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| Open AccessMuscle abnormalities worsen after post-exertional malaise in long COVID
In this longitudinal, case-controlled, cohort design study, authors show that post-exertional malaise is associated with severe exercise-induced myopathy, local and systemic metabolic disturbances and infiltration of amyloid-containing deposits in skeletal muscles of patients with long COVID.
- Brent Appelman
- , Braeden T. Charlton
- & Rob C. I. Wüst
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Article
| Open AccessPara-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses
COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.
- Benedict D. Michael
- , Cordelia Dunai
- & David K. Menon
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Article
| Open AccessTrue prevalence of long-COVID in a nationwide, population cohort study
Determining the prevalence of Long COVID is challenging because many symptoms attributed to the syndrome could have other causes. Here, the authors estimate the prevalence of Long COVID in Scotland by comparing rates of symptoms reported by people with and without history of SARS-CoV-2 infection.
- Claire E. Hastie
- , David J. Lowe
- & Jill P. Pell
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| Open AccessThe burden of post-acute COVID-19 symptoms in a multinational network cohort analysis
Post-acute COVID-19 condition is difficult to quantify because it includes a range of symptoms that may have other causes. In this study, the authors use primary care data from England and Catalonia, Spain, to estimate the incidence of the condition and identify symptoms that occur more frequently following infection than in uninfected controls.
- Kristin Kostka
- , Elena Roel
- & Annika M. Jödicke
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Article
| Open AccessDiurnal rhythms of wrist temperature are associated with future disease risk in the UK Biobank
Many chronic diseases present with desynchronized sleep-wake cycles, indicative of disrupted biorhythms. Here, the authors propose peripheral thermoregulation as a digital biomarker based on the association between lower temperature rhythms measured from wearable activity trackers with future onset of disease, such as type 2 diabetes, non-alcoholic fatty liver disease, hypertension and pneumonia.
- Thomas G. Brooks
- , Nicholas F. Lahens
- & Carsten Skarke
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Article
| Open AccessA preclinical secondary pharmacology resource illuminates target-adverse drug reaction associations of marketed drugs
In vitro secondary pharmacology assays are used to predict the clinical adverse event risks of new drugs. Here, the authors describe a new database, identify the most predictive assays for estimating risk, and propose candidate mechanisms to explain clinically observed risk profiles.
- Jeffrey J. Sutherland
- , Dimitar Yonchev
- & Laszlo Urban
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Article
| Open AccessHypoxia-reprogramed megamitochondrion contacts and engulfs lysosome to mediate mitochondrial self-digestion
Several organelle membranes make contact in the cell, with many contacts being spatially segregated sites dedicated to specific functions. Here, Hao et al. show that hypoxia increases mitochondria-lysosome contacts, leading to engulfment and degradation of the mitochondria.
- Tianshu Hao
- , Jianglong Yu
- & Zhiyin Song
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Article
| Open AccessNatural history of long-COVID in a nationwide, population cohort study
The long-term natural history of long-COVID is not well understood. In this population-based cohort study from Scotland, the authors describe symptom prevalence and health-related quality of life up to 18 months after a positive SARS-CoV-2 test and compare with matched test-negative controls.
- Claire E. Hastie
- , David J. Lowe
- & Jill P. Pell
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Article
| Open AccessA photoswitchable inhibitor of TREK channels controls pain in wild-type intact freely moving animals
Research on pain often relies on animals, and there is always a need for more precise and more ethical tools. Here, authors present a light-activatable molecule that induces pain in freely moving animal models in a reversible, non-invasive, and spatiotemporally defined way.
- Arnaud Landra-Willm
- , Ameya Karapurkar
- & Guillaume Sandoz
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Article
| Open AccessTEFM variants impair mitochondrial transcription causing childhood-onset neurological disease
Van Haute et al describe autosomal recessive TEFM variants that impair mitochondrial transcription elongation and reduce the levels of promoter distal mitochondrial RNA transcripts, leading to heterogeneous mitochondrial diseases with a treatable neuromuscular transmission defect.
