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Treatment of acute lung injury by targeting MG53-mediated cell membrane repair
MG53 acts as a membrane repair protein in striatal muscle. Here the authors report that MG53 is also expressed in the lung, where it exerts a similar repair function in the context of pulmonary epithelial damage, and show that administration of recombinant MG53 ameliorates lung injury in mice.
- Yanlin Jia
- , Ken Chen
- & Jianjie Ma
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LRRC19 expressed in the kidney induces TRAF2/6-mediated signals to prevent infection by uropathogenic bacteria
The immune system plays an important role in preventing microbial colonization in the urinary tract but the mechanism of this protection is not completely understood. Here, the authors identify LRRC19 expressed in the kidneys as a pathogen-recognition receptor involved in the immune response to uropathogenic bacteria.
- Xiaomin Su
- , Siping Min
- & Rongcun Yang
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| Open AccessIdentification of platelet function defects by multi-parameter assessment of thrombus formation
Platelets from patients with bleeding disorders often display altered adherence to surface proteins. In this study, de Witt et al.design a flow chamber for the systematic interrogation of platelets attaching to 52 adhesive surfaces, which may be helpful for the diagnosis of platelet disorders.
- Susanne M. de Witt
- , Frauke Swieringa
- & Judith M.E.M. Cosemans
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Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy
Defective autophagy is associated with the pathogenesis of Duchenne muscular dystrophy (DMD). Pal et al. reveal that activation of Src kinase by oxidative stress is responsible for impairment of autophagy in the muscles of mdxmice, and show that reducing oxidative stress rescues autophagy in this DMD model.
- Rituraj Pal
- , Michela Palmieri
- & George G. Rodney
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| Open AccessGlucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR
Patients with cystic fibrosis harbour mutations in the CFTR chloride channel and often develop diabetes for reasons that are poorly understood. Here Guo et al.show that CFTR is involved in the regulation of glucose-stimulated insulin secretion from pancreatic β-cells.
- Jing Hui Guo
- , Hui Chen
- & Hsiao Chang Chan
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The adipokine Retnla modulates cholesterol homeostasis in hyperlipidemic mice
Retnla is an adipokine with known roles in tissue repair and inflammation. Here Lee et al. show that Retnla also promotes cholesterol metabolism and excretion, thereby lowering blood cholesterol levels and reducing the development of atherosclerosis in mice.
- Mi-Ran Lee
- , Chae-ji Lim
- & Goo Taeg Oh
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Amyloid-associated activity contributes to the severity and toxicity of a prion phenotype
The yeast prion Sup35/[PSI+] confers a translation termination defect in its amyloid form. Pezza et al.reveal that aggregated Sup35 retains translation termination activity, and find that fluctuations in the size and composition of aggregates play an important role in determining their activity and toxicity.
- John A. Pezza
- , Janice Villali
- & Tricia R. Serio
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| Open AccessAstrocyte response to motor neuron injury promotes structural synaptic plasticity via STAT3-regulated TSP-1 expression
Perineuronal astrocyte reactivity is implicated in functional recovery following nerve injury but exactly how this happens is unclear. Tyzack et al. show that perineuronal astrocytes facilitate the recovery of synaptic inputs to damaged neurons via STAT3-dependent upregulation of the astrocytic protein TSP-1.
- Giulia E. Tyzack
- , Sergey Sitnikov
- & András Lakatos
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Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men
Differential selection on sex-specific genes facilitates propagation of deleterious mutations. Here, the authors show that genes exclusively expressed in human testes harbour a greater number of deleterious mutations than genes expressed in both sexes, due to reduced selection in females.
- Moran Gershoni
- & Shmuel Pietrokovski
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| Open AccessThe Opisthorchis viverrini genome provides insights into life in the bile duct
The Asian liver fluke is a parasitic worm that is linked to an increased risk of malignant cancer. Here, the authors sequence the draft genome and transcriptome of this fluke and provide insight into how the species has adapted to be able to survive in the bile duct.
