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Article
| Open AccessEpigenetically-driven anatomical diversity of synovial fibroblasts guides joint-specific fibroblast functions
Arthritis affects different joints variably despite systemic inflammatory cues. Here the authors show anatomical differences in the transcriptome, epigenome and function of synovial fibroblasts that might affect susceptibility to site-specific joint diseases.
- Mojca Frank-Bertoncelj
- , Michelle Trenkmann
- & Caroline Ospelt
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Article
| Open AccessRegulation of hepatic lipogenesis by the zinc finger protein Zbtb20
De novo lipogenesis is tightly controlled by hormonal and nutritional signals and plays an important role in energy homoeostasis. Here, Liu et al. show that zinc finger protein ZBTB20 regulates the expression of key glycolytic and lipogenic genes by modulating ChREBP expression and transcriptional activity.
- Gan Liu
- , Luting Zhou
- & Weiping J. Zhang
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Article
| Open AccessPharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice
The enzyme Atgl participates in the breakdown of lipids in adipose tissue. Here the authors show that pharmacological inhibition of Atgl reduces weight gain and improves metabolic health in mice fed a high-fat diet, without causing adverse effects in cardiac muscle associated with genetic depletion ofAtgl.
- Martina Schweiger
- , Matthias Romauch
- & Rudolf Zechner
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Article
| Open AccessNrl knockdown by AAV-delivered CRISPR/Cas9 prevents retinal degeneration in mice
Retinitis pigmentosa is mainly caused by mutations that initially affect survival of rod photoreceptors, leading to secondary loss of cones. Here the authors use gene editing to prevent rod degeneration, leading to survival of cones and improved vision in mice.
- Wenhan Yu
- , Suddhasil Mookherjee
- & Zhijian Wu
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Article
| Open AccessSingle-cell tracking of flavivirus RNA uncovers species-specific interactions with the immune system dictating disease outcome
Analysis of virus replication on a single-cell level is often hampered by a lack of specific or sensitive enough reagents. Here, Douamet al. use RNA-flow technique to track (+) and (−) strand RNA of yellow fever virus in hematopoietic cells in mouse models and identify virus-host interactions that affect disease outcome.
- Florian Douam
- , Gabriela Hrebikova
- & Alexander Ploss
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Article
| Open AccessE3 ligase FBXW7 is critical for RIG-I stabilization during antiviral responses
The innate immune response to many RNA viruses depends on recognition of viral RNA by RIG-I. Here the authors show that, upon virus infection, FBXW7 interacts with RIG-I and inhibits ubiquitin-mediated degradation of RIG-I, resulting in increased interferon signallingin vitro and in vivo.
- Yinjing Song
- , Lihua Lai
- & Qingqing Wang
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Article
| Open AccessA potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue
Benzoxaboroles have been shown to be active against different pathogens. Here, the authors show that the benzoxaborole AN3661 inhibitsPlasmodium falciparum in vitroand in mouse models, and identify a homologue of a mammalian cleavage and polyadenylation specificity factor as a drug target.
- Ebere Sonoiki
- , Caroline L. Ng
- & Philip J. Rosenthal
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Article
| Open AccessSmad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development
Smad3, a transcription factor activated by TGF-β, has been implicated in tumorigenesis. Here the authors show that Smad3 inhibits NK cell differentiation and effector function by repressing NFIL3, and that genetic or pharmacological blockade of Smad3 expands tumour-suppressive NK cells and restricts tumour growth in mice.
- Patrick Ming-Kuen Tang
- , Shuang Zhou
- & Hui-Yao Lan
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Article
| Open AccessActivation of E-prostanoid 3 receptor in macrophages facilitates cardiac healing after myocardial infarction
Acute myocardial infarction (AMI) triggers sterile inflammatory reaction mediated by prostaglandin E2 (PGE2). Tang et al. show that the PGE2 via its receptor EP3 promotes cardiac healing after AMI by recruiting reparative Ly6Clowmonocytes/macrophages, which is mediated by TGF-β-driven regulation of CX3CR1 expression and VEGF secretion.
