An antiviral response directed by PKR phosphorylation of the RNA helicase A

The double-stranded RNA-activated protein kinase R (PKR) is a key regulator of the innate immune response. Activation of PKR during viral infection culminates in phosphorylation of the α subunit of the eukaryotic translation initiation factor 2 (eIF2α) to inhibit protein translation. A broad range of regulatory functions has also been attributed to PKR. However, as few additional PKR substrates have been identified, the mechanisms remain unclear. Here, PKR is shown to interact with an essential RNA helicase, RHA. Moreover, RHA is identified as a substrate for PKR, with phosphorylation perturbing the association of the helicase with double-stranded RNA (dsRNA). Through this mechanism, PKR can modulate transcription, as revealed by its ability to prevent the capacity of RHA to catalyze transactivating response (TAR)–mediated type 1 human immunodeficiency virus (HIV-1) gene regulation. Consequently, HIV-1 virions packaged in cells also expressing the decoy RHA peptides subsequently had enhanced infectivity. The data demonstrate interplay between key components of dsRNA metabolism, both connecting RHA to an important component of innate immunity and delineating an unanticipated role for PKR in RNA metabolism.

RNA interference : more than a research tool in the vertebrates' adaptive immunity

In recent years, RNA silencing, usage of small double stranded RNAs of ~21 – 25 base pairs to regulate gene expression, has emerged as a powerful research tool to dissect the role of unknown host cell factors in this 'post-genomic' era. While the molecular mechanism of RNA silencing has not been precisely defined, the revelation that small RNA molecules are equipped with this regulatory function has transformed our thinking on the role of RNA in many facets of biology, illustrating the complexity and the dynamic interplay of cellular regulation. As plants and invertebrates lack the protein-based adaptive immunity that are found in jawed vertebrates, the ability of RNA silencing to shut down gene expression in a sequence-specific manner offers an explanation of how these organisms counteract pathogen invasions into host cells. It has been proposed that this type of RNA-mediated defence mechanism is an ancient form of immunity to offset the transgene-, transposon- and virus-mediated attack. However, whether 1) RNA silencing is a natural immune response in vertebrates to suppress pathogen invasion; or 2) vertebrate cells have evolved to counteract invasion in a 'RNA silencing' independent manner remains to be determined. A number of recent reports have provided tantalizing clues to support the view that RNA silencing functions as a physiological response to regulate viral infection in vertebrate cells. Amongst these, two manuscripts that are published in recent issues of Science and Immunity, respectively, have provided some of the first direct evidences that RNA silencing is an important component of antiviral defence in vertebrate cells. In addition to demonstrating RNA silencing to be critical to vertebrate innate immunity, these studies also highlight the potential of utilising virus-infection systems as models to refine our understanding on the molecular determinants of RNA silencing in vertebrate cells.

Instrumental vision

This chapter interrogates stereo-immersive ‘virtual reality’ (VR), the technology that enables a perceiver to experience what it is like to be immersed in a simulated environment. While the simulation is powered by the “geometry engine” (Cutting, 1997: 31) associated with high-end computer imaging technology, the visual experience itself is powered by ordinary human vision: the vision system’s innate capacity to see “in 3D”. To understand and critically appraise stereo-immersive VR, we should study not its purported ‘virtuality’, but its specific visuality, because the ‘reality’ of a so-called ‘virtual environment’ is afforded by the stereoacuity of binocular vision itself. By way of such a critique of the visuality of stereo-immersive VR, this chapter suggests that we think about the ‘practice’ of vision, and consider on what basis vision can have its own ‘materiality’. Pictorial perception is proposed as an exemplary visual mode in which the possibilities of perception might emerge. Against the ‘possibilities’ of vision associated with pictures, the visuality of stereo-immersive VR emerges as a harnessing, or ‘instrumentalisation’ of vision’s innate capabilities. James J. Gibson’s ‘ecological’ approach to vision studies is referenced to show the degree to which developers of VR have sought — and succeeded — to mimic the ‘realness’ of ordinary perceptual reality. This raises a question concerning whether the success of stereo-immersive VR is simultaneously the source of its own perceptual redundancy: for to bring into being the perceptual basis of ordinary ‘real’ reality, is to return the perceiver to what is already familiar and known.

