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| Open AccessDepleting the methyltransferase Suv39h1 improves DNA repair and extends lifespan in a progeria mouse model
Accelerated cellular ageing in patients with progeria can be caused by the accumulation of nuclear lamins, leading to DNA damage and histone methylation. Here Liu et al. show that the metyltransferase SUV39H1 regulates lamin A stability, and that SUV39H1 depletion extends lifespan in a progeria mouse model.
- Baohua Liu
- , Zimei Wang
- & Zhongjun Zhou
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Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels
Dehydrated hereditary stomatocytosis is a genetic condition in which the permeability of red blood cells to cations in increased. Albuisson and colleagues find that mutations in the mechanically-activated PIEZO1 ion channel are the major cause of the disease and result in more slowly inactivating currents.
- Juliette Albuisson
- , Swetha E Murthy
- & Ardem Patapoutian
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Article
| Open AccessProthymosin α overexpression contributes to the development of pulmonary emphysema
Pulmonary emphysema obstruct airflow in the lung and often develop in smokers. Here Su et al. show that prothymosin α contributes to emphysema development through alterations in the acetylation of histones and the transcription factor NF-κB, and that exposure to cigarette smoke increases prothymosin α expression.
- Bing-Hua Su
- , Yau-Lin Tseng
- & Chao-Liang Wu
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Tribbles 3 mediates endoplasmic reticulum stress-induced insulin resistance in skeletal muscle
Endoplasmic reticulum (ER) stress is observed in diabetes and has been linked to insulin resistance in various tissues. Here, Koh and colleagues show the protein Tribbles 3, which is induced by ER stress and obesity in mice and humans, is an inhibitor of insulin signalling in skeletal muscle.
- Ho-Jin Koh
- , Taro Toyoda
- & Laurie J. Goodyear
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Prions disturb post-Golgi trafficking of membrane proteins
Prion protein accumulation in endosomal vesicles has been implicated in the progression of prion diseases. Uchiyama and colleagues infect neuronal cells with prion proteins and find that this delays post-Golgi vesicular trafficking of membrane proteins and impairs insulin signalling.
- Keiji Uchiyama
- , Naomi Muramatsu
- & Suehiro Sakaguchi
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Article
| Open AccessTransmission-blocking interventions eliminate malaria from laboratory populations
Transmission-blocking interventions aim to interrupt progression of Plasmodium parasites from the vertebrate host to the mosquito. Blagborough et al. demonstrate that only partially reducing transmission can be sufficient to eliminate experimental Plasmodiuminfection in successive mosquito and mice populations when biting rates are low.
- A. M. Blagborough
- , T. S. Churcher
- & R. E. Sinden
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Article
| Open AccessThe gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43
The gut microbiota produces metabolites such as short-chain fatty acids (SCFAs), which can influence the development of obesity. Here Kimura et al.show that SCFAs act via the receptor GPR43, which acts as a sensor for excessive dietary energy and controls body energy utilization as well as metabolic homoeostasis.
- Ikuo Kimura
- , Kentaro Ozawa
- & Gozoh Tsujimoto
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Control of lung vascular permeability and endotoxin-induced pulmonary oedema by changes in extracellular matrix mechanics
Vascular permeability is increased by inflammation and in disorders such as acute respiratory distress syndrome. Mammoto et al. show that lung vascular permeability is controlled by the stiffness of the extracellular matrix and identify lysyl oxidase as a regulator of vascular leakage in pulmonary oedema in mice.
- Akiko Mammoto
- , Tadanori Mammoto
- & Donald E. Ingber
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Magnetic barcode assay for genetic detection of pathogens
Detecting and phenotyping Mycobacterium tuberculosis, especially in resource-limited settings, is important for global tuberculosis control. Here Liong et al. report a point-of-care diagnostic platform based on magnetic barcoding and nuclear magnetic resonance for the detection of mycobacterial nucleic acids.
- Monty Liong
- , Anh N. Hoang
- & Ralph Weissleder
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Externally controlled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers
Magneto-electric nanoparticles may facilitate the low-energy and dissipation-free field-triggered release of drugs across the blood–brain barrier. Here, the authors demonstrate the a.c. field-triggered release of anti-HIV drugs and confirm the in vitrodrug integrity after release.
- Madhavan Nair
- , Rakesh Guduru
- & Sakhrat Khizroev
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Expansion of host cellular niche can drive adaptation of a zoonotic malaria parasite to humans
The number of human infections caused by the primate malaria parasite P. knowlesi is increasing. Lim et al. demonstrate that host specificity is due to the preference of the parasite for young blood cells, and that the parasite can adapt to proliferate in human blood containing a range of differently aged cells.