- Neil D. Young
- , Niranjan Nagarajan
- & Robin B. Gasser
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| Open AccessPrion neuropathology follows the accumulation of alternate prion protein isoforms after infective titre has peaked
Prions (PrP) are infectious agents that cause lethal neurodegenerative diseases. Here the authors study the kinetics of prion propagation in mice and show that the onset of neuropathology occurs during the late phase of disease and is hypothesized to be due to increases in a toxic isoform of PrP that is different from the infectious species.
- Malin K. Sandberg
- , Huda Al-Doujaily
- & John Collinge
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Sequencing-based approach identified three new susceptibility loci for psoriasis
Although psoriasis is a chronic disorder affecting approximately 2% of the population, little is known about the underlying genetic architecture. Here, the authors carry out exome sequencing in a large Han Chinese cohort of psoriasis patients and healthy controls, and identify three new genes that may increase risk of developing the disease.
- Yujun Sheng
- , Xin Jin
- & Xuejun Zhang
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Modelling Fanconi anemia pathogenesis and therapeutics using integration-free patient-derived iPSCs
Fanconi anaemia (FA) is a genetic disease associated with low levels of blood stem cells. Here Liu et al.report an improved method to generate genetically corrected induced pluripotent stem cells from an FA patient, and perform a screening to identify drugs that improve their differentiation into blood stem cells.
- Guang-Hui Liu
- , Keiichiro Suzuki
- & Juan Carlos Izpisua Belmonte
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| Open AccessEXOSC8 mutations alter mRNA metabolism and cause hypomyelination with spinal muscular atrophy and cerebellar hypoplasia
The exosome is responsible for mRNA degradation, which is an important step in the regulation of gene expression. Here the authors report that homozygous missense mutations in the exosome subunit, EXOSC8, may cause neurodegenerative disease in infants through the dysregulation of myelin expression.
- Veronika Boczonadi
- , Juliane S. Müller
- & Rita Horvath
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Rag GTPases are cardioprotective by regulating lysosomal function
Rag family proteins control activation of the mTORC1 complex at the lysosome. Here the authors show that loss of RagA/B causes cardiac hypertrophy in mice, revealing an mTORC-independent function of Rag GTPAses as regulators of lysosome function and autophagic flux in cardiomyocytes.
- Young Chul Kim
- , Hyun Woo Park
- & Kun-Liang Guan
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| Open AccessTM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is characterized by increased hepatic triglyceride content (HTGC) in the absence of high alcohol consumption. Here the authors show that a genetic variant in TM6SF2, which is known to be associated with HTGC, is a clinically relevant modifier of hepatic fibrogenesis and increases the risk of progressive NAFLD.
- Yang-Lin Liu
- , Helen L. Reeves
- & Quentin M. Anstee
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Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis
Mycobacterium tuberculosisis intrinsically resistant to most antibiotics. Here, the authors show that the pathogen’s tolerance to three antibiotics, each one targeting a distinct cellular process, is mediated by an antioxidant response that requires the activation of isocitrate lyases.
- Madhumitha Nandakumar
- , Carl Nathan
- & Kyu Y. Rhee
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FOXO1 inhibition yields functional insulin-producing cells in human gut organoid cultures
The transcription factor FOXO1 has been shown to control the differentiation of enteroendocrine cells in mice. Here the authors extend these findings to humans by showing that FOXO1-expressing cells also exist in the human gut, and that inhibition of FOXO1 generates insulin-secreting cells in human gut organoid cultures.
- Ryotaro Bouchi
- , Kylie S. Foo
- & Domenico Accili
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Activity-dependent facilitation of Synaptojanin and synaptic vesicle recycling by the Minibrain kinase
Dysregulation of the kinase Mnb is implicated in autism spectrum disorder and Down’s syndrome. Here the authors demonstrate that Mnb is required for correct synaptic morphology and synaptic vesicle endocytosis, which it achieves via phosphorylation of the synaptic endocytosis protein Synaptojanin.
- Chun-Kan Chen
- , Catherine Bregere
- & Karen T. Chang
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Hepatoprotective role of Sestrin2 against chronic ER stress
When exposed to chronic endoplasmic reticulum (ER) stress, cells downregulate protein synthesis by inhibiting mTOR signalling. Park et al.identify Sestrin2 as a transcriptional target of the ER stress pathway and an important mediator of this protective response in the liver.