- Juan Tang
- , Yujun Shen
- & Ying Yu
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Article
| Open AccessPNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide
Loss-of-function mutations in an enzyme of unknown function, PNPLA1, cause dry and scaling skin in humans. Here Ohnoet al. show that PNPLA1 is a transacylase that acts in the final step of acylceramide production- esterification between ω-hydroxyceramide and linoleic acid acylceramide, yielding a lipid essential for skin barrier function.
- Yusuke Ohno
- , Nozomi Kamiyama
- & Akio Kihara
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Article
| Open AccessPNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis
Loss-of-function mutations inPNPLA1, a gene encoding an enzyme with unknown function, cause dry and scaling skin in humans. Using mouse models with PNPLA1 deficiency, the authors show that PNPLA1 participates in the biosynthesis of acylceramide, a lipid component essential for skin barrier function.
- Tetsuya Hirabayashi
- , Tatsuki Anjo
- & Makoto Murakami
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Article
| Open AccessEnsemble forecast of human West Nile virus cases and mosquito infection rates
Since its introduction to the US in 1999, the West Nile virus (WNV) has become endemic in the Americas. Here, the authors develop a model of WNV transmission dynamics between birds, mosquitoes and humans, which they integrate in conjunction with data assimilation methods, mosquito infection data and reported human cases in a New York county to show its utility for forecasting infection rates.
- Nicholas B. DeFelice
- , Eliza Little
- & Jeffrey Shaman
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Article
| Open AccessGenome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity
Non-syndromic cleft lip with palate is a common birth defect of unknown aetiology. Here, the authors discover 14 new genes associated with this condition, and show genetic heterogeneity in this and other non-syndromic orofacial clefting disorders.
- Yanqin Yu
- , Xianbo Zuo
- & Zhuan Bian
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Article
| Open AccessIn vivo genome editing with a small Cas9 orthologue derived from Campylobacter jejuni
The amount of genetic material that can be packaged in AAV vectors used for genome editing is limited. Here the authors show that the smallest known Cas9 orthologue, cjCas9, can be packaged in a single AAV vector along with sgRNA and a marker gene, and demonstrate efficient gene editing in mice.
- Eunji Kim
- , Taeyoung Koo
- & Jin-Soo Kim
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Article
| Open AccessIntrauterine Zika virus infection of pregnant immunocompetent mice models transplacental transmission and adverse perinatal outcomes
Zika virus infection of pregnant women is associated with congenital neurological disorders. Here, Vermillionet al. develop an immunocompetent mouse model for identification of factors at the maternal-fetal interface that contribute to adverse perinatal outcomes.
- Meghan S. Vermillion
- , Jun Lei
- & Irina Burd
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Article
| Open AccessSMURF2 regulates bone homeostasis by disrupting SMAD3 interaction with vitamin D receptor in osteoblasts
The balance between osteoclast and osteoblast-mediated bone turnover is essential for bone health and homeostasis. Here the authors show that both germline and osteoblast-specificSmurf2-deficient mice have osteoporosis as a result of increased osteoblast RANKL production and excess osteoclastogenesis.
- Zhan Xu
- , Matthew B. Greenblatt
- & Weiguo Zou
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Article
| Open AccessArylmethylamino steroids as antiparasitic agents
Steroid units can facilitate membrane permeation and bioavailability in drugs. Here, using a medicinal chemistry program, Krieget al. identify an arylmethylamino steroid that kills Plasmodium parasites, likely through a chelate-based quinone methide mechanism, and has activity against Schistosoma mansoni.
- Reimar Krieg
- , Esther Jortzik
- & Katja Becker
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Article
| Open AccessMuscle-specific CRISPR/Cas9 dystrophin gene editing ameliorates pathophysiology in a mouse model for Duchenne muscular dystrophy
CRISPR/Cas9-mediated gene editing is an emerging strategy to treat Duchenne muscular dystrophy. Here the authors develop multiple CRISPR/Cas9-based approaches to correct different dystrophin gene mutations, and show significant restoration of dystrophin expression in skeletal and cardiac muscle in mice.
- Niclas E. Bengtsson
- , John K. Hall
- & Jeffrey S. Chamberlain
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Article
| Open AccessIFI16 and cGAS cooperate in the activation of STING during DNA sensing in human keratinocytes
The role of IFI16 as a DNA sensor is highly controversial. With support from aNature Communications back-to-back publication from Jønsson et al., the authors here provide functional evidence that IFI16 is involved in DNA sensing via the cGAS-STING pathway in human keratinocytes.
