HCV NS5A inhibitors disrupt replication factory formation: a novel mechanism of antiviral action

EditorialNicholas S. Eyre, Michael R. Bear

The molecular interactions of ZIKV and DENV with the type-i IFN response

Zika Virus (ZIKV) and Dengue Virus (DENV) are related viruses of the Flavivirus genus that cause significant disease in humans. Existing control measures have been ineffective at curbing the increasing global incidence of infection for both viruses and they are therefore prime targets for new vaccination strategies. Type-I interferon (IFN) responses are important in clearing viral infection and for generating efficient adaptive immune responses towards infection and vaccination. However, ZIKV and DENV have evolved multiple molecular mechanisms to evade type-I IFN production. This review covers the molecular interactions, from detection to evasion, of these viruses with the type-I IFN response. Additionally, we discuss how this knowledge can be exploited to improve the design of new vaccine strategies.Rosa C. Coldbeck-Shackley, Nicholas S. Eyre and Michael R. Bear

Geographical information retrieval with ontologies of place

Geographical context is required of many information retrieval tasks in which the target of the search may be documents, images or records which are referenced to geographical space only by means of place names. Often there may be an imprecise match between the query name and the names associated with candidate sources of information. There is a need therefore for geographical information retrieval facilities that can rank the relevance of candidate information with respect to geographical closeness of place as well as semantic closeness with respect to the information of interest. Here we present an ontology of place that combines limited coordinate data with semantic and qualitative spatial relationships between places. This parsimonious model of geographical place supports maintenance of knowledge of place names that relate to extensive regions of the Earth at multiple levels of granularity. The ontology has been implemented with a semantic modelling system linking non-spatial conceptual hierarchies with the place ontology. An hierarchical spatial distance measure is combined with Euclidean distance between place centroids to create a hybrid spatial distance measure. This is integrated with thematic distance, based on classification semantics, to create an integrated semantic closeness measure that can be used for a relevance ranking of retrieved objects

Viperin is anti-viral in vitro but is dispensable for restricting dengue virus replication or induction of innate and inflammatory responses in vivo

Viperin has antiviral function against many viruses, including dengue virus (DENV), when studied in cells in culture. Here, the antiviral actions of viperin were defined both in vitro and in a mouse in vivo model of DENV infection. Murine embryonic fibroblasts (MEFs) derived from mice lacking viperin (vip(-/-)) showed enhanced DENV infection, accompanied by increased IFN-β and induction of ISGs; IFIT1 and CXCL-10 but not IRF7, when compared to wild-type (WT) MEFs. In contrast, subcutaneous challenge of immunocompetent WT and vip(-/-) mice with DENV did not result in enhanced infection. Intracranial infection with DENV resulted in body weight loss and neurological disease with a moderate increase in mortality in vip(-/)- compared with WT mice, although this was not accompanied by altered brain morphology, immune cell infiltration or DENV RNA level in the brain. Similarly, DENV induction of IFN-β, IFIT1, CXCL-10, IRF7 and TNF-α was not significantly different in WT and vip(-/-) mouse brain, although there was a modest but significant increase in DENV induction of IL-6 and IfI27la in the absence of viperin. NanoString nCounter analysis confirmed no significant difference in induction of a panel of inflammatory genes in WT compared to vip(-/-) DENV-infected mouse brains. Further, polyI:C stimulation of bone marrow-derived macrophages (BMDMs) induced TNF-α, IFN-β, IL-6 and Nos-2, but responses were not different in BMDMs generated from WT or vip(-/-) mice. Thus, while there is significant evidence of anti-DENV actions of viperin in some cell types in vitro, for DENV infection in vivo a lack of viperin does not affect systemic or brain susceptibility to DENV or induction of innate and inflammatory responses.Wisam-Hamzah Al Shujairi, Luke P. Kris, Kylie van der Hoek, Evangeline Cowell, Gustavo Bracho-Granado, Tahlia Woodgate, Michael R. Beard and Jillian M. Car

First detection of the outer edge of an AGN accretion disc: very fast multiband optical variability of NGC 4395 with GTC/HiPERCAM and LT/IO:O

We present fast (∼200 s sampling) ugriz photometry of the low -mass AGN NGC 4395 with the Liverpool Telescope, followed by very fast (3 s sampling) us, gs, rs, is, and zs simultaneous monitoring with HiPERCAM on the 10.4m GTC. These observations provide the fastest ever AGN multiband photometry and very precise lag measurements. Unlike in all other AGN, gs lags us by a large amount, consistent with disc reprocessing but not with reprocessing in the broad-line region (BLR). There is very little increase in lag with wavelength at long wavelengths, indicating an outer edge (Rout) to the reprocessor. We have compared truncated disc reprocessing models to the combined HiPERCAM and previous X-ray/UV lags. For the normally accepted mass of 3.6 × 105M⊙, we obtain reasonable agreement with zero spin, Rout ∼ 1700Rg and the DONE physically motivated temperature-dependent disc colour-correction factor (fcol ⁠). A smaller mass of 4 × 104M⊙ can only be accommodated if fcol=2.4⁠, which is probably unrealistically high. Disc self gravity is probably unimportant in this low-mass AGN but an obscuring wind may provide an edge. For the small mass, the dust sublimation radius is similar to Rout so the wind could be dusty. However, for the more likely large mass, the sublimation radius is further out so the optically thick base of a line-driven gaseous wind is more likely. The inner edge of the BLR is close to Rout in both cases. These observations provide the first good evidence for a truncated AGN disc and caution that truncation should be included in reverberation lag modelling

Constitutive expression and distinct properties of IFN-epsilon protect the female reproductive tract from Zika virus infection

The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFNε) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs α, β and λ. We show the necessity of IFNε for Zika Virus (ZIKV) protection by: increased susceptibility of IFNε -/- mice; their “rescue” by intravaginal recombinant IFNε treatment and blockade of protective endogenous IFNε by neutralising antibody. Complementary studies in human FRT cell lines showed IFNε had potent anti-ZIKV activity, associated with transcriptome responses similar to IFNλ but lacking the proinflammatory gene signature of IFNα. IFNε activated STAT1/2 pathways similar to IFNα and λ that were inhibited by ZIKV-encoded non-structural (NS) proteins, but not if IFNε exposure preceded infection. This scenario is provided by the constitutive expression of endogenous IFNε. However, the IFNε expression was not inhibited by ZIKV NS proteins despite their ability to antagonise the expression of IFNβ or λ. Thus, the constitutive expression of IFNε provides cellular resistance to viral strategies of antagonism and maximises the antiviral activity of the FRT. These results show that the unique spatiotemporal properties of IFNε provides an innate immune surveillance network in the FRT that is a significant barrier to viral infection with important implications for prevention and therapy.Rosa C. Coldbeck-Shackley, Ornella Romeo, Sarah Rosli, Linden J. Gearing, Jodee A. Gould, San S. Lim, Kylie H. Van der Hoek, Nicholas S. Eyre, Byron Shue, Sarah A. Robertson, Sonja M. Best, Michelle D. Tate, Paul J. Hertzog, Michael R. Bear

Evolution of a Metal to Insulator Transition in Ca2−x_{2-x}Nax_{x}CuO2_{2}Cl2_{2}, as seen by ARPES

We present angle resolved photoemission (ARPES) data on Na-doped Ca$_2$CuO$_2$Cl$_2$. We demonstrate that the chemical potential shifts upon doping the system across the insulator to metal transition. The resulting low energy spectra reveal a gap structure which appears to deviate from the canonical $d_{x2-y2} ~ |cos(k_x a)-cos(k_y a)|$ form. To reconcile the measured gap structure with d-wave superconductivity one can understand the data in terms of two gaps, a very small one contributing to the nodal region and a very large one dominating the anti-nodal region. The latter is a result of the electronic structure observed in the undoped antiferromagnetic insulator. Furthermore, the low energy electronic structure of the metallic sample contains a two component structure in the nodal direction, and a change in velocity of the dispersion in the nodal direction at roughly 50 meV. We discuss these results in connection with photoemission data on other cuprate systems.Comment: 10 pages, 12 figures, accepted by PRB; a high quality pdf is available at http://helios.physics.utoronto.ca/~fronning/RonningNaCCOCResub.pdf (2.2MB

Tenth Scientific Biennial Meeting of the Australasian Virology Society-AVS10 2019

The Australasian Virology Society (AVS) aims to promote, support and advocate for the discipline of virology in the Australasian region. The society was incorporated in 2011 after 10 years operating as the Australian Virology Group (AVG) founded in 2001, coinciding with the inaugural biennial scientific meeting. AVS conferences aim to provide a forum for the dissemination of all aspects of virology, foster collaboration, and encourage participation by students and post-doctoral researchers. The tenth Australasian Virology Society (AVS10) scientific meeting was held on 2–5 December 2019 in Queenstown, New Zealand. This report highlights the latest research presented at the meeting, which included cutting-edge virology presented by our international plenary speakers Ana Fernandez-Sesma and Benjamin tenOever, and keynote Richard Kuhn. AVS10 honoured female pioneers in Australian virology, Lorena Brown and Barbara Coulson. We report outcomes from the AVS10 career development session on “Successfully transitioning from post-doc to lab head”, winners of best presentation awards, and the AVS gender equity policy, initiated in 2013. Plans for the 2021 meeting are underway which will celebrate the 20th anniversary of AVS where it all began, in Fraser Island, Queensland, Australia.Karla J. Helbig ... Michael R. Beard ... et al

The TESS-Keck Survey. II. An Ultra-Short-Period Rocky Planet And Its Siblings Transiting The Galactic Thick-Disk Star TOI-561

We report the discovery of TOI-561, a multiplanet system in the galactic thick disk that contains a rocky, ultra-short-period planet. This bright (V = 10.2) star hosts three small transiting planets identified in photometry from the NASA TESS mission: TOI-561 b (TOI-561.02, P = 0.44 days, Rp = 1.45 ± 0.11 R⊕), c (TOI-561.01, P = 10.8 days, Rp = 2.90 ± 0.13 R⊕), and d (TOI-561.03, P = 16.3 days, Rp = 2.32 ± 0.16 R⊕). The star is chemically ([Fe/H] = −0.41 ± 0.05, [α/Fe] = +0.23 ± 0.05) and kinematically consistent with the galactic thick-disk population, making TOI-561 one of the oldest (10 ± 3 Gyr) and most metal-poor planetary systems discovered yet. We dynamically confirm planets b and c with radial velocities from the W. M. Keck Observatory High Resolution Echelle Spectrometer. Planet b has a mass and density of 3.2 ± 0.8 M⊕ and ${5.5}_{-1.6}^{+2.0}$g cm−3, consistent with a rocky composition. Its lower-than-average density is consistent with an iron-poor composition, although an Earth-like iron-to-silicates ratio is not ruled out. Planet c is 7.0 ± 2.3 M⊕ and 1.6 ± 0.6 g cm−3, consistent with an interior rocky core overlaid with a low-mass volatile envelope. Several attributes of the photometry for planet d (which we did not detect dynamically) complicate the analysis, but we vet the planet with high-contrast imaging, ground-based photometric follow-up, and radial velocities. TOI-561 b is the first rocky world around a galactic thick-disk star confirmed with radial velocities and one of the best rocky planets for thermal emission studies

Effects of environmental pollutants on the reproduction and welfare of ruminants

Anthropogenic pollutants comprise a wide range of synthetic organic compounds and heavy metals, which are dispersed throughout the environment, usually at low concentrations. Exposure of ruminants, as for all other animals, is unavoidable and while the levels of exposure to most chemicals are usually too low to induce any physiological effects, combinations of pollutants can act additively or synergistically to perturb multiple physiological systems at all ages but particularly in the developing foetus. In sheep, organs affected by pollutant exposure include the ovary, testis, hypothalamus and pituitary gland and bone. Reported effects of exposure include changes in organ weight and gross structure, histology and gene and protein expression but these changes are not reflected in changes in reproductive performance under the conditions tested. These results illustrate the complexity of the effects of endocrine disrupting compounds on the reproductive axis, which make it difficult to extrapolate between, or even within, species. Effects of pollutant exposure on the thyroid gland, immune, cardiovascular and obesogenic systems have not been shown explicitly, in ruminants, but work on other species suggests that these systems can also be perturbed. It is concluded that exposure to a mixture of anthropogenic pollutants has significant effects on a wide variety of physiological systems, including the reproductive system. Although this physiological insult has not yet been shown to lead to a reduction in ruminant gross performance, there are already reports indicating that anthropogenic pollutant exposure can compromise several physiological systems and may pose a significant threat to both reproductive performance and welfare in the longer term. At present, many potential mechanisms of action for individual chemicals have been identified but knowledge of factors affecting the rate of tissue exposure and of the effects of combinations of chemicals on physiological systems is poor. Nevertheless, both are vital for the identification of risks to animal productivity and welfare