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| Open AccessMaternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life
This study shows that maternal and perinatal obesity cause bronchial and vascular smooth muscle cell proliferation through an IL-6-FoxO1 axis, and favor thereby the emergence of bronchial obstruction and pulmonary hypertension later in life.
- Jaco Selle
- , Katharina Dinger
- & Miguel A. Alejandre Alcazar
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Article
| Open AccessDysfunctional ERG signaling drives pulmonary vascular aging and persistent fibrosis
Vascular dysfunction is associated with ageing and chronic diseases, but its role in lung repair and fibrosis is unclear. Here, the authors show that the endothelial transcription factor ERG is a mediator of vascular repair whose function declines in aged lungs resulting in sustained fibrosis
- Nunzia Caporarello
- , Jisu Lee
- & Giovanni Ligresti
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Article
| Open AccessCigarette smoke aggravates asthma by inducing memory-like type 3 innate lymphoid cells
Cigarette smoking may exacerbate asthma, but the underlying mechanisms have not been studied extensively in human patients. Here authors show that type 3 innate lymphoid cells with activated phenotypes are found in the sputum and blood of smokers in higher frequencies, which might result in the aggravation of asthma.
- Jongho Ham
- , Jihyun Kim
- & Hye Young Kim
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Article
| Open AccessHost lung microbiota promotes malaria-associated acute respiratory distress syndrome
The reasons why malaria manifests with a variety of well-recognized clinical phenotypes remain poorly understood. Here, using distinct rodent models, the authors reveal that the microbiota colonizing the lung promotes respiratory distress syndrome and mortality during malaria infections.
- Debanjan Mukherjee
- , Ângelo Ferreira Chora
- & Maria M. Mota
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Article
| Open AccessGene-specific nonsense-mediated mRNA decay targeting for cystic fibrosis therapy
The W1282X nonsense mutation in the CFTR gene causes cystic fibrosis by reducing its mRNA and functional protein levels. Here the authors developed antisense-oligonucleotide cocktails that restore CFTR protein function by gene-specific stabilization of CFTR mRNA.
- Young Jin Kim
- , Tomoki Nomakuchi
- & Adrian R. Krainer
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Article
| Open AccessCFTR mRNAs with nonsense codons are degraded by the SMG6-mediated endonucleolytic decay pathway
Currently, there is no therapy for patients with cystic fibrosis caused by nonsense mutations. Here the authors show that CFTR mRNAs with nonsense codons are predominantly degraded by the SMG6-mediated branch of the NMD pathway, providing potential therapeutic strategies for the devastating disease.
- Edward J. Sanderlin
- , Melissa M. Keenan
- & Lulu Huang
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Article
| Open AccessEndothelial progenitor cells stimulate neonatal lung angiogenesis through FOXF1-mediated activation of BMP9/ACVRL1 signaling
The molecular mechanisms through which pulmonary endothelial progenitor cells stimulate lung angiogenesis are not clear. Here, authors show that these cells stimulate the growth of alveolar capillaries and alveoli of newborn mice through FOXF1 and FLI1 nuclear protein-activation of the BMP9/ACVRL1/SMAD1 signaling pathway.
- Guolun Wang
- , Bingqiang Wen
- & Vladimir V. Kalinichenko
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Article
| Open AccessNasal airway transcriptome-wide association study of asthma reveals genetically driven mucus pathobiology
Understanding regulation of genes associated to disease can reveal insights into disease mechanisms. Here, the authors perform an airway epithelial transcriptome-wide association analysis to elucidate genetic determinants of airway dysfunction in asthma, identifying genetic mechanisms of mucus pathobiology.
- Satria P. Sajuthi
- , Jamie L. Everman
- & Max A. Seibold
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Article
| Open AccessThe arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD
Chronic obstructive pulmonary disease is a progressive and incurable chronic condition that involves accumulation of inflammatory macrophages in the lung tissue. Authors here show in mouse models of lung disease that PRMT7, a protein arginine methyltransferase, is an important regulator of recruitment and the pro-inflammatory phenotype of macrophages.
