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| Open AccessCD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens
Autoreactive T cells are suspected to destroy hypocretin-producing neurons in narcolepsy. Here the authors detect CD8 T cells recognizing narcolepsy-related proteins in healthy individuals and in patients with narcolepsy, and show that the frequency of self-reactive CD8 T cells differs between patients and controls sharing the same HLA-II risk allele.
- Natasja Wulff Pedersen
- , Anja Holm
- & Birgitte Rahbek Kornum
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Article
| Open AccessPLCβ2 negatively regulates the inflammatory response to virus infection by inhibiting phosphoinositide-mediated activation of TAK1
Phospholipase C β (PLCβ) exhibits immuno-modulatory functions but its role in antiviral innate responses is unclear. Here, the authors provide evidence that PLCβ2 down regulates enterovirus-induced pro-inflammatory responses via inhibition of TAK1 activation, and suggest PLC as a potential therapeutic target.
- Lin Wang
- , Yilong Zhou
- & Baoxue Ge
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Article
| Open AccessRole of NS1 antibodies in the pathogenesis of acute secondary dengue infection
The antibody response during infection with dengue virus is a key component involved in the pathogenesis during secondary infection. Here the authors show antibodies targeting NS1 and the epitopes targeted can be associated with disease severity during human infection.
- Deshni Jayathilaka
- , Laksiri Gomes
- & Gathsaurie Neelika Malavige
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Article
| Open AccessInvasive Salmonella exploits divergent immune evasion strategies in infected and bystander dendritic cell subsets
Salmonella employ a range of strategies to counter host defences during infection. Here, Aulicino et al. use single-cell RNA-sequencing to examine the effects of invasive and non-invasive strains of Salmonella, revealing discrete and divergent immune evasion strategies in infected and bystander dendritic cells.
- Anna Aulicino
- , Kevin C. Rue-Albrecht
- & Alison Simmons
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Article
| Open AccessMechanical strain determines the site-specific localization of inflammation and tissue damage in arthritis
Pro-inflammatory factors implicated for the onset of arthritis often have systematic effects, yet arthritis symptoms are mostly limited to the joints. Here the authors show that mechanical strain at the joints promotes the recruitment of monocyte and their differentiation into bone-eroding osteoclast to contribute this tissue specificity.
- Isabelle Cambré
- , Djoere Gaublomme
- & Dirk Elewaut
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Article
| Open AccessMicroRNA-27a controls the intracellular survival of Mycobacterium tuberculosis by regulating calcium-associated autophagy
How Mycobacterium tuberculosis (Mtb) escapes autophagy-mediated clearance is poorly understood. Here, Liu et al. show that Mtb-induced MicroRNA-27a targets the ER-associated calcium transporter CACNA2D3, leading to suppression of antimicrobial autophagy and to enhanced intracellular survival of Mtb.
- Feng Liu
- , Jianxia Chen
- & Baoxue Ge
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Article
| Open AccessThe olfactory epithelium as a port of entry in neonatal neurolisteriosis
Listeria monocytogenes causes meningitis in newborns. Here, Pägelow et al. present a mouse model of neonatal cerebral listeriosis, and show that nasal inoculation, but not intragastric administration, leads to early brain infection in the absence of bacteraemia during the neonatal period.
- Dennis Pägelow
- , Chintan Chhatbar
- & Marcus Fulde
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Article
| Open AccessEVI1 overexpression reprograms hematopoiesis via upregulation of Spi1 transcription
Chr3q26 rearrangements cause overexpression of EVI1 and associate with myeloid neoplasms, but the mechanism behind this association is unclear. Here, using a novel mouse model they show that EVI1 causes premalignant myeloid expansion with suppression of other lineages through upregulation of Spi1/PU.1.
