The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication

Most RNA viruses infecting mammals and other vertebrates show profound suppression of CpG and UpA dinucleotide frequencies. To investigate this functionally, mutants of the picornavirus, echovirus 7 (E7), were constructed with altered CpG and UpA compositions in two 1.1–1.3 Kbase regions. Those with increased frequencies of CpG and UpA showed impaired replication kinetics and higher RNA/infectivity ratios compared with wild-type virus. Remarkably, mutants with CpGs and UpAs removed showed enhanced replication, larger plaques and rapidly outcompeted wild-type virus on co-infections. Luciferase-expressing E7 sub-genomic replicons with CpGs and UpAs removed from the reporter gene showed 100-fold greater luminescence. E7 and mutants were equivalently sensitive to exogenously added interferon-β, showed no evidence for differential recognition by ADAR1 or pattern recognition receptors RIG-I, MDA5 or PKR. However, kinase inhibitors roscovitine and C16 partially or entirely reversed the attenuated phenotype of high CpG and UpA mutants, potentially through inhibition of currently uncharacterized pattern recognition receptors that respond to RNA composition. Generating viruses with enhanced replication kinetics has applications in vaccine production and reporter gene construction. More fundamentally, the findings introduce a new evolutionary paradigm where dinucleotide composition of viral genomes is subjected to selection pressures independently of coding capacity and profoundly influences host–pathogen interactions

Modelling environmental factors correlated with podoconiosis: a geospatial study of non-filarial elephantiasis

Introduction The precise trigger of podoconiosis — endemic non-filarial elephantiasis of the lower legs — is unknown. Epidemiological and ecological studies have linked the disease with barefoot exposure to red clay soils of volcanic origin. Histopathology investigations have demonstrated that silicon, aluminium, magnesium and iron are present in the lower limb lymph node macrophages of both patients and non-patients living barefoot on these clays. We studied the spatial variation (variations across an area) in podoconiosis prevalence and the associated environmental factors with a goal to better understanding the pathogenesis of podoconiosis. Methods Fieldwork was conducted from June 2011 to February 2013 in 12 kebeles (administrative units) in northern Ethiopia. Geo-located prevalence data and soil samples were collected and analysed along with secondary geological, topographic, meteorological and elevation data. Soil data were analysed for chemical composition, mineralogy and particle size, and were interpolated to provide spatially continuous information. Exploratory, spatial, univariate and multivariate regression analyses of podoconiosis prevalence were conducted in relation to primary (soil) and secondary (elevation, precipitation, and geology) covariates. Results Podoconiosis distribution showed spatial correlation with variation in elevation and precipitation. Exploratory analysis identified that phyllosilicate minerals, particularly clay (smectite and kaolinite) and mica groups, quartz (crystalline silica), iron oxide, and zirconium were associated with podoconiosis prevalence. The final multivariate model showed that the quantities of smectite (RR = 2.76, 95% CI: 1.35, 5.73; p = 0.007), quartz (RR = 1.16, 95% CI: 1.06, 1.26; p = 0.001) and mica (RR = 1.09, 95% CI: 1.05, 1.13; p < 0.001) in the soil had positive associations with podoconiosis prevalence. Conclusions More quantities of smectite, mica and quartz within the soil were associated with podoconiosis prevalence. Together with previous work indicating that these minerals may influence water absorption, potentiate infection and be toxic to human cells, the present findings suggest that these particles may play a role in the pathogenesis of podoconiosis and acute adenolymphangitis, a common cause of morbidity in podoconiosis patients

Verifying the Kugo-Ojima Confinement Criterion in Landau Gauge Yang-Mills Theory

Expanding the Landau gauge gluon and ghost two-point functions in a power series we investigate their infrared behavior. The corresponding powers are constrained through the ghost Dyson-Schwinger equation by exploiting multiplicative renormalizability. Without recourse to any specific truncation we demonstrate that the infrared powers of the gluon and ghost propagators are uniquely related to each other. Constraints for these powers are derived, and the resulting infrared enhancement of the ghost propagator signals that the Kugo-Ojima confinement criterion is fulfilled in Landau gauge Yang-Mills theory.Comment: 4 pages, no figures; version to be published in Physical Review Letter

A state of delirium: deciphering the effect of inflammation on tau pathology in Alzheimer's disease

Alzheimer's disease (AD), the predominant form of dementia, is highly correlated with the abnormal hyperphosphorylation and aggregation of tau. Immune responses are key drivers of AD and how they contribute to tau pathology in human disease remains largely unknown. This review summarises current knowledge on the association between inflammatory processes and tau pathology. While, preclinical evidence suggests that inflammation can indeed induce tau hyperphosphorylation at both pre- and post-tangles epitopes, a better understanding of whether this develops into advanced pathological features such as neurofibrillary tangles is needed. Microglial cells, the immune phagocytes in the central nervous system, appear to play a key role in regulating tau pathology, but the underlying mechanisms are not fully understood. Their activation can be detrimental via the secretion of pro-inflammatory mediators, particularly interleukin-1β, but also potentially beneficial through phagocytosis of extracellular toxic tau oligomers. Nevertheless, anti-inflammatory treatments in animal models were found protective, but whether or not they affect microglial phagocytosis of tau species is unknown. However, one major challenge to our understanding of the role of inflammation in the progression of tau pathology is the preclinical models used to address this question. They mostly rely on the use of septic doses of lipopolysaccharide that do not reflect the inflammatory conditions experienced AD patients, questioning whether the impact of inflammation on tau pathology in these models is dose-dependent and relevant to the human disease. The use of more translational models of inflammation corroborated with verification in clinical investigations are necessary to progress our understanding of the interplay between inflammation and tau pathology