- Hwan-Woo Park
- , Haeli Park
- & Jun Hee Lee
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| Open Access2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy
Studies have shown that breast cancer prognosis is hereditary. Here the authors show that a genetic variant in CCL20, a chemokine ligand involved in immune response, is significantly associated with breast cancer survival and may therefore represent an important therapeutic or prognostic target.
- Jingmei Li
- , Linda S. Lindström
- & Kamila Czene
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Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women
Uterine muscle contracts rhythmically during labour but the underlying electrophysiological mechanisms are not fully understood. The authors of this study show that hERG1 potassium channels reduce human uterine contractions in pregnancy and are suppressed during labour in lean but not in obese women.
- Helena C. Parkington
- , Janet Stevenson
- & Roger Smith
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| Open AccessPredicting the risk of avian influenza A H7N9 infection in live-poultry markets across Asia
An avian influenza virus of the H7N9 type, associated with live-poultry markets, has caused two human epidemics in China. Here, the authors develop a statistical model that predicts the risk of H7N9 infection in live-poultry markets across Asia, as a tool for disease surveillance and control.
- Marius Gilbert
- , Nick Golding
- & Hongjie Yu
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| Open AccessThe impact of the metabotropic glutamate receptor and other gene family interaction networks on autism
The autism spectrum disorders are complex genetic traits characterized by various neurodevelopmental deficits. Here, the authors analyse defective gene family interaction networks in autism cases and healthy controls and identify potential gene family interactions that may contribute to autism aetiology.
- Dexter Hadley
- , Zhi-liang Wu
- & Hakon Hakonarson
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Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model
Altered GABAergic synaptic transmission is implicated in Alzheimer’s disease pathology. Here, Wu et al. show that GABA content is increased in brain samples from human patients and that in mouse models of the disease, the increase in GABA leads to an increase in tonic inhibition in the dentate gyrus.
- Zheng Wu
- , Ziyuan Guo
- & Gong Chen
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A mutation burst during the acute phase of Helicobacter pylori infection in humans and rhesus macaques
Helicobacter pylori chronically infects humans, and this is associated with high mutation and recombination rates in the bacterium. Here the authors provide evidence that genome evolution in H. pyloriduring acute infection of the host is orders of magnitude faster than any previously determined mutation rates in bacteria.
- Bodo Linz
- , Helen M. Windsor
- & Barry J. Marshall
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Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors
Histone-like HU proteins play roles in chromatin architecture and DNA-dependent processes in bacteria. Here, the authors describe the crystal structure of the DNA-binding domain of HU from Mycobacterium tuberculosis, and show that the pathogen’s growth can be inhibited using HU-targeting small molecules.
- Tuhin Bhowmick
- , Soumitra Ghosh
- & Valakunja Nagaraja
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iPSC-derived neurons from GBA1-associated Parkinson’s disease patients show autophagic defects and impaired calcium homeostasis
Mutations in the gene, GBA1, cause Gaucher’s disease, and are a strong risk factor for the development of Parkinson’s disease. Here the authors use cells derived from Parkinson’s patients with GBA1mutations to model the disease, and reveal changes in cellular recycling systems that may promote neurodegeneration.
- David C. Schöndorf
- , Massimo Aureli
- & Michela Deleidi
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| Open AccessEvidence of natural Wolbachia infections in field populations of Anopheles gambiae
Wolbachia bacteria live within the cells of many insect species, manipulating their hosts’ reproduction and immune responses. Here, the authors show that these microbes also infect wild populations of malaria-spreading Anopheles mosquitoes, supporting a potential use of Wolbachiato limit malaria transmission.
- Francesco Baldini
- , Nicola Segata
- & Flaminia Catteruccia
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| Open AccessDynamic haematopoietic cell contribution to the developing and adult epicardium
The murine epicardium forms an envelope around the heart and contains cells that can participate in cardiac repair. Here the authors discover a population of epicardial cells derived from blood cells, which proliferate and change their surrounding extracellular matrix in response to cardiac injury.