- Edward Ayoub
- , Michael P. Wilson
- & Archibald S. Perkins
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Article
| Open AccessGenome-scale metabolic reconstructions of multiple Salmonella strains reveal serovar-specific metabolic traits
Salmonella serovars colonize a wide range of hosts but the underlying genetic determinants remain poorly understood. Here, Seif et al. use a network-based computational analysis to link specific metabolic capabilities with host range and nutritional niche.
- Yara Seif
- , Erol Kavvas
- & Jonathan M. Monk
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Article
| Open AccessFactor H binding proteins protect division septa on encapsulated Streptococcus pneumoniae against complement C3b deposition and amplification
Streptococcus pneumoniae evades the action of the complement system by expressing an immuno-protective polysaccharide capsule as well as Factor H-binding proteins. Here, Pathak et al. show that these two defence mechanisms are functionally and spatially coordinated on the bacterial cell surface.
- Anuj Pathak
- , Jan Bergstrand
- & Birgitta Henriques-Normark
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Article
| Open AccessZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response
cGAS is an important mediator of antiviral immune responses, but the regulation of its activity is unknown. Here, the authors identify a zinc finger protein, ZCCHC3, that enhances the binding of cGAS to dsDNA and is important for its activation following viral infection.
- Huan Lian
- , Jin Wei
- & Hong-Bing Shu
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Article
| Open AccessIron restriction inside macrophages regulates pulmonary host defense against Rhizopus species
Mucormycosis is a life-threatening respiratory fungal infection that typically occurs in patients with abnormalities in iron metabolism. Here the authors show that iron restriction inside the phagosome of macrophages is an essential component of the host defense against Rhizopus, the main species causing mucormycosis.
- Angeliki M. Andrianaki
- , Irene Kyrmizi
- & Georgios Chamilos
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Article
| Open AccessSLC10A7 mutations cause a skeletal dysplasia with amelogenesis imperfecta mediated by GAG biosynthesis defects
The majority of skeletal dysplasia are caused by pathogenic variants in genes required for glycosaminoglycan (GAG) metabolism. Here, Dubail et al. identify genetic variants in the solute carrier family protein SLC10A7 in families with skeletal dysplasia and amelogenesis imperfecta that disrupt GAG synthesis.
- Johanne Dubail
- , Céline Huber
- & Valérie Cormier-Daire
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Article
| Open AccessGenetic deficiency of NOD2 confers resistance to invasive aspergillosis
NOD2 has been shown to be crucial for immune recognition of Aspergillus infection. Here the authors show that a common NOD2 genetic variant associated with Crohn’s disease is associated with reduced risk of disease due to enhanced antifungal activates of monocytes and macrophages.
- Mark S. Gresnigt
- , Cristina Cunha
- & Frank L. van de Veerdonk
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Article
| Open AccessIntermedin protects against sepsis by concurrently re-establishing the endothelial barrier and alleviating inflammatory responses
Sepsis is a life-threatening condition. Here, the authors show that intermedin alleviates organ injury and decreases mortality in septic mice by concurrently alleviating vascular leakage and inflammatory responses. Patients with high intermedin levels exhibit a low risk of shock, lower severity scores, and greatly improved survival outcomes.
- Fei Xiao
- , Denian Wang
- & Wei Zhang
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Article
| Open AccessMultiple communication mechanisms between sensor kinases are crucial for virulence in Pseudomonas aeruginosa
Bacteria respond to stresses using two-component systems consisting of sensor kinases (SKs) and response regulators. Here, Francis et al. reveal three specific interaction mechanisms between a pair of SKs that are important for regulation of virulence in the pathogen Pseudomonas aeruginosa.
- Vanessa I. Francis
- , Elaine M. Waters
- & Steven L. Porter
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Article
| Open AccessThe hepcidin-ferroportin axis controls the iron content of Salmonella-containing vacuoles in macrophages
The effects of iron on vacuole-resident Salmonella in macrophages are unclear. Here the authors show that the bacteria are not subject to nutritional inhibition by iron deprivation, but that iron depletion in the vacuole, via the hepcidin-ferroportin axis, inhibits the bactericidal effect of oxidative burst.
