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Selective cancer targeting with prodrugs activated by histone deacetylases and a tumour-associated protease
Selective targeting of cancer cells may improve therapeutic efficacy while reducing adverse effects. Here, Ueki et al.report selective activation of an anticancer drug upon removal of an acetylated lysine group by histone deacetylases and the tumour-associated protease cathepsin L.
- Nobuhide Ueki
- , Siyeon Lee
- & Michael J. Hayman
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Methylphenidate amplifies the potency and reinforcing effects of amphetamines by increasing dopamine transporter expression
Methylphenidate, the active compound in Ritalin, is used to treat attention and hyperactivity disorders, but it is also taken for recreational use. Calipari et al.show that high-dose methylphenidate leads to enhanced dopaminergic responses to amphetamines, and enhanced amphetamine-seeking behaviour in rats.
- Erin S. Calipari
- , Mark J. Ferris
- & Sara R. Jones
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Mepenzolate bromide displays beneficial effects in a mouse model of chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD) is a serious respiratory disease that is resistant to many forms of treatment. Tanake et al.screen compounds from a library of medicines and find that mepenzolate bromide reduces inflammatory responses and improves respiration in a mouse model of COPD.
- Ken-Ichiro Tanaka
- , Tomoaki Ishihara
- & Tohru Mizushima
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| Open AccessAnti-ghrelin immunoglobulins modulate ghrelin stability and its orexigenic effect in obese mice and humans
Obesity is often associated with increased appetite and food intake, despite normal blood levels of the hunger hormone ghrelin. Here the authors show that ghrelin-reactive antibodies in the blood of obese mice and humans enhance the orexigenic effect of ghrelin by protecting it from degradation.
- Kuniko Takagi
- , Romain Legrand
- & Sergueï O. Fetissov
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Cdkn1b overexpression in adult mice alters the balance between genome and tissue ageing
Reduced rates of cell proliferation are thought to contribute to age-related tissue dysfunction. Here Pruitt et al.induce expression of the cell cycle inhibitor Cdkn1b in adult mice and show that this recapitulates ageing-related defects in tissue maintenance.
- Steven C. Pruitt
- , Amy Freeland
- & Gillian K. Cady
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Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma
Hepatocytes use gluconeogenesis to produce glucose, but whether this process is altered in hepatocellular carcinoma (HCC) is unclear. Here, the loss of gluconeogenesis in HCC and altered glucocorticoid regulation is demonstrated and glucocorticoid treatment is shown to reduce tumour burden.
- Ruihua Ma
- , Wanguang Zhang
- & Bo Huang
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Real-time in vivo imaging of invasive- and biomaterial-associated bacterial infections using fluorescently labelled vancomycin
Invasive and biomaterial-associated infections in humans are often difficult to diagnose and treat. Here, the authors demonstrate that real-time in vivodetection and imaging of these bacterial infections can be successfully performed with fluorescently labelled vancomycin.
- Marleen van Oosten
- , Tina Schäfer
- & Gooitzen M. van Dam
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Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice
The enzyme Elovl6 catalyses a rate-limiting step in the elongation of fatty acids. Here Sunaga et al. show that Elovl6 knockout mice are more susceptible to pulmonary fibrosis, suggesting that the dysregulation of lipid components impairs alveolar epithelial cell function and pulmonary homeostasis.
- Hiroaki Sunaga
- , Hiroki Matsui
- & Masahiko Kurabayashi
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| Open AccessFunctional lacrimal gland regeneration by transplantation of a bioengineered organ germ
Lacrimal glands maintain a healthy corneal epithelium but are dysfunctional for example in dry-eye disease. Here, the authors transplant bioengineered lacrimal and harderian gland germs into mice, where they connect to the host duct and nervous system and restore lacrimal gland function.
- Masatoshi Hirayama
- , Miho Ogawa
- & Takashi Tsuji
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| Open AccessAngiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels
Hyaluronan is a component of the tumour extracellular matrix. Here, Chauhan et al. show that hyaluronan increases blood pressure in collagen-rich tumours by compressing vessel walls, and that reducing the level of hyaluranon with an angiotensin II inhibitor increases blood flow and drug penetrance in tumours.
