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| Open AccessThe scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation
Beta-adrenergic stimulation of brown adipose tissue leads to thermogenesis via the activating transcription factor 2 (ATF2) mediated expression of the thermogenic genes Ucp1 and Pgc-1α. Here, the authors show that the scaffold protein p62 regulates brown adipose tissue function through modifying ATF2 genomic binding and subsequent Ucp1 and Pgc-1α induction.
- Katrin Fischer
- , Anna Fenzl
- & Timo D. Müller
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Article
| Open AccessA RUNX2 stabilization pathway mediates physiologic and pathologic bone formation
Runx2 is essential for tuning the generation of bone from skeletal stem cells (SSCs). Here, the authors demonstrate that the CK2/HAUSP pathway stabilizes RUNX2 protein thereby regulating the commitment of SSCs to osteoprogenitors as well as their subsequent maturation, and that inhibition of this pathway can block heterotopic ossification.
- Jung-Min Kim
- , Yeon-Suk Yang
- & Jae-Hyuck Shim
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Article
| Open AccessSomatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease
Chronic graft versus host disease (cGvHD) is a major cause of morbidity and mortality in allogeneic bone marrow transplantation. Here the authors identify a recurrent activating mTOR mutation in expanded donor T-cell clones of 3 cGvHD patients, which suggests somatic mutations may contribute to GvHD pathogenesis and opens avenues to targeted therapies.
- Daehong Kim
- , Giljun Park
- & Satu Mustjoki
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Article
| Open AccessContrast-enhanced ultrasound with sub-micron sized contrast agents detects insulitis in mouse models of type1 diabetes
Infiltration of immune cells to the pancreatic islets precedes clinical symptoms of type 1 diabetes, and lack of methods to detect this insulitis impedes early interventions. Here the authors report a contrast enhanced ultrasound method that can detect early insulitis in mouse models of type 1 diabetes, based on increased microvascular permeability.
- David G. Ramirez
- , Eric Abenojar
- & Richard K. P. Benninger
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Article
| Open AccessA microsporidian impairs Plasmodium falciparum transmission in Anopheles arabiensis mosquitoes
Mircobial symbionts of mosquitoes can affect transmission of human pathogens. Here, Herren et al. identify a microsporidian symbiont in Anopheles gambiae that impairs transmission without affecting mosquito fecundity or survival.
- Jeremy K. Herren
- , Lilian Mbaisi
- & Steven P. Sinkins
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Article
| Open AccessTRAF3IP3 negatively regulates cytosolic RNA induced anti-viral signaling by promoting TBK1 K48 ubiquitination
RNA viruses can be detected by immune cell pattern recognition receptors, such as RLRs, resulting in MAVS-TBK1-IRF3 signalling and production of antiviral type 1 interferons. Here the authors show that macrophage TRAF3-interacting protein 3 regulates this signalling pathway by interacting with TRAF3 and TBK1 to suppress interferon responses.
- Meng Deng
- , Jason W. Tam
- & Jenny P. -Y. Ting
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Article
| Open AccessA PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis
Molecular mechanisms linking myocardial insulin resistance to diabetic cardiomyopathy are incompletely understood. Here the authors show that myocardial insulin resistance impairs a PKB-SPEG-SERCA2a signaling axis, which contributes to the development of diabetic cardiomyopathy.
- Chao Quan
- , Qian Du
- & Shuai Chen
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Article
| Open AccessComprehensive aptamer-based screening identifies a spectrum of urinary biomarkers of lupus nephritis across ethnicities
Developing noninvasive diagnostic biomarkers for lupus nephritis (LN) diagnosis is an important clinical goal. Here the authors identify urinary proteins correlated with active LN and disease severity, which differ across ethnicities but collectively outperform the current clinical method.
- Samantha Stanley
- , Kamala Vanarsa
- & Chandra Mohan
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Article
| Open AccessMD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy
The mechanisms underlying cardiac inflammation in diabetic cardiomyopathy are incompletely understood. Here the authors show that advanced glycation end products bind to the TLR4 co-receptor MD2 initiating pro-inflammatory pathways.
- Yi Wang
- , Wu Luo
- & Guang Liang
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Article
| Open AccessMidkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth
The role of neurons and T cells in glioma progression remains poorly understood. Here the authors show that midkine-dependent activation of a neuron-T cell-microglia axis promotes the growth of optic pathway gliomas.
- Xiaofan Guo
- , Yuan Pan
- & David H. Gutmann
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Article
| Open AccessThe impact of antimalarial resistance on the genetic structure of Plasmodium falciparum in the DRC
The genome of the malaria parasite Plasmodium falciparum contains a record of past evolutionary forces. Here, using 2537 parasite sequences from the Democratic Republic of the Congo, the authors demonstrate how drug pressure and human movement have shaped the present-day parasite population.
- Robert Verity
- , Ozkan Aydemir
- & Jonathan J. Juliano
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Article
| Open AccessDysregulation of bile acids increases the risk for preterm birth in pregnant women
Preterm birth (PTB) is the leading cause of perinatal mortality and newborn complications with limited treatment options. Here the authors show that dysregulation of bile acids increases risk for PTB in pregnant women while restoring bile acid homeostasis delays or prevents PTB in the mouse models.
- Sangmin You
- , Ai-Min Cui
- & Ruitang Deng
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Article
| Open AccessNon-Invasive MRI of Blood–Cerebrospinal Fluid Barrier Function
The blood–cerebrospinal fluid barrier (BCSFB) is an important interface for brain homeostasis. Here the authors describe a non-invasive MRI technique for the quantitative assessment of BCSFB function.
- P. G. Evans
- , M. Sokolska
- & J. A. Wells
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Article
| Open AccessNeutralization of SARS-CoV-2 spike pseudotyped virus by recombinant ACE2-Ig
SARS-CoV-2 uses ACE2 as the entry receptor. Here, the authors show that an ACE2-Ig fusion protein inhibits entry of virus pseudotyped with the SARS-CoV-2 spike protein, show differential binding kinetics of SARS-CoV and SARSCoV-2 spike proteins to ACE2, and determine pharmakocinetic parameters of ACE2-Ig in mice.
- Changhai Lei
- , Kewen Qian
- & Shi Hu
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Article
| Open AccessUncoupling of invasive bacterial mucosal immunogenicity from pathogenicity
Virulent pathogens generally induce a stronger mucosal immunity than avirulent strains, but whether the associated inflammation is necessary for this is unclear. Here, using auxotrophic Salmonella enterica, the authors show that virulence factor function determines induction of protective IgA.
- Simona P. Pfister
- , Olivier P. Schären
- & Siegfried Hapfelmeier
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Article
| Open AccessConditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice
Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis. Here, the authors show that deficiency of the E3 ubiqutin-protein ligase Nedd4-2 in airway epithelial cells causes IPF-like disease in adult mice. This model may aid studies of the pathogenesis and therapy of IPF.
- Julia Duerr
- , Dominik H. W. Leitz
- & Marcus A. Mall
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Article
| Open AccessIdentification of therapeutics that target eEF1A2 and upregulate utrophin A translation in dystrophic muscles
One potential approach for the treatment of Duchenne muscular dysrophy is to increase expression of the dystrophin homolog utrophin. Here, the authors show that eEF1A2 regulates utrophin expression, and show that 2 FDA-approved drugs upregulate eEIF1A2 and utrophin level in mice, leading to improvement of the dystrophic phenotype.
- Christine Péladeau
- , Nadine Adam
- & Bernard J. Jasmin
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Article
| Open AccessA vaccine-based nanosystem for initiating innate immunity and improving tumor immunotherapy
Immune checkpoint blockade (ICB) immunotherapy efficacy has still limitations. Here, the authors generate a vaccine that integrates CD274 siRNA into the L1 protein of human papillomavirus, which cooperates with ICB by activating innate immunity in breast cancer models.
- Di-Wei Zheng
- , Fan Gao
- & Xian-Zheng Zhang
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Article
| Open AccessLoss of MBNL1 induces RNA misprocessing in the thymus and peripheral blood
The activity of the RNA splicing factor MBNL1 is altered in myotonic dystrophy (DM) patients. Here the authors characterize the thymic phenotype of Mbnl1 knockout mice, including developmental defects, transcriptome changes, and RNA mis-splicing of transcripts encoding thymic transcription factors.
- Łukasz J. Sznajder
- , Marina M. Scotti
- & Maurice S. Swanson
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Article
| Open AccessCollagen-producing lung cell atlas identifies multiple subsets with distinct localization and relevance to fibrosis
Collagen production by lung cells is critical to maintain organ architecture but can also drive pathological scarring. Here the authors perform single cell RNA sequencing of collagen-producing lung cells identifying a subset of pathologic fibroblasts characterized by Cthrc1 expression which are concentrated within fibroblastic foci in fibrotic lungs and show a pro-fibrotic phenotype.
- Tatsuya Tsukui
- , Kai-Hui Sun
- & Dean Sheppard
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Article
| Open AccessA double-hit of stress and low-grade inflammation on functional brain network mediates posttraumatic stress symptoms
Low-grade systemic inflammation and stress increase vulnerability to neuropsychiatric disorders. Here, the authors show that inflammation and stress-induced changes in higher order cognitive networks increase vulnerability to posttraumatic stress disorder.
- Jungyoon Kim
- , Sujung Yoon
- & In Kyoon Lyoo
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Article
| Open AccessParacrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes
Glucagon is elevated Type-2 diabetes, which contributes to poor glucose control in patients with the disease. Here the authors report that secretion of the hormone is controlled by paracrine inhibition, and that resistance of α-cells to somatostatin can explain hyperglucagonemia in type-2 diabetes.
- Muhmmad Omar-Hmeadi
- , Per-Eric Lund
- & Sebastian Barg
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Article
| Open AccessIncreased burden of ultra-rare structural variants localizing to boundaries of topologically associated domains in schizophrenia
Common variants identified by large-scale genomewide association studies cannot account fully account for the heritability of schizophrenia (SCZ). Here, the authors report high-coverage whole-genome sequencing of 1162 SCZ cases and 936 controls and explore the contribution of different types of variants to SCZ.
- Matthew Halvorsen
- , Ruth Huh
- & Jin P. Szatkiewicz
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Article
| Open AccessGenome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma
Asthma is a common disease of the airways for which numerous genetic loci have been identified. Here, Han et al. carry out a genome-wide analysis for asthma to identify additional loci, report sex-stratified and genetic risk score analyses, and functionally follow-up one locus using a murine model of airway hyperreactivity.
- Yi Han
- , Qiong Jia
- & Hooman Allayee
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Article
| Open AccessObesity-induced overexpression of miR-802 impairs insulin transcription and secretion
Obesity predisposes to type 2 diabetes, but the mechanisms of obesity-associated β cell dysfunction are incompletely understood. Here the authors report that obesity increases the levels of miR-802, which impairs insulin transcription and secretion by targeting NeuroD1 and Fzd5.
- Fangfang Zhang
- , Dongshen Ma
- & Liang Jin
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Article
| Open AccessGlycogen metabolism regulates macrophage-mediated acute inflammatory responses
Glycogen can be metabolized via glycogenolysis and the pentose phosphate pathway as well as into the production of UDP glucose, which when secreted can bind the P2Y14 receptor. Here the authors show how these glycogen metabolism pathways contribute to proinflammatory macrophage activation and susceptibility to sepsis.
- Jingwei Ma
- , Keke Wei
- & Bo Huang
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Article
| Open AccessAn intracellular membrane protein GEP1 regulates xanthurenic acid induced gametogenesis of malaria parasites
Mosquito-derived xanthurenic acid (XA) is a trigger for gametogenesis of Plasmodium parasites. Here the authors show that the putative amino acid transporter GEP1 is required for XA-stimulated gametogenesis in Plasmodium yoelii and that it interacts with guanylyl cyclase α (GCα), a cGMP synthesizing enzyme in gametocytes.
- Yuanyuan Jiang
- , Jun Wei
- & Jing Yuan
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Article
| Open AccessDiagnosis and prognosis of myocardial infarction on a plasmonic chip
The gold standard for diagnosis and monitoring of myocardial infarction is a chemiluminescence assay based on the detection of cardian troponin I (cTnI). Here, the authors develop a plasmonic gold nano-island chip assay for ultrasensitive detection of cTnI in as little as 10 μL of serum.
- Wei Xu
- , Lin Wang
- & Kun Qian
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Article
| Open AccessPyrazinamide triggers degradation of its target aspartate decarboxylase
It has been shown that the bioactive component of pyrazinamide, pyrazinoic acid (POA), blocks coenzyme A biosynthesis in M. tuberculosis by binding to the aspartate decarboxylase PanD. Here the authors show that pyrazinamide triggers degradation of PanD by stimulating its degradation by the caseinolytic protease Clp.
- Pooja Gopal
- , Jickky Palmae Sarathy
- & Thomas Dick
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Article
| Open AccessMETTL3 is essential for postnatal development of brown adipose tissue and energy expenditure in mice
N6-methyladenosine (m6A) is one of the most prevalent mRNA modifications in eukaryotes. Here the authors show that the m6A writer protein methyltransferase-like (METTL) 3 plays an important role for the development of brown adipose tissue.
- Yuqin Wang
- , Ming Gao
- & Zheng Chen
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Article
| Open AccessExome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes
Around half of the heritability underpinning familial high-grade serous ovarian carcinoma remains unidentified. Here, the authors show that extremely rare protein encoding loss-of-function variants, with a high degree of genetic heterogeneity, may account for some of this missing heritability.
- Deepak N. Subramanian
- , Magnus Zethoven
- & Ian G. Campbell
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Article
| Open AccessGenome-wide association study identifies 143 loci associated with 25 hydroxyvitamin D concentration
Vitamin D is a precursor of the steroid hormone 1,25-dihydroxyvitamin D3, and its deficiency is associated with many adverse health outcomes. Here, Revez et al. perform a genome-wide association study for circulating 25-hydroxyvitamin D in 417,580 individuals and test for potential causal relationships with other traits using Mendelian randomization.
- Joana A. Revez
- , Tian Lin
- & John J. McGrath
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Article
| Open AccessMetagenome-wide association of gut microbiome features for schizophrenia
Gut microbiome has been linked to neurogenerative diseases. Here, the authors present a metagenome-wide association study of schizophrenia (SZ) in human cohorts and identify SZ-associated specific gut-brain functional modules and pathways including SCFAs and neurotransmitters.
- Feng Zhu
- , Yanmei Ju
- & Xiancang Ma
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Article
| Open AccessCharacterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV
SARS-CoV-2 has spread globally. Here, the authors characterize the entry pathway of SARS-CoV-2, show that the SARS-CoV-2 spike protein is less stable than that of SARS-CoV, and show limited cross-neutralization activities between SARS-CoV and SARS-CoV-2 sera.
- Xiuyuan Ou
- , Yan Liu
- & Zhaohui Qian
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Article
| Open AccessLeptin receptor-expressing neuron Sh2b1 supports sympathetic nervous system and protects against obesity and metabolic disease
Leptin regulates the sympathetic nervous system, energy expenditure and body weight through incompletely understood mechanisms. Here the authors report that Sh2b1 in leptin receptor positive neurons mediates the ability of leptin to stimulate sympathetic nerve activity in brown adipose tissue, body temperature and cold tolerance.
- Lin Jiang
- , Haoran Su
- & Liangyou Rui
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Article
| Open AccessLipid analogs reveal features critical for hemolysis and diminish granadaene mediated Group B Streptococcus infection
Granadaene, produced by Group B Streptococcus (GBS), is a long polyene lipid involved in cellular toxicity and hemolytic activity. Here, the authors synthesize and characterize granadaene-like compounds and show that a non-toxic analog diminishes GBS infection in mice when incorporated into a vaccine formulation.
- Blair Armistead
- , Pilar Herrero-Foncubierta
- & Lakshmi Rajagopal
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Article
| Open AccessPerivascular localization of macrophages in the intestinal mucosa is regulated by Nr4a1 and the microbiome
Lamina propria macrophages are at the frontline of defense against intestinal pathogens. Here the authors reveal that CCR2 and NR4A1-dependent CX3CR1+ macrophages form a dense network around the vessels in the lamina propria, and implicate this anatomical structure into prevention of systemic bacterial dissemination.
- Masaki Honda
- , Bas G. J. Surewaard
- & Paul Kubes
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Article
| Open AccessDigenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome
While biallelic mutations of the SLC26A4 gene cause non-syndromic hearing loss with enlarged vestibular aqueducts or Pendred syndrome, a considerable number of patients carry mono-allelic mutations. Here the authors identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4.
- Mengnan Li
- , Shin-ya Nishio
- & Masanori Nakayama
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Article
| Open AccessPharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy
Inhibition of PERK, an endoplasmic reticulum (ER) unfolded protein response (UPR) protein, is a potential pharmacological target for cancer treatment. Here, the authors show that inhibition of PERK under ER stress affects trafficking from the ER to the surface of several key receptor tyrosine kinases, suggesting a selective ER retention.
- Mohamed Mahameed
- , Shatha Boukeileh
- & Boaz Tirosh
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Article
| Open AccessTIGIT limits immune pathology during viral infections
TIGIT is a lymphocyte co-inhibitory receptor that can limit type 1 and cytotoxic T cell responses and maintain immunological tolerance. Here the authors show that TIGIT also limits immune pathology during LCMV or influenza infections in mice by driving IL-10 expression without negatively affecting the viral load.
- Michelle Schorer
- , Nikolas Rakebrandt
- & Nicole Joller
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Article
| Open AccessMaltotriose-based probes for fluorescence and photoacoustic imaging of bacterial infections
Sensitive diagnostic tools for bacterial infections of wounds and surgical sites are necessary to enable early detection and determine optimal means of treatment. Here, the authors develop a fluorescent and optoacoustic probe based on a maltotriose scaffold, which is selectively taken up by gram-positive and gram-negative bacteria.
- Aimen Zlitni
- , Gayatri Gowrishankar
- & Sanjiv Sam Gambhir
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Article
| Open AccessVascular progenitors generated from tankyrase inhibitor-regulated naïve diabetic human iPSC potentiate efficient revascularization of ischemic retina
hPSCs in culture acquire a more naïve pluripotent state upon tankyrase inhibition. Here, the authors show that tankyrase inhibitor-regulated naïve hiPSCs from diabetic donors generate more vascular progenitors and more efficient engraftment into mouse retina than conventional PSCs.
- Tea Soon Park
- , Ludovic Zimmerlin
- & Elias T. Zambidis
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Article
| Open AccessA generalizable 29-mRNA neural-network classifier for acute bacterial and viral infections
Diagnosing acute infections based on transcriptional host response shows promise, but generalizability is wanting. Here, the authors use a co-normalization framework to train a classifier to diagnose acute infections and apply it to independent data on a targeted diagnostic platform.
- Michael B. Mayhew
- , Ljubomir Buturovic
- & Timothy E. Sweeney
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Article
| Open AccessThe mTOR pathway is necessary for survival of mice with short telomeres
Telomerase deficiency leads to age-related diseases and shortened lifespan, while inhibition of the mTOR pathway delays aging. Here, the authors show that inhibition of mTORC1 signaling shortens the lifespan of telomerase deficient mice.
- Iole Ferrara-Romeo
- , Paula Martinez
- & Maria A. Blasco
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Article
| Open AccessGenome-wide association and multi-omic analyses reveal ACTN2 as a gene linked to heart failure
Heart failure has a heterogeneous etiology and the genetic underpinnings are not well understood. Here, Arvanitis et al. perform GWAS meta-analysis including 10,976 heart failure cases and 437,573 controls, identify new loci near ABO and ACTN2 and show that deletion of a ACTN2 enhancer leads to reduced ACTN2 expression in differentiating cardiomyocytes.
- Marios Arvanitis
- , Emmanouil Tampakakis
- & Alexis Battle
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Article
| Open AccessInhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease and adult lung spheroid cells have been shown to promote regeneration in animal models of IPF. Here the authors show that the secretome and exosomes of lung spheroid cells is effective as inhalation treatment in rodent models of lung injury and fibrosis and superior to the counterparts derived from mesenchymal stem cells.
- Phuong-Uyen C. Dinh
- , Dipti Paudel
- & Ke Cheng
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Article
| Open AccessCryo-EM structures of the XPF-ERCC1 endonuclease reveal how DNA-junction engagement disrupts an auto-inhibited conformation
The endonuclease XPF-ERCC1 is a key component of the repair machinery to process both intra-strand and inter-strand DNA crosslinks. Here the authors present the cryo-EM structures of DNA-free and DNA-bound human XPF-ERCC1 and find that DNA-free XPF-ERCC1 adopts an auto-inhibited conformation, which is opened up upon DNA binding and they also characterise the biochemical properties of patient-derived XPF-ERCC1 mutations.
- Morgan Jones
- , Fabienne Beuron
- & Neil Q. McDonald
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Article
| Open AccessPathogenic POGZ mutation causes impaired cortical development and reversible autism-like phenotypes
De novo mutations significantly contribute to autism spectrum disorders (ASD). Here, the authors demonstrate that ASD-associated de novo mutations in the POGZ gene, one of a high-confidence ASD gene, lead to ASD-related impaired neuronal development and disrupted mature cortical network function.
- Kensuke Matsumura
- , Kaoru Seiriki
- & Takanobu Nakazawa
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Article
| Open AccessHuman FCHO1 deficiency reveals role for clathrin-mediated endocytosis in development and function of T cells
FCH domain only 1 (FCHO1) is a key molecule involved in clathrin-mediated endocytosis (CME). Here, the authors report homozygous FCHO1 mutations in individuals with variable T and B cell lymphopenia, which are associated with loss-of-function of FCHO1 and impaired formation of clathrin-coated pits in T cells.
- Marcin Łyszkiewicz
- , Natalia Ziętara
- & Christoph Klein
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