281 research outputs found

    Genetic and antigenic characterization of influenza A/H5N1 viruses isolated from patients in Indonesia, 2008–2015

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    Since the initial detection in 2003, Indonesia has reported 200 human cases of highly pathogenic avian influenza H5N1 (HPAI H5N1), associated with an exceptionally high case fatality rate (84%) compared to other geographical regions affected by other genetic clades of the virus. However, there is limited information on the genetic diversity of HPAI H5N1 viruses, especially those isolated from humans in Indonesia. In this study, the genetic and antigenic characteristics of 35 HPAI H5N1 viruses isolated from humans were analyzed. Full genome sequences were analyzed for the presence of substitutions in the receptor binding site, and p

    A rare SNP in pre-miR-34a is associated with increased levels of miR-34a in pancreatic beta cells.

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    Open Access Article.Changes in the levels of specific microRNAs (miRNAs) can reduce glucose-stimulated insulin secretion and increase beta-cell apoptosis, two causes of islet dysfunction and progression to type 2 diabetes. Studies have shown that single nucleotide polymorphisms (SNPs) within miRNA genes can affect their expression. We sought to determine whether miRNAs, with a known role in beta-cell function, possess SNPs within the pre-miRNA structure which can affect their expression. Using published literature and dbSNP, we aimed to identify miRNAs with a role in beta-cell function that also possess SNPs within the region encoding its pre-miRNA. Following transfection of plasmids, encoding the pre-miRNA and each allele of the SNP, miRNA expression was measured. Two rare SNPs located within the pre-miRNA structure of two miRNA genes important to beta-cell function (miR-34a and miR-96) were identified. Transfection of INS-1 and MIN6 cells with plasmids encoding pre-miR-34a and the minor allele of rs72631823 resulted in significantly (p < 0.05) higher miR-34a expression, compared to cells transfected with plasmids encoding the corresponding major allele. Similarly, higher levels were also observed upon transfection of HeLa cells. Transfection of MIN6 cells with plasmids encoding pre-miR-96 and each allele of rs41274239 resulted in no significant differences in miR-96 expression. A rare SNP in pre-miR-34a is associated with increased levels of mature miR-34a. Given that small changes in miR-34a levels have been shown to cause increased levels of beta-cell apoptosis this finding may be of interest to studies looking at determining the effect of rare variants on type 2 diabetes susceptibility

    Inhibition of SLPI ameliorates disease activity in experimental autoimmune encephalomyelitis

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    <p>Abstract</p> <p>Background</p> <p>The secretory leukocyte protease inhibitor (SLPI) exerts wide ranging effects on inflammatory pathways and is upregulated in EAE but the biological role of SLPI in EAE, an animal model of multiple sclerosis is unknown</p> <p>Methods</p> <p>To investigate the pathophysiological effects of SLPI within EAE, we induced SLPI-neutralizing antibodies in mice and rats to determine the clinical severity of the disease. In addition we studied the effects of SLPI on the anti-inflammatory cytokine TGF-β.</p> <p>Results</p> <p>The induction of SLPI neutralizing antibodies resulted in a milder disease course in mouse and rat EAE. SLPI neutralization was associated with increased serum levels of TGF-β and increased numbers of FoxP3+ CD4+ T cells in lymph nodes. <it>In vitro</it>, the addition of SLPI significantly decreased the number of functional FoxP3+ CD25<sup>hi </sup>CD4+ regulatory T cells in cultures of naive human CD4+ T cells. Adding recombinant TGF-β to SLPI-treated human T cell cultures neutralized SLPI's inhibitory effect on regulatory T cell differentiation.</p> <p>Conclusion</p> <p>In EAE, SLPI exerts potent pro-inflammatory actions by modulation of T-cell activity and its neutralization may be beneficial for the disease.</p

    Study of e+eppˉe^+e^- \rightarrow p\bar{p} in the vicinity of ψ(3770)\psi(3770)