- Caeul Lim
- , Elsa Hansen
- & Manoj T. Duraisingh
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Interstitial cells of Cajal integrate excitatory and inhibitory neurotransmission with intestinal slow-wave activity
Interstitial cells of Cajal generate rhythmic pacemaker currents, which result in rhythmic bowel contractions. Klein and colleagues use knock-in mutations to inactivate these cells in mice and find that they modulate bowel contractions by integrating excitatory and inhibitory neurotransmission in the gut.
- Sabine Klein
- , Barbara Seidler
- & Dieter Saur
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An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells
Patient-specific induced pluripotent stem (iPS) cells hold great potential for regenerative cell therapies. Here Filareto et al. genetically correct iPS cells from mice with muscular dystrophy and use these cells to treat the same animals, providing a proof-of-principle for autologous iPS cell therapy.
- Antonio Filareto
- , Sarah Parker
- & Rita C. R. Perlingeiro
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Article
| Open AccessInterferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals
A variant in the IFITM3gene increases the risk of severe influenza, but homozygosity is rare in Caucasians. The authors show that the variant gene is homozygous in 25% of healthy Chinese people, and 69% of those with severe pandemic influenza, suggesting that this gene influences the epidemiology of influenza in South-East Asia.
- Yong-Hong Zhang
- , Yan Zhao
- & Tao Dong
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Article
| Open AccessSpatial association with PTEX complexes defines regions for effector export into Plasmodium falciparum-infected erythrocytes
During red blood cell infection, malaria parasites export hundreds of proteins that remodel the host cell surface. Cowman and colleagues identify a putative protein translocator complex spatially associated with exported proteins, revealing the cellular domains involved in protein export.
- David T. Riglar
- , Kelly L. Rogers
- & Alan F. Cowman
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Heat shock factor-1 influences pathological lesion distribution of polyglutamine-induced neurodegeneration
Heat shock factor-1 is a transcriptional regulator of heat shock proteins that is implicated in neurodegeneration. Kondo and colleagues study the effects of deleting heat shock factor-1 in a mouse model of muscular dystrophy and find that this augments the condition via the accumulation of androgen receptors.
- Naohide Kondo
- , Masahisa Katsuno
- & Gen Sobue
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MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11
The role of microRNAs in chemotherapy resistance remains to be elucidated. Bockhorn et al.report that microRNA-30c, a human breast tumour prognostic marker, has a key role by targeting the epithelial-to-mesenchymal transition promoter twinfilin 1 and downstream interleukin-11 expression.
- Jessica Bockhorn
- , Rachel Dalton
- & Huiping Liu
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Article
| Open AccessProteome-wide selected reaction monitoring assays for the human pathogen Streptococcus pyogenes
Selected reaction monitoring mass spectrometry (SRM-MS) can quantify dynamic changes in protein expression with high sensitivity. Karlsson et al. define optimal detection parameters for 10,412 distinct group A Streptococcus pyogenespeptides, which facilitates proteome-wide SRM-MS studies in this bacterium.
- Christofer Karlsson
- , Lars Malmström
- & Johan Malmström
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Article
| Open AccessExhaustion of nucleus pulposus progenitor cells with ageing and degeneration of the intervertebral disc
Back pain and sciatica are often caused by intervertebral disc degeneration. Sakai and colleagues identify a subset of nucleus pulposus progenitor cells from the intervertebral disc and show that loss of these progenitor cells correlates with ageing and intervertebral disc degeneration.
- Daisuke Sakai
- , Yoshihiko Nakamura
- & Joji Mochida
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Article
| Open AccessSymptomatic atherosclerosis is associated with an altered gut metagenome
The gut microbiota has emerged as an environmental factor that can influence the development of obesity and diabetes. Here, Karlsson et al. report compositional and functional alterations of the gut metagenome in patients with symptomatic atherosclerosis.
- Fredrik H. Karlsson
- , Frida Fåk
- & Jens Nielsen
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Article
| Open AccessFactors determining the occurrence of submicroscopic malaria infections and their relevance for control
Malaria can persist at levels that escape detection by standard microscopy, but can be detected by PCR. Okell et al.now show that rates of submicroscopic infection can be predicted using more widely available microscopy data, and are most epidemiologically significant in areas with low malaria transmission.
- Lucy C. Okell
- , Teun Bousema
- & Chris J. Drakeley
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Molecular mechanism of the assembly of an acid-sensing receptor ion channel complex
Polycystic kidney disease family proteins form heteromeric complexes with transient receptor potential channel subunits of the TRPP subfamily. Yu and colleagues find that the polycystic kidney disease protein, PKD1L3, is an ion channel pore-forming subunit in the acid-sensing PKD1L3/TRPP3 complex.