- Vikash P. Chauhan
- , John D. Martin
- & Rakesh K. Jain
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| Open AccessFunctional salivary gland regeneration by transplantation of a bioengineered organ germ
Salivary gland dysfunction as a result of diseases or ageing reduces the quality of life and causes various oral health problems. Here the authors show that the salivary gland function of mice can be recovered by orthotopic transplantation of a bioengineered salivary gland germ.
- Miho Ogawa
- , Masamitsu Oshima
- & Takashi Tsuji
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Dependence of fertility on kisspeptin–Gpr54 signaling at the GnRH neuron
The kisspeptin receptor GPR54 is implicated in the maintenance of mammalian fertility. Kirilov et al.study GPR54 mutant mice and identify a subset of neurons in the brain expressing gonadotropin-releasing hormone as the critical site for kisspeptin action.
- Milen Kirilov
- , Jenny Clarkson
- & Allan E. Herbison
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Ecscr regulates insulin sensitivity and predisposition to obesity by modulating endothelial cell functions
The transmembrane protein Ecscr has been implicated in the regulation of endothelial cell signalling. Here, the authors show that Ecscr regulates systemic insulin sensitivity and glucose homeostasis in mice by modulating insulin signalling in endothelial cells.
- Yoshiki Akakabe
- , Masahiro Koide
- & Koji Ikeda
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Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome
Consumption of high amounts of glucose leads to the development of insulin resistance and metabolic syndrome. Here, Lanaspa et al.show that the hepatic conversion of glucose into fructose is a key step in the development of glucose-induced metabolic syndrome and fatty liver in mice.
- Miguel A. Lanaspa
- , Takuji Ishimoto
- & Richard J. Johnson
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The carotid body as a putative therapeutic target for the treatment of neurogenic hypertension
Enhanced sympathetic drive from chemoreceptors in the carotid body contributes to hypertension. Here McBryde et al. show that carotid sinus denervation is an effective antihypertensive treatment in rats with neurogenic hypertension even if performed in addition to renal denervation.
- Fiona D. McBryde
- , Ana P. Abdala
- & Julian F. R. Paton
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In vivo cardiac phase response curve elucidates human respiratory heart rate variability
Many biological processes are oscillatory and their rhythms shift in response to external stimuli. Here Kralemann et al. present a method to describe the sensitivity of an oscillator to external influences based on non-invasive observation of the system, and use it to study cardiac–respiratory interactions in humans.
- Björn Kralemann
- , Matthias Frühwirth
- & Maximilian Moser
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A comprehensive multiscale framework for simulating optogenetics in the heart
Optogenetics can be used to induce an electrical response in cardiac cells and could become an alternative to electrical cardiac pacing. Here, Boyleet al.present a modelling framework for cardiac optogenetics and explore how optogenetic stimulation might be used to alter cardiac function.
- Patrick M. Boyle
- , John C. Williams
- & Natalia A. Trayanova
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Patterned prevascularised tissue constructs by assembly of polyelectrolyte hydrogel fibres
Tissue engineering relies on the vascular compatibility of the synthesised constructs with target tissues. Here, the authors fabricate a prevascularised tissue construct of cell-laden hydrogel fibres as a framework that allows the formation of vascularised adipose and hepatic tissues.
- Meng Fatt Leong
- , Jerry K. C. Toh
- & Jackie Y. Ying
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Repopulation of decellularized mouse heart with human induced pluripotent stem cell-derived cardiovascular progenitor cells
Artificial heart tissue may find application in novel therapies of cardiac disease in the future. Here, Lu et al. take a step towards the creation of personalized heart tissue by repopulating decellularized mouse hearts with cells derived from human induced pluripotent stem cells.
- Tung-Ying Lu
- , Bo Lin
- & Lei Yang
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| Open AccessOverexpression of Atg5 in mice activates autophagy and extends lifespan
Changes in autophagy have been shown to modulate lifespan in lower organisms. Here, Pyo et al.show that mice globally overexpressing the autophagy protein Atg5 live longer and are leaner than normal mice, providing the first evidence that increased autophagy extends lifespan in mammals.