- Daejin Lim
- , Kwang Soo Kim
- & Hyon E. Choy
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Article
| Open AccessIntron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
Intron retention (IR) can increase protein diversity and function, and yet unregulated IR may be detrimental to cellular health. This study shows that aberrant IR occurs in ALS and finds nuclear loss of an RNA-binding protein called SFPQ as a new molecular hallmark in this devastating condition.
- Raphaelle Luisier
- , Giulia E. Tyzack
- & Rickie Patani
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| Open AccessSpecies-specific host factors rather than virus-intrinsic virulence determine primate lentiviral pathogenicity
In contrast to HIV, simian immunodeficiency viruses (SIV) do not cause disease in their hosts, and the reasons for this are unclear. Here, Joas et al. incorporate two putative HIV virulence factors into SIV and study effects in infected monkeys, suggesting that species-specific host factors are responsible for HIV pathogenesis.
- Simone Joas
- , Erica H. Parrish
- & Frank Kirchhoff
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Article
| Open AccessDirect conversion of injury-site myeloid cells to fibroblast-like cells of granulation tissue
At the site of injury, macrophages exit their characteristic phenotype undergoing direct conversion to fibroblasts. Keratinocyte-derived miR-21, packaged in extracellular vesicles, enables such plasticity which accounts for the vast majority of all fibroblasts in the granulation tissue.
- Mithun Sinha
- , Chandan K. Sen
- & Sashwati Roy
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Article
| Open AccessDevelopment of a chimeric Zika vaccine using a licensed live-attenuated flavivirus vaccine as backbone
Given the recent Zika virus (ZIKV) epidemic, development of an effective vaccine is of high importance. Here, the authors use a licensed live-attenuated flavivirus vaccine backbone to develop a ZIKV vaccine and determine immunogenicity, safety and protection profiles in different animal models.
- Xiao-Feng Li
- , Hao-Long Dong
- & Cheng-Feng Qin
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Article
| Open AccessIL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells
XLP-2 syndrome is caused by XIAP mutation. Here the authors show that mouse and human XIAP-deficient regulatory T cells have defective suppressive function as a result of conversion to proinflammatory cytokine producing cells, an effect that can be prevented by blocking the IL-6 receptor.
- Wan-Chen Hsieh
- , Tzu-Sheng Hsu
- & Ming-Zong Lai
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Article
| Open AccessStaphylococcus aureus produces pain through pore-forming toxins and neuronal TRPV1 that is silenced by QX-314
Bacterial infection can cause pain but the underlying mechanism is unclear. This study shows pain induced in mice by methicillin-resistant Staphylococcus aureus infection is mediated by bacterial pore-forming toxins, and a sodium channel blocker QX-314 can alleviate infection-associated pain.
- Kimbria J. Blake
- , Pankaj Baral
- & Isaac M. Chiu
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Article
| Open AccessHepatic protein tyrosine phosphatase receptor gamma links obesity-induced inflammation to insulin resistance
During obesity, chronic inflammation leads to insulin resistance and diabetes. Here, Brenachot et al. show that Protein Tyrosine Phosphatase Receptor Gamma is upregulated in obesity by inflammatory signals and correlates with insulin resistance in humans. Its deletion in mouse models of obesity and inflammation ameliorates insulin resistance by suppressing glucose production.
- Xavier Brenachot
- , Giorgio Ramadori
- & Roberto Coppari
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Article
| Open AccessROCK regulates the intermittent mode of interstitial T cell migration in inflamed lungs
ROCK is associated with T cell movement in lymph nodes. Here the authors use an LPS lung damage model and two-photon imaging to show that CD8+ T cells in lung tissue engage in ROCK-dependent fast linear migration alternating with bursts of slower confined migration that together optimize contact with target cells.
