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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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Article
| Open AccessProtein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism
Autism spectrum disorder (ASD) is a complex genetic trait that encompasses a range of neurodevelopmental disorders. Here, the authors clone brain-expressed alternatively-spliced isoforms of ASD risk factors and construct a network of protein interactions that provides further insight into the disease aetiology.
- Roser Corominas
- , Xinping Yang
- & Lilia M. Iakoucheva
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| Open AccessProtein accumulation in the endoplasmic reticulum as a non-equilibrium phase transition
Misfolded protein accumulation is a hallmark of many neurodegenerative diseases. Here Budrikis et al. model protein aggregation in the endoplasmic reticulum and show that it is the result of a non-equilibrium phase transition caused by tipping the balance from the rates of protein production to degradation.
- Zoe Budrikis
- , Giulio Costantini
- & Stefano Zapperi
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| Open AccessCell wall precursors are required to organize the chlamydial division septum
Cell division in Chlamydiales remains mysterious as it occurs in the absence of a cytokinetic tubulin and a classical peptidoglycan cell wall. Jacquier et al. show that the actin homologue MreB is recruited to the division site in Waddliaand that this depends on synthesis of the peptidoglycan precursor lipid II.
- Nicolas Jacquier
- , Antonio Frandi
- & Gilbert Greub
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| Open AccessUltra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen
The potential of extracellular vesicles (EVs) as cancer biomarkers is substantial. Here, Yoshioka et al. describe a sensitive technique to analyse EVs directly from blood samples of patients with colorectal cancer, highlighting a liquid biopsy technique with cancer-detection possibilities.
- Yusuke Yoshioka
- , Nobuyoshi Kosaka
- & Takahiro Ochiya
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| Open AccessFragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density
Mutations in the fragile X mental retardation protein are implicated in synaptic dysfunction in fragile X syndrome. Here, Ferron et al. show that fragile X mental retardation protein maintains proper neurotransmission by regulating the density of N-type calcium channels in the presynaptic terminal.
- Laurent Ferron
- , Manuela Nieto-Rostro
- & Annette C. Dolphin
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Direct visualization of HIV-enhancing endogenous amyloid fibrils in human semen
Semen-derived peptides can form amyloid fibrils that boost HIV infection in vitro, but the existence of such fibrils in semen remained to be demonstrated. Here, the authors show that human semen contains amyloid fibrils, which can bind HIV particles and increase their infectiveness.
- Shariq M. Usmani
- , Onofrio Zirafi
- & Jan Münch
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| Open AccessSLC7A14 linked to autosomal recessive retinitis pigmentosa
Retinitis pigmentosa is the leading cause of inherited blindness worldwide. Here, the authors use exome sequencing to identify mutations in SLC7A14that may be linked to the disease, and provide functional support for the role of this gene in retinal development and visual function in mice and zebrafish.
- Zi-Bing Jin
- , Xiu-Feng Huang
- & Jia Qu
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Mutations in epigenetic regulators including SETD2 are gained during relapse in paediatric acute lymphoblastic leukaemia
Epigenetic regulators have been proposed to be modulators of chemoresistance in acute lymphoblastic leukaemia. Here, the authors find enrichment of mutations in epigenetic regulators at relapse, including somatic mutations in SETD2.
- Brenton G. Mar
- , Lars B. Bullinger
- & Scott A. Armstrong
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EphrinB2 affects apical constriction in Xenopus embryos and is regulated by ADAM10 and flotillin-1
ADAM metalloproteases cleave ephrin signalling proteins and their receptors. Here, the authors show that ADAM10-mediated cleavage of ephrinB2 is inhibited by the lipid raft protein flotillin-1 and that ephrinB2 regulates apical constriction during neural tube closure in Xenopusembryos.
- Yon Ju Ji
- , Yoo-Seok Hwang
- & Ira O. Daar
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Disrupting MLC1 and GlialCAM and ClC-2 interactions in leukodystrophy entails glial chloride channel dysfunction
Defects in the cell adhesion molecule GlialCAM, the membrane protein MLC1 and the chloride channel ClC-2 are implicated in leukodystrophy. Here, Hoegg-Beiler et al.show that these proteins form a functional complex to maintain homoeostatic chloride ion transport supporting normal glial function in mice.
