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    ABSTRACT: Melatonin protects the heart against myocardial ischemia/reperfusion injury via the activation of the Survivor Activating Factor Enhancement (SAFE) pathway which involves tumor necrosis factor alpha (TNFα) and the signal transducer and activator of transcription 3 (STAT3). Toll-like receptor 4 (TLR4) plays a crucial role in myocardial ischemia/reperfusion injury and activates TNFα. In the present study, we investigated whether melatonin may target TLR4 to activate the SAFE pathway. Isolated hearts from rats or mice were subjected to ischemia/reperfusion injury. Melatonin (75ng/L) or/and TAK242 (a specific inhibitor of TLR4 signaling, 500 nM) were administered to the rat hearts before the induction of ischemia. Pre-ischemic myocardial STAT3 was evaluated by western blotting. Lipopolysaccharide (LPS, a stimulator of TLR4) was administered to wild type, TNFα receptor 2 knockout or cardiomyocyte-specific STAT3-deficient mice (2.8 mg/kg, i.p) 45 min before the heart isolation. Myocardial infarct size was measured as an end-point. Compared to the control, administration of melatonin reduced myocardial infarct size (34.7±2.8% versus 62.6±2.7%, p<0.01). This protective effect was abolished in the presence of TAK242 (49.2±6.5%). Melatonin administered alone increased the pre-ischemic activation of mitochondrial STAT3 and this effect was attenuated with TAK242. Furthermore, stimulation of TLR4 with LPS pre-treatment to mice reduced myocardial infarct size of the hearts isolated from wild type animals but failed to protect the hearts isolated from TNFα receptor 2 knockout or cardiomyocyte-specific STAT3-deficient mice (p<0.001). Taken together, these data suggest that cardioprotection induced by melatonin is mediated by TLR4 to activate the SAFE pathway.
    Full-text · Article · Jan 2016 · Journal of Pineal Research
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    ABSTRACT: Bluetongue virus (BTV) causes severe disease in domestic and wild ruminants, and has recently caused several outbreaks in Europe. Current vaccines include live-attenuated and inactivated viruses; while these are effective, there is risk of reversion to virulence by mutation or reassortment with wild type viruses. Subunit or virus-like particle (VLP) vaccines are safer options: VLP vaccines produced in insect cells by expression of the four BTV capsid proteins are protective against challenge; however, this is a costly production method. We investigated production of BTV VLPs in plants via Agrobacterium -mediated transient expression, an inexpensive production system very well suited to developing country use. Leaves infiltrated with recombinant pEAQ-HT vectors separately encoding the four BTV-8 capsid proteins produced more proteins than recombinant pTRA vectors. Plant expression using the pEAQ-HT vector resulted in both BTV-8 core-like particles (CLPs) and VLPs; differentially controlling the concentration of infiltrated bacteria significantly influenced yield of the VLPs. In situ localisation of assembled particles was investigated by using transmission electron microscopy (TEM) and it was shown that a mixed population of core-like particles (CLPs, consisting of VP3 and VP7) and VLPs were present as paracrystalline arrays in the cytoplasm of plant cells co-expressing all four capsid proteins.
    Full-text · Article · Dec 2015 · Biotechnology Reports
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    ABSTRACT: The contention in this paper is that Henri Fauconnier's renowned novel The Soul of Malaya (Malaisie) written and set in colonial Malaya, deserves a closer reading within the context of the Modernist genre, and beyond. The novel's wider significance often has been overlooked in favour of viewing it as symptomatic of a colonial mindset. In part this is a fair assessment, but there are other aspects of this award-winning novel that deserve a deeper exploration and hence a wider readership and scholarship. Fauconnier's novel echoes much of what was to come after him. While the novel merits inclusion into the Modernist canon, Malaisie also – takes the reader of Camus, for example, into familiar territory. Existentialism and Dasein (“Being in the World”) are central concerns which are deftly explored and articulated in this remarkable homage to humanity's quest for meaning.
    Full-text · Article · Nov 2015 · Procedia - Social and Behavioral Sciences


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