosis remained both statistically and clinically significant (multivariable-adjusted odds ratio 12.5; 95% CI, 1.1–146.1, P = 0.0438). CONCLUSION. Using a well-phenotyped familial cohort, we demonstrated that first-degree relatives of probands with NAFLD-cirrhosis have a 12 times higher risk of advanced fibrosis. Advanced fibrosis screening may be considered in first-degree relatives of NAFLD-cirrhosis patients. TRIAL REGISTRATION. UCSD IRB: 140084. FUNDING. National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Environmental Health Sciences, NIH.

Authors

Cyrielle Caussy, Meera Soni, Jeffrey Cui, Ricki Bettencourt, Nicholas Schork, Chi-Hua Chen, Mahdi Al Ikhwan, Shirin Bassirian, Sandra Cepin, Monica P. Gonzalez, Michel Mendler, Yuko Kono, Irine Vodkin, Kristin Mekeel, Jeffrey Haldorson, Alan Hemming, Barbara Andrews, Joanie Salotti, Lisa Richards, David A. Brenner, Claude B. Sirlin, Rohit Loomba, the Familial NAFLD Cirrhosis Research Consortium

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Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration
Véronique Giroux, … , Timothy C. Wang, Anil K. Rustgi
Véronique Giroux, … , Timothy C. Wang, Anil K. Rustgi
Published May 8, 2017
Citation Information: J Clin Invest. 2017. https://doi.org/10.1172/JCI88941.
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Long-lived keratin 15+ esophageal progenitor cells contribute to homeostasis and regeneration

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Abstract

The esophageal lumen is lined by a stratified squamous epithelium comprised of proliferative basal cells that differentiate while migrating toward the luminal surface and eventually desquamate. Rapid epithelial renewal occurs, but the specific cell of origin that supports this high proliferative demand remains unknown. Herein, we have described a long-lived progenitor cell population in the mouse esophageal epithelium that is characterized by expression of keratin 15 (Krt15). Genetic in vivo lineage tracing revealed that the Krt15 promoter marks a long-lived basal cell population able to self-renew, proliferate, and generate differentiated cells, consistent with a progenitor/stem cell population. Transcriptional profiling demonstrated that Krt15+ basal cells are molecularly distinct from Krt15– basal cells. Depletion of Krt15-derived cells resulted in decreased proliferation, thereby leading to atrophy of the esophageal epithelium. Further, Krt15+ cells were radioresistant and contributed to esophageal epithelial regeneration following radiation-induced injury. These results establish the presence of a long-lived and indispensable Krt15+ progenitor cell population that provides additional perspective on esophageal epithelial biology and the widely prevalent diseases that afflict this epithelium.

Authors

Véronique Giroux, Ashley A. Lento, Mirazul Islam, Jason R. Pitarresi, Akriti Kharbanda, Kathryn E. Hamilton, Kelly A. Whelan, Apple Long, Ben Rhoades, Qiaosi Tang, Hiroshi Nakagawa, Christopher J. Lengner, Adam J. Bass, E. Paul Wileyto, Andres J. Klein-Szanto, Timothy C. Wang, Anil K. Rustgi

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Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma
Derek Lee, … , Irene Oi-Lin Ng, Carmen Chak-Lui Wong
Derek Lee, … , Irene Oi-Lin Ng, Carmen Chak-Lui Wong
Published April 10, 2017
Citation Information: J Clin Invest. 2017. https://doi.org/10.1172/JCI90253.
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Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma

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Abstract

Cancer cells preferentially utilize glucose and glutamine, which provide macromolecules and antioxidants that sustain rapid cell division. Metabolic reprogramming in cancer drives an increased glycolytic rate that supports maximal production of these nutrients. The folate cycle, through transfer of a carbon unit between tetrahydrofolate and its derivatives in the cytoplasmic and mitochondrial compartments, produces other metabolites that are essential for cell growth, including nucleotides, methionine, and the antioxidant NADPH. Here, using hepatocellular carcinoma (HCC) as a cancer model, we have observed a reduction in growth rate upon withdrawal of folate. We found that an enzyme in the folate cycle, methylenetetrahydrofolate dehydrogenase 1–like (MTHFD1L), plays an essential role in support of cancer growth. We determined that MTHFD1L is transcriptionally activated by NRF2, a master regulator of redox homeostasis. Our observations further suggest that MTHFD1L contributes to the production and accumulation of NADPH to levels that are sufficient to combat oxidative stress in cancer cells. The elevation of oxidative stress through MTHFD1L knockdown or the use of methotrexate, an antifolate drug, sensitizes cancer cells to sorafenib, a targeted therapy for HCC. Taken together, our study identifies MTHFD1L in the folate cycle as an important metabolic pathway in cancer cells with the potential for therapeutic targeting.

Authors

Derek Lee, Iris Ming-Jing Xu, David Kung-Chun Chiu, Robin Kit-Ho Lai, Aki Pui-Wah Tse, Lynna Lan Li, Cheuk-Ting Law, Felice Ho-Ching Tsang, Larry Lai Wei, Cerise Yuen-Ki Chan, Chun-Ming Wong, Irene Oi-Lin Ng, Carmen Chak-Lui Wong

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Loss of intestinal integrity
Rocío López-Posadas and colleagues reveal that loss of Rho-A activation and signaling promotes loss of intestinal barrier function in inflammatory bowel disease…
Published January 11, 2016
Scientific Show StopperGastroenterology
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Insight into neonatal necrotizing enterocolitis
Charlotte Egan and colleagues reveal that intestinal TLR4-mediated lymphocyte infiltration and polarization toward a Th17 population promotes neonatal necrotizing enterocolitis…
Published December 21, 2015
Scientific Show StopperGastroenterology
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The intestinal healing power of mesenchymal stem cells
Nicholas Manieri and colleagues demonstrate that mesenchymal stem cells inhibit intestinal ulcer formation by stimulating angiogenesis …
Published August 17, 2015
Scientific Show StopperGastroenterology
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Repairing wounds with annexin A1
Giovanna Leoni and colleagues demonstrate that extracellular vesicles and nanoparticles contacting annexin A1 activate mucosal wound repair pathways…
Published February 9, 2015
Scientific Show StopperGastroenterology
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Goblet cells contribute to a sticky situation
Liu and colleges demonstrate that goblet cell dysfunction in the cystic fibrosis mouse intestine results from an epithelial-autonomous effect of CFTR-deficiency...
Published February 2, 2015
Scientific Show StopperGastroenterology
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Enteroendocrine cells make the connection
Diego Bohórquez and colleagues demonstrate that enteroendocrine cells directly interact with nerves in the gut mucosa…
Published January 2, 2015
Scientific Show StopperGastroenterology
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