- Lindsey Van Haute
- , Emily O’Connor
- & Rita Horvath
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Article
| Open AccessClinical phenotypes and outcomes associated with SARS-CoV-2 variant Omicron in critically ill French patients with COVID-19
SARS-CoV-2 variant Omicron has been suggested to cause less severe disease. This prospective study shows that the clinical phenotype in patients infected with Omicron differs from patients infected with Delta but no association between Delta and Omicron including sublineages and mortality was observed.
- Nicolas de Prost
- , Etienne Audureau
- & Slim Fourati
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Article
| Open AccessA prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity
Some patients experience long-lasting symptoms after coronavirus disease (COVID-19). Here the authors report the clinical and laboratory parameters in patients with post-COVID-19 syndrome from a prospective observational cohort study.
- Claudia Kedor
- , Helma Freitag
- & Carmen Scheibenbogen
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| Open AccessCombining rapid antigen testing and syndromic surveillance improves community-based COVID-19 detection in a low-income country
Rapid antigen tests and syndromic surveillance for identification of COVID-19 cases are limited by low sensitivity and specificity, respectively. Here, the authors use data from Bangladesh and show that combining the two methods improves diagnostic accuracy in a range of epidemiological scenarios.
- Fergus J. Chadwick
- , Jessica Clark
- & Ayesha Sania
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Article
| Open AccessCourse of post COVID-19 disease symptoms over time in the ComPaRe long COVID prospective e-cohort
Long-term complications and persistent symptoms occur following COVID-19, but the nature and duration of the long-term symptoms are not fully characterised. Here the authors report the evolution of post COVID-19 symptoms using a validated self-reported questionnaire assessing 53 symptoms over time in the ComPaRe long COVID prospective e-cohort.
- Viet-Thi Tran
- , Raphaël Porcher
- & Philippe Ravaud
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Article
| Open AccessMicrobial-driven preterm labour involves crosstalk between the innate and adaptive immune response
Gaining mechanistic insight into the microbiological and immunological factors that are associated with spontaneous preterm birth is important for the development of prevention strategies. Here authors show that the complement system in conjunction with specific vaginal microbial and associated immunological changes are contributing to this condition.
- Denise Chan
- , Phillip R. Bennett
- & Lynne Sykes
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Article
| Open AccessRare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology
Little is known about the biology of back pain, a leading cause of disability. Here the authors report 30 new back pain loci, implicating genes involved in cartilage/bone biology, as well as neurological and inflammatory processes.
- Gyda Bjornsdottir
- , Lilja Stefansdottir
- & Kari Stefansson
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Article
| Open AccessMaternal-fetal immune responses in pregnant women infected with SARS-CoV-2
As pregnant women are considered vulnerable to SARSCoV-2 infection, it is important to investigate the actual risks involved. The authors show here that, while a T cell-dominant inflammatory response is observed at the maternal-foetal interface, the virus remains undetectable in the placenta but triggers specific immune responses in the neonatal (umbilical cord blood) circulation.
- Valeria Garcia-Flores
- , Roberto Romero
- & Nardhy Gomez-Lopez
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Article
| Open AccessNaked mole-rat brown fat thermogenesis is diminished during hypoxia through a rapid decrease in UCP1
Naked mole-rats are hypoxia-tolerant mammals, and during hypoxia their body temperature decreases via unknown mechanisms. Here the authors report that the hypoxia-induced body temperature decrease in naked mole rats occurs through decreased brown adipose tissue thermogenesis via decreases in a key thermogenic mitochondrial protein: UCP1.
- Hang Cheng
- , Rajaa Sebaa
- & Matthew E. Pamenter
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Article
| Open AccessAssociations between patterns in comorbid diagnostic trajectories of individuals with schizophrenia and etiological factors
Schizophrenia is a complex disorder where individuals experience different symptoms and outcomes that can be captured by patterns in other diagnoses. Here the authors use computational approaches to summarize these patterns and suggest they are associated with genetic and environmental exposure.
- Morten Dybdahl Krebs
- , Gonçalo Espregueira Themudo
- & Wesley K. Thompson
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Article
| Open AccessA novel nairovirus associated with acute febrile illness in Hokkaido, Japan
Here, Kodama et al. describe the discovery, isolation and characterization of a novel tick-borne orthonairovirus, designated Yezo virus (YEZV), from patients with an acute febrile illness in Japan. Serological testing of wildlife and molecular screening of ticks suggest an endemic circulation of YEZV in Japan.
