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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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| 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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