Advances in infection and immunity : from bench to bedside

Following the successful inaugural Lorne Infection and Immunity Conference in 2011, scientists have gathered again on 15–17 February 2012 for a second round of this multidisciplinary international meeting. Sessions covered a range of different topics, including innate and adaptive immune responses to infection, host–pathogen interactions, systems biology, as well as clinical and translational research. Here we summarize some of the main concepts discussed at the meeting and the progress on the development of new therapeutic approaches for the control of infectious diseases.

Functional similarities between pigeon 'milk' and mammalian milk : induction of immune gene expression and modification of the microbiota

Pigeon ‘milk’ and mammalian milk have functional similarities in terms of nutritional benefit and delivery of immunoglobulins to the young. Mammalian milk has been clearly shown to aid in the development of the immune system and microbiota of the young, but similar effects have not yet been attributed to pigeon ‘milk’. Therefore, using a chicken model, we investigated the effect of pigeon ‘milk’ on immune gene expression in the Gut Associated Lymphoid Tissue (GALT) and on the composition of the caecal microbiota. Chickens fed pigeon ‘milk’ had a faster rate of growth and a better feed conversion ratio than control chickens. There was significantly enhanced expression of immune-related gene pathways and interferon-stimulated genes in the GALT of pigeon ‘milk’-fed chickens. These pathways include the innate immune response, regulation of cytokine production and regulation of B cell activation and proliferation. The caecal microbiota of pigeon ‘milk’-fed chickens was significantly more diverse than control chickens, and appears to be affected by prebiotics in pigeon ‘milk’, as well as being directly seeded by bacteria present in pigeon ‘milk’. Our results demonstrate that pigeon ‘milk’ has further modes of action which make it functionally similar to mammalian milk. We hypothesise that pigeon ‘lactation’ and mammalian lactation evolved independently but resulted in similarly functional products.

Promotion of Hendra virus replication by microRNA 146a

Hendra virus is a highly pathogenic zoonotic paramyxovirus in the genus Henipavirus. Thirty-nine outbreaks of Hendra virus have been reported since its initial identification in Queensland, Australia, resulting in seven human infections and four fatalities. Little is known about cellular host factors impacting Hendra virus replication. In this work, we demonstrate that Hendra virus makes use of a microRNA (miRNA) designated miR-146a, an NF-κB-responsive miRNA upregulated by several innate immune ligands, to favor its replication. miR-146a is elevated in the blood of ferrets and horses infected with Hendra virus and is upregulated by Hendra virus in human cells in vitro. Blocking miR-146a reduces Hendra virus replication in vitro, suggesting a role for this miRNA in Hendra virus replication. In silico analysis of miR-146a targets identified ring finger protein (RNF)11, a member of the A20 ubiquitin editing complex that negatively regulates NF-κB activity, as a novel component of Hendra virus replication. RNA interference-mediated silencing of RNF11 promotes Hendra virus replication in vitro, suggesting that increased NF-κB activity aids Hendra virus replication. Furthermore, overexpression of the IκB superrepressor inhibits Hendra virus replication. These studies are the first to demonstrate a host miRNA response to Hendra virus infection and suggest an important role for host miRNAs in Hendra virus disease.

Malicious code detection architecture inspired by human immune system

Malicious code is a threat to computer systems globally. In this paper, we outline the evolution of malicious code attacks. The threat is evolving, leaving challenges for attackers to improve attack techniques and for researchers and security specialists to improve detection accuracy. We present a novel architecture for an effective defense against malicious code attack, inspired by the human immune system. We introduce two phases of program execution: Adolescent and Mature Phase. The first phase uses a malware profile matching mechanism, whereas the second phase uses a program profile matching mechanism. Both mechanisms are analogous to the innate immune system

Characterisation of an ancient S100 protein with multiple functions

 This project focused on the novel S100A19 protein, expressed exclusively in marsupials and monotremes, identifying it as an important component of the innate immune system. Data showed that S100A19 is differentially regulated in the pouch and mammary gland of the wallaby to protect the infant when most susceptible to infection.

