• Article |

    The detection of subclonal variants in heterogeneous cancer specimens is a challenge due to errors that occur during sequencing. In this study, a statistical algorithm and a sequencing strategy are reported that circumvent this issue and can accurately detect variants at a frequency as low as 1/10,000.

    • Moritz Gerstung
    • , Christian Beisel
    •  & Niko Beerenwinkel
  • Article
    | Open Access

    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
  • Article |

    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
  • Article |

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article |

    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
  • Article |

    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
  • Article
    | Open Access

    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
  • Article |

    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
  • Article |

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article |

    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
  • Article |

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    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
  • Article
    | Open Access

    The risk factors associated with both ischemic and haemorrhagic stroke are not fully understood. Here a certain strain of the bacteria,Streptococcus mutans, which expresses a collagen-binding protein, is shown to be associated with haemorrhagic stroke in both animal models and human patients.

    • Kazuhiko Nakano
    • , Kazuya Hokamura
    •  & Takashi Ooshima
  • Article |

    Cellular senescence is characterized by the cessation of cell growth and the expression of the p16 protein. In this study, inhibition or loss of p300, a histone acetyltransferase, is shown to result in senescence that occurs independently of p16 and is associated with histone hypoacetylation and altered replication timing.

    • Alexandre Prieur
    • , Emilie Besnard
    •  & Jean-Marc Lemaitre
  • Article |

    Protein microarrays are useful both in basic research and also in disease monitoring and diagnosis, but their dynamic range is limited. By using plasmonic gold substrates with near-infrared fluorescent enhancement, Tabakman et al. demonstrate a multiplexed protein array with improved detection limits and dynamic range.

    • Scott M. Tabakman
    • , Lana Lau
    •  & Hongjie Dai
  • Article
    | Open Access

    Pluripotent stem cells can be generated from the somatic cells of humans and are a useful model to study disease. Here, pluripotent stem cells are made from a patient with familial Parkinson's disease, and the resulting neurons exhibit elevated levels of α-synuclein, recapitulating the molecular features of the patient's disease.

    • Michael J. Devine
    • , Mina Ryten
    •  & Tilo Kunath
  • Article |

    MITF is a transcription factor required for melanocyte development, which is activated in some melanomas. Zhao and colleagues show that USP13 removes ubiquitin from MITF, stabilizes MITF protein levels and enhances colony formation, suggesting that USP13 may be a therapeutic target in melanoma.

    • Xiansi Zhao
    • , Brian Fiske
    •  & David E Fisher
  • Article
    | Open Access

    Polo-like kinase 1 is a key regulator of mitosis and is a candidate for drug development to treat cancer. Here, reduced expression of polo-like kinase 1 in adult mice has a minor impact on animal physiology, suggesting that polo-like kinase 1 inhibitors may be useful in the killing of tumour cells while sparing normal cells.

    • Monika Raab
    • , Sven Kappel
    •  & Klaus Strebhardt
  • Article
    | Open Access

    Chk2 is a kinase that is a potential chemotherapeutic target. Here, Chk2 and the kinase ERK are shown to functionally interact, and are elevated in expression in human diffuse B-cell lymphomas. Combinatorial inhibition of the kinases was also shown to block tumour growth in anin vivomouse model.

    • Bojie Dai
    • , X. Frank Zhao
    •  & Ronald B. Gartenhaus
  • Article |

    The torsinA protein localizes to the endoplasmic reticulum and, when mutated, causes early onset torsion dystonia. The authors reveal a new role for torsinA in proteosome-mediated degradation of misfolded proteins, and relate this to endoplasmic reticulum stress, in aCaenorhabditis elegansmodel and patient fibroblasts.

    • Flávia C. Nery
    • , Ioanna A. Armata
    •  & Xandra O. Breakefield
  • Article |

    Mutations in the DNA helicaseBLM cause Bloom syndrome, which is characterized by slow replication fork progression and genetic instability. Here, cells lacking BLMare shown to have a defect in cytidine deaminase, which alters the pyrimidine pool and results in replication fork progression with altered velocity.

    • Pauline Chabosseau
    • , Géraldine Buhagiar-Labarchède
    •  & Mounira Amor-Guéret
  • Article |

    Class I anti-arrhythmic drugs act at cardiac sodium channels and are subdivided into classes Ia-c based on their effects on the electrocardiogram. Here, class Ib drugs are found to rely on cation–pi interactions for their activity, whereas class Ib and Ic drugs rely significantly less on this interaction.

    • Stephan A. Pless
    • , Jason D. Galpin
    •  & Christopher A. Ahern
  • Article
    | Open Access

    The ability of synthetic amyloid β-protein to bind to prion proteins and alter synaptic plasticity has been previously reported. Here the relevance of this binding is investigated in brains of Alzheimer's disease patients and the interaction is shown to be blocked by antibodies to two distinct regions of prion proteins.

    • Darragh B. Freir
    • , Andrew J. Nicoll
    •  & John Collinge