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ABSTRACT: Motivated by measurements made in the 2004 Long-Range Ocean Acoustic Propagation Experiment (LOAPEX), the problem of mode processing transient acoustic signals collected on two nearby vertical line arrays is considered. The first three moments (centroid, variance, and skewness) of broadband distributions of acoustic energy with fixed mode number (referred to as modal group arrivals) are estimated. It is shown that despite the absence of signal coherence between the two arrays and poor high mode number energy resolution, the centroid and variance of these distributions can be estimated with tolerable errors using piecewise coherent mode processing as described in this paper.
The Journal of the Acoustical Society of America 06/2012; 131(6):EL492-8. · 1.55 Impact Factor
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ABSTRACT: The results of mode-processing measurements of broadband acoustic wavefields made in the fall of 2004 as part of the Long-Range Ocean Acoustic Propagation Experiment (LOAPEX) in the eastern North Pacific Ocean are reported here. Transient wavefields in the 50-90 Hz band that were recorded on a 1400-m long 40 element vertical array centered near the sound channel axis are analyzed. This array was designed to resolve low-order modes. The wavefields were excited by a ship-suspended source at seven ranges, between approximately 50 and 3200 km, from the receiving array. The range evolution of broadband modal arrival patterns corresponding to fixed mode numbers ("modal group arrivals") is analyzed with an emphasis on the second (variance) and third (skewness) moments. A theory of modal group time spreads is described, emphasizing complexities associated with energy scattering among low-order modes. The temporal structure of measured modal group arrivals is compared to theoretical predictions and numerical simulations. Theory, simulations, and observations generally agree. In cases where disagreement is observed, the reasons for the disagreement are discussed in terms of the underlying physical processes and data limitations.
The Journal of the Acoustical Society of America 06/2012; 131(6):4409-27. · 1.55 Impact Factor
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ABSTRACT: Dengue hemorrhagic fever and/or dengue shock syndrome represent the most serious pathophysiological manifestations of human dengue virus infection. Despite intensive research, the mechanisms and important cellular players that contribute to dengue disease are unclear. Mast cells are tissue-resident innate immune cells that play a sentinel cell role in host protection against infectious agents via pathogen-recognition receptors by producing potent mediators that modulate inflammation, cell recruitment and normal vascular homeostasis. Most importantly, mast cells are susceptible to antibody-enhanced dengue virus infection and respond with selective cytokine and chemokine responses. In order to obtain a global view of dengue virus-induced gene regulation in mast cells, primary human cord blood-derived mast cells (CBMCs) and the KU812 and HMC-1 mast cell lines were infected with dengue virus in the presence of dengue-immune sera and their responses were evaluated at the mRNA and protein levels. Mast cells responded to antibody-enhanced dengue virus infection or polyinosiniċpolycytidylic acid treatment with the production of type I interferons and the rapid and potent production of chemokines including CCL4, CCL5 and CXCL10. Multiple interferon-stimulated genes were also upregulated as well as mRNA and protein for the RNA sensors PKR, RIG-I and MDA5. Dengue virus-induced chemokine production by KU812 cells was significantly modulated by siRNA knockdown of RIG-I and PKR, in a negative and positive manner, respectively. Pretreatment of fresh KU812 cells with supernatants from dengue virus-infected mast cells provided protection from subsequent infection with dengue virus in a type I interferon-dependent manner. These findings support a role for tissue-resident mast cells in the early detection of antibody-enhanced dengue virus infection via RNA sensors, the protection of neighbouring cells through interferon production and the potential recruitment of leukocytes via chemokine production.
PLoS ONE 01/2012; 7(3):e34055. · 4.09 Impact Factor
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ABSTRACT: Vascular perturbation is a hallmark of severe forms of dengue disease. We show here that antibody-enhanced dengue virus infection of primary human cord blood-derived mast cells (CBMCs) and the human mast cell-like line HMC-1 results in the release of factor(s) which activate human endothelial cells, as evidenced by increased expression of the adhesion molecules ICAM-1 and VCAM-1. Endothelial cell activation was prevented by pretreatment of mast cell-derived supernatants with a tumor necrosis factor (TNF)-specific blocking antibody, thus identifying TNF as the endothelial cell-activating factor. Our findings suggest that mast cells may represent an important source of TNF, promoting vascular endothelial perturbation following antibody-enhanced dengue virus infection.