- Jong-Ok Pyo
- , Seung-Min Yoo
- & Yong-Keun Jung
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Human-relevant levels of added sugar consumption increase female mortality and lower male fitness in mice
Animal experiments to study the detrimental health effects of sugar usually involve far higher doses than those consumed by humans. Here, Ruff et al.show that house mice consuming comparatively low amounts of added sugar are impaired in their ability to compete for territories, reproduce and survive in a seminatural environment.
- James S. Ruff
- , Amanda K. Suchy
- & Wayne K. Potts
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| Open AccessPrelamin A causes progeria through cell-extrinsic mechanisms and prevents cancer invasion
Mutations in the metalloproteinase Zmpste24 preclude prelamin A processing and cause premature ageing. Here, de la Rosaet al.create mosaic Zmpste24 mice, revealing that cell-extrinsic effects are essential for accelerated ageing caused by prelamin A accumulation and that prelamin A reduces invasiveness of cancer cells.
- Jorge de la Rosa
- , José M.P. Freije
- & Carlos López-Otín
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Cytosolic p53 inhibits Parkin-mediated mitophagy and promotes mitochondrial dysfunction in the mouse heart
Damaged mitochondria are removed from cells through a process called mitophagy. Here, Hoshino et al. show that the cytosolic fraction of the protein p53 inhibits mitophagy by sequestering the mitophagy regulator Parkin, leading to impaired mitochondrial integrity and cardiac function in aged or damaged mouse hearts.
- Atsushi Hoshino
- , Yuichiro Mita
- & Satoaki Matoba
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Disrupting malaria parasite AMA1–RON2 interaction with a small molecule prevents erythrocyte invasion
Invasion of host erythrocytes is an essential step in the life cycle of P. falciparum. Srinivasan et al.demonstrate that small-molecule inhibitors can block the entry of the parasite into erythrocytes, highlighting the potential of invasion inhibitors as antimalarials.
- Prakash Srinivasan
- , Adam Yasgar
- & Louis H. Miller
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Metformin improves healthspan and lifespan in mice
The anti-diabetic drug metformin has been shown to increase lifespan of some model organisms, but results have been conflicting. Here, Martin-Montalvo et al. administer one of two doses of metformin to male mice and show that the lower dose increases healthspan and lifespan, while the higher dose is toxic.
- Alejandro Martin-Montalvo
- , Evi M. Mercken
- & Rafael de Cabo
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Metagenome-wide analysis of antibiotic resistance genes in a large cohort of human gut microbiota
The appearance of antibiotic resistance has been attributed to the misuse of antibiotics. By analysing the diversity of antibiotic resistance genes present in 162 human gut microbiota samples, the authors find that Chinese individuals harbour a larger pool of resistance genes than Spanish or Danish counterparts.
- Yongfei Hu
- , Xi Yang
- & Baoli Zhu
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| Open AccessBio-responsive polymer hydrogels homeostatically regulate blood coagulation
Implementing biomolecular recognition mechanisms in synthetic materials may enable a wealth of biomedical and related applications. Here Maitz et al. present a bio-responsive hydrogel that releases the anticoagulant heparin in amounts proportional to the environmental levels of the procoagulatory protein thrombin.
- Manfred F. Maitz
- , Uwe Freudenberg
- & Carsten Werner
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| Open AccessStructural modulation of gut microbiota in life-long calorie-restricted mice
Calorie restriction has been shown to extend lifespan in diverse model systems, however, the mechanisms underlying this effect remain unclear. Zhang et al.show that calorie restriction changes the structure of the gut microbiota in mice, enriching for phylotypes positively correlated with lifespan.
- Chenhong Zhang
- , Shoufeng Li
- & Liping Zhao
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Tumour PDGF-BB expression levels determine dual effects of anti-PDGF drugs on vascular remodelling and metastasis
Anti-cancer drugs inhibiting platelet-derived growth factor (PDGF) can either promote or inhibit tumour growth and metastasis. Here, Hosaka et al.ascribe this dual effect of anti-PDGF drugs to the production of the angiogenic ligand PDGF-BB by tumours, which is shown to regulate PDGFR-β signalling in pericytes.