- Gizem Günes Günsel
- , Thomas M. Conlon
- & Ali Önder Yildirim
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| Open AccessCharacterization of the COPD alveolar niche using single-cell RNA sequencing
Chronic obstructive pulmonary disease is a leading cause of death worldwide, while our understanding of cell-specific mechanisms underlying its pathobiology remains incomplete. Here the authors perform scRNA-seq of human lung tissue to identify transcriptional changes in alveolar niche cells associated with the disease.
- Maor Sauler
- , John E. McDonough
- & Ivan O. Rosas
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Article
| Open AccessTartrate-resistant acid phosphatase 5 promotes pulmonary fibrosis by modulating β-catenin signaling
Idiopathic pulmonary fibrosis is a fatal lung disease with limited treatment options. Here the authors show that tartrate-resistant acid phosphatase 5 (Acp5) promotes lung fibrosis by enhancing beta-catenin signaling and that inhibition of Acp5 can reverse stablished pulmonary fibrosis.
- Yinan Hu
- , Qi Wang
- & Yi Wang
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Article
| Open AccessDistinct roles of KLF4 in mesenchymal cell subtypes during lung fibrogenesis
The pluripotency factor KLF4 has been described as pro-fibrotic or anti-fibrotic in various diseases. Herein, the authors show that during lung fibrosis, these distinct effects can be attributed to mesenchymal cell-type specific functions of KLF4.
- Rachana R. Chandran
- , Yi Xie
- & Daniel M. Greif
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Article
| Open AccessOxidative stress-induced FABP5 S-glutathionylation protects against acute lung injury by suppressing inflammation in macrophages
Redox-dependent regulation plays a key role in the pathogenesis of acute lung injury, but its mechanism is unclear. Here the authors show Grx1-regulated S-glutathionylation of FABP5 controls macrophage inflammation and alleviates acute lung injury.
- Yuxian Guo
- , Yaru Liu
- & Xue Zhang
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Article
| Open AccessACE2-like carboxypeptidase B38-CAP protects from SARS-CoV-2-induced lung injury
Endogenous ACE2 is a receptor for SARS-CoV-2 and a recombinant soluble ACE2 protein can inhibit SARS-CoV-2 infection acting as a decoy. Here the authors show that B38-CAP, an ACE2-like enzyme but not a decoy for the virus, is protective against SARS-CoV-2-induced lung injury in animal models.
- Tomokazu Yamaguchi
- , Midori Hoshizaki
- & Keiji Kuba
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Article
| Open AccessEpigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
Muco-obstructive lung diseases are characterised by airway macrophage (AM) populations which may have epigenetic changes. Here using a mouse model the authors show epigenetic alteration of AMs with changes in LPS response, phagocytosis and efferocytosis similar to culture with mucus in vitro.
- Joschka Hey
- , Michelle Paulsen
- & Marcus A. Mall
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Article
| Open AccessAn innate contribution of human nicotinic receptor polymorphisms to COPD-like lesions
Human polymorphisms in nicotinic acetylcholine receptor genes have been linked to both smoking and lung diseases like Chronic Obstructive Pulmonary Disease (COPD) or lung cancer. Here the authors identify a direct role for a human coding polymorphism in COPD-like lesions independent of smoke or nicotine exposure.
- Julie Routhier
- , Stéphanie Pons
- & Uwe Maskos
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Article
| Open AccessMolecular programs of fibrotic change in aging human lung
Age is associated with increasing vulnerability to both acute and chronic lung diseases. Employing genomic analysis and live lung imaging, this study reveals a profile of increased cellular senescence, telomere shortening, and fibrosis-induced impaired alveolar function in the natural history of human lung aging.
- Seoyeon Lee
- , Mohammad Naimul Islam
- & Mallar Bhattacharya
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Article
| Open AccessClonal hematopoiesis with JAK2V617F promotes pulmonary hypertension with ALK1 upregulation in lung neutrophils
Pulmonary hypertension is characterized by increased pulmonary arterial pressure, driven in part by inflammatory infiltrates. Here, the authors show that in mice, transgenic expression of mutant JAK2 leads to clonal hematopoiesis and lung accumulation of elastase- and cytokine-expressing neutrophils, and that the phenotype can be reversed by ALK1 inhibition.