Monotreme lactation protein is highly expressed in monotreme milk and provides antimicrobial protection

Monotremes (platypus and echidna) are the descendants of the oldest ancestor of all extant mammals distinguished from other mammals by mode of reproduction. Monotremes lay eggs following a short gestation period and after an even briefer incubation period, altricial hatchlings are nourished over a long lactation period with milk secreted by nipple-less mammary patches located on the female's abdomen. Milk is the sole source of nutrition and immune protection for the developing young until weaning. Using transcriptome and mass spectrometry analysis of milk cells and milk proteins, respectively, a novel Monotreme Lactation Protein (MLP) was identified as a major secreted protein in milk. We show that platypus and short-beaked echidna MLP genes show significant homology and are unique to monotremes. The MLP transcript was shown to be expressed in a variety of tissues; however, highest expression was observed in milk cells and was expressed constitutively from early to late lactation. Analysis of recombinant MLP showed that it is an N-linked glycosylated protein and biophysical studies predicted that MLP is an amphipathic, α-helical protein, a typical feature of antimicrobial proteins. Functional analysis revealed MLP antibacterial activity against both opportunistic pathogenic Staphylococcus aureus and commensal Enterococcus faecalis bacteria but showed no effect on Escherichia coli, Pseudomonas aeruginosa, Staphylococcus epidermidis, and Salmonella enterica. Our data suggest that MLP is an evolutionarily ancient component of milk-mediated innate immunity absent in other mammals. We propose that MLP evolved specifically in the monotreme lineage supporting the evolution of lactation in these species to provide bacterial protection, at a time when mammals lacked nipples.

Variation of yield loci in finite element analysis by considering texture evolution for AA5042 aluminum sheets

 Yield function has various material parameters that describe how materials respond plastically in given conditions. However, a significant number of mechanical tests are required to identify the many material parameters for yield function. In this study, an effective method using crystal plasticity through a virtual experiment is introduced to develop the anisotropic yield function for AA5042. The crystal plasticity approach was used to predict the anisotropic response of the material in order to consider a number of stress or strain modes that would not otherwise be evident through mechanical testing. A rate-independent crystal plasticity model based on a smooth single crystal yield surface, which removes the innate ambiguity problem within the rate-independent model and Taylor model for polycrystalline deformation behavior were employed to predict the material’s response in the balanced biaxial stress, pure shear, and plane strain states to identify the parameters for the anisotropic yield function of AA5042.

Ontogeny of long distance migration

The movements of some long-distance migrants are driven by innate compass headings that they follow on their first migrations (e.g., some birds and insects), while the movements of other first-time migrants are learned by following more experienced conspecifics (e.g., baleen whales). However, the overall roles of innate, learned, and social behaviors in driving migration goals in many taxa are poorly understood. To look for evidence of whether migration routes are innate or learned for sea turtles, here for 42 sites around the world we compare the migration routes of >400 satellite-tracked adults of multiple species of sea turtle with ∼45 000 Lagrangian hatchling turtle drift scenarios. In so doing, we show that the migration routes of adult turtles are strongly related to hatchling drift patterns, implying that adult migration goals are learned through their past experiences dispersing with ocean currents. The diverse migration destinations of adults consistently reflected the diversity in sites they would have encountered as drifting hatchlings. Our findings reveal how a simple mechanism, juvenile passive drift, can explain the ontogeny of some of the longest migrations in the animal kingdom and ensure that adults find suitable foraging sites.

Interactive exploration of data with visual metaphors

Visual Analytics (VA) is an approach to data analysis by means of visual manipulation of data representation, which relies on innate human abilities of perception and cognition. Even though current visual toolkits in the Business Analytics (BA) domain have improved the effectiveness of data exploration, analysis and reporting, their features are often not intuitive, and can be confusing and difficult to use. Moreover, visualizations generated from these toolkits are mostly accessible to specialist users. Thus, there is a need for analytic environments that support data exploration, interpretation and communication of insight that do not add to the cognitive load of the analyst and their non-technical clients. In this conceptual paper, we explore the potential of primary metaphors, which arise out of human lived and sensory-motor experiences, in the design of immersive visual analytics environments. Primary metaphors provide ideas for representation of time, space, quantity, similarity, actions and team work. Using examples developed in our own work, we also explain how to combine such metaphors to create complex and cognitively acceptable visual metaphors, such as 3D data terrains that approximate our intuition of reality and create opportunities for data to be viewed, navigated, explored, touched, changed, discussed, reported and described to others, individually or collaboratively.

Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via upregulation of SOCS1 and SOCS3.

Highly pathogenic avian influenza virus infection is associated with severe mortality in both humans and poultry. The mechanisms of disease pathogenesis and immunity are poorly understood although recent evidence suggests that cytokine/chemokine dysregulation contributes to disease severity following H5N1 infection. Influenza A virus infection causes a rapid influx of inflammatory cells, resulting in increased reactive oxygen species production, cytokine expression, and acute lung injury. Proinflammatory stimuli are known to induce intracellular reactive oxygen species by activating NADPH oxidase activity. We therefore hypothesized that inhibition of this activity would restore host cytokine homeostasis following avian influenza virus infection. A panel of airway epithelial and immune cells from mammalian and avian species were infected with A/Puerto Rico/8/1934 H1N1 virus, low-pathogenicity avian influenza H5N3 virus (A/duck/Victoria/0305-2/2012), highly pathogenic avian influenza H5N1 virus (A/chicken/Vietnam/0008/2004), or low-pathogenicity avian influenza H7N9 virus (A/Anhui/1/2013). Quantitative real-time reverse transcriptase PCR showed that H5N1 and H7N9 viruses significantly stimulated cytokine (interleukin-6, beta interferon, CXCL10, and CCL5) production. Among the influenza-induced cytokines, CCL5 was identified as a potential marker for overactive immunity. Apocynin, a Nox2 inhibitor, inhibited influenza-induced cytokines and reactive oxygen species production, although viral replication was not significantly altered in vitro. Interestingly, apocynin treatment significantly increased influenza virus-induced mRNA and protein expression of SOCS1 and SOCS3, enhancing negative regulation of cytokine signaling. These findings suggest that apocynin or its derivatives (targeting host responses) could be used in combination with antiviral strategies (targeting viruses) as therapeutic agents to ameliorate disease severity in susceptible species.

Defining the interaction of HIV-1 with the mucosal barriers of the female reproductive tract

Worldwide, HIV-1 infects millions of people annually, the majority of whom are women. To establish infection in the female reproductive tract (FRT), HIV-1 in male ejaculate must overcome numerous innate and adaptive immune factors, traverse the genital epithelium, and establish infection in underlying CD4(+) target cells. How the virus achieves this remains poorly defined. By utilizing a new technique, we define how HIV-1 interacts with different tissues of the FRT using human cervical explants and in vivo exposure in the rhesus macaque vaginal transmission model. Despite previous claims of the squamous epithelium being an efficient barrier to virus entry, we reveal that HIV-1 can penetrate both intact columnar and squamous epithelial barriers to depths where the virus can encounter potential target cells. In the squamous epithelium, we identify virus entry occurring through diffusive percolation, penetrating areas where cell junctions are absent. In the columnar epithelium, we illustrate that virus does not transverse barriers as well as previously thought due to mucus impediment. We also show a statistically significant correlation between the viral load of inocula and the ability of HIV-1 to pervade the squamous barrier. Overall, our results suggest a diffusive percolation mechanism for the initial events of HIV-1 entry. With these data, we also mathematically extrapolate the number of HIV-1 particles that penetrate the mucosa per coital act, providing a biological description of the mechanism for HIV-1 transmission during the acute and chronic stages of infection.