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Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma
Despite the treatment efficacy of combining BRAF and MEK inhibitors, a third of BRAF-mutant metastatic melanoma patients treated with this therapy progress within 6 months. Here, the authors sequence tumours from patients with BRAFV600-mutant melanoma metastases and identify mutations that confer resistance to combination therapy.
- Georgina V. Long
- , Carina Fung
- & Helen Rizos
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Tolerance induction to human stem cell transplants with extension to their differentiated progeny
Immunosuppression has been shown to induce tolerance to transplanted stem cells, but differentiation of these cells may trigger immune rejection later on. Here, Lui et al. show that a short-term immunosuppression regimen confers long-term tolerance to stem cells and their differentiated progeny.
- Kathy O. Lui
- , Duncan Howie
- & Herman Waldmann
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| Open AccessContrasting benefits of different artemisinin combination therapies as first-line malaria treatments using model-based cost-effectiveness analysis
Several drug combinations with different properties are used for malaria treatment. Here, Okell et al. use a mathematical model to simulate malaria transmission and treatment with two drug combinations in Africa, and find that locally optimized policies can be highly cost effective for reducing malaria burden.
- Lucy C. Okell
- , Matthew Cairns
- & Azra C. Ghani
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A viral peptide that targets mitochondria protects against neuronal degeneration in models of Parkinson’s disease
Mitochondrial dysfunction is associated with a number of neurodegenerative diseases. Szelechowski et al.take advantage of a viral protein that suppresses apoptosis in neurons to isolate a peptide that protects mitochondria and reduces neuronal cell death in a mouse model of Parkinson’s disease.
- Marion Szelechowski
- , Alexandre Bétourné
- & Daniel Gonzalez-Dunia
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Neuroplasticity-based computerized cognitive remediation for treatment-resistant geriatric depression
As well as substantial changes in mood, geriatric depression is also characterized by executive dysfunction (ED). Morimoto et al.show that some sufferers of geriatric depression do not respond to conventional drugs, and that ED in these patients can be alleviated with computerized cognitive remediation therapy.
- Sarah Shizuko Morimoto
- , Bruce E. Wexler
- & George S. Alexopoulos
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| Open AccessDevelopment of pro-apoptotic peptides as potential therapy for peritoneal endometriosis
Endometriosis is a painful condition in which endometrial cells are found outside the womb. Here, the authors identify a peptide that specifically binds to a receptor expressed on endometrial epithelial cells and use it to induce apoptosis in both cultured cells and baboons with endometriosis.
- K. Sugihara
- , Y. Kobayashi
- & M.N. Fukuda
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Offspring production with sperm grown in vitro from cryopreserved testis tissues
As the fertility of pre-pubertal male patients undergoing chemotherapy cannot be preserved using semen cryopreservation, alternative approaches are needed. Here the authors generate live mouse offspring via assisted reproduction technologies, using round spermatids or sperm derived from neonatal mouse cryopreserved testis tissues.
- Tetsuhiro Yokonishi
- , Takuya Sato
- & Takehiko Ogawa
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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 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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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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Inhibition of miR-146a prevents enterovirus-induced death by restoring the production of type I interferon
Enterovirus 71 (EV71) is one of the causative agents of hand-food-mouth disease and to date, effective vaccines or antivirals against the disease have not been developed. Here, the authors show that blocking miR-146a upregulation induced upon EV71 infection can have a positive effect on the resolution of infection.
- Bing-Ching Ho
- , I-Shing Yu
- & Sung-Liang Yu
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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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Indoleamides are active against drug-resistant Mycobacterium tuberculosis
New classes of antitubercular drugs are in constant demand as drug-resistant strains of Mycobacterium tuberculosis become more prevalent. Here, the authors characterize a class of drugs that are active against various M. tuberculosisstrains, including those resistant to currently used antituberculars.
- Shichun Lun
- , Haidan Guo
- & William R. Bishai
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Postnatal muscle modification by myogenic factors modulates neuropathology and survival in an ALS mouse model
MyoD and myogenin are muscle regulatory factors that are involved in muscle development. Park et al.study a mouse model of amyotrophic lateral sclerosis and find that MyoD and myogenin have positive and negative effects, respectively, on motor neuron degeneration and muscle denervation.
