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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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Functional evaluation of autism-associated mutations in NHE9
Mutations in the gene that encodes the endosomal cation/proton antiporter NHE9 are implicated in neuropsychiatric disorders. In this study, the authors screen autism-associated variants in the human population and identify specific variants of NHE9 that are characterized by a loss of function in astrocytes.
- Kalyan C. Kondapalli
- , Anniesha Hack
- & Rajini Rao
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Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity
Tempol is an antioxidant that reduces the body weight of mice on a high-fat diet. Li et al.now provide a mechanistic link by demonstrating that tempol affects the intestinal microbiota, which leads to a change in the composition of bile acids and suppression of FXR signalling.
- Fei Li
- , Changtao Jiang
- & Frank J. Gonzalez
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ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48
ORMDL3has been identified as a gene associated with asthma susceptibility, but its exact role in the pathogenesis of this disease is not well known. Here, the authors propose that induction of ORMDL3 in eosinophils modulates the expression of integrins, which could contribute to a key inflammatory event in asthma.
- Sung Gil Ha
- , Xiao Na Ge
- & P. Sriramarao
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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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A peptide probe for targeted brown adipose tissue imaging
Current methods to image brown adipose tissue rely on radioactive tracers and specialized imaging equipment. Here Azhdarinia et al.report a peptide-based probe that selectively binds to the vascular endothelium of brown adipose tissue and allows the near-infrared imaging of brown fat in mice.
- Ali Azhdarinia
- , Alexes C. Daquinag
- & Mikhail G. Kolonin
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| Open AccessGenome-wide mapping of gene–microbiota interactions in susceptibility to autoimmune skin blistering
The pathogenesis of inflammatory disorders afflicting the skin is multifactorial. Srinivas et al. show that diversity of the skin microbiota is a critical factor determining the susceptibility to epidermolysis bullosa acquisita, a chronic mucocutaneous autoimmune skin blistering disease.
- Girish Srinivas
- , Steffen Möller
- & Saleh M. Ibrahim
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| Open AccessHuman gut microbiota community structures in urban and rural populations in Russia
The structure of the human gut microbiota has been shown to vary between populations. Tyakht et al.analyse the gut microbiota assembly from Russian individuals living in urban and rural areas, and compare these with previously studied populations.
- Alexander V. Tyakht
- , Elena S. Kostryukova
- & Vadim M. Govorun
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| Open AccessGenome signature-based dissection of human gut metagenomes to extract subliminal viral sequences
Bacteriophages have a significant impact on microbial ecosystems, but additional tools are needed to assess viral communities. Ogilvie et al.present a new strategy to extract viral sequences from metagenomic data sets, and present new insights on their function in the gut ecosystem.
- Lesley A. Ogilvie
- , Lucas D. Bowler
- & Brian V. Jones
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Activation of the central nervous system induced by micro-magnetic stimulation
Magnetic stimulation is used therapeutically for neurological disorders, but its effectiveness is hindered by efficacy and safety limitations due to large device sizes. Here the authors show that sub-millimetre, micro-magnetic coils effectively stimulate hamster cochlear neurons, with minimal side effects.
- Hyun-Joo Park
- , Giorgio Bonmassar
- & John T. Gale
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| Open AccessAmyloid-β nanotubes are associated with prion protein-dependent synaptotoxicity
Prion protein has been suggested to bind toxic amyloid-ß oligomers. Nicollet al.demonstrate that binding to prion protein and prion protein-dependent synaptotoxicity correlate with the presence of a tubular form of amyloid-ß with a defined triple helical structure.
- Andrew J. Nicoll
- , Silvia Panico
- & John Collinge
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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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HuR and miR-1192 regulate myogenesis by modulating the translation of HMGB1 mRNA
The nuclear protein HMGB1 is involved in muscle fibre formation. Here, Dormoy-Raclet et al. show that during muscle cell differentiation, the RNA-binding protein HuR promotes HMGB1mRNA translation by preventing its repression by miR-1192.
- Virginie Dormoy-Raclet
- , Anne Cammas
- & Imed-Eddine Gallouzi
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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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| Open Accessp53 increases MHC class I expression by upregulating the endoplasmic reticulum aminopeptidase ERAP1
The protein p53 is an important tumour suppressor. Here Wanget al.show that p53 can induce expression of MHC class I on the cell surface by promoting expression of the aminopeptidase ERAP1, and that this mechanism operates in cancer cells as well as those infected with influenza virus.
- Bei Wang
- , Dandan Niu
- & Ee Chee Ren
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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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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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| 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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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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Phosphatidylinositol-3-phosphate regulates sorting and processing of amyloid precursor protein through the endosomal system
Endosomal sorting is regulated by phosphatidylinositol-3-phosphate and anomalies in this process are implicated in Alzheimer’s disease. Here the authors show that deficiency of phosphatidylinositol-3-phosphate in vitroenhances the pathological trafficking and processing of amyloid precursor protein.
- Etienne Morel
- , Zeina Chamoun
- & Gilbert Di Paolo
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Octapod iron oxide nanoparticles as high-performance T2 contrast agents for magnetic resonance imaging
Spherical superparamagnetic iron oxide nanoparticles are potentially attractive MRI contrast agents, but their low transverse relaxivity has hindered their application. Here, the authors report size and shape control of octapod iron oxide nanoparticles with extremely high transverse relaxivity.
- Zhenghuan Zhao
- , Zijian Zhou
- & Jinhao Gao
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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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Article
| Open AccessVariability in visual cortex size reflects tradeoff between local orientation sensitivity and global orientation modulation
Surface area features of developing visual cortices are implicated in visual perception. Songet al.measure visual discrimination sensitivity in humans and find that an increase in visual cortical surface area activity is associated with improved discrimination sensitivity and degraded contextual illusions.
- Chen Song
- , Dietrich S. Schwarzkopf
- & Geraint Rees
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Frequency of TERT promoter mutations in human cancers
Reactivation of telomerase has been implicated in human tumorigenesis. Here, somatic mutations in the TERT promoter are reported in cancers of the central nervous system, bladder, follicular cell-derived thyroid and melanoma, thus demonstrating that TERTpromoter mutations are a frequent event in human cancer.
- João Vinagre
- , Ana Almeida
- & Paula Soares
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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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A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle
Interactions between mitochondrial respiratory chain complexes control electron transfer and oxidative phosphorylation. Here, the authors find that COX7RP regulates supercomplex assembly, and show that decreasing or increasing COX7RP expression, respectively, reduces and enhances muscular performance in mice.
- Kazuhiro Ikeda
- , Sachiko Shiba
- & Satoshi Inoue
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Large fibre size in skeletal muscle is metabolically advantageous
Energy demand in muscle is largely due to maintaining the membrane potential of muscle fibres. Jimenez et al.study the metabolic cost of maintaining the membrane potential of muscle fibres across different species of crustaceans and fishes, and find that larger fibres are metabolically cheaper to maintain.
- Ana Gabriela Jimenez
- , Richard M. Dillaman
- & Stephen T. Kinsey
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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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Thymosin β4-sulfoxide attenuates inflammatory cell infiltration and promotes cardiac wound healing
Hydrogen peroxide attracts immune cells and induces wound inflammation. Evans et al. show that hydrogen peroxide also leads to the production of thymosin β4–sulfoxide in zebrafish wounds and in mouse hearts after myocardial infarction, where it acts as an anti-inflammatory factor that promotes wound healing.
- Mark A. Evans
- , Nicola Smart
- & Paul R. Riley
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Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules
Myotonic dystrophy type 1 (DM1) is caused by defects in the alternative splicing of pre-mRNA. Childs-Disney and colleagues report two small molecules that either induce or reverse DM1-associated splicing defects by modulating the binding of pre-mRNA to muscleblind-like 1 protein.
- Jessica L. Childs-Disney
- , Ewa Stepniak-Konieczna
- & Matthew D. Disney
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| Open AccessChemical and genetic validation of thiamine utilization as an antimalarial drug target
The malaria parasite Plasmodium falciparum utilizes thiamine for the production of essential enzymatic cofactors. Chan et al. show that inhibition of thiamine utilization with oxythiamine inhibits proliferation of P. falciparumand reduces parasite growth in a mouse model of malaria infection.
- Xie Wah Audrey Chan
- , Carsten Wrenger
- & Kevin J. Saliba
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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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Scara1 deficiency impairs clearance of soluble amyloid-β by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression
The scavenger receptor Scara1, expressed on microglia and macrophages, binds beta amyloid aggregates. In a mouse model of Alzheimer’s disease, the authors show that Scara1deficiency is associated with reduced clearance and increased deposition of aggregates in the brain, which results in early mortality.
- Dan Frenkel
- , Kim Wilkinson
- & Joseph El Khoury
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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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Solution-based circuits enable rapid and multiplexed pathogen detection
Rapid, highly multiplexed molecular detection platforms may enable more specific and effective disease diagnosis. Here, a solution-based circuit is reported that enables the analysis of samples for panels of pathogens and antibiotic-resistance profiles at clinically relevant levels in less than 2 min.
- Brian Lam
- , Jagotamoy Das
- & Shana O. Kelley
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Persistent infection with Crohn’s disease-associated adherent-invasive Escherichia coli leads to chronic inflammation and intestinal fibrosis
Intestinal infection with adherent-invasive Escherichia coliis associated with Crohn’s disease in humans; however, its functional role remains unclear, in part due to a lack of animal models, which sustain chronic disease. Here the authors establish such a model in mice and show that it shares features with human Crohn’s disease.
- Cherrie-Lee N. Small
- , Sarah A. Reid-Yu
- & Brian K. Coombes
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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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Collagen VI regulates satellite cell self-renewal and muscle regeneration
Satellite cells have important roles in homeostasis and regeneration of skeletal muscles. Urciuolo et al. show that the extracellular matrix protein collagen VI is required for preserving satellite cell self-renewal and muscle regeneration in vitro and in vivoby modulating muscle mechanical properties.
- Anna Urciuolo
- , Marco Quarta
- & Paolo Bonaldo
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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