Journal of Virology 11/2010; 85(2):1145-50. · 5.40 Impact Factor
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12/2008: pages 113-133;
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ABSTRACT: Severe forms of dengue virus disease, known as dengue hemorrhagic fever and dengue shock syndrome, result from an aberrant immune response involving antibody-dependent enhancement of infection, thrombocytopenia, and a loss of vascular integrity, culminating in hemorrhage, shock, and in some cases, death. Several studies have indicated that dengue virus infection results in the induction of apoptosis of certain cells believed to be contributory players in dengue pathogenesis. However, none have specifically examined the role of antibody enhancement in the context of induction of apoptosis. Here, we show that antibody-enhanced dengue virus infection of the FcR-bearing mast cell/basophil KU812 cell line results in a massive induction of apoptosis. Confocal microscopy and flow cytometry indicate two distinct subpopulations consisting of productively infected cells and apoptotic-uninfected bystanders. Apoptosis was found to be caspase-dependent, involving global caspase activation and cleavage of poly-ADP-ribose polymerase (PARP) and D4-guanosine diphosphate dissociation inhibitor (D4-GDI). Additional FcR-bearing cells, including K562, U937, and human mast cell 1 (HMC-1), were analyzed for apoptosis induction following infection. Although all cells displayed high susceptibility to antibody-enhanced dengue virus infection, only cells of a mast cell phenotype (KU812 and HMC-1) were found to undergo apoptosis. Dengue-induced apoptosis of KU812 cells was shown to require antibody-enhanced dengue virus infection by blockade of FcgammaRII. Transfection of KU812 cells with L-SIGN/DC-SIGNR was able to overcome the requirement for antibody enhancement with regard to dengue virus infection and apoptosis.
Journal of Leukocyte Biology 10/2008; 85(1):71-80. · 4.99 Impact Factor
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ABSTRACT: Strategies to promote intracellular ceramide accumulation in cancer cells may have therapeutic utility because ceramide is an important second messenger during apoptosis. Exposure to cell-permeable C(6) ceramide or tricyclodecan-9-yl-xanthate (an inducer of de novo ceramide synthesis and an inhibitor of sphingomyelin synthase) caused MDA-MB-435 human breast carcinoma cells to die by apoptosis. Concomitant treatment with the ceramidase inhibitor D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (MAPP) or the glucosylceramide synthase inhibitor 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP) potentiated the cytotoxic effect of C(6) ceramide, indicating that C(6) ceramide-mediated cytotoxicity was antagonized by the action of ceramidases and glucosylceramide synthase. Interestingly, treatment with PPMP alone, but not MAPP alone, also induced apoptosis in MDA-MB-435 cells, suggesting that conversion to glucosylceramide rather than catabolism by ceramidases prevented endogenous ceramide from reaching cytotoxic levels. C(6) ceramide-induced apoptosis in MDA-MB-435 cells was associated with the generation of reactive oxygen species, and was inhibited by the antioxidants N-acetylcysteine and glutathione. Although mitochondrial membrane integrity was disrupted in C(6) ceramide-treated MDA-MB-435 cells, apoptosis was not mediated by caspases because there was no protective effect by the pan-caspase inhibitor z-VAD-fmk. Collectively, these findings indicate that strategies to enhance intracellular ceramide accumulation in malignant cells might offer a novel approach to the treatment of breast cancer.
Experimental and Molecular Pathology 03/2007; 82(1):1-11. · 2.42 Impact Factor
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ABSTRACT: Dengue virus is a major mosquito-borne human pathogen with four known serotypes. The presence of antidengue virus antibodies in the serum of individuals prior to dengue virus infection is believed to be an important risk factor for severe dengue virus disease as a result of the phenomenon of antibody-dependent enhancement operating on Fc receptor (FcR)-bearing cells. In addition to blood monocytes, mast cells are susceptible to antibody-enhanced dengue virus infection, producing a number of inflammatory mediators including IL-1, IL-6, and CCL5. Using the human mast cell-like lines KU812 and HMC-1 as well as primary cultures of human cord blood-derived mast cells (CBMC), we aimed to identify the participating FcRs in antibody-enhanced mast cell dengue virus infection, as FcRs represent a potential site for therapeutic intervention. CBMC expressed significant levels of FcgammaRI, FcgammaRII, and FcgammaRIII, and mast cell-like HMC-1 and KU812 cells expressed predominantly FcgammaRII. All four serotypes of dengue virus showed antibody-enhanced binding to KU812 cells. Specific FcgammaRII blockade with mAb IV.3 was found to significantly abrogate dengue virus binding to KU812 cells and CBMC in the presence of dengue-specific antibody. Dengue virus infection and the production of CCL5 by KU812 cells were also inhibited by FcgammaRII blockade.
Journal of Leukocyte Biology 01/2007; 80(6):1242-50. · 4.99 Impact Factor