- Paulus Mrass
- , Sreenivasa Rao Oruganti
- & Judy L. Cannon
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Article
| Open AccessRegulation of endothelial intracellular adenosine via adenosine kinase epigenetically modulates vascular inflammation
The molecular mechanisms underlying vascular inflammation are unclear. Here the authors show that pro-inflammatory stimuli lead to endothelial inflammation by increasing adenosine kinase expression, and that its knockdown in endothelial cells inhibits atherosclerosis and cerebral ischemic injury in mice.
- Yiming Xu
- , Yong Wang
- & Yuqing Huo
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Article
| Open AccessCombined activation of MAP kinase pathway and β-catenin signaling cause deep penetrating nevi
Deep penetrating nevi (DPN) are unusual melanocytic neoplasms with unknown genetic drivers. Here the authors show that majority of DPN harbor activating mutations in the β-catenin and the MAP-kinase pathways; this characteristic can help in the classification and grading of these distinctive neoplasms.
- Iwei Yeh
- , Ursula E. Lang
- & Arnaud de la Fouchardière
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Article
| Open AccessActivated NK cells cause placental dysfunction and miscarriages in fetal alloimmune thrombocytopenia
Fetal/neonatal alloimmune thrombocytopenia (FNAIT) is a gestational disease caused by maternal immune responses against fetal platelets. Using a FNAIT mouse model and human trophoblast cell lines, here the authors show that uterine natural killer cell-mediated trophoblast apoptosis contributes to FNAIT pathogenesis.
- Issaka Yougbaré
- , Wei-She Tai
- & Heyu Ni
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Article
| Open AccessEndosomal NOX2 oxidase exacerbates virus pathogenicity and is a target for antiviral therapy
Production of reactive oxygen species is an ancient antimicrobial mechanism, but its role in antiviral defense in mammals is unclear. Here, To et al. show that virus infection activates endosomal NOX2 oxidase and restricts TLR7 signaling, and that an endosomal NOX2 inhibitor decreases viral pathogenicity.
- Eunice E. To
- , Ross Vlahos
- & Stavros Selemidis
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Article
| Open AccessPseudoexfoliation syndrome-associated genetic variants affect transcription factor binding and alternative splicing of LOXL1
LOXL1 is a genetic risk factor for pseudoexfoliation syndrome of the eye but a causal variant has not been identified. Here, Pasutto et al., find intronic LOXL1 risk variants influence transcription factor binding and alternative splicing of LOXL1 in affected tissues reducing levels of LOXL1mRNA.
- Francesca Pasutto
- , Matthias Zenkel
- & Ursula Schlötzer-Schrehardt
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Article
| Open AccessEndogenous adenosine maintains cartilage homeostasis and exogenous adenosine inhibits osteoarthritis progression
Osteoarthritis (OA) is a debilitating and destructive joint disease for which disease modifying drugs are not available. Here the authors show that extracellular adenosine signalling via the A2AR receptor on chondrocytes is needed to prevent OA and that liposome-bound adenosine injection can treat the pathology in rats.
- Carmen Corciulo
- , Matin Lendhey
- & Bruce N. Cronstein
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Article
| Open AccessCommon variants in ZMIZ1 and near NGF confer risk for primary dysmenorrhoea
Primary dysmenorrhoea, the most common gynaecologic complaint, remains genetically and pathophysiologically elusive. Here, Li and colleagues identify common variants inZMIZ1 and near NGFconferring risk for primary dysmenorrhoea using genome-wide association study in a Chinese population.
- Zhiqiang Li
- , Jianhua Chen
- & Yongyong Shi
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Article
| Open AccessTopical tacrolimus for the treatment of secondary lymphedema
Secondary lymphedema is a debilitating disease with no cure. Here the authors show that topical application of an FDA-approved anti-T cell drug tacrolimus potently prevents development and alleviates pathologic changes of established lymphedema in mice, suggesting a new treatment for human patients.
- Jason C. Gardenier
- , Raghu P. Kataru
- & Babak J. Mehrara
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Article
| Open AccessHigh-throughput automated microfluidic sample preparation for accurate microbial genomics
Shotgun DNA sequencing experiments for microbial genomic analysis are often impractical due to minimum sample input requirements. Here the authors develop a microfluidic sample preparation platform that reduces sample input requirements 100-fold and enables high throughput sequencing from low numbers of cells.
- Soohong Kim
- , Joachim De Jonghe
- & Paul C. Blainey
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Article
| Open AccessTransitional changes in the CRP structure lead to the exposure of proinflammatory binding sites
C-reactive protein is a pentameric protein secreted by the liver in response to injury and infection. Here Braiget al. show that conformational changes in CRP on the surface of monocyte-derived microvesicles enable binding of complement C1q and lead to activation of the complement cascade and aggravation of inflammation.
- David Braig
- , Tracy L. Nero
- & Steffen U. Eisenhardt
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Article
| Open AccessTNFα drives pulmonary arterial hypertension by suppressing the BMP type-II receptor and altering NOTCH signalling
Reduced BMP receptor II signalling underlies pulmonary arterial hypertension (PAH). Here, Hurstet al. show that TNFα subverts BMP signalling by increasing BMP6 expression and signalling via an alternative BMP receptor, ALK2, in pulmonary artery smooth muscle cells to drive abnormal proliferation and PAH.
- Liam A. Hurst
- , Benjamin J. Dunmore
- & Nicholas W. Morrell
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Article
| Open AccessThe mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia
Non-resolving bacterial pneumonia results in lung tissue damage owing to overactive inflammation. Here the authors show that the mitochondrial DAMP cardiolipin contributes to persistent inflammation by SUMOylating PPARγ, which promotes binding of the corepressor NCOR/HDAC3 complex to the IL-10 promoter.
- Krishnendu Chakraborty
- , Mahesh Raundhal
- & Prabir Ray
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Article
| Open AccessAltered intestinal microbiota–host mitochondria crosstalk in new onset Crohn’s disease
Crohn’s disease is associated with altered intestinal microbiota. Here, the authors show that the microbe Atopobium parvulumis associated with Crohn’s disease patients, triggers colitis in a mouse model, and that scavenging microbe-induced hydrogen sulfide improved symptoms in mice.
- Walid Mottawea
- , Cheng-Kang Chiang
- & Alain Stintzi
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Article
| Open AccesstRNA-mediated codon-biased translation in mycobacterial hypoxic persistence
Mycobacteria can adapt to the stress of human infection by entering a dormant state. Here the authors show that hypoxia-induced dormancy in M. bovisBCG involves the reprogramming of tRNA wobble modifications and copy numbers, coupled with biased use of synonymous codons in survival genes.
- Yok Hian Chionh
- , Megan McBee
- & Peter C. Dedon
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Article
| Open AccessHyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes
Patients with diabetes often have delayed wound healing, associated with excessive inflammation. Here the authors report that REG3A inhibits TLR3-driven inflammation in skin wounds, and show that REG3A is reduced in models of diabetes, which exacerbates inflammation in diabetic wounds.
- Yelin Wu
- , Yanchun Quan
- & Yuping Lai
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Article
| Open AccessOxidative insult can induce malaria-protective trait of sickle and fetal erythrocytes
Carriers of haemoglobinopathies are protected from severe malaria, likely due to reduced surface expression of virulence factors. Here, Cyrklaff et al. show that, similar to haemoglobinopathies, a transient oxidative insult affects actin reorganization and mitigates the development of cerebral malaria in mice.
- Marek Cyrklaff
- , Sirikamol Srismith
- & Michael Lanzer
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Article
| Open AccessIdentification of Siglec-1 null individuals infected with HIV-1
Binding of virus, HIV-1, to cellular protein Siglec-1 is important for infection of immune cells. Here the authors show that a natural mutation leading to production of truncated Siglec-1 reduces HIV binding and infectivity transfer in vitro, but does not substantially affect infection or AIDS outcome in patients.
- Javier Martinez-Picado
- , Paul J. McLaren
- & Amalio Telenti
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Article
| Open AccessThe neuritic plaque facilitates pathological conversion of tau in an Alzheimer’s disease mouse model
Alzheimer’s disease (AD) is pathologically characterized by the accumulation of neuritic plaques and neurofibrillary tangles but it is not known whether the neuritic plaque is necessary to drive the conversion of wild-type tau. Here the authors developed a mouse model in which wild-type tau is converted into pathological tau in a neuritic plaque-dependent manner.
- Tong Li
- , Kerstin E. Braunstein
- & Philip C. Wong
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Article
| Open AccessThe landscape of chromosomal aberrations in breast cancer mouse models reveals driver-specific routes to tumorigenesis
Genetically engineered mouse models of cancer are useful in identifying oncogenes and tumour suppressors. Here, the authors use gene expression profiles to generate a catalogue of copy number aberrations in 45 mouse models, and compare mouse and human tumours to identify additional drivers of tumorigenesis.
- Uri Ben-David
- , Gavin Ha
- & Todd R. Golub
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Article
| Open AccessIL-13 from intraepithelial lymphocytes regulates tissue homeostasis and protects against carcinogenesis in the skin
Epidermal intraepithelial lymphocytes (IEL) produce IL-13, but the physiological role of this cytokine production is not clear. Here the authors show that IEL-production of IL-13 is a vital lymphoid stress surveillance mechanism driving crosstalk with epithelial cells to maintain tissue homeostasis and inhibit chemical carcinogenesis in mice.
- Tim Dalessandri
- , Greg Crawford
- & Jessica Strid
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Article
| Open AccessTumour-initiating cell-specific miR-1246 and miR-1290 expression converge to promote non-small cell lung cancer progression
miRNAs can function either as proto-oncogenes or tumour suppressors in several cancers; however their function in tumour initiating cells is unclear. Here, Zhang et al. show that tumour initiating cell-specific miR-1246 and miR-1290 promote lung cancer initiation and metastasis and could serve as prognostic markers.
- Wen Cai Zhang
- , Tan Min Chin
- & Bing Lim
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Article
| Open AccessKRT14 marks a subpopulation of bladder basal cells with pivotal role in regeneration and tumorigenesis
It is unclear whether there is a progenitor/stem cell in the basal layer of the urothelium in the bladder. Here, the authors identify Keratin14 positive cells that can regenerate the bladder in both a natural and injury-induced manner, and following neoplastic transformation, can give rise to tumours.
- George Papafotiou
- , Varvara Paraskevopoulou
- & Apostolos Klinakis
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Article
| Open AccessHomeobox NKX2-3 promotes marginal-zone lymphomagenesis by activating B-cell receptor signalling and shaping lymphocyte dynamics
The homeobox NKX2 family of transcriptional factors has been shown to regulate fundamental developmental processes. Here, the authors show that NKX2-3 is a bona fideoncogenic driver in marginal-zone B-cell lymphoma and that it promotes lymphomagenesis by shaping lymphocyte dynamics and promoting BCR signalling.
- Eloy F. Robles
- , Maria Mena-Varas
- & Jose A. Martinez-Climent
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Article
| Open AccessA splicing isoform of TEAD4 attenuates the Hippo–YAP signalling to inhibit tumour proliferation
The Hippo/Yap signalling pathway is found deregulated in several cancers. Here, the authors uncover an additional mechanism of YAP regulation that occurs via alternately spliced isoform of TEAD4, which acts as a dominant negative regulator of YAP-TEAD signalling.
- Yangfan Qi
- , Jing Yu
- & Zefeng Wang