- Fumihiro Kodama
- , Hiroki Yamaguchi
- & Keita Matsuno
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Perspective
| Open AccessConsensus statement on the role of health systems in advancing the long-term well-being of people living with HIV
- Jeffrey V. Lazarus
- , Kelly Safreed-Harmon
- & Laura Waters
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Article
| Open AccessSingle-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human fibrotic skin diseases
Fibroblasts are found to be heterogeneous in multiple fibrotic diseases, but fibroblast heterogeneity in fibrotic skin diseases is not well characterized. Here the authors employ scRNA-seq to explore fibroblast heterogeneity in keloid, a paradigm of fibrotic skin diseases.
- Cheng-Cheng Deng
- , Yong-Fei Hu
- & Bin Yang
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Article
| Open AccessAssociations between frontal lobe structure, parent-reported obstructive sleep disordered breathing and childhood behavior in the ABCD dataset
Parents often report behavioral problems in children with symptoms of sleep disordered breathing (oSDB), such as snoring. Here, the authors show that lower brain volumes within the frontal lobe are associated with parent-reported problem behaviors in children with parent-reported symptoms of oSDB.
- Amal Isaiah
- , Thomas Ernst
- & Linda Chang
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Article
| Open AccessMeta-analysis of neural systems underlying placebo analgesia from individual participant fMRI data
The neural mechanisms of placebo analgesia are not fully understood. Here the authors conducted a large scale meta-analysis of individual data from fMRI studies of pain and placebo conditions.
- Matthias Zunhammer
- , Tamás Spisák
- & Fadel Zeidan
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Article
| Open AccessSingle-cell transcriptome profiling of the vaginal wall in women with severe anterior vaginal prolapse
Anterior vaginal prolapse (AVP), the most common form of pelvic organ prolapse, has deleterious effects on women’s health. Here the authors employ single-cell RNA-seq to construct a transcriptomic atlas of vaginal wall cells from AVP patients, and find that extracellular matrix dysregulation and immune reaction are associated with AVP.
- Yaqian Li
- , Qing-Yang Zhang
- & Lan Zhu
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Article
| Open AccessLongitudinal symptom dynamics of COVID-19 infection
Although many COVID-19 cases are mild, most information about symptoms is derived from hospitalized patients. Here, the authors link self-reported symptom surveys to primary care data to describe the longitudinal dynamics of COVID-19 in non-hospitalized individuals.
- Barak Mizrahi
- , Smadar Shilo
- & Eran Segal
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Article
| Open AccessDisease trajectory browser for exploring temporal, population-wide disease progression patterns in 7.2 million Danish patients
The Danish health system has been collecting health-related data on the entire Danish population for years. Here the authors present the Danish Disease Trajectory Browser (DTB), which allows users to explore population-wide disease progression patterns from data collected between 1994 and 2018.
- Troels Siggaard
- , Roc Reguant
- & Søren Brunak
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Article
| Open AccessExplainable artificial intelligence model to predict acute critical illness from electronic health records
Acute critical illness is often preceded by deterioration of routinely measured clinical parameters, e.g., blood pressure and heart rate. Here, the authors develop an explainable artificial intelligence early warning score system for its early detection.
- Simon Meyer Lauritsen
- , Mads Kristensen
- & Bo Thiesson
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Article
| Open AccessInsights into the aetiology of snoring from observational and genetic investigations in the UK Biobank
Snoring is common in the population and tends to be more prevalent in older and/or male individuals. Here, the authors perform GWAS for habitual snoring, identify 41 genomic loci and explore potential causal relationships with anthropometric and cardiometabolic disease traits.
- Adrián I. Campos
- , Luis M. García-Marín
- & Miguel E. Rentería
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Article
| Open AccessIntestinal microbiome composition and its relation to joint pain and inflammation
Alterations to the microbiome are now associated with various diseases. Here the authors analyze microbiomes from a large population based cohort and show positive correlations between abundance of Streptococcus spp. and osteoarthritis-related knee pain.