- Gemma M. Balmer
- , Sveva Bollini
- & Paul R. Riley
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Cathepsin K-mediated notch1 activation contributes to neovascularization in response to hypoxia
The cathepsin family of proteases cleaves intracellular as well as extracellular proteins. Here the authors implicate cathepsin K in ischaemia-induced neovascularization by showing that cathepsin K increases the levels of cleaved Notch1 and downstream Notch signalling in endothelial cells.
- Haiying Jiang
- , Xian Wu Cheng
- & Masafumi Kuzuya
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The FAM3 superfamily member ILEI ameliorates Alzheimer’s disease-like pathology by destabilizing the penultimate amyloid-β precursor
γ-secretase is a major target for treating Alzheimer’s disease (AD). Here, the authors screen various binding proteins against the γ-secretase complex and find that the evolutionarily conserved secretory protein ILEI interferes with γ-secretase-dependent production of β-amyloid, which is implicated in AD.
- Hiroshi Hasegawa
- , Lei Liu
- & Masaki Nishimura
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| Open AccessER–mitochondria associations are regulated by the VAPB–PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43
Mutations in the protein TDP-43 are implicated in amyotrophic lateral sclerosis. Here, the authors show that mutant TDP-43 perturbs endoplasmic reticulum (ER)–mitochondria associations by altering interactions between the mitochondrial protein PTPIP51 and the ER protein VAPB.
- Radu Stoica
- , Kurt J. De Vos
- & Christopher C. J. Miller
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| Open AccessAmerindian-specific regions under positive selection harbour new lipid variants in Latinos
Dyslipidemia and obesity have a high prevalence in populations with Amerindian backgrounds, such as Mexican–Americans. Here, the authors design an approach to identify Amerindian risk genes in Mexicans and identify five genomic loci, which include RORA and SIK3that may contribute to the risk of dyslipidemia and obesity in Amerindian populations.
- Arthur Ko
- , Rita M. Cantor
- & Päivi Pajukanta
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De novo SOX11 mutations cause Coffin–Siris syndrome
Coffin–Siris syndrome (CSS) is a genetic disorder characterized by growth deficiency, microcephaly, intellectual disability and nail hypoplasia of the fifth digits. Here, the authors identify de novo mutations in the SOX11 gene of CSS patients and show that knockdown of sox11a/bcauses brain abnormalities in zebrafish.
- Yoshinori Tsurusaki
- , Eriko Koshimizu
- & Naomichi Matsumoto
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Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size
Mutations in WD-repeat-containing protein 62 (Wdr62) are associated with microcephaly, a congenital disorder characterized by reduced brain size. The authors show that Wdr62 deficiency in mouse embryos leads to mitotic arrest of neural progenitors and that Wdr62 genetically interacts with Aurora kinase Ato control mitotic progression of neural progenitors.
- Jian-Fu Chen
- , Ying Zhang
- & Lee Niswander
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| Open AccessPathological α-synuclein impairs adult-born granule cell development and functional integration in the olfactory bulb
Aggregation-prone forms of α-synuclein lead to degeneration of midbrain dopaminergic neurons, as seen in Parkinson’s disease, but less is known about the effects that the noxious protein has in other brain regions. Here, the authors investigate the effect of a pathological form of α-synuclein on the functional integration of new neurons into the olfactory bulb of adult mice.
- Johanna Neuner
- , Saak V. Ovsepian
- & Jochen Herms
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| Open AccessConformational targeting of intracellular Aβ oligomers demonstrates their pathological oligomerization inside the endoplasmic reticulum
Intracellular Aß oligomers have been linked to Alzheimer’s disease but details about their biosynthesis and function have been hard to obtain due to the lack of selective approaches for targeting them. Here, Meli et al.develop a strategy using recombinant antibodies to target Aß oligomers in the endoplasmic reticulum of cells, and perform mechanistic studies in cellular models of the disease.
- Giovanni Meli
- , Agnese Lecci
- & Antonino Cattaneo
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Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men
Non-obstructive azoospermia (NOA) is a major cause of male infertility. Here, the authors provide insight into the genetic basis of NOA by identifying three new genetic risk loci in a genome-wide association study and reporting a fourth potential NOA susceptibility locus based on a Drosophilaknockdown experiment.
- Zhibin Hu
- , Zheng Li
- & Jiahao Sha
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NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity
Autophagosome biogenesis depends on the lipid kinase Vps34 and its binding proteins Beclin 1 and Atg14L. Lu et al.identify nuclear receptor binding factor 2 (NRBF2) as a regulator of this complex, and show that loss of NRBF2 impairs autophagy, enhances cell vulnerability to endoplasmic reticulum stress and promotes necrosis in the liver.
- Jiahong Lu
- , Liqiang He
- & Zhenyu Yue
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High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model
The influence of diet on the establishment of gut microbiota early in life is poorly understood. Here the authors show, in a primate model, that maternal diet during pregnancy affects the offspring’s microbiome, and that dietary intervention after weaning only partially reverses this effect.
- Jun Ma
- , Amanda L. Prince
- & Kjersti M. Aagaard
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Emergent properties of the interferon-signalling network may underlie the success of hepatitis C treatment
The standard treatment for hepatitis C virus (HCV) infection, combining interferon (IFN) α and ribavirin, fails in a number of patients. Here, the authors use a mathematical model of the IFN signalling network in the presence of HCV to explain the success or failure of hepatitis C treatment.
- Pranesh Padmanabhan
- , Urtzi Garaigorta
- & Narendra M. Dixit
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| Open AccessMutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy
Parkinson’s disease can be caused by a rare mutation in the protein VPS35, but the mechanism responsible for this is largely unknown. Here, Zavodszky et al.show that this mutation leads to defects in the recruitment of endosomal protein sorting machinery and consequent inhibition of autophagy in cells.
- Eszter Zavodszky
- , Matthew N.J. Seaman
- & David C. Rubinsztein
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| Open AccessTranscription factor IRF5 drives P2X4R+-reactive microglia gating neuropathic pain
In response to neuronal injury or disease, microglia adopt distinct reactive phenotypes via the expression of proteins, such as the purinergic P2X4 receptor. Here, Masuda et al.show that the transcription factor axis, interferon regulatory factor-8 and -5, drives the expression of P2X4 receptor in microglia and the adoption of a reactive phenotype after peripheral nerve injury.
- Takahiro Masuda
- , Shosuke Iwamoto
- & Kazuhide Inoue
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| Open AccessExercise training reduces resting heart rate via downregulation of the funny channel HCN4
Endurance athletes are known to have a low resting heart rate. Here, D'Souza et al.propose that training-induced bradycardia is the result of electrophysiological changes in the sinus node, challenging the classical view that training-induced bradycardia is caused by increased activity of the autonomic nervous system.
- Alicia D’Souza
- , Annalisa Bucchi
- & Mark R. Boyett
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Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance
Mice lacking Toll-like receptor 4 (Tlr4) do not develop diet-induced insulin resistance. Here Jia et al.create two tissue-specific Tlr4 knockouts to demonstrate that hepatic Tlr4, but not Tlr4 expressed in myeloid cells, is driving obesity-induced inflammation and insulin resistance.
- Lin Jia
- , Claudia R. Vianna
- & Joel K. Elmquist
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Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients
An avian influenza H7N9 virus causes severe human disease, including acute and often lethal respiratory failure. Here, the authors report that plasma levels of angiotensin II, a regulatory peptide of the renin–angiotensin system, are associated with disease severity and fatal outcome in infected patients.
- Fengming Huang
- , Jing Guo
- & Lanjuan Li
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Angiotensin-converting enzyme 2 protects from lethal avian influenza A H5N1 infections
H5N1 avian influenza viruses can be highly pathogenic. Here, the authors show that H5N1 infection leads to increased serum levels of angiotensin II in patients and mice, and that administration of angiotensin-converting enzyme 2 ameliorates lung injury in infected mice.
- Zhen Zou
- , Yiwu Yan
- & Chengyu Jiang
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Cellular protection using Flt3 and PI3Kα inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity
Cellular oxidative stress is implicated in neurodegeneration. Here, Kang et al.show that the receptor tyrosine kinase Flt3 and the signalling molecule PI3Kα play key roles in glutamate-mediated oxidative stress in neuronal cells, which can be prevented by Flt3- or PI3Kα-specific inhibitors.
- Yunyi Kang
- , Stefano Tiziani
- & Giovanni Paternostro
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