- Kayoko Hosaka
- , Yunlong Yang
- & Yihai Cao
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Choroid plexus transcytosis and exosome shuttling deliver folate into brain parenchyma
Impairments in cerebral folate transport are implicated in childhood-onset neurodegeneration. Grapp et al. show that folate receptors in the choroid plexus mediate folate transport by delivering folate receptor-containing exosomes into the brain parenchyma.
- Marcel Grapp
- , Arne Wrede
- & Robert Steinfeld
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FAK-heterozygous mice display enhanced tumour angiogenesis
Focal adhesion kinase (FAK) regulates angiogenesis and FAK inhibitors are currently developed as anticancer drugs. Here Kostourou and colleagues show that genetic FAK heterozygosity or low doses of a pharmacological FAK inhibitor unexpectedly increase angiogenesis and tumour growth in vitro and in vivo.
- Vassiliki Kostourou
- , Tanguy Lechertier
- & Kairbaan Hodivala-Dilke
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Fibroblast growth factor 21 protects against cardiac hypertrophy in mice
Fibroblast growth factor 21 (FGF21) regulates energy metabolism in peripheral tissues. Here Planavila and colleagues show that FGF21 also acts directly on cardiomyocytes, thereby protecting mice against cardiac hypertrophy.
- A. Planavila
- , I. Redondo
- & F. Villarroya
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Model-based rational design of an oncolytic virus with improved therapeutic potential
Oncolytic viruses can serve as self-replicating anticancer agents. Le Bœuf et al. combine synthetic modelling and molecular biology approaches to create a virus with enhanced oncolytic activity in vitro and in vivodue to its expression of an interferon antagonist.
- Fabrice Le Bœuf
- , Cory Batenchuk
- & John C. Bell
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A common functional promoter variant links CNR1 gene expression to HDL cholesterol level
Haplotypes in CNR1, the gene encoding the cannabinoid receptor CB1, are known to influence HDL cholesterol levels. Here Feng and colleagues identify rs806371 as a novel regulatory element reducing CNR1 gene expression and as the causal allele driving the association between CNR1 and HDL cholesterol levels in humans.
- Q. Feng
- , K.C. Vickers
- & R.A. Wilke
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TRF1 is a stem cell marker and is essential for the generation of induced pluripotent stem cells
TRF-1 is a telomere-binding protein that protects chromosome ends from degradation. Schneider and colleagues show that TRF1 is a marker of adult stem cell compartments and of induced pluripotent stem cells, and that TRF1 is essential for the induction and maintenance of pluripotency.
- Ralph P. Schneider
- , Ianire Garrobo
- & Maria A. Blasco
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A mouse model of adult-onset anaemia due to erythropoietin deficiency
Kidney diseases often cause anaemia due to damage of renal erythropoietin-producing cells. Yamazaki et al. identify a new population of erythropoietin-producing cells in the renal cortex and outer medulla by establishing a mouse model for adult-onset erythropoietin-deficient anaemia.
- Shun Yamazaki
- , Tomokazu Souma
- & Masayuki Yamamoto
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The antiparasitic drug ivermectin is a novel FXR ligand that regulates metabolism
The nuclear Farnesoid X receptor (FXR) regulates bile acid and cholesterol production. Here Jin et al. identify the clinically approved antiparasitic drug ivermectin as a novel FXR ligand and show that it has antidiabetic effects in mice.
- Lihua Jin
- , Xuhui Feng
- & Yong Li
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| Open AccessDepleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model
Accelerated cellular ageing in patients with progeria can be caused by the accumulation of nuclear lamins, leading to DNA damage and histone methylation. Here Liu et al. show that the metyltransferase SUV39H1 regulates lamin A stability, and that SUV39H1 depletion extends lifespan in a progeria mouse model.
- Baohua Liu
- , Zimei Wang
- & Zhongjun Zhou
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Delivery of therapeutic agents by nanoparticles made of grapefruit-derived lipids
Nanoparticles released from living cells can be used as drug delivery vehicles, but scaling up their production is challenging. Here, Wang and colleagues create nanoparticles from natural lipids contained in grapefruit juice that can encapsulate various types of therapeutics and deliver them to cells in vitro and in vivo.
- Qilong Wang
- , Xiaoying Zhuang
- & Huang-Ge Zhang
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Flexible polymer transistors with high pressure sensitivity for application in electronic skin and health monitoring
Flexible pressure sensors may be key in realising biomedical prostheses and robots that can interact with their environment. Here, Schwartz et al.report an organic thin film pressure sensing device that combines fast response times with low power consumption and cyclic stability.
- Gregor Schwartz
- , Benjamin C.-K. Tee
- & Zhenan Bao
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SMRT compounds abrogate cellular phenotypes of ataxia telangiectasia in neural derivatives of patient-specific hiPSCs
Ataxia telangiectasia is a genetic disease that results in various pathological disorders. In this study, the authors develop an in vitromodel of Ataxia telangiectasia using human induced pluripotent stem cells, and find that physiological defects can be alleviated by small molecule read-through compounds.
- Peiyee Lee
- , Nathan T. Martin
- & William E. Lowry
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Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis
Cancer-associated fibroblasts promote tumour growth and metastasis by secreting signalling molecules. Jung and colleagues show that prostate cancer cells secrete CXC chemokine ligand 16, which recruits mesenchymal stem cells and converts them into cancer-associated fibroblasts.
- Younghun Jung
- , Jin Koo Kim
- & Russell S. Taichman
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Trapping red blood cells in living animals using optical tweezers
Optical tweezers based on focused laser beams are widely used for biophysical measurements of single molecules in vitro. Here Zhong et al. use infrared optical tweezers to trap and manipulate red blood cells within subdermal capillaries in living mice.
- Min-Cheng Zhong
- , Xun-Bin Wei
- & Yin-Mei Li
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Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics
Vascular permeability is increased by inflammation and in disorders such as acute respiratory distress syndrome. Mammoto et al. show that lung vascular permeability is controlled by the stiffness of the extracellular matrix and identify lysyl oxidase as a regulator of vascular leakage in pulmonary oedema in mice.
- Akiko Mammoto
- , Tadanori Mammoto
- & Donald E. Ingber
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Magnetic barcode assay for genetic detection of pathogens
Detecting and phenotyping Mycobacterium tuberculosis, especially in resource-limited settings, is important for global tuberculosis control. Here Liong et al. report a point-of-care diagnostic platform based on magnetic barcoding and nuclear magnetic resonance for the detection of mycobacterial nucleic acids.
- Monty Liong
- , Anh N. Hoang
- & Ralph Weissleder
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Titanium dioxide nanomaterials cause endothelial cell leakiness by disrupting the homophilic interaction of VE–cadherin
Nanoparticles can accumulate in tissues but how they interact with cells is poorly understood. Here Setyawati and colleagues report that titanium dioxide nanoparticles disrupt protein complexes of the tight junction protein VE-cadherin on endothelial cells to increase blood vessel permeability.
- M.I. Setyawati
- , C.Y. Tay
- & D.T. Leong
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Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81
The skeletal muscle has a remarkable capacity to regenerate after injury. Here Charrin et al. reveal that restoration of muscle architecture after injury requires a tight control of muscle cell fusion by the tetraspanin proteins CD9 and CD81 through their interaction with the cell surface protein CD9P-1.
- Stéphanie Charrin
- , Mathilde Latil
- & Eric Rubinstein
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| Open AccessA chronic model of arthritis supported by a strain-specific periarticular lymph node in BALB/c mice
Mouse models of arthritis generally do not result in both chronic disease and autoantibody production—two key features of the human disease. Here the authors obtain both features by combining two common protocols, and find that disease severity is associated with the presence of a previously unidentified lymph node.
- Uta Baddack
- , Sven Hartmann
- & Gerd Müller
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Microbiota-derived lactate accelerates colon epithelial cell turnover in starvation-refed mice
Epithelial cells in the colon mainly use microbial fermentation products as energy sources. Here Okada et al. find that lactate produced by commensal Lactobacillus murinusregulates colonic epithelial cell proliferation and show that mice are more susceptible to carcinogens when refed after a period of starvation.
- Toshihiko Okada
- , Shinji Fukuda
- & Taeko Dohi