Retinoic acid inducible gene I Activates innate antiviral response against human parainfluenza virus type 3

Human parainfluenza virus type 3 (HPIV3) is a respiratory paramyxovirus that infects lung epithelial cells to cause high morbidity among infants and children. To date, no effective vaccine or antiviral therapy exists for HPIV3 and therefore, it is important to study innate immune antiviral response induced by this virus in infected cells. Type-I interferons (IFN, interferon-α/β) and tumor necrosis factor-α (TNFα activated by NFκB) are potent antiviral cytokines that play an important role during innate immune antiviral response. A wide-spectrum of viruses utilizes pattern recognition receptors (PRRs) like toll-like receptors (TLRs) and RLH (RIG like helicases) receptors such as RIGI (retinoic acid inducible gene -I) and Mda5 to induce innate antiviral response. Previously it was shown that both TNFα and IFNβ are produced from HPIV3 infected cells. However, the mechanism by which infected cells activated innate response following HPIV3 infection was not known. In the current study, we demonstrated that RIGI serves as a PRR in HPIV3 infected cells to induce innate antiviral response by expressing IFNβ (via activation of interferon regulatory factor-3 or IRF3) and TNFα (via activation of NF-κB)

Channel flow, tectonic overpressure, and exhumation of high-pressure rocks in the greater himalayas

The Himalayas are the archetype of continental collision, where a number of long-standing fundamental problems persist in the Greater Himalayan Sequence (GHS): (1) contemporaneous reverse and normal faulting, (2) inversion of metamorphic grade, (3) origin of high-(HP) and ultrahigh-pressure (UHP) rocks, (4) mode of ductile extrusion and exhumation of HP and UHP rocks close to the GHS hanging wall, (5) flow kinematics in the subduction channel, and (6) tectonic overpressure, here defined as TOP  Combining double low line Pĝ•PL where P is total (dynamic) pressure and PL is lithostatic pressure. In this study we couple Himalayan geodynamics to numerical simulations to show how one single model, upward-Tapering channel (UTC) flow, can be used to find a unified explanation for the evidence. The UTC simulates a flat-ramp geometry of the main underthrust faults, as proposed for many sections across the Himalayan continental subduction. Based on the current knowledge of the Himalayan subduction channel geometry and geological/geophysical data, the simulations predict that a UTC can be responsible for high TOP ( > 2). TOP increases exponentially with a decrease in UTC mouth width, and with an increase in underthrusting velocity and channel viscosity. The highest overpressure occurs at depths < ĝ'60 km, which, combined with the flow configuration in the UTC, forces HP and UHP rocks to exhume along the channel's hanging wall, as in the Himalayas. By matching the computed velocities and pressures wi

Sedimentation patterns during the Precambrian : a unique record?

Although the similarities between depositional processes and products as well as the analogous controls on basin-filling and evolution appear to have enjoyed great uniformity throughout the sedimentary rock record, a noticeable distinction exists in the rates and intensities of a broad range of geological processes in the Precambrian epoch. This paper searches for distinctiveness in the Precambrian sedimentary record, both siliciclastic and carbonate, through an extensive, though not exhaustive, review of the relevant literature augmented by new observations. While differences in Precambrian deltaic, aeolian, glacial and possibly also lacustrine deposits and settings appear to have been small, their large-scale development was controlled largely by a combination of temporal and geodynamic influences, essentially of global compass. In this regard the onset of the supercontinent cycle and major perturbations in palaeo-atmospheric composition appear to have been significant. Marine environments provide a poor platform for PrecambrianePhanerozoic comparisons of sedimentation patterns, as those from the former period are preserved almost exclusively in epeiric settings, an environment essentially lacking on modern Earth. For the shallow marine carbonates, biological mediation of chemical sediment deposition changed radically from dominance by microbial biota in the Precambrian to a combination of metazons, protozoans and algae for the skeletal carbonates of the Phanerozoic. Despite it being widely recognized that Precambrian channel systems were braided in all environments (deltaic, tidal, alluvial, fluvial) as a consequence of the lack of vegetation and poor development of soils, the fluvial setting has some enigmatic aspects. Amongst these is evidence for ponding of muddy detritus in apparently sandstone bed-load dominated braided systems, with effects on local palaeoslopes which have resulted in unusual palaeohydraulic parameters for Precambrian fluvial systems. This is perhaps a field of research which holds greater promise when investigating sedimentation patterns prior to the Phanerozoic.SS acknowledges field grants from the CSIR, Government of India and the INSA-DFG for providing a fellowship to work with WA in Munich on molar tooth structure. PGE thanks both the University of Pretoria and the National Research Foundation of South Africa for funding.http://www.elsevier.com/locate/marpetgeonf201

TLR2/MyD88/NF-κB Pathway, Reactive Oxygen Species, Potassium Efflux Activates NLRP3/ASC Inflammasome during Respiratory Syncytial Virus Infection

Human respiratory syncytial virus (RSV) constitute highly pathogenic virus that cause severe respiratory diseases in newborn, children, elderly and immuno-compromised individuals. Airway inflammation is a critical regulator of disease outcome in RSV infected hosts. Although “controlled” inflammation is required for virus clearance, aberrant and exaggerated inflammation during RSV infection results in development of inflammatory diseases like pneumonia and bronchiolitis. Interleukin-1β (IL-1β) plays an important role in inflammation by orchestrating the pro-inflammatory response. IL-1β is synthesized as an immature pro-IL-1β form. It is cleaved by activated caspase-1 to yield mature IL-1β that is secreted extracellularly. Activation of caspase-1 is mediated by a multi-protein complex known as the inflammasome. Although RSV infection results in IL-1β release, the mechanism is unknown. Here in, we have characterized the mechanism of IL-1β secretion following RSV infection. Our study revealed that NLRP3/ASC inflammasome activation is crucial for IL-1β production during RSV infection. Further studies illustrated that prior to inflammasome formation; the “first signal” constitutes activation of toll-like receptor-2 (TLR2)/MyD88/NF-κB pathway. TLR2/MyD88/NF-κB signaling is required for pro-IL-1β and NLRP3 gene expression during RSV infection. Following expression of these genes, two “second signals” are essential for triggering inflammasome activation. Intracellular reactive oxygen species (ROS) and potassium (K+) efflux due to stimulation of ATP-sensitive ion channel promote inflammasome activation following RSV infection. Thus, our studies have underscored the requirement of TLR2/MyD88/NF-κB pathway (first signal) and ROS/potassium efflux (second signal) for NLRP3/ASC inflammasome formation, leading to caspase-1 activation and subsequent IL-1β release during RSV infection