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    Using 2917 pb1\rm{pb}^{-1} of data accumulated at 3.773~GeV\rm{GeV}, 44.5~pb1\rm{pb}^{-1} of data accumulated at 3.65~GeV\rm{GeV} and data accumulated during a ψ(3770)\psi(3770) line-shape scan with the BESIII detector, the reaction e+eppˉe^+e^-\rightarrow p\bar{p} is studied considering a possible interference between resonant and continuum amplitudes. The cross section of e+eψ(3770)ppˉe^+e^-\rightarrow\psi(3770)\rightarrow p\bar{p}, σ(e+eψ(3770)ppˉ)\sigma(e^+e^-\rightarrow\psi(3770)\rightarrow p\bar{p}), is found to have two solutions, determined to be (0.059±0.032±0.0120.059\pm0.032\pm0.012) pb with the phase angle ϕ=(255.8±37.9±4.8)\phi = (255.8\pm37.9\pm4.8)^\circ (<<0.11 pb at the 90% confidence level), or σ(e+eψ(3770)ppˉ)=(2.57±0.12±0.12\sigma(e^+e^-\rightarrow\psi(3770)\rightarrow p\bar{p}) = (2.57\pm0.12\pm0.12) pb with ϕ=(266.9±6.1±0.9)\phi = (266.9\pm6.1\pm0.9)^\circ both of which agree with a destructive interference. Using the obtained cross section of ψ(3770)ppˉ\psi(3770)\rightarrow p\bar{p}, the cross section of ppˉψ(3770)p\bar{p}\rightarrow \psi(3770), which is useful information for the future PANDA experiment, is estimated to be either (9.8±5.79.8\pm5.7) nb (<17.2<17.2 nb at 90% C.L.) or (425.6±42.9)(425.6\pm42.9) nb

    Inhibition of Hedgehog Signaling Antagonizes Serous Ovarian Cancer Growth in a Primary Xenograft Model

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    Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth.We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926.Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival.IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting

    SABRE: A bio-inspired fault-tolerant electronic architecture

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    As electronic devices become increasingly complex, ensuring their reliable, fault-free operation is becoming correspondingly more challenging. It can be observed that, in spite of their complexity, biological systems are highly reliable and fault tolerant. Hence, we are motivated to take inspiration for biological systems in the design of electronic ones. In SABRE (self-healing cellular architectures for biologically inspired highly reliable electronic systems), we have designed a bio-inspired fault-tolerant hierarchical architecture for this purpose. As in biology, the foundation for the whole system is cellular in nature, with each cell able to detect faults in its operation and trigger intra-cellular or extra-cellular repair as required. At the next level in the hierarchy, arrays of cells are configured and controlled as function units in a transport triggered architecture (TTA), which is able to perform partial-dynamic reconfiguration to rectify problems that cannot be solved at the cellular level. Each TTA is, in turn, part of a larger multi-processor system which employs coarser grain reconfiguration to tolerate faults that cause a processor to fail. In this paper, we describe the details of operation of each layer of the SABRE hierarchy, and how these layers interact to provide a high systemic level of fault tolerance. © 2013 IOP Publishing Ltd

    Co-encapsulation of human serum albumin and superparamagnetic iron oxide in PLGA nanoparticles: Part I. Effect of process variables on the mean size

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    PLGA (poly d,l-lactic-co-glycolic acid) nanoparticles (NPs) encapsulating magnetite nanoparticles (MNPs) along with a model drug human serum albumin (HSA) were prepared by double emulsion solvent evaporation method. This Part I will focus on size and size distribution of prepared NPs, whereas encapsulation efficiency will be discussed in Part II. It was found that mean hydrodynamic particle size was influenced by five important process variables. To explore their effects, a five-factorial, three-level experimental design and statistical analysis were carried out using STATISTICA® software. Effect of process variables on the mean size of nanoparticles was investigated and finally conditions to minimize size of NPs were proposed. GAMS™/MINOS software was used for optimization. The mean hydrodynamic size of nanoparticles ranged from 115 to 329 nm depending on the process conditions. Smallest possible mean particle size can be achieved by using low polymer concentration and high dispersion energy (enough sonication time) along with small aqueous/organic volume ratio
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