- Kevin H. J. Park
- , Sonia Franciosi
- & Blair R. Leavitt
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| Open AccessProtective CD8+ T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation
Induction of protective immunity mediated by CD8+ T cells has been a long sought goal in vaccinology. Here, Ewer et al. report induction of protective efficacy against Plasmodium falciparummalaria in a phase IIa prime-boost vaccine trial where efficacy correlates strongly with induced CD8 T-cell responses.
- Katie J. Ewer
- , Geraldine A. O’Hara
- & Adrian V. S. Hill
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Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma
Hepatocytes use gluconeogenesis to produce glucose, but whether this process is altered in hepatocellular carcinoma (HCC) is unclear. Here, the loss of gluconeogenesis in HCC and altered glucocorticoid regulation is demonstrated and glucocorticoid treatment is shown to reduce tumour burden.
- Ruihua Ma
- , Wanguang Zhang
- & Bo Huang
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Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity
Tempol is an antioxidant that reduces the body weight of mice on a high-fat diet. Li et al.now provide a mechanistic link by demonstrating that tempol affects the intestinal microbiota, which leads to a change in the composition of bile acids and suppression of FXR signalling.
- Fei Li
- , Changtao Jiang
- & Frank J. Gonzalez
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Activation of the central nervous system induced by micro-magnetic stimulation
Magnetic stimulation is used therapeutically for neurological disorders, but its effectiveness is hindered by efficacy and safety limitations due to large device sizes. Here the authors show that sub-millimetre, micro-magnetic coils effectively stimulate hamster cochlear neurons, with minimal side effects.
- Hyun-Joo Park
- , Giorgio Bonmassar
- & John T. Gale
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Metformin improves healthspan and lifespan in mice
The anti-diabetic drug metformin has been shown to increase lifespan of some model organisms, but results have been conflicting. Here, Martin-Montalvo et al. administer one of two doses of metformin to male mice and show that the lower dose increases healthspan and lifespan, while the higher dose is toxic.
- Alejandro Martin-Montalvo
- , Evi M. Mercken
- & Rafael de Cabo
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Model-based rational design of an oncolytic virus with improved therapeutic potential
Oncolytic viruses can serve as self-replicating anticancer agents. Le Bœuf et al. combine synthetic modelling and molecular biology approaches to create a virus with enhanced oncolytic activity in vitro and in vivodue to its expression of an interferon antagonist.
- Fabrice Le Bœuf
- , Cory Batenchuk
- & John C. Bell
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Mycobacterium tuberculosis is extraordinarily sensitive to killing by a vitamin C-induced Fenton reaction
New approaches to kill Mycobacterium tuberculosis are required to improve TB therapy. Vilchèze et al. now demonstrate that vitamin C-derived reactive oxygen species lead to sterilization of drug-susceptible and drug-resistant M. tuberculosisoffering new possibilities for drug development.
- Catherine Vilchèze
- , Travis Hartman
- & William R. Jacobs Jr
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| 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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Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction
A debilitating side effect of radiotherapy in patients with head and neck cancers is xerostomia as a result of salivary gland dysfunction. Here Liu et al. show that activation of the calcium channel TRPM2 in salivary gland cells contributes to irradiation-induced loss of salivary fluid secretion.
- Xibao Liu
- , Ana Cotrim
- & Indu Ambudkar
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Holographic optogenetic stimulation of patterned neuronal activity for vision restoration
Photo-stimulation can be used to control neuronal circuits, but current strategies lack optimal precision and resolution. Reutsky-Gefen et al. demonstrate a potential approach for vision restoration via holographically patterned, optogenetic stimulation of retinal ganglion cells, with temporal precision.
- Inna Reutsky-Gefen
- , Lior Golan
- & Shy Shoham
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Direct isolation and RNA-seq reveal environment-dependent properties of engrafted neural stem/progenitor cells
Studies on neural stem and progenitor cells have shown they may be useful in treating spinal cord injuries, but the results are variable. Kumamaruet al.transplant these cells in injured spinal cords of mice, and find that their therapeutic properties are dynamically altered depending on their environment.
- Hiromi Kumamaru
- , Yasuyuki Ohkawa
- & Seiji Okada
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| 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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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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