- Maja B. Hoegg-Beiler
- , Sònia Sirisi
- & Thomas J. Jentsch
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Endotrophin triggers adipose tissue fibrosis and metabolic dysfunction
The adipokine endotrophin promotes tumour inflammation and angiogenesis, but its effects on adipose tissue are unclear. Here, Sun et al.show that endotrophin promotes adipose tissue inflammation and fibrosis, and that injections of an anti-endotrophin antibody improve metabolic parameters of mice on a high-fat diet.
- Kai Sun
- , Jiyoung Park
- & Philipp E. Scherer
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Ionizing irradiation induces acute haematopoietic syndrome and gastrointestinal syndrome independently in mice
Ionizing radiation damages the gastrointestinal system, but the cell types involved in intestinal damage and repair are controversial. Here the authors use bone marrow transplantation models and various irradiation regimes to rule out a role of bone marrow-derived cells in acute gastrointestinal injury and recovery in mice.
- Brian J. Leibowitz
- , Liang Wei
- & Jian Yu
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| Open AccessBlockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome
Ionizing radiation damages small intestinal crypt cells, including epithelial stem cells and their progeny. Here the authors show that radiation-induced crypt cell death is amplified by the release of cellular RNA from apoptotic epithelial cells, which then triggers pro-apoptotic TLR3 signalling on neighbouring cells.
- Naoki Takemura
- , Takumi Kawasaki
- & Satoshi Uematsu
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PI3Kδ inhibition reduces TNF secretion and neuroinflammation in a mouse cerebral stroke model
PI 3-kinase is a major regulator of inflammatory responses. In this study, the authors show that inhibition of the delta isoform of PI 3-kinase attenuates the release of tumour necrosis factor from microglia as well as the signs and symptoms associated with cerebral stroke in an in vivomouse model.
- Pei Ching Low
- , Silvia Manzanero
- & Frédéric A. Meunier
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Ablation of TrkB signalling in CCK neurons results in hypercortisolism and obesity
Glucocorticoid levels in the body are controlled by an intricate feedback system acting on the hypothalamus. Here the authors provide molecular insight into this process, identifying TrkB signalling in cholecystokinin-GABAergic neurons as a key component of hypothalamic glucocorticoid signalling.
- Mirjam Geibel
- , Sylvia Badurek
- & Liliana Minichiello
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| Open AccessThe serine protease prostasin regulates hepatic insulin sensitivity by modulating TLR4 signalling
Hepatic insulin resistance is a hallmark of diabetes, but its aetiology is incompletely understood. Here, Uchimura and colleagues show that the serine protease prostasin cleaves Toll-like receptor 4 (TLR4) and regulates hepatic insulin sensitivity by modulating TLR4-mediated signalling.
- Kohei Uchimura
- , Manabu Hayata
- & Kenichiro Kitamura
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Genome-wide association study reveals two new risk loci for bipolar disorder
Bipolar disorder (BD) is a severe mood disorder, which has been shown to have a large genetic component. Here the authors identify two previously unreported BD risk loci and provide further insights into the biological mechanisms underlying BD development.
- Thomas W. Mühleisen
- , Markus Leber
- & Sven Cichon
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| Open AccessHACE1-dependent protein degradation provides cardiac protection in response to haemodynamic stress
HACE1 is an E3 ubiquitin ligase known to regulate various cell biological processes. Here, Zhang et al.identify HACE1 as a protective factor in the heart, demonstrating that HACE1 inhibits the development of heart failure in response to haemodynamic stress by regulating protein degradation pathways.
- Liyong Zhang
- , Xin Chen
- & Peter P. Liu
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Mutations in Alström protein impair terminal differentiation of cardiomyocytes
Cardiomyocyte cell cycle arrest is important for mammalian heart maturation, but the process is poorly understood. Here, the authors use exome sequencing to identify compound heterozygous ALMS1mutations associated with cardiomyocyte replication and provide evidence that Alström protein deficiency impairs postnatal cardiomyocyte cell cycle arrest.
- Lincoln T. Shenje
- , Peter Andersen
- & Daniel P. Judge
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HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells
Lipoproteins such as HDL can bind and transport microRNAs throughout the body. Here the authors provide a new mechanism contributing to the anti-inflammatory effects of HDL by which HDL-associated miR-223 is transferred to endothelial cells, where it inhibits expression of the adhesion molecule ICAM-1.
- Fatiha Tabet
- , Kasey C. Vickers
- & Kerry-Anne Rye
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Decreased CALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase
CALM is an adaptor protein required for clathrin-mediated endocytosis, and is a protective factor in Alzheimer’s disease. Here, Kanatsu et al.show that CALM can reduce the production of toxic Aß42 protein by driving clathrin-mediated endocytosis of γ-secretase.
- Kunihiko Kanatsu
- , Yuichi Morohashi
- & Takeshi Iwatsubo
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| Open AccessDelayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism
The delayed onset of bactericidal activity of the anti-tuberculosis antibiotic bedaquiline is puzzling. Here, Koul and colleagues show, using a multi-omics approach, that the drug triggers a metabolic remodelling in Mycobacterium tuberculosisthat enables the pathogen’s transient survival.
- Anil Koul
- , Luc Vranckx
- & Dirk Bald
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| Open AccessHistamine H3 receptors aggravate cerebral ischaemic injury by histamine-independent mechanisms
Histamine H3 receptor dysregulation is a hallmark of pathological conditions in the central nervous system, and H3 receptor antagonism is neuroprotective. Here Chen et al.show that histamine-independent H3 receptor activation can enhance neuronal cell death during cerebral ischaemia by suppressing autophagy.
- Haijing Yan
- , Xiangnan Zhang
- & Zhong Chen
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NF-Y inactivation causes atypical neurodegeneration characterized by ubiquitin and p62 accumulation and endoplasmic reticulum disorganization
Nuclear transcription factor-Y is a cell cycle regulator that remains active in differentiated neurons. Here, Yamanaka et al.show that nuclear transcription factor-Y activity in neurons is required for the proper organization of the endoplasmic reticulum.
- Tomoyuki Yamanaka
- , Asako Tosaki
- & Nobuyuki Nukina
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African origin of the malaria parasite Plasmodium vivax
Plasmodium vivax, the leading cause of human malaria in Asia and Latin America, is thought to have an Asian origin. Here, the authors show that wild chimpanzees and gorillas in Africa are infected with parasites that are closely related to P. vivax, indicating an African origin for this species.
- Weimin Liu
- , Yingying Li
- & Paul M. Sharp
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Notch2 activation ameliorates nephrosis
The Notch signalling pathway is normally inactive in adult kidneys, but reactivated in kidney diseases. Here the authors show that activation of Notch2 receptors protects renal podocytes from apoptosis, which contrasts with the known detrimental effects of Notch1 signalling on the progression of kidney disease.
- Eriko Tanaka
- , Katsuhiko Asanuma
- & Yasuhiko Tomino
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A sensitive two-photon probe to selectively detect monoamine oxidase B activity in Parkinson’s disease models
Monoamine oxidase B is an enzyme that is unusually active in Parkinson’s disease, a feature that makes it an ideal diagnostic biomarker. Here, Li et al. create a highly specific fluorogenic probe that can selectively detect monoamine oxidase B activity in vivoto effectively diagnose Parkinson’s disease.
- Lin Li
- , Cheng-Wu Zhang
- & Shao Q. Yao
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| Open AccessEstimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa
Reduction in malaria transmission has changed the age pattern of malaria incidence. This study brings insights into the changes in age distributions of clinical malaria across Africa, with importance for improving within-population targeting of malaria control interventions.
- Jamie T. Griffin
- , Neil M. Ferguson
- & Azra C. Ghani
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A novel allosteric mechanism in the cysteine peptidase cathepsin K discovered by computational methods
Allosteric sites are an increasingly used target for drug design. Here, the authors computationally predict an allosteric site in cathepsin K and subsequently identify a small-molecule allosteric modifier.
- Marko Novinec
- , Matevž Korenč
- & Antonio Baici
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Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy
N-methyl-D-aspartate receptors (NMDARs) are key regulators of neuronal excitability in the brain and NMDAR mutations are implicated in epilepsy. Here, the authors identify a NMDAR subunit mutation in a child with epileptic encephalopathy, and show that this mutation increases the activity of NMDAR channels.
- Hongjie Yuan
- , Kasper B. Hansen
- & Stephen F. Traynelis
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Gene co-expression network analysis reveals common system-level properties of prognostic genes across cancer types
Many studies provide evidence of genes that are associated with cancer prognosis but a global view of these genes is lacking. Using data from ‘The Cancer Genome Atlas’, Yang et al.investigate the network properties of prognostic genes and show that these genes tend to be within highly interconnected groups but not the most connected nodes in the gene co-expression network.
- Yang Yang
- , Leng Han
- & Han Liang
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Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor
MERS-CoV is a novel human coronavirus that has recently caused outbreaks of respiratory illness with high case fatality rate. Here the authors characterize the membrane fusion apparatus of MERS-CoV and develop a peptide that can inhibit virus fusion and replication in vitro.
- Lu Lu
- , Qi Liu
- & Shibo Jiang
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Dynamic reassortments and genetic heterogeneity of the human-infecting influenza A (H7N9) virus
H7N9 influenza A viruses capable of infecting humans have recently emerged in China. Here, the authors show that these viruses remain genetically diverse, suggesting that they are still in the process of adapting to human hosts.
- Lunbiao Cui
- , Di Liu
- & George F. Gao
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Autotransporters but not pAA are critical for rabbit colonization by Shiga toxin-producing Escherichia coli O104:H4
An outbreak of diarrhoea and haemolytic uraemic syndrome in Germany in 2011 was caused by a Shiga toxin-producing enteroaggregative E. coli, which carried the aggregative adherence plasmid pAA. Here, the authors show that autotransporters, but not pAA, are required for intestinal colonization in an infant rabbit model.
- Diana Munera
- , Jennifer M. Ritchie
- & Matthew K. Waldor
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MafB promotes atherosclerosis by inhibiting foam-cell apoptosis
In the early stages of atherosclerosis, macrophages in the vessel wall convert into foam cells, which promote the rise of atherosclerotic plaques. Here Hamada et al. show that the macrophage transcription factor MafB inhibits foam-cell apoptosis, and that its absence promotes atherosclerosis development in mice.
- Michito Hamada
- , Megumi Nakamura
- & Satoru Takahashi
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Antibiotic-induced shifts in the mouse gut microbiome and metabolome increase susceptibility to Clostridium difficile infection
Antibiotics alter the intestinal microbiota and facilitate colonization of pathogens such as Clostridium difficile. Here, the authors show that antibiotic-induced shifts in the mouse gut microbiome are correlated with changes in levels of certain metabolites that C. difficilecan use for germination and growth.
- Casey M. Theriot
- , Mark J. Koenigsknecht
- & Vincent B. Young
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Kinase fusions are frequent in Spitz tumours and spitzoid melanomas
Spitzoid neoplasms constitute a spectrum of melanocytic tumours, characterized by distinct clinical, pathological and genetic features. Here, Wiesner et al. show that kinase fusions represent the majority of oncogenic aberrations in spitzoid neoplasms and may serve as therapeutic targets for metastatic spitzoid melanoma.
- Thomas Wiesner
- , Jie He
- & Boris C. Bastian
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A statin-loaded reconstituted high-density lipoprotein nanoparticle inhibits atherosclerotic plaque inflammation
Inflammatory processes in atherosclerotic lesions promote disease progression and plaque rupture. Here the authors load the drug statin into nanoparticles made of recombinant high-density lipoprotein and show that these accumulate in atherosclerotic plaques and reduce plaque inflammation in mice.
- Raphaël Duivenvoorden
- , Jun Tang
- & Willem J. M. Mulder
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| Open AccessTRPA1 channels mediate acute neurogenic inflammation and pain produced by bacterial endotoxins
Gram-negative bacterial infections can often cause inflammation and pain. Meseguer et al. show that the inflammation and pain result from the direct activation of nociceptor TRPA1 channels by lipopolysaccharide, a major component of the outer membrane of Gram-negative bacteria.
- Victor Meseguer
- , Yeranddy A. Alpizar
- & Félix Viana
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