Genetic Interactions between Chromosomes 11 and 18 Contribute to Airway Hyperresponsiveness in Mice

We used two-dimensional quantitative trait locus analysis to identify interacting genetic loci that contribute to the native airway constrictor hyperresponsiveness to methacholine that characterizes A/J mice, relative to C57BL/6J mice. We quantified airway responsiveness to intravenous methacholine boluses in eighty-eight (C57BL/6J X A/J) F2 and twenty-seven (A/J X C57BL/6J) F2 mice as well as ten A/J mice and six C57BL/6J mice; all studies were performed in male mice. Mice were genotyped at 384 SNP markers, and from these data two-QTL analyses disclosed one pair of interacting loci on chromosomes 11 and 18; the homozygous A/J genotype at each locus constituted the genetic interaction linked to the hyperresponsive A/J phenotype. Bioinformatic network analysis of potential interactions among proteins encoded by genes in the linked regions disclosed two high priority subnetworks - Myl7, Rock1, Limk2; and Npc1, Npc1l1. Evidence in the literature supports the possibility that either or both networks could contribute to the regulation of airway constrictor responsiveness. Together, these results should stimulate evaluation of the genetic contribution of these networks in the regulation of airway responsiveness in humans

Lytic Cell Death Mechanisms in Human Respiratory Syncytial Virus-Infected Macrophages: Roles of Pyroptosis and Necroptosis

Human respiratory syncytial virus (RSV) is the most common cause of viral bronchiolitis and pneumonia in infants and children worldwide. Inflammation induced by RSV infection is responsible for its hallmark manifestation of bronchiolitis and pneumonia. The cellular debris created through lytic cell death of infected cells is a potent initiator of this inflammation. Macrophages are known to play a pivotal role in the early innate immune and inflammatory response to viral pathogens. However, the lytic cell death mechanisms associated with RSV infection in macrophages remains unknown. Two distinct mechanisms involved in lytic cell death are pyroptosis and necroptosis. Our studies revealed that RSV induces lytic cell death in macrophages via both of these mechanisms, specifically through the ASC (Apoptosis-associated speck like protein containing a caspase recruitment domain)-NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome activation of both caspase-1 dependent pyroptosis and receptor-interacting serine/threonine-protein kinase 3 (RIPK3), as well as a mixed lineage kinase domain like pseudokinase (MLKL)-dependent necroptosis. In addition, we demonstrated an important role of reactive oxygen species (ROS) during lytic cell death of RSV-infected macrophages

Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense

<p>Abstract</p> <p>Background</p> <p>Oncolytic virotherapy for cancer treatment utilizes viruses for selective infection and death of cancer cells without any adverse effect on normal cells. We previously reported that the human respiratory syncytial virus (RSV) is a novel oncolytic virus against androgen-independent PC-3 human prostate cancer cells. The present study extends the result to androgen-dependent prostate cancer, and explores the underlying mechanism that triggers RSV-induced oncolysis of prostate cancer cells.</p> <p>Methods</p> <p>The oncolytic effect of RSV on androgen-sensitive LNCaP human prostate cancer cells and on androgen-independent RM1 murine prostate cancer cells was studied <it>in vitro </it>in culture and <it>in vivo </it>in a xenograft or allograft tumor model. <it>In vitro</it>, cell viability, infectivity and apoptosis were monitored by MTT assay, viral plaque assay and annexin V staining, respectively. <it>In vivo </it>studies involved virus administration to prostate tumors grown in immune compromised nude mice and in syngeneic immune competent C57BL/6J mice. Anti-tumorogenic oncolytic activity was monitored by measuring tumor volume, imaging bioluminescent tumors in live animals and performing histopathological analysis and TUNEL assay with tumors</p> <p>Results</p> <p>We show that RSV imposes a potent oncolytic effect on LNCaP prostate cancer cells. RSV infectivity was markedly higher in LNCaP cells compared to the non-tumorigenic RWPE-1 human prostate cells. The enhanced viral burden led to LNCaP cell apoptosis and growth inhibition of LNCaP xenograft tumors in nude mice. A functional host immune response did not interfere with RSV-induced oncolysis, since growth of xenograft tumors in syngeneic C57BL/6J mice from murine RM1 cells was inhibited upon RSV administration. LNCaP cells failed to activate the type-I interferon (IFNα/β)-induced transcription factor STAT-1, which is required for antiviral gene expression, although these cells could produce IFN in response to RSV infection. The essential role of IFN in restricting infection was further borne out by our finding that neutralizing IFN activity resulted in enhanced RSV infection in non-tumorigenic RWPE-1 prostate cells.</p> <p>Conclusions</p> <p>We demonstrated that RSV is potentially a useful therapeutic tool in the treatment of androgen-sensitive and androgen-independent prostate cancer. Moreover, impaired IFN-mediated antiviral response is the likely cause of higher viral burden and resulting oncolysis of androgen-sensitive prostate cancer cells.</p