- Jessica F. Almine
- , Craig A. J. O’Hare
- & Leonie Unterholzner
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Article
| Open AccessMolecular dissection of colorectal cancer in pre-clinical models identifies biomarkers predicting sensitivity to EGFR inhibitors
The heterogeneity of colorectal cancer has important clinical and therapeutic implications. Here the authors analysed the responses of a large biobank of organoids and xenografts derived from colorectal patients to a panel of clinically relevant therapeutic agents to identify genes signatures associated with drug response.
- Moritz Schütte
- , Thomas Risch
- & Marie-Laure Yaspo
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Article
| Open AccessIFI16 is required for DNA sensing in human macrophages by promoting production and function of cGAMP
The role of IFI16 as a DNA sensor is highly controversial. With support from a Nature Communications back-to-back publication from Almineet al. the authors here provide functional evidence that IFI16 is required for DNA sensing via the cGAS-STING pathway in human macrophages.
- K. L. Jønsson
- , A. Laustsen
- & M. R. Jakobsen
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Article
| Open AccessP113 is a merozoite surface protein that binds the N terminus of Plasmodium falciparum RH5
The secretedPlasmodium falciparum protein RH5 is essential for invasion of erythrocytes and is a promising vaccine candidate. Here, Galaway et al. show that the N-terminal region of RH5 binds the GPI-anchored merozoite surface protein P113 and can elicit invasion-blocking antibodies.
- Francis Galaway
- , Laura G. Drought
- & Gavin J. Wright
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Review Article
| Open AccessThe molecular basis of endothelial cell plasticity
Vascular endothelium possesses remarkable plasticity in response to cues from its surroundings, leading to great heterogeneity of endothelial cells in different vascular beds. Here the authors explain the molecular basis of endothelial plasticity during embryogenesis and in various diseases.
- Elisabetta Dejana
- , Karen K. Hirschi
- & Michael Simons
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Article
| Open AccessArmc5 deletion causes developmental defects and compromises T-cell immune responses
Mutations in ARMC5 are associated with risk of primary macronodular adrenal gland hyperplasia. Here the authors show that mice lacking Armc5 have adrenal gland hyperplasia and defective T-cell proliferation, differentiation, survival andin vivoT-cell-mediated immune responses.
- Yan Hu
- , Linjiang Lao
- & Jiangping Wu
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Article
| Open AccessComparative influenza protein interactomes identify the role of plakophilin 2 in virus restriction
Protein interaction networks can identify host proteins that affect virus replication. Here, the authors compare the protein interactomes of several influenza A virus strains and identify plakophilin 2 as a restriction factor that inhibits formation of the viral polymerase complex.
- Lingyan Wang
- , Bishi Fu
- & Shitao Li
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Article
| Open AccessA defined syphilis vaccine candidate inhibits dissemination of Treponema pallidum subspecies pallidum
There are no vaccines for the prevention of syphilis, a disease caused by the bacteriumTreponema pallidum subsp. pallidum. Here, the authors use an animal model of infection to show that immunization with the Tp0751 bacterial protein inhibits the pathogen’s spread within the body.
- Karen V. Lithgow
- , Rebecca Hof
- & Caroline E. Cameron
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Article
| Open Accessβ-arrestin-2 is an essential regulator of pancreatic β-cell function under physiological and pathophysiological conditions
Beta-arrestins have key roles in development and metabolic functions as euglycaemic control and insulin sentitivity. Here Zhuet al. show that beta-arrestin-2 regulates insulin secretion and glucose tolerance in mice by promoting CAMKII functions in beta cells.
- Lu Zhu
- , Joana Almaça
- & Jürgen Wess
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Article
| Open AccessSC83288 is a clinical development candidate for the treatment of severe malaria
Severe malaria is a life-threatening infection with limited treatment options. Here, using a medicinal chemistry approach starting from amicarbalide, Pegoraroet al. identify a compound that, when delivered intravenously, can cure Plasmodium falciparuminfection in a humanized mouse model.
- Stefano Pegoraro
- , Maëlle Duffey
- & Michael Lanzer
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Article
| Open AccessExperimental evidence for circular inference in schizophrenia
Schizophrenia is a mental disorder characterized by hallucinations and delusions. Here the authors report a novel probabilistic inference task in which compared to healthy subjects, schizophrenia patients show greater degree of circular inference that matches the severity of their clinical symptoms.