- Cindy G. Boer
- , Djawad Radjabzadeh
- & Joyce B. J. van Meurs
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Article
| Open AccessDifferent brain networks mediate the effects of social and conditioned expectations on pain
Our experience of pain can be affected by our expectations about how much pain we will feel. Here, the authors show that both social information-driven expectations, and those based on personal experience, are both able to modulate pain, but by different neural pathways.
- Leonie Koban
- , Marieke Jepma
- & Tor D. Wager
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Article
| Open AccessVariants in the fetal genome near pro-inflammatory cytokine genes on 2q13 associate with gestational duration
Gestational duration depends on both maternal and fetal genetic influences. Here, the authors perform a fetal genome-wide association meta-analysis and find that a locus on 2q13 is associated with pregnancy duration and further show that the lead SNP rs7594852 changes the binding properties of transcriptional repressor HIC1.
- Xueping Liu
- , Dorte Helenius
- & Bjarke Feenstra
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Article
| Open AccessMacrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M
Fibrosis is a hallmark of several cardiac pathologies and its underlying mechanisms are still poorly defined. Here the authors show that macrophage hypoxia signaling following transverse aortic constriction in mice suppresses the activation of cardiac fibroblasts by secreting oncostatin M.
- Hajime Abe
- , Norihiko Takeda
- & Issei Komuro
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Article
| Open AccessBrain and psychological determinants of placebo pill response in chronic pain patients
People vary in the extent to which they feel better after taking an inert, placebo, treatment, but the basis for individual placebo response is unclear. Here, the authors show how brain structural and functional variables, as well as personality traits, predict placebo response in those with chronic back pain.
- Etienne Vachon-Presseau
- , Sara E. Berger
- & A. Vania Apkarian
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Article
| Open AccessHypoxia induces senescence of bone marrow mesenchymal stem cells via altered gut microbiota
Systemic chronic hypoxia is a feature of many diseases and may influence the communication between bone marrow and gut microbiota. Here, the authors show that chronic hypoxia predisposes bone marrow stem cells to premature senescence, which may be due to gut dysbiosis and gut microbiota-derived d-galactose accumulation.
- Junyue Xing
- , Yongquan Ying
- & Hao Zhang
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Article
| Open AccessHyperoxia causes miR-34a-mediated injury via angiopoietin-1 in neonatal lungs
Hyperoxia contributes to lung injury in bronchopulmonary dysplasia. The authors show that hyperoxia increases miR-34a expression in human neonates and in mouse models, and that pathology is ameliorated by miR-34a inhibition or by administration of its target angiopoietin-1
- Mansoor Syed
- , Pragnya Das
- & Vineet Bhandari
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Article
| Open AccessCellular senescence mediates fibrotic pulmonary disease
Removal of senescent cells rejuvenates lungs of aged mice. Here the authors show that elimination of senescent cells using either genetic or pharmacological means improves lung function and physical health in a mouse model of idiopathic pulmonary fibrosis (IPF), suggesting potential therapy for treatment of human IPF.
- Marissa J. Schafer
- , Thomas A. White
- & Nathan K. LeBrasseur
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Article
| Open AccessHyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in diabetes
Patients with diabetes often have delayed wound healing, associated with excessive inflammation. Here the authors report that REG3A inhibits TLR3-driven inflammation in skin wounds, and show that REG3A is reduced in models of diabetes, which exacerbates inflammation in diabetic wounds.
- Yelin Wu
- , Yanchun Quan
- & Yuping Lai
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Article
| Open AccessSphingosine-1-phosphate promotes erythrocyte glycolysis and oxygen release for adaptation to high-altitude hypoxia
The presence of the signalling lipid Sphingosine 1-phosphate (S1P) in erythrocytes has unclear physiological implications. Here the authors show that the S1P-generating enzyme Sphingosine kinase type 1 and its product S1P play an important role in the red blood cell adaptation to hypoxic environments in mice and humans.
- Kaiqi Sun
- , Yujin Zhang
- & Yang Xia
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Article
| Open AccessConvulsive seizures from experimental focal cortical dysplasia occur independently of cell misplacement
The etiology of focal cortical dysplasia (FCD) is not fully understood. Here authors generate an mTORC1 overactivation mouse model that recapitulates hallmarks of type II FCDs, including spontaneous seizures, and suggest that neuronal defects, rather than macrostructural changes, lead to seizures.
- Lawrence S. Hsieh
- , John H. Wen
- & Angelique Bordey
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Article
| Open AccessHypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells
Hypoxia promotes tumour aggressiveness and resistance of cancers to oncological treatment. Here, the authors show that caveolin-1 can down-regulate global membrane protein endocytosis in hypoxic cells with potential implications for targeting the hypoxic 3microenvironment of aggressive tumours.
- E. Bourseau-Guilmain
- , J. A. Menard
- & M. Belting
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Article
| Open AccessMeta-analysis identifies seven susceptibility loci involved in the atopic march
The development of asthma following eczema is known as the atopic march. Here the authors conduct a GWAS on affected children and identify two novel loci associated with the disease phenotype.
- Ingo Marenholz
- , Jorge Esparza-Gordillo
- & Young Ae Lee
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Article
| Open AccessThe matrix protein Fibulin-5 is at the interface of tissue stiffness and inflammation in fibrosis
Stiffness in the extracellular matrix is thought to contribute to pathological cutaneous fibrosis. Here, the authors identify the elastic fibre protein Fibulin-5 as a link and potential therapeutic target mediating the transition of cutaneous stiffening to fibrosis.
- Manando Nakasaki
- , Yongsung Hwang
- & Colin Jamora
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Article |
Redefining the concept of protease-activated receptors: cathepsin S evokes itch via activation of Mrgprs
Sensory neurons that mediate histamine-independent itch express Mas-related G protein coupled receptors (Mrgprs). Here, Reddy et al.show that the cysteine protease cathepsin S cleaves and activates MrgpcrC11 without the generation of a tethered ligand, in contrast to other protease activated receptors.
- Vemuri B. Reddy
- , Shuohao Sun
- & Ethan A. Lerner
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Article |
Granulocyte macrophage colony-stimulating factor is required for aortic dissection/intramural haematoma
Aortic dissection and intramural haematoma are caused by separation of the aortic wall via an unknown mechanism. Here the authors show that the inflammatory cytokine, granulocyte macrophage colony-stimulating factor, is a central regulatory molecule causative of these conditions in mice and humans.
- Bo-Kyung Son
- , Daigo Sawaki
- & Toru Suzuki
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Article |
Impedance sensing device enables early detection of pressure ulcers in vivo
Sustained pressure on the skin reduces blood flow and causes wounds. Here the authors describe a flexible electronic ‘bandage’ that measures changes in tissue impedance spectra and detects early tissue damage in rats before it can be visualized, thus enabling possible prevention of pressure ulcers.
- Sarah L. Swisher
- , Monica C. Lin
- & Michel M. Maharbiz
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Article
| Open AccessSteroidal and non-steroidal third-generation aromatase inhibitors induce pain-like symptoms via TRPA1
Use of aromatase inhibitors for breast cancer therapy is associated with severe pain symptoms, the underlying mechanism of which is unknown. Here the authors show that in mice, TRPA1 is a major mediator of the proinflammatory and proalgesic actions of aromatase inhibitors.
- Camilla Fusi
- , Serena Materazzi
- & Romina Nassini
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Article |
Human symptoms–disease network
Unravelling the relationships between disease symptoms and underlying molecular origins is an important task in biomedical research. Here, Zhou et al.link diseases via their symptom overlap, and show that similar phenotypes are mirrored in networks that connect diseases with common genes or protein interactions.
- XueZhong Zhou
- , Jörg Menche
- & Amitabh Sharma
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Article
| Open AccessActivation of TRPC6 channels is essential for lung ischaemia–reperfusion induced oedema in mice
The signalling cascade involved in lung ischaemia–reperfusion-induced oedema is poorly understood. Using knockout mice, Weissmannet al. propose a model in which reactive oxygen species production by endothelial NOX2 leads to phospholipase C-γ activation, DAG kinase inhibition and subsequent TRPC6 activation.
- Norbert Weissmann
- , Akylbek Sydykov
- & Alexander Dietrich