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Adaptive mutations in NEP compensate for defective H5N1 RNA replication in cultured human cells
Adaptive mutations in the avian influenza virus permit replication in mammals but how these mutations enable this effect is unclear. In this study, mutations found in the nuclear export protein of human isolates of H5N1 are shown to enhance the replication of viral RNA in human cells in culture.
- Benjamin Mänz
- , Linda Brunotte
- & Martin Schwemmle
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| Open AccessDistinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons
Sodium channel Nav1.7 is essential for acute human pain but its role in chronic neuropathic pain is unclear. Minett and colleagues show that Nav1.7 expression specifically in sympathetic neurons, rather than sensory neurons, is required for the development of chronic neuropathic pain after injury.
- Michael S. Minett
- , Mohammed A. Nassar
- & John N. Wood
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| Open AccessBats host major mammalian paramyxoviruses
The large virus family,Paramyxoviridae, includes several human and livestock viruses. This study, testing 119 bat and rodent species distributed globally, identifies novel putative paramyxovirus species, providing data with potential uses in predictions of the emergence of novel paramyxoviruses in humans and livestock.
- Jan Felix Drexler
- , Victor Max Corman
- & Christian Drosten
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| Open AccessCancer cells that survive radiation therapy acquire HIF-1 activity and translocate towards tumour blood vessels
Radiotherapy is used to treat many cancers but radiation-resistant cells can result in recurrence of the tumour. Here, Harada and colleagues develop a method to track cells that persist after radiation treatment and show that the cells acquire transcriptional activity of HIF-1 and move towards blood vessels.
- Hiroshi Harada
- , Masahiro Inoue
- & Masahiro Hiraoka
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The structure of the FANCM–MHF complex reveals physical features for functional assembly
Fanconi's anaemia is characterized by an inability to repair DNA damage and is associated with mutations in the Fanconi anaemia nuclear complex, which includes the protein FANCM. This study reports the crystal structures of a fragment of FANCM bound to the histone-fold-containing protein complex, MHF1–MHF2.
- Yuyong Tao
- , Changjiang Jin
- & Maikun Teng
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Convergence and coevolution of Hepatitis B virus drug resistance
Lamivudine treatment of hepatitis B is associated with drug-resistance mutations in the virus’ DNA polymerase. In this study, 11 patients with drug resistance are investigated and the primary mutation in the DNA polymerase shown to be essential but not sufficient for establishing drug resistance.
- Hong Thai
- , David S. Campo
- & Yury Khudyakov
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| Open AccessCYLD negatively regulates transforming growth factor-β-signalling via deubiquitinating Akt
Lung injury initiates a series of wound-healing responses, which if unregulated, can lead to fibrosis. Liet al. show that the deubquitinase CYLD has a key role in the prevention of fibrosis by inhibiting transforming growth factor β-signalling through the direct deubiquitination of the protein kinase Akt.
- Jae Hyang Lim
- , Hirofumi Jono
- & Jian-Dong Li
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Soluble amyloid precursor protein-α modulates β-secretase activity and amyloid-β generation
The loss of neurotrophic factors is responsible for key neurodegenerative processes in Alzheimer's disease. In this study, Obregon and colleagues treat amyloidogenic cells with the neurotrophin soluble amyloid precursor protein-α and find that it halts amyloidogenesis by interacting with the β-secretase BACE1.
- Demian Obregon
- , Huayan Hou
- & Jun Tan
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| Open AccessStaged decline of neuronal function in vivo in an animal model of Alzheimer's disease
The amyloid-β-peptide is pivotal to the pathology of Alzheimer's disease, but its mechanism of action remains uncertain. This study utilizesin vivotwo-photon calcium imaging to investigate the effects of this peptide on single cortical neurons of the visual cortex in a mouse model of Alzheimer's disease.
- Christine Grienberger
- , Nathalie L. Rochefort
- & Arthur Konnerth
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Dissecting a central flip-flop circuit that integrates contradictory sensory cues in C. elegans feeding regulation
Animals sense multiple environmental cues simultaneously and use this sensory information to regulate feeding behaviour, which is fundamental to survival. Li and co-workers describe a central circuit inCaenorhabditis elegansthat can be activated by attractive odours or repellents to facilitate or suppress feeding behaviour.
- Zhaoyu Li
- , Yidong Li
- & Tao Xu
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| Open AccessDecreased extra-renal urate excretion is a common cause of hyperuricemia
Hyperuricemia, or gout, is thought to arise either from urate overproduction or from decreased renal excretion of urate. Ichidaet al. show that the extra-renal excretion of urate also has a role in the pathogenesis of hyperuricemia, and propose a new classification for patients with this disease.
- Kimiyoshi Ichida
- , Hirotaka Matsuo
- & Hiroshi Suzuki
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Isoniazid resistance without a loss of fitness in Mycobacterium tuberculosis
The treatment ofMycobacterium tuberculosis with drugs such as isoniazid often results in drug resistance, but the mechanisms leading to the resistance are not fully known. In this study, an M. tuberculosisstrain lacking the sigma factor I is shown to be resistant to isoniazid.
- Jong-Hee Lee
- , Nicole C. Ammerman
- & William R. Bishai
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Fast and ultrasensitive method for quantitating prion infectivity titre
Bioassays are the standard way to measure prion infectivity titres, but can be time-consuming. In this study, bioassays are compared with a modified version of the protein misfolding cyclic amplification technique with beads (PMCAb), demonstrating that PMCAb can be more precise and faster than bioassays.
- Natallia Makarava
- , Regina Savtchenko
- & Ilia V. Baskakov
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| Open AccessActivation of canonical Wnt signalling is required for TGF-β-mediated fibrosis
Aberrant activation of the TGF-β pathway leads to fibrotic disease. Distler and colleagues show that TGF-β-mediated fibrosis requires the decrease of Dickkopf-1, an antagonist of canonical Wnt signalling, suggesting that the two pathways interact for the manifestation of this disease.
- Alfiya Akhmetshina
- , Katrin Palumbo
- & Jörg H.W. Distler
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Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release
Accumulation of lysosomal lipids is a feature of Niemann'-Picks (NP) disease, but how these lipids contribute to the disease is unclear. In this study, calcium released via the lysosomal TRPML1 channel is shown to be reduced in NP-type C cells, and sphingomyelins are found to inhibit the channel's activity.
- Dongbiao Shen
- , Xiang Wang
- & Haoxing Xu
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Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs
Human immunodeficiency virus patients who maintain low levels of virus or have undetectable levels of virus exist. In this study, the HIV found in two of these patients is shown to replicatein vitro, suggesting that host factors have a role in suppressing virus levels.
- Robert W. Buckheit III
- , Tracy G. Allen
- & Joel N. Blankson
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Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance
B-RAF is mutated in a large proportion of melanomas, and the first small molecule inhibitor has recently been approved for melanoma treatment. Here, by exome sequencing melanoma samples, Shi and colleagues show that B-RAF is amplified in tumours that have acquired resistance to the B-RAF inhibitor vemurafenib.
- Hubing Shi
- , Gatien Moriceau
- & Roger S. Lo
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RUNX1-induced silencing of non-muscle myosin heavy chain IIB contributes to megakaryocyte polyploidization
Megakaryocytes undergo polyploidization prior to forming platelets but this process is poorly characterised. In this study, non-muscle myosin IIB heavy chain, that localizes to the contractile ring during mitosis, is shown to be silenced prior to polyploidization in a RUNX1-dependent manner.
- Larissa Lordier
- , Dominique Bluteau
- & Yunhua Chang
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| Open AccessMale pygmy hippopotamus influence offspring sex ratio
Some animal populations are able to shift their birth sex ratio from the expected unity. This study shows, using fluorescencein situhybridization, that in a captive population of pygmy hippopotamus the males appear to be able to adjust the ratio of X- and Y-chromosome-bearing spermatozoa in their ejaculates.
- Joseph Saragusty
- , Robert Hermes
- & Thomas B. Hildebrandt
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Perturbation of sodium channel structure by an inherited Long QT Syndrome mutation
Perturbation of the cardiac voltage-gated sodium channel, NaV1.5, by drugs or inherited mutation can underlie and trigger cardiac arrhythmias. Here, the role of the NaV1.5 carboxy terminus in channel inactivation is investigated, and structural details of an arrhythmia associated H6 mutant are reported.
- Ian W. Glaaser
- , Jeremiah D. Osteen
- & Robert S. Kass
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miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia
HOX9AandMEIS1are key oncogenes in MLL-rearranged leukaemia. miRNA-196b is shown here to directly suppress their expression and delay MLL-fusion-mediated leukaemia, but to also cause an aggressive leukaemia phenotype when expressed ectopically, suggesting that it targets tumour suppressors as well.
- Zejuan Li
- , Hao Huang
- & Jianjun Chen
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Sensing of mammalian IL-17A regulates fungal adaptation and virulence
It is unclear whether pathogens can advantageously exploit the host's immune response. UsingCandida albicans, the authors show that host IL-17A binds to the fungi and induces nutrient starvation and autophagy, which eventually leads to enhanced biofilm formation and resistance to the hosts' defence.
- Teresa Zelante
- , Rossana G. Iannitti
- & Luigina Romani
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| Open AccessAn intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid
β-Catenin can be oncogenic but finding inhibitors has been a challenge. Here, five compounds are identified, which attenuate transcriptional β-catenin outputs in colorectal cancer cells, and the response to one of them is shown to require an intrinsically labile α-helix next to the BCL9-binding site in β-catenin.
- Marc de la Roche
- , Trevor J. Rutherford
- & Mariann Bienz
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| Open AccessWind direction and proximity to larval sites determines malaria risk in Kilifi District in Kenya
Spatial epidemiology studies identify malaria hotspots, which sustain transmission and so could be targeted by control programmes. This study uses spatial data on larval sites and malaria episodes to show that transmission can be disrupted by targeting vector breeding sites close to and downwind of malaria hotspots.
- Janet T. Midega
- , Dave L. Smith
- & Philip Bejon
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| Open AccessPPARγ contributes to PKM2 and HK2 expression in fatty liver
Molecular factors, regulating the expression of specific glycolytic enzymes that favour biosynthetic processes, have remained unknown. Panasyuket al. identify PPARγ as a novel transcription factor turning on pyruvate kinase M2 and hexokinase 2, which are frequently upregulated in pathophysiological growth.
- Ganna Panasyuk
- , Catherine Espeillac
- & Mario Pende
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| Open AccessInterferon-γ-producing immature myeloid cells confer protection against severe invasive group A Streptococcus infections
Myeloid cells are important in the response to severe infection by invasiveStreptococcusGroup A. In this study, a distinct population of immature myeloid cells with ring shaped nuclei that produce interferon-γ are shown to be important for protection of mice against the early stages of invasive infection.
- Takayuki Matsumura
- , Manabu Ato
- & Kazuo Kobayashi
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Regulation of histone modification and chromatin structure by the p53–PADI4 pathway
PADI4 is an enzyme that converts arginine residues to citrulline. Here, Tanikawa and colleagues show that, in response to DNA damage, histone H4 and Lamin C are citrullinated in a p53 and PADI4-dependent manner andPadi4-dependent manner and Padi4 null mice are resistant to radiation-induced apoptosis in the thymus.
- Chizu Tanikawa
- , Martha Espinosa
- & Koichi Matsuda
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Parkin controls dopamine utilization in human midbrain dopaminergic neurons derived from induced pluripotent stem cells
Mutations in parkin, an ubiquitin ligase, cause an inherited form of Parkinson's disease. Here, Jianget al. generate induced pluripotent stem cells from two patients with parkin mutations and find that neurons derived from the stem cells have defects in dopamine release, dopamine uptake and oxidative metabolism.
- Houbo Jiang
- , Yong Ren
- & Jian Feng
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EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A/RACK1/Akt signalling complex
The role of ephrin receptors in tumour development and progression has remained controversial. Liet al. show that kinase activation of ephrin-B3 inhibits non-small-cell lung cancer migration both in vitro and in vivo, which depends on a novel interacting partner, RACK 1, in a ternary complex with PP2A and Akt.
- Guo Li
- , Xiao-Dan Ji
- & Dong Xie
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| Open AccessModification of the carboxy-terminal flanking region of a universal influenza epitope alters CD4+ T-cell repertoire selection
Epitopes presented by MHC-II molecules bind to T-cell receptors to activate CD4+ T cells. In this study, changes in the carboxy-terminal region of the influenza hemagglutinin epitope HA305-320alters the strength of binding to the T-cell receptor, thus modulating T-cell receptor usage and activation.
- David K. Cole
- , Kathleen Gallagher
- & Andrew Godkin
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| 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
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c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling
Osteoblast maturation is regulated by c-Src and IL-6, but how these signalling pathways are integrated is not known. Here c-Src is shown to induce 1GFBP5 in immature osteoblasts in a STAT3 and IL-6-dependent manner, in mature osteoblasts, which express lower levels of c-Src, this signalling is lost.
- Barbara Peruzzi
- , Alfredo Cappariello
- & Anna Teti
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| Open AccessRapid and adaptive evolution of MHC genes under parasite selection in experimental vertebrate populations
In vertebrates parasite-mediated selection is thought to maintain polymorphism in MHC genes where specific resistance MHC alleles increase under emerging selection. Here, experimental evidence is shown from six stickleback fish populations that varying parasite selection helps maintain MHC polymorphism.
- Christophe Eizaguirre
- , Tobias L. Lenz
- & Manfred Milinski
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Ectopic expression of the histone methyltransferase Ezh2 in haematopoietic stem cells causes myeloproliferative disease
The histone methyltransferase Ezh2 is thought to have a dual function both as a tumour suppressor and an oncogene. Using mouse models with Ezh2 gain-of-function, Herrera-Merchanet al. show that Ezh2 expression in HSCs severely compromises hematopoietic function, leading to myeloproliferative disease.
- A. Herrera-Merchan
- , L. Arranz
- & S. Gonzalez
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| Open AccessMuscle-derived stem/progenitor cell dysfunction limits healthspan and lifespan in a murine progeria model
The function of adult stem cells is diminished with age but the role this dysfunction plays in the aging process is unknown. Here, the injection of muscle-derived stem/progenitor cells from young mice rescues symptoms in progeroid mice and is shown to regenerate tissues independent of engraftment.
- Mitra Lavasani
- , Andria R. Robinson
- & Johnny Huard
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| Open AccessPromotion of plasma membrane repair by vitamin E
Membrane repair of myocytes is important to prevent such disease as muscular dystrophy but the properties of this repair are not well characterised. In this study, vitamin E is shown to be important in the repair of myocyte cell membranes in cultured cells and in intact muscle.
- Amber C. Howard
- , Anna K. McNeil
- & Paul L. McNeil
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A role for T-bet-mediated tumour immune surveillance in anti-IL-17A treatment of lung cancer
The tumour microenvironment is often found to be immunosuppressive. Reppert and colleagues show that human and murine lung tumours harbour IL-17A-producing T cells, and that blocking IL-17A increases survival in mice, suggesting that anti-IL-17A therapy may be useful in treating lung cancer.
- S. Reppert
- , I. Boross
- & S. Finotto
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| Open AccessCompetition for FcRn-mediated transport gives rise to short half-life of human IgG3 and offers therapeutic potential
The half-life of IgG is regulated by binding to the neonatal Fc receptor and, in the case of IgG3, is reduced compared to other IgG proteins. In this study, a mutation in IgG3 is shown to reduce binding to the neonatal Fc receptor, which can be competitively blocked by IgG1.
- Nigel M. Stapleton
- , Jan Terje Andersen
- & Gestur Vidarsson
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Evolution of the base of the brain in highly encephalized human species
Encephalization—increase of brain size relative to body size—has occurred in two distinct evolutionary lineages; Neanderthals and modern humans. However, the 3D endocranial surface shape analysis reported here reveals unique structures at the base of the brain inHomo sapiens, which may have contributed to learning and social capacities.
- Markus Bastir
- , Antonio Rosas
- & Jean-Jacques Hublin
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Article
| Open AccessActivin enhances skin tumourigenesis and malignant progression by inducing a pro-tumourigenic immune cell response
Activin is known to have a role in wound healing, but its role in skin cancer is unknown. Antsiferovaet al. show that activin is elevated in human skin tumours, and by modulating epidermal immune cells, exacerbates tumour progression in a mouse model of skin cancer.
- Maria Antsiferova
- , Marcel Huber
- & Sabine Werner
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Article
| Open AccessGlobal kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum
New approaches are required to combatPlasmodium falciparuminfection. In this proteome-wide study, 1305 phosphorylation sites are identified and 36 kinases are shown to have crucial roles in parasite survival, providing new insights into parasite biology and potential new drug targets for anti-malarial chemotherapy.
- Lev Solyakov
- , Jean Halbert
- & Christian Doerig
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| Open AccessGenome-wide functional screening of miR-23b as a pleiotropic modulator suppressing cancer metastasis
microRNAs are known to be deregulated in cancer. Using a screen for microRNAs that alter cell migration, Zhanget al. show that mir-23b blocks cell migration in vitro and in vivoand is reduced in expression in human colon cancer, suggesting a therapeutic potential for this microRNA.
- Hanshuo Zhang
- , Yang Hao
- & Jianzhong Jeff Xi
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gp96 expression in neutrophils is critical for the onset of Escherichia coli K1 (RS218) meningitis
E. coliK1 can elude the innate immune system and cause neonatal meningitis. This study shows thatE. coli K1 enters polymorphonuclear leukocytes (PMNs) using gp96 to reduce the oxidative burst, and that PMN-depleted mice are resistant to E. coliK1 infection, suggesting that PMNs permit bacterial survival in the host.
- Rahul Mittal
- & Nemani V. Prasadarao
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P-Rex1 is required for efficient melanoblast migration and melanoma metastasis
The processes that regulate melanoblast migration during development are also thought to be involved in melanoma metastasis. Here, Prex1 null mice are shown to have a melanoblast migration defect and, when crossed to a mouse model of melanoma, are resistant to metastasis, suggesting a role for Prex1 in metastatic melanoma.
- Colin R. Lindsay
- , Samuel Lawn
- & Owen J. Sansom
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Genetic dissection of axon regeneration via in vivo electroporation of adult mouse sensory neurons
Dorsal root ganglion neurons can regenerate after injury, but the mechanisms underlying axon regrowth are unclear. To address this, an electroporation transfection method is developed that can alter the gene expression of dorsal root ganglion cells in a living adult mouse, providing a tool to study axon regeneration.
- Saijilafu
- , Eun-Mi Hur
- & Feng-Quan Zhou
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CD91-dependent programming of T-helper cell responses following heat shock protein immunization
Heat shock proteins bind to CD91 on antigen presenting cells, resulting in the presentation of chaperoned peptides to T cells. Here, heat shock protein binding is shown to induce phosphorylation of CD91 and stimulate the production of cytokines, thus priming various T-helper cell responses.
- Sudesh Pawaria
- & Robert J. Binder
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Disrupted erythropoietin signalling promotes obesity and alters hypothalamus proopiomelanocortin production
Erythropoietin circulates in the blood and is essential for erythropoiesis but its role in metabolic homeostasis has not been examined. Tenget al. show that when the erythropoietin receptor is only expressed in erthyroid cells, mice develop obesity and insulin resistance, suggesting that the receptor has a key role in fat mass accumulation.
- Ruifeng Teng
- , Oksana Gavrilova
- & Constance Tom Noguchi
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| Open AccessSelective inhibition of microRNA accessibility by RBM38 is required for p53 activity
MicroRNAs bind to the 3′-untranslated region of genes to regulate expression. In this study, an RNA-binding protein, RMB38, is shown to selectively regulate the access of some microRNAs to their targets, and control the expression of some p53 target genes.
- Nicolas Léveillé
- , Ran Elkon
- & Reuven Agami
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| Open AccessProliferating versus differentiating stem and cancer cells exhibit distinct midbody-release behaviour
During cell division, a cytoplasmic bridge—the midbody—forms between the nascent daughter cells, but it has been unclear under which conditions this is retained by a daughter cell or released. Now, Ettinger and colleagues show that midbody-release occurs more frequently in stem cells compared with cancer cells.
- Andreas W. Ettinger
- , Michaela Wilsch-Bräuninger
- & Wieland B. Huttner