- Renaud Jardri
- , Sandrine Duverne
- & Sophie Denève
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Article
| Open AccessThe tumour suppressor APC promotes HIV-1 assembly via interaction with Gag precursor protein
The tumour suppressor APC is a multifunctional protein implicated in intracellular localization of mRNAs and WNT signalling. Here, Miyakawaet al. show that, via interaction with the HIV Gag precursor protein, APC promotes membrane targeting of viral components and cell-to-cell spread of HIV.
- Kei Miyakawa
- , Mayuko Nishi
- & Akihide Ryo
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Article
| Open AccessRhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16
Keratin 16 is an epithelial protein highly expressed at pressure bearing sites and during wound healing and cancer. Here the authors show that K16 interacts with the inactive protease Rhbdf2, associated with Tylosis with oesophageal cancer, and that this interaction drives increased keratinocyte proliferation.
- Thiviyani Maruthappu
- , Anissa Chikh
- & David P. Kelsell
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Article
| Open AccessDisruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias
Catheter ablation is a common therapy for atrial fibrillation but disrupts cardiac cholinergic neurons. Here the authors report that cholinergic neurons innervate heart ventricles and show that their ablation leads to increased susceptibility to ventricular arrhythmias in mouse models and in patients.
- Christiane Jungen
- , Katharina Scherschel
- & Christian Meyer
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Article
| Open AccessDrug regimens identified and optimized by output-driven platform markedly reduce tuberculosis treatment time
Current antibiotic therapies for tuberculosis are lengthy and onerous. Here, the authors use an output-driven approach to optimize drug doses for two experimental drug regimens in a mouse model of tuberculosis, leading to improved regimens that reduce treatment time by 75%.
- Bai-Yu Lee
- , Daniel L. Clemens
- & Marcus A. Horwitz
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Article
| Open AccessA human immunodeficiency syndrome caused by mutations in CARMIL2
CARMIL2 (Rltpr) is involved in T-cell function. Here, the authors identify human CARMIL2-deficiency as an autosomal recessive primary immunodeficiency disorder characterized by EBV+smooth muscle tumours, CD28 co-signalling deficiency and impaired cytoskeletal dynamics.
- T. Schober
- , T. Magg
- & F. Hauck
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Article
| Open AccessEsterase mutation is a mechanism of resistance to antimalarial compounds
Pepstatin is a known inhibitor of malarial proteases, but its activity varies between sources. Here, Istvanet al. identify a pepstatin ester as the active component of pepstatin preparations and show that this prodrug is activated by a Plasmodiumesterase, mutation of which can confer resistance to pepstatin and other compounds.
- Eva S. Istvan
- , Jeremy P. Mallari
- & Daniel E. Goldberg
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Article
| Open AccessSMARCA4-inactivating mutations increase sensitivity to Aurora kinase A inhibitor VX-680 in non-small cell lung cancers
Lung cancers often harbour loss-of-function mutations inSMARCA4. Here, the authors demonstrate a vulnerability of SMARCA4-deficient lung cancers for Aurora kinase A inhibition associated with mitotic defects.
- Vural Tagal
- , Shuguang Wei
- & Michael G. Roth
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Article
| Open AccessGα13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3β-NFATc1 signalling pathway
Osteoclasts are bone resorptive cells and an attractive target to treat diseases characterized by excessive bone loss, but little is known about osteoclast inhibition. Here the authors identify Gα13 as an intracellular inhibitor of osteoclastogenesis that can prevent bone loss in mice via Akt activation and inhibition of RhoA signalling.
- Mengrui Wu
- , Wei Chen
- & Yi-Ping Li
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Article
| Open AccessA mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis
In patients with cystic fibrosis, IL-9 signalling is increased. The authors describe an inflammatory loop in which IL-9 produced by Th9 cells drives mast cells to produce IL-2, resulting in ILC2 cell activation, and show inhibition of this loop with blocking antibodies to IL-9 in a mouse model of pulmonary infection.
- Silvia Moretti
- , Giorgia Renga
- & Luigina Romani
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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 AccessProphylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys
Acute kidney injury can progress to chronic kidney disease. Here Dehnadiet al. develop a post-ischaemic chronic kidney disease model in cynomolgus monkeys and show that prophylactic inhibition of CD11b/CD18 leukocyte receptor via a monoclonal antibody inhibits progression of kidney disease and fibrosis.
- Abbas Dehnadi
- , A. Benedict Cosimi
- & M. Amin Arnaout
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Article
| Open AccessThe transcription factor EPAS1 links DOCK8 deficiency to atopic skin inflammation via IL-31 induction
DOCK8-deficiency can cause atopic dermatitis but the mechanism is unclear. Here the authors use mice and human samples to show ARNT-independent DOCK8 inhibition of EPAS1 increases transcription of IL-31 in CD4+T cells, thus driving skin inflammation.
- Kazuhiko Yamamura
- , Takehito Uruno
- & Yoshinori Fukui
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Article
| Open AccessThe microbiota maintain homeostasis of liver-resident γδT-17 cells in a lipid antigen/CD1d-dependent manner
γδ T cells are major producers of IL-17A in response to microbial infection. Here the authors show that a high load of commensal microbes can maintain homeostasis of IL-17A+γδ T cells in the liver via CD1d antigen presentation, with implications for liver diseases.
- Fenglei Li
- , Xiaolei Hao
- & Zhigang Tian
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Article
| Open AccessCD8+ T cells stimulate Na-Cl co-transporter NCC in distal convoluted tubules leading to salt-sensitive hypertension
T cells contribute to development of high blood pressure but their role in salt-sensitive hypertension is less clear. Liuet al. show that CD8+ T cells upregulate and activate Na-Cl co-transporter NCC in distal convoluted tubules via direct cell-cell contact and ROS-Src activation, leading to Na+retention and salt-sensitive hypertension.
- Yunmeng Liu
- , Tonya M. Rafferty
- & Shengyu Mu
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Article
| Open AccessBiallelic JAK1 mutations in immunodeficient patient with mycobacterial infection
JAK1 mediates intracellular signalling from multiple cytokine receptors. Here, Elettoet al. identify JAK1 mutations that disrupt multiple signalling pathways and are associated with primary immunodeficiency, atypical mycobacterial infection susceptibility and early-onset metastatic bladder carcinoma.
- Davide Eletto
- , Siobhan O. Burns
- & Sergey Nejentsev
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Article
| Open AccessHepcidin inhibits Smad3 phosphorylation in hepatic stellate cells by impeding ferroportin-mediated regulation of Akt
The peptide hormone hepcidin is released from hepatocytes and regulates iron homoeostasis. Here, the authors show that hepcidin also regulates the activation of hepatic stellate cells (HSCs) in mouse models of liver fibrosis by reducing ferroportin expression and inhibiting the HSC response to TGFβ.
- Chang Yeob Han
- , Ja Hyun Koo
- & Sang Geon Kim
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Article
| Open AccessTemporal stability and molecular persistence of the bone marrow plasma cell antibody repertoire
Longevity of antibody responses has been attributed to persistence of plasma cells in mice. Here the authors provide human data in support of this model by immunoglobulin sequencing bone marrow sections from two human donors over 6.5 years to show temporal stability of plasma cell clonotypes, but not other B cells.
- Gabriel C. Wu
- , Nai-Kong V. Cheung
- & Gregory C. Ippolito
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Article
| Open AccessA cell-autonomous tumour suppressor role of RAF1 in hepatocarcinogenesis
The kinase RAF1 usually exerts pro-tumorigenic functions promoting proliferation in RAS-driven cancers. Here, the authors using a mouse model of HCC and clinical data describe an unexpected oncosuppressor role of RAF1 in hepatocarcinoma development linked to a gp130-dependent Stat3 activation and YAP1 regulation.
- Ines Jeric
- , Gabriele Maurer
- & Manuela Baccarini
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Article
| Open AccessProduction of individualized V gene databases reveals high levels of immunoglobulin genetic diversity
Current databases of V genes for antibody repertoire have limitations. Here Corcoran et al. develop a computational approach named IgDiscover that can identify germline V gene sequences from expressed antibody repertoires to high specificity and completeness.
- Martin M. Corcoran
- , Ganesh E. Phad
- & Gunilla B. Karlsson Hedestam
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