- Yusuke Kimishima
- , Tomofumi Misaka
- & Yasuchika Takeishi
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| Open AccessEtiological and epidemiological features of acute respiratory infections in China
China operates a national surveillance program for acute respiratory infections and sampled over 200,000 patients between 2009–2019. Here, the authors present results from this program and describe patterns by age, pathogen type, presence of pneumonia, and season.
- Zhong-Jie Li
- , Hai-Yang Zhang
- & Jun Wang
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Article
| Open AccessPulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional
Environmental and genetic risk factors affect the distal airway epithelium in idiopatic pulmonary fibrosis (IPF) but the role of the epithelium in IPF remains unclear. Here the authors show that pathologic activation of the ERBB-YAP axis induces dynamic and structural dysfunction in the distal airway epithelium eliciting a pro-fibrotic phenotype in mesenchymal cells.
- Ian T. Stancil
- , Jacob E. Michalski
- & David A. Schwartz
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| Open AccessMolecular evidence of SARS-CoV-2 in New York before the first pandemic wave
Matthew M. Hernandez and Ana S. Gonzalez-Reiche and colleagues report evidence of SARSCoV-2 infections in respiratory pathogen-negative nasopharyngeal specimens collected in New York, which date back to over one month before the first officially documented case in the state. The findings provide insights in to the origins of the virus in New York.
- Matthew M. Hernandez
- , Ana S. Gonzalez-Reiche
- & Emilia Mia Sordillo
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| Open AccessSevere T cell hyporeactivity in ventilated COVID-19 patients correlates with prolonged virus persistence and poor outcomes
Perturbed T cell responses and disturbed cytokine secretion have been shown during SARS-CoV2 infection in patients. Here the authors show reduced polyclonal T cell activity in COVID-19 patients that is caused by plasma factors and linked to poor prognosis and viral persistence.
- Kerstin Renner
- , Tobias Schwittay
- & Matthias Mack
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Article
| Open AccessClub cell-specific role of programmed cell death 5 in pulmonary fibrosis
Idiopathic pulmonary fibrosis (IPF) is a fatal adult lung disease. Here the authors investigate the functional significance of PDCD5 in club cells as a mediator of lung fibrosis and potential therapeutic target for IPF.
- Soo-Yeon Park
- , Jung Yeon Hong
- & Ho-Geun Yoon
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Article
| Open AccessCD200–CD200R immune checkpoint engagement regulates ILC2 effector function and ameliorates lung inflammation in asthma
The role of the CD200–CD200R axis in regulating pulmonary inflammation is not completely understood. Here the authors show CD200R is expressed on type 2 innate lymphoid cells (ILC2s), and its engagement by CD200 ameliorates airway hyperreactivity and allergic asthma via inhibition of NF-κB signaling.
- Pedram Shafiei-Jahani
- , Doumet Georges Helou
- & Omid Akbari
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Article
| Open AccessExposure to SARS-CoV-2 generates T-cell memory in the absence of a detectable viral infection
T cells compose a critical component of the immune response to coronavirus infection with SARS-CoV-2. Here the authors characterise the T cell response to SARS CoV-2 in patients and their close contacts, and show the presence of SARS-CoV-2 specific T cells in the absence of detectable virus infection.
- Zhongfang Wang
- , Xiaoyun Yang
- & Pixin Ran
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Article
| Open AccessGenetic determinants of risk in autoimmune pulmonary alveolar proteinosis
Autoimmune pulmonary alveolar proteinosis (aPAP) is a complex lung disease caused by abnormal surfactant homeostasis. Here, the authors carry out a genome-wide association study of aPAP in a Japanese cohort, finding variants in the MHC and suggesting predisposition to abnormal antibody production.
- Saori Sakaue
- , Etsuro Yamaguchi
- & Yukinori Okada
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Article
| Open AccessNanoparticle delivery of microRNA-146a regulates mechanotransduction in lung macrophages and mitigates injury during mechanical ventilation
There are no targeted pharmacologic therapies to treat lung injury during mechanical ventilation (MV). Here the authors identify a mechanosensitive microRNA (miR-146a) in alveolar macrophages during MV and increase miR-146a to supraphysiological levels in these cells to mitigate ventilator induced lung injury.