A Services\u27 Frameworks And Support Services For Environmental Information Communities

For environmental datasets to be used effectively via the Internet, they must present standardized data and metadata services and link the two. The Open Geospatial Consortium\u27s (OGC) web services (WFS, WMS, CSW etc.), have seen widespread use over many years however few organizations have deployed information architectures based solely on OGC standards for all their datasets. Collections of organizations within a thematically-based community certainly cannot realistically be expected to do so. To enable service use flexibility we present a services framework - a Data Brokering Layer (DBL). A DBL presents access to data and metadata services for datasets, and links between them, in a standardized manner based on Linked Data and Semantic Web principles. By specifying regular access methods to any data or metadata service relevant for a dataset, community organizers allow a wide range of services for use within their community. Additionally, a community service profile testing service – a Conformance Service – may be run that reveals the day-to-day status of all of a community’s services to be known allowing both better end-user experiences and also that data providers’ data is acceptable to a community and continues to remains available for use. We present DBL and Conformance Service designs as well as a whole-of-community architecture that facilitates the use of the two. We describe implementations of them within two Australian environmental information communities: eReefs and Bioregional Assessments and plans for wider deployment

Halocarbons associated with Arctic sea ice

Short-lived halocarbons were measured in Arctic sea-ice brine, seawater and air above the Greenland and Norwegian seas (∼81°N, 2 to 5°E) in mid-summer, from a melting ice floe at the edge of the ice pack. In the ice floe, concentrations of C2H5I, 2-C3H7I and CH2Br2 showed significant enhancement in the sea ice brine, of average factors of 1.7, 1.4 and 2.5 times respectively, compared to the water underneath and after normalising to brine volume. Concentrations of mono-iodocarbons in air are the highest ever reported, and our calculations suggest increased fluxes of halocarbons to the atmosphere may result from their sea-ice enhancement. Some halocarbons were also measured in ice of the sub-Arctic in Hudson Bay (∼55°N, 77°W) in early spring, ice that was thicker, colder and less porous than the Arctic ice in summer, and in which the halocarbons were concentrated to values over 10 times larger than in the Arctic ice when normalised to brine volume. Concentrations in the Arctic ice were similar to those in Antarctic sea ice that was similarly warm and porous. As climate warms and Arctic sea ice becomes more like that of the Antarctic, our results lead us to expect the production of iodocarbons and so of reactive iodine gases to increase

Increasing Tau 4R Tau Levels Exacerbates Hippocampal Tau Hyperphosphorylation in the hTau Model of Tauopathy but Also Tau Dephosphorylation Following Acute Systemic Inflammation

Copyright © 2020 Barron, Gartlon, Dawson, Atkinson and Pardon. Inflammation is considered a mechanistic driver of Alzheimer's disease, thought to increase tau phosphorylation, the first step to the formation of neurofibrillary tangles (NFTs). To further understand how inflammation impacts the development of tau pathology, we used (hTau) mice, which express all six, non-mutated, human tau isoforms, but with an altered ratio of tau isoforms favoring 3R tau due to the concomitant loss of murine tau (mTau) that is predominantly 4R. Such an imbalance pattern has been related to susceptibility to NFTs formation, but whether or not this also affects susceptibility to systemic inflammation and related changes in tau phosphorylation is not known. To reduce the predominance of 3R tau by increasing 4R tau availability, we bred hTau mice on a heterozygous mTau background and compared the impact of systemic inflammation induced by lipopolysaccharide (LPS) in hTau mice hetero- or homozygous mTau knockout. Three-month-old male wild-type (Wt), mTau+/-, mTau-/-, hTau/mTau+/-, and hTau/mTau-/- mice were administered 100, 250, or 330 μg/kg of LPS or its vehicle phosphate buffer saline (PBS) [intravenously (i.v.), n = 8-9/group]. Sickness behavior, reflected by behavioral suppression in the spontaneous alternation task, hippocampal tau phosphorylation, measured by western immunoblotting, and circulating cytokine levels were quantified 4 h after LPS administration. The persistence of the LPS effects (250 μg/kg) on these measures, and food burrowing behavior, was assessed at 24 h post-inoculation in Wt, mTau+/-, and hTau/mTau+/- mice (n = 9-10/group). In the absence of immune stimulation, increasing 4R tau levels in hTau/mTau+/- exacerbated pS202 and pS396/404 tau phosphorylation, without altering total tau levels or worsening early behavioral perturbations characteristic of hTau/mTau-/- mice. We also show for the first time that modulating 4R tau levels in hTau mice affects the response to systemic inflammation. Behavior was suppressed in all genotypes 4 h following LPS administration, but hTau/mTau+/- exhibited more severe sickness behavior at the 100 μg/kg dose and a milder behavioral and cytokine response than hTau/mTau-/- mice at the 330 μg/kg dose. All LPS doses decreased tau phosphorylation at both epitopes in hTau/mTau+/- mice, but pS202 levels were selectively reduced at the 100 μg/kg dose in hTau/mTau-/- mice. Behavioral suppression and decreased tