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Whole-exome sequencing implicates UBE3D in age-related macular degeneration in East Asian populations
Age-related macular degeneration is a prominent cause of irreversible blindness among the elderly. Here Huang et al.identify a novel missense variant in UBE3D that sheds new light on the pathogenesis of the disease.
- Lv-Zhen Huang
- , Ying-Jie Li
- & Xiao-Xin Li
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| Open AccessReduced Tyk2 gene expression in β-cells due to natural mutation determines susceptibility to virus-induced diabetes
Diabetes can be caused by viral infections in humans and some inbred mice, suggesting genetic predisposition. Here the authors show that mutations in Tyk2 gene underlie susceptibility to virus-induced diabetes in mice, due to Tyk2requirement for antiviral response in insulin-producing cells.
- Kenichi Izumi
- , Keiichiro Mine
- & Seiho Nagafuchi
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| Open AccessTracking the origins and drivers of subclonal metastatic expansion in prostate cancer
Primary prostate tumours are known to be genetically heterogeneous and clonal selection has the potential to drive metastasis. Here Hong et al. show that the acquisition of TP53 mutations is linked to clonal expansion and metastatic progression to lethality.
- Matthew K.H. Hong
- , Geoff Macintyre
- & Christopher M. Hovens
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Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo
Inhibiting the interaction between the membrane protein P-selectin and its ligand PSGL-1 is thought to block inflammation. Here the authors report an efficient stereoselective synthesis for PSGL-1 glycopeptide mimics and show that these compounds inhibit PSGL-1/P-selectin in vitro and in vivo.
- Venkata R. Krishnamurthy
- , Mohammed Y. R. Sardar
- & Elliot L. Chaikof
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Identification of myopia-associated WNT7B polymorphisms provides insights into the mechanism underlying the development of myopia
Myopia is a significant and increasing public health concern. Here Miyake et al. conduct a genome-wide association study and identify WNT7Bas a susceptibility gene across different ethnic groups, suggesting a possible role in the development of myopia.
- Masahiro Miyake
- , Kenji Yamashiro
- & Nagahisa Yoshimura
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Skp2–MacroH2A1–CDK8 axis orchestrates G2/M transition and tumorigenesis
Skp2 forms part of the SCF complex—an E3 ubiquitin ligase. Here the authors identify macroH2A1 as a novel target of Skp2 and propose an axis of regulation involving Skp2-macroH2A1-CDK8-p27 in cancer.
- Dazhi Xu
- , Chien-Feng Li
- & Hui-Kuan Lin
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| Open AccessA PAX1 enhancer locus is associated with susceptibility to idiopathic scoliosis in females
Girls are tenfold more likely than boys to require surgical treatment for idiopathic scoliosis, a common paediatric skeletal disorder. Here, Sharma et al. identify the first sexually dimorphic idiopathic scoliosis risk locus, and demonstrate that it may play a role in the regulation of spinal cells.
- Swarkar Sharma
- , Douglas Londono
- & Carol A. Wise
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| Open AccessIL-23-mediated mononuclear phagocyte crosstalk protects mice from Citrobacter rodentium-induced colon immunopathology
Macrophages and dendritic cells contribute to gut homeostasis and mucosal immune defense. Here, Aychek et al. describe an IL-23-based crosstalk between these cells that prevents lethal immunopathology during Citrobacter rodentiuminfection.
- Tegest Aychek
- , Alexander Mildner
- & Steffen Jung
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| Open AccessRB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer
Resistance to tyrosine kinase inhibitors occurs in treatments of non-small-cell lung cancers (NSCLCs) with EGFR mutations but the mechanisms underlying this acquired resistance are unknown. Here the authors examine the molecular changes that occur in resistant cancers that transition from NSCLC to small-cell lung cancer phenotype and implicate loss of retinoblastoma in this process.
- Matthew J. Niederst
- , Lecia V. Sequist
- & Jeffrey A. Engelman
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The reverse evolution from multicellularity to unicellularity during carcinogenesis
Multicellularity relies on molecular mechanisms that promote cooperation of individual cells and limit their inappropriate expansion. Here Chen et al. show that genes unique to multicellular organisms are preferentially inactivated during tumour evolution.
- Han Chen
- , Fangqin Lin
- & Xionglei He
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Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia
Acinar-to-ductal metaplasia (ADM) is a potential early step in the development of pancreatic cancer. Here, using an in vitromodel of ADM, the authors show that protein kinase D1 (PKD1) is required for TGFα- or KRAS-induced ADM through Notch activation.
- Geou-Yarh Liou
- , Heike Döppler
- & Peter Storz
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Integration of Hippo signalling and the unfolded protein response to restrain liver overgrowth and tumorigenesis
The Hippo pathway is a major regulator of organ size and growth control. Here Wu et al. provide evidence for a novel link between the Hippo signalling pathway and the unfolded protein response (UPR) in regulating organ growth and tumorigenesis.
- Hongtan Wu
- , Luyao Wei
- & Dawang Zhou
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The polymeric mucin Muc5ac is required for allergic airway hyperreactivity
Asthma is associated with mucus overproduction; however, the immunological consequences of excess mucus remain poorly understood. Here the authors show that formation of airway plugs by mucus promotes airway hypersensitivity, while deletion of mucous component Muc5acablates it independently of inflammation.
- Christopher M. Evans
- , Dorota S. Raclawska
- & Burton F. Dickey
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Activating CAR and β-catenin induces uncontrolled liver growth and tumorigenesis
Activation of the liver receptor CAR and β-catenin are both involved in hepatocellular carcinoma. Here, the authors show that combined activation of both CAR and β-catenin in mice can drive uncontrolled liver growth and is sufficient for hepatocarcinogenesis.
- Bingning Dong
- , Ju-Seog Lee
- & David D. Moore
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| Open AccessAn oncogenic role of Agrin in regulating focal adhesion integrity in hepatocellular carcinoma
The proteoglycan Agrin is known to be expressed in neurons and muscle and to bind ECM protein laminin. Here the authors report that Agrin promotes hepatocellular carcinoma by stimulating proliferation, decreasing focal adhesion, increasing invasiveness and promoting an epithelial-to-mesenchymal transition.
- Sayan Chakraborty
- , Manikandan Lakshmanan
- & Wanjin Hong
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Coexistent ARID1A–PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling
ARID1A is frequently mutated in ovarian clear-cell carcinoma. Here the authors show that ARID1A loss in mice cooperates with PI3K activation to recapitulate the human disease, and implicate IL-6 signalling as the underlying mechanism.
- Ronald L. Chandler
- , Jeffrey S. Damrauer
- & Terry Magnuson
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Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci
Alopecia areata (AA) is a common autoimmune disease with a known genetic component. Here, the authors analyse 3,253 AA patients and 7,543 healthy controls, and identify two new risk loci and disrupted immune response pathways associated with the disease.
- Regina C. Betz
- , Lynn Petukhova
- & Angela M. Christiano
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| Open AccessInterfering with stem cell-specific gatekeeper functions controls tumour initiation and malignant progression of skin tumours
The presence of multiple stem and progenitor cells in the skin has a major impact on the formation of different epidermal tumours. Here the authors identify bulge stem cells as the cells of origin of sebaceous tumours through genetic lineage tracing and molecular studies in a mouse model.
- Monika Petersson
- , Karen Reuter
- & Catherin Niemann
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IL-10 engages macrophages to shift Th17 cytokine dependency and pathogenicity during T-cell-mediated colitis
The pro-inflammatory cytokine IL-1ß promotes the accumulation of pathologic Th17 lymphocytes that contribute to colitis. Here the authors show that the critical role of IL-10 in colitis suppression can be explained by its inhibition of IL-1ß production in macrophages.
- Bofeng Li
- , Prajwal Gurung
- & Terrence L. Geiger
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| Open AccessA genome-wide association study of marginal zone lymphoma shows association to the HLA region
Marginal zone lymphoma (MZL) is a common subtype of B-cell non-Hodgkin lymphoma. Here the authors carry out a two-stage genome-wide association study in over 8,000 Europeans and identify two new MZL risk loci at chromosome 6p, implicating the major histocompatibility complex in the disease for the first time.
- Joseph Vijai
- , Zhaoming Wang
- & Alexandra Nieters
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| Open AccessDietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation
Chronic consumption of a Western-type diet leads to systemic inflammation of undefined origin, which contributes to metabolic disease. Here Progatzky et al. identify an immediate early step in the process by showing that dietary cholesterol rapidly activates inflammasomes in the gut epithelium.
- Fränze Progatzky
- , Navjyot J. Sangha
- & Margaret J. Dallman
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Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis
Systemic sclerosis (SSc) is an incurable disease of unknown cause, characterized by vasculopathy, autoimmunity and fibrosis. Here the authors show that simultaneous decrease in two transcription factors, KLF5 and Fli1, underlies SSc development in mice and represents a signature trait of SSc patients.
- Shinji Noda
- , Yoshihide Asano
- & Shinichi Sato
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| Open AccessTranscriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism
Autism spectrum disorder (ASD) is a common, highly heritable neurodevelopmental condition characterized by marked genetic heterogeneity. In this study, the authors use RNA sequencing analyses to characterize differences in the transcriptome between autistic and typically developing brains.
- Simone Gupta
- , Shannon E. Ellis
- & Dan E. Arking
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| Open AccessOncogenic Kit signals on endolysosomes and endoplasmic reticulum are essential for neoplastic mast cell proliferation
Activating mutations of the tyrosine kinase Kit are commonly found in mast cell neoplasms and gastrointestinal stromal tumours. Here the authors show that mutant Kit, through the activation of PI3K and STAT3 pathways, elicits proliferative and survival signals from endolysosomes and from the endoplasmic reticulum.
- Yuuki Obata
- , Shota Toyoshima
- & Ryo Abe
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Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner
The anti-apoptotic protein Mcl-1 and haplo-insufficient tumour suppressor Beclin-1 are deregulated in several cancers. Here the authors show that Mcl-1 and Beclin-1 compete for binding to the deubiquitinase USP9X, resulting in a reciprocal regulation during melanoma progression.
- Mohamed Elgendy
- , Marco Ciro
- & Saverio Minucci
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The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis
LL37 is an antimicrobial peptide that is overexpressed in skin lesions from psoriasis patients and activates innate immunity. Here the authors show that CD4 and CD8 T cells specific for LL37 are present in the circulation of patients with psoriasis, produce inflammatory cytokines and correlate with disease activity.
- Roberto Lande
- , Elisabetta Botti
- & Loredana Frasca
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| Open AccessA nairovirus isolated from African bats causes haemorrhagic gastroenteritis and severe hepatic disease in mice
Bats carry viruses that can cause disease in other animals and in humans. Here, Ishii et al.identify new nairoviruses from African bats and show that some of them can produce a severe haemorrhagic disease in laboratory mice that is similar to Crimean–Congo haemorrhagic fever in humans.
- Akihiro Ishii
- , Keisuke Ueno
- & Hirofumi Sawa
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Different thresholds of ZEB1 are required for Ras-mediated tumour initiation and metastasis
The transcription factor ZEB1 has been implicated in different steps of the metastatic cascade. Here the authors show that heterozygous loss of ZEB1in a K-Ras-driven mouse model of lung cancer inhibits progression from lung adenomas to adenocarcinomas.
- Yongqing Liu
- , Xiaoqin Lu
- & Douglas C. Dean
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| Open AccessPathological roles of the VEGF/SphK pathway in Niemann–Pick type C neurons
Sphingosine is abnormally accumulated in Niemann–Pick type C disease (NP–C), but the causes of this accumulation have not been fully characterized. Here the authors show that sphingosine kinase activity is reduced in NP–C patient fibroblasts and NP–C mouse neurons due to defective vascular endothelial growth factor levels, suggesting therapeutic avenues.
- Hyun Lee
- , Jong Kil Lee
- & Hee Kyung Jin
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PKM2 phosphorylates MLC2 and regulates cytokinesis of tumour cells
The pyruvate kinase type M2 (PKM2) has a well-established role in cancer due to its functions in regulating glucose metabolism, G1-S transition and mitotic checkpoint. Here the authors identified a novel role for PKM2 in regulating cytokinesis in cancer cells through the phosphorylation of the myosin light chain 2 at the contractile ring.
- Yuhui Jiang
- , Yugang Wang
- & Zhimin Lu
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GWAS identifies four novel eosinophilic esophagitis loci
Eosinophilic oesophagitis (EoE) is an allergic, inflammatory disorder of the oesophagus. Here the authors carry out a genome-wide association study in over 5,000 individuals and identify four genetic loci that affect the onset of EoE.
- Patrick M. A. Sleiman
- , Mei-Lun Wang
- & Hakon Hakonarson
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Decreased tumorigenesis in mice with a Kras point mutation at C118
The Ras family of proteins is frequently mutated in cancer, and free radical oxidants can also activate these proteins via modifications at cysteine 118 (C118). Here the authors introduce a C118S mutant Krasgene into mice and show that this mutant allele results in a reduction in lung tumorigenesis.
- Lu Huang
- , John Carney
- & Christopher M. Counter
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CSN6 drives carcinogenesis by positively regulating Myc stability
The COP9 signalosome (CSN) is a protein complex involved in protein degradation and tumorigenesis. Here the authors show that the CSN6 subunit antagonizes the deneddylation function of CSN5 towards ubiquitin ligase Cullin-1, resulting in Fbxw7 ubiquitin ligase degradation and thereby stabilization of the Fbxw7 target Myc.
- Jian Chen
- , Ji-Hyun Shin
- & Mong-Hong Lee
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| Open AccessChlamydia infection depends on a functional MDM2-p53 axis
Protein p53 plays key roles in cellular stress responses and is frequently deregulated in cancer. Here the authors show that infection with chlamydiae activates the ubiquitin ligase MDM2 in infected cells, leading to proteasomal degradation of p53 and thus promoting apoptosis resistance.
- Erik González
- , Marion Rother
- & Thomas F. Meyer
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Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents
Cilia are hair-like protuberances on the cellular surface that have been implicated in sensing and signal transduction. Here Gerdes et al. show cilia are involved in insulin signalling and secretion in pancreatic β-cells of rodents, and suggest that ciliary dysfunction could contribute to type 2 diabetes.
- Jantje M. Gerdes
- , Sonia Christou-Savina
- & Per-Olof Berggren
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| Open AccessNF-κB-induced KIAA1199 promotes survival through EGFR signalling
The cross-talk between constitutively active EGFR- and NF-κB-dependent pathways in cancer is poorly understood. Here, the authors identify KIAA1199 as a BCL3 and NF-κB-regulated protein that is expressed in cervical lesions and promotes tumorigenesis through Plexin A2 binding and regulation of EGFR stability.
- Kateryna Shostak
- , Xin Zhang
- & Alain Chariot
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| Open AccessGenomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis
Loss-of-function mutations in tumour suppressor genes are associated with oesophageal adenocarcinoma (EAC), but the mechanisms underlying EAC development remain unclear. Here, the authors show that EACs present a high frequency of genomic catastrophes resulting in amplification of potent oncogenes.
- Katia Nones
- , Nicola Waddell
- & Andrew P. Barbour
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Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis
Iron deficiency is the leading cause of anaemia and is known to compromise immune function. Here, the authors identify several new genes associated with iron status in European populations and provide insight into how iron levels may be linked to the risk of metabolic disease.
- Beben Benyamin
- , Tonu Esko
- & John B. Whitfield
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| Open AccessIncreasing microtubule acetylation rescues axonal transport and locomotor deficits caused by LRRK2 Roc-COR domain mutations
Mutations in the kinase LRRK2 are associated with Parkinson’s disease. Godena et al. find that disease-associated LRRK2 mutations promote its binding to deacetylated microtubules, and cause defects in axonal transport and Drosophilalocomotor behaviour that can be reversed by enhancing tubulin acetylation.
- Vinay K. Godena
- , Nicholas Brookes-Hocking
- & Kurt J. De Vos
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| Open AccessParkin regulates kainate receptors by interacting with the GluK2 subunit
Loss-of-function mutations in the PARK2gene are implicated in autosomal recessive juvenile parkinsonism, but the mechanisms are unclear. Here, the authors show that these mutations cause accumulation of the kainate receptor subunit GluK2 in the plasma membrane of neurons, which facilitates neuronal death.
- AnnaMaria Maraschi
- , Andrea Ciammola
- & Jenny Sassone
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| Open AccessGermline variants in the SEMA4A gene predispose to familial colorectal cancer type X
It is known that hereditary factors contribute to familial colorectal cancer type X. Here, the authors uncover the SEMA4A p.Val78Met germline mutation and show that the protein product is associated with changes in cell cycle progression in colorectal cancer cells.
- Eduard Schulz
- , Petra Klampfl
- & Heinz Sill
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Inflammation-driven carcinogenesis is mediated through STING
Chronic inflammation is known to promote tumorigenesis, but the mechanisms underlying this are incompletely understood. Here, the authors show that several carcinogens induce DNA leakage into the cytoplasm, which activates STING-dependent cytokine production and inflammation-driven tumorigenesis.
- Jeonghyun Ahn
- , Tianli Xia
- & Glen N. Barber
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Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity
Critical period plasticity describes a developmental process whereby neural circuits are fine-tuned for specific functions. Here, the authors show that the Rett syndrome protein MeCP2 in GABAergic parvalbumin-expressing neurons is required for critical period plasticity of the visual cortex.
- Ling-jie He
- , Nan Liu
- & Xiao-hui Zhang
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Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells
Genetic studies have connected polymorphisms in the IL-2 receptor alpha (IL2RA) gene with susceptibility to multiple sclerosis, but the mechanisms underlying this association are not clear. Here, the authors show that a polymorphism in IL2RA increases responsiveness to IL-2 and GM-CSF production in human THcells.
- Felix J. Hartmann
- , Mohsen Khademi
- & Burkhard Becher
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Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis
Focal adhesion kinase (FAK) is frequently overexpressed in solid tumours. Here Batista et al.show that loss of FAK skews hematopoietic progenitors toward myeloid differentiation and promotes metastases, warning against the use of FAK inhibitors in anticancer therapies.
- Silvia Batista
- , Eleni Maniati
- & Kairbaan Hodivala-Dilke
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Systemic autophagy insufficiency compromises adaptation to metabolic stress and facilitates progression from obesity to diabetes
The mechanisms underlying the relationship between autophagy and metabolism remain unclear. Here, the authors demonstrate that mice with a systemic reduction in the autophagy pathway have an impaired response to metabolic stress, developing insulin resistance and an increase in intracellular lipid content.
- Yu-Mi Lim
- , Hyejin Lim
- & Myung-Shik Lee
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| Open AccessPICALM modulates autophagy activity and tau accumulation
The protein PICALM/CALM is implicated in Alzheimer’s disease (AD) pathology, but it is unclear how. In this study, the authors show that CALM regulates clearance of the protein tau, which is also implicated in AD pathology, by facilitating endocytosis-dependent autophagy.
- Kevin Moreau
- , Angeleen Fleming
- & David C. Rubinsztein
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Macrophage-inducible C-type lectin underlies obesity-induced adipose tissue fibrosis
The protein Mincle can sense pathogens and molecules associated with cell death. Here the authors show that Mincle expressed in macrophages is a mediator of obesity-induced fibrosis and inflammation of adipose tissue, and that Mincle knockout mice are protected from diet-induced metabolic dysfunction.
- Miyako Tanaka
- , Kenji Ikeda
- & Yoshihiro Ogawa
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Genetic deficiency of the mitochondrial protein PGAM5 causes a Parkinson’s-like movement disorder
Mitophagy selectively disposes of dysfunctional mitochondria and defects in this process lead to a variety of mitochondrial diseases. Here the authors report that the mitochondrial protein PGAM5 is required for the stabilization of mitophagy-inducing protein PINK1, and that mice deficient for the gene coding for PGAM5 show signs of neurodegeneration.
- Wei Lu
- , Senthilkumar S. Karuppagounder
- & Michael Lenardo