- Yong Yu
- , Maximilian H. Ulbrich
- & Jian Yang
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Article
| Open AccessFibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation
Multiple sclerosis is characterized by the activation of microglia cells. Davalos et al. investigate the early stages of neuroinflammation in mice and reveal that the plasma protein fibrinogen induces microglial clustering around the brain vasculature, which facilitates lesion formation and focal axonal damage.
- Dimitrios Davalos
- , Jae Kyu Ryu
- & Katerina Akassoglou
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The metastasis-promoting S100A4 protein confers neuroprotection in brain injury
Multifunctional S100 proteins are upregulated in brain injury, but their role in neurodegeneration is not clear. Dmytriyeva and colleagues study in vivomodels of brain trauma and find that the S100A4 protein and its peptide mimetics protect neurons via the interleukin-10 receptor and the Janus kinase (JAK)/STAT pathway.
- Oksana Dmytriyeva
- , Stanislava Pankratova
- & Darya Kiryushko
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Detection and differential diagnosis of colon cancer by a cumulative analysis of promoter methylation
Changes in the methylation pattern of gene promoters are hallmarks of certain cancers, such as colon cancer. Here Yang et al.identify and validate a set of genes and measure the cumulative methylation of promoters, which allows them to distinguish between two stages of colon cancer.
- Qiong Yang
- , Ying Dong
- & Shu Wang
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CaV1.3-selective L-type calcium channel antagonists as potential new therapeutics for Parkinson's disease
L-type calcium channels comprising the CaV1.3 subunit have been linked to the generation of mitochondrial oxidant stress in Parkinson’s disease. Kang et al. identify pyrimidine-2,4,6-triones as a potential molecular scaffold, which they modify to develop a potent and highly selective CaV1.3 antagonist.
- Soosung Kang
- , Garry Cooper
- & Richard B. Silverman
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Article
| Open AccessPrion protein facilitates uptake of zinc into neuronal cells
Prion proteins are implicated in a range of neurodegenerative diseases, which are, in part, due to a disruption of metal homeostasis. Wattet al.use selective antagonists to show that prion proteins mediate zinc uptake by interacting with GluA2-lacking, GluA1-containing AMPA receptors.
- Nicole T. Watt
- , David R. Taylor
- & Nigel M. Hooper
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MyD88 signalling in colonic mononuclear phagocytes drives colitis in IL-10-deficient mice
Mice lacking the anti-inflammatory cytokine IL-10 can develop colitis, which depends on inappropriate responses to commensal bacteria. Hoshiet al. now show that these responses are driven by colonic mononuclear phagocytes, providing insight to the initiating events, which may underlie inflammatory bowel disease.
- Namiko Hoshi
- , Dominik Schenten
- & Ruslan Medzhitov
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Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia
One of the five IL-17 receptors, IL-17RD lacks a motif thought to be required for downstream signalling. Melletet al. show that IL-17RD tunes IL-17A-dependent signalling; in its absence, MAPK signalling and neutrophil recruitment are impaired, but NF-κB activation is enhanced.
- Mark Mellett
- , Paola Atzei
- & Paul N. Moynagh
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The nuclear hormone receptor PPARγ counteracts vascular calcification by inhibiting Wnt5a signalling in vascular smooth muscle cells
Vascular calcification is commonly associated with advanced stages of atherosclerosis. Woldtet al. show that the nuclear hormone receptor PPARγ in vascular smooth muscle cells protects mice from vascular calcification by inhibiting Wnt5a signalling triggered by activation of the cell-surface receptor LRP1.
- Estelle Woldt
- , Jérome Terrand
- & Philippe Boucher
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Article
| Open AccessUncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome
Fragile X syndrome is a major genetic cause of autism and is caused by loss of the fragile X mental retardation protein. In a mouse model of fragile X syndrome, Junget al. show that an absence of neuronal endocannabinoid signalling is responsible for the neurophysiological and behavioural defects.
- Kwang-Mook Jung
- , Marja Sepers
- & Olivier J. Manzoni
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Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology
The protein α-synuclein is implicated in Parkinson's disease. Rhinn and colleagues perform gene expression analysis and find that specific α-synuclein transcripts are preferentially associated with Parkinson's disease, and that they potentiate the accumulation of α-synuclein protein.
- Herve Rhinn
- , Liang Qiang
- & Asa Abeliovich
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Article
| Open AccessHigh-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring
Environmental factors can influence one's susceptibility to cancer, but it is not clear whether such an influence extends beyond the directly exposed generations. Here, feeding pregnant rats with a high-fat diet or a hormone derivative, the authors observe increased breast cancer risk in up to three subsequent generations.
- Sonia de Assis
- , Anni Warri
- & Leena Hilakivi-Clarke
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TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer
TGF-β signalling suppresses tumorigenesis in breast cancer cells but its effects on breast cancer initiating cells have not been reported. Using cells in culture, Brunaet al. show that TGF-β increases breast cancer initiating cell numbers in cells that have low levels of the tight junction protein claudin.
- Alejandra Bruna
- , Wendy Greenwood
- & Carlos Caldas
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Article
| Open AccessExtracellular ATP mediates mast cell-dependent intestinal inflammation through P2X7 purinoceptors
Mast cells are mediators of type I allergic disease and inflammation. Here, Kurashimaet al. show that mast cells are increased in the colons of mice with colitis, and that activation of the cells and subsequent inflammation can be blocked by inhibition of the purinoceptor, P2X7.
- Yosuke Kurashima
- , Takeaki Amiya
- & Hiroshi Kiyono
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Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo
The amyloid beta peptide can aggregate into insoluble plaques, which may indicate the onset of Alzheimer's disease. In a mouse model of Alzheimer's disease, Cao and colleagues report a phenotype of altered connectivity in the olfactory neuronal circuit that precedes amyloid plaque deposition.
- Luxiang Cao
- , Benjamin R. Schrank
- & Mark W. Albers
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Article
| Open AccessPINK1 autophosphorylation upon membrane potential dissipation is essential for Parkin recruitment to damaged mitochondria
The kinase PINK1 is mutated in Parkinson's disease and accumulates in defective mitochondria, where it recruits Parkin. Here, PINK1 is shown to be autophosphorylated and this is required for the localization of PINK1 to mitochondria with a reduced membrane potential, and for the recruitment of Parkin.
- Kei Okatsu
- , Toshihiko Oka
- & Noriyuki Matsuda
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Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis
Fas-associated protein with death domain (FADD) is part of a signalling complex that controls some forms of programmed cell death. Lee and colleagues demonstrate that FADD ubiquitination by the E3 ubiquitin ligase MKRN1 regulates FADD protein stability and thereby cell death.
- Eun-Woo Lee
- , Jung-Hoon Kim
- & Jaewhan Song
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Article
| Open AccessEstimating the potential public health impact of seasonal malaria chemoprevention in African children
Seasonal malaria chemoprevention can lower the incidence of malaria in areas where transmission is highly periodical. Combining data on rainfall, population and malaria endemicity, Cairnset al. identify geographical areas in sub-Saharan Africa where this intervention is likely to be effective and cost-effective.
- Matthew Cairns
- , Arantxa Roca-Feltrer
- & Brian M. Greenwood
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Differentiation of multipotent vascular stem cells contributes to vascular diseases
De-differentiation and proliferation of vascular smooth muscle cells is thought to have a dominant role in vascular remodelling. Here, Tanget al. identify a new type of multipotent vascular stem cell in the blood vessel wall that contributes to this process, thereby challenging the established hypothesis.
- Zhenyu Tang
- , Aijun Wang
- & Song Li
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Article
| Open AccessTargeted suppression of claudin-5 decreases cerebral oedema and improves cognitive outcome following traumatic brain injury
Claudin-5 is a component of tight junctions and has important roles in mediating the permeability of the blood-brain barrier. Campbell and co-workers administer short interfering RNA against claudin-5 in a model of brain injury, finding that it enhances water movement from the brain to the blood and alleviates swelling.
- Matthew Campbell
- , Finnian Hanrahan
- & Peter Humphries
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An atlas of DNA methylomes in porcine adipose and muscle tissues
Epigenetic and genetic factors have a role in obesity but the role of epigenetics in this disease is unclear. Here, Liet al. investigated global DNA methylation patterns in three breeds of pigs that have different fat contents, providing a resource for the further analysis of differentially methylated gene promoters in obesity.
- Mingzhou Li
- , Honglong Wu
- & Ruiqiang Li
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Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression
Tumour cells are subject to replication stress but how cells overcome damage without inducing senescence and apoptotic pathways is unclear. Here, the authors study polyploidy in cancer cells and show that this blocks apoptotic and senescent pathways, resulting in the induction of proteins involved in DNA repair.
- Li Zheng
- , Huifang Dai
- & Binghui Shen
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Reliable detection of subclonal single-nucleotide variants in tumour cell populations
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
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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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Article
| 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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Article
| 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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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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