- Christopher M. Bobba
- , Qinqin Fei
- & Joshua A. Englert
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Article
| Open AccessDisulfide disruption reverses mucus dysfunction in allergic airway disease
In asthma, mucus plugging is an important cause of airflow obstruction, but it is not targeted by widely used bronchodilator and anti-inflammatory drugs. Here the authors show that reduction of disulfide bonds that hold mucin polymers together reverses asthma-like obstruction in mice.
- Leslie E. Morgan
- , Ana M. Jaramillo
- & Christopher M. Evans
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Article
| Open AccessFUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses
Genetic variants discovered through genome-wide association studies for asthma together account for a small portion of the heritability. Here, the authors identify a possible epistatic relationship between coding variants in FUT2 and ABO, especially pronounced in severe and early onset asthma.
- Tarunveer S. Ahluwalia
- , Anders U. Eliasen
- & Klaus Bønnelykke
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Article
| Open AccessClinical transplantation using negative pressure ventilation ex situ lung perfusion with extended criteria donor lungs
Preclinical studies have shown that negative pressure ventilation ex situ lung perfusion results in less ventilator-induced lung injury compared to positive pressure ventilation of donor lungs during transplantation procedures. Here the authors perform a single-arm clinical trial with 12 participants to study patient survival and primary graft dysfunction with ex situ lung perfusion.
- Max T. Buchko
- , Nasim Boroumand
- & Jayan Nagendran
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Article
| Open AccessSub-nanoliter metabolomics via mass spectrometry to characterize volume-limited samples
The analysis of metabolites offers promises in biomarker discovery. Here the authors demonstrate the metabolomics analysis of sub-nanoliter samples using triboelectric nanogenerator inductive nanoelectrospray ionization, which they apply to exhaled breath condensate from cystic fibrosis patients and mesenchymal stromal cells.
- Yafeng Li
- , Marcos Bouza
- & Facundo M. Fernández
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Article
| Open AccessACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs
Understanding how SARS-CoV-2 gains initial entry into the human body is a key step towards the development of prophylaxes and therapeutics for COVID-19. Here, the authors show that ACE2, the receptor for SARS-CoV-2, is abundantly expressed in the motile cilia of the human nasal and respiratory tract and is not affected by the use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers.
- Ivan T. Lee
- , Tsuguhisa Nakayama
- & Peter K. Jackson
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Article
| Open AccessWhole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants
Chronic obstructive pulmonary disease is a leading cause of morbidity and mortality. Here, the authors analyse whole genome sequence data and find new loci associated with lung function and COPD.
- Xutong Zhao
- , Dandi Qiao
- & Ani Manichaikul
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Article
| Open AccessTranslational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis
The αvβ6 integrin is key in activating the pro-fibrotic cytokine TGFβ in idiopathic pulmonary fibrosis. Here, the authors show an inhaled small molecule αvβ6 inhibitor GSK3008348 induces prolonged inhibition of TGFβ signaling pathways in human and murine models of lung fibrosis via αvβ6 degradation.
- Alison E. John
- , Rebecca H. Graves
- & Robert J. Slack
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Article
| Open AccessFibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization
Pulmonary fibrosis is a major public health problem with unclear mechanism and limited therapeutic options. Here the authors show that a fibroblast-enriched endoplasmic reticulum protein, TXNDC5, promotes pulmonary fibrosis by stabilizing TGFBR1 and show the potential of TXNDC5 as a therapeutic target against pulmonary fibrosis.
- Tzu-Han Lee
- , Chih-Fan Yeh
- & Kai-Chien Yang
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Article
| Open AccessA lung tropic AAV vector improves survival in a mouse model of surfactant B deficiency
Surfactant protein B (SP-B) deficiency is a genetic lung disease that results in lethal respiratory distress within months of birth. Here, the authors describe a gene therapy strategy using a rationally designed AAV6 capsid that restores surfactant homeostasis, prevents lung injury, and improves survival in a mouse model of SP-B deficiency.
- Martin H. Kang
- , Laura P. van Lieshout
- & Bernard Thébaud
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Article
| Open AccessAlveolar regeneration through a Krt8+ transitional stem cell state that persists in human lung fibrosis
Injury repair is characterized by the generation of transient cell states important for tissue recovery. Here, the authors present a single cell RNA-seq map of recovery from bleomycin lung injury in mice and uncover a Krt8+ transitional stem cell state that precedes the regeneration of AT1 cells and persists in human lung fibrosis.
- Maximilian Strunz
- , Lukas M. Simon
- & Herbert B. Schiller
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Article
| Open AccessRieske iron-sulfur protein induces FKBP12.6/RyR2 complex remodeling and subsequent pulmonary hypertension through NF-κB/cyclin D1 pathway
Pulmonary hypertension is a devastating disease with elevation of pulmonary artery pressure and related to abnormal calcium signalling. Here, the authors show that suppression or stabilization of the calcium channel ryanodine receptor 2 may be a potential treatment approach for this disease.
- Lin Mei
- , Yun-Min Zheng
- & Yong-Xiao Wang
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Article
| Open AccessActivation of JUN in fibroblasts promotes pro-fibrotic programme and modulates protective immunity
Fibroblast contributions to lung fibrosis and in particular their crosstalk with immune cells in the lung are incompletely understood. Here, the authors show an overall immune suppressive environment transcriptionally controlled and maintained by fibroblasts in lung fibrosis with possible therapeutic implications.
- Lu Cui
- , Shih-Yu Chen
- & Gerlinde Wernig
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Article
| Open AccessReversal of the seasonality of temperature-attributable mortality from respiratory diseases in Spain
Potential changes in the seasonality of temperature-attributable mortality due to climate warming have been poorly investigated. Here, the authors show that the projected decrease in the number of moderate and extreme cold days will not contribute to a further reduction of cold-attributable deaths.
- Hicham Achebak
- , Daniel Devolder
- & Joan Ballester
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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 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 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 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 AccessDiscovering the genes mediating the interactions between chronic respiratory diseases in the human interactome
Complex diseases often share genetic determinants and symptoms, but the mechanistic basis of disease interactions remains elusive. Here, the authors propose a network topological measure to identify proteins linking complex diseases in the interactome, and identify mediators between COPD and asthma.
- Enrico Maiorino
- , Seung Han Baek
- & Amitabh Sharma
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Article
| Open AccessPrenatal dietary supplements influence the infant airway microbiota in a randomized factorial clinical trial
Here, the authors present the results of a mother–child cohort randomized clinical trial of n-3 LCPUFA and vitamin D maternal supplementation, finding an association between supplement-induced microbiota changes in infant airways at age 1-month but not the infant fecal or maternal vaginal microbiome.
- Mathis H. Hjelmsø
- , Shiraz A. Shah
- & Hans Bisgaard
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Article
| Open AccessEighty-eight variants highlight the role of T cell regulation and airway remodeling in asthma pathogenesis
Asthma is a common allergic airway disease with significant inter-individual heterogeneity. Here, Olafsdottir et al. report a genome-wide meta-analysis of two large population-based cohorts to identify sequence variants that associate with asthma risk and perform follow-up functional analyses on a protective loss-of-function variant in TNFRSF8.
- Thorunn A. Olafsdottir
- , Fannar Theodors
- & Kari Stefansson
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Article
| Open AccessInfant airway microbiota and topical immune perturbations in the origins of childhood asthma
Here, Thorsen et al. examine the microbiota during the first three months of life in a cohort of 700 children and find that microbial diversity and the relative abundances of Veillonella and Prevotella in the airways at one month of age are associated with topical immune mediators and asthma by age 6 years.
- Jonathan Thorsen
- , Morten A. Rasmussen
- & Hans Bisgaard
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| Open AccessA Chlamydia pneumoniae adhesin induces phosphatidylserine exposure on host cells
The Chlamydia pneumoniae adhesin LIPP plays a role in host cell entry and infection. Here, the authors find that LIPP binds to the host plasma membrane and mediates phosphatidylserine translocation, enhancing pathogen internalization without induction of apoptosis.
- Jan N. Galle
- , Tim Fechtner
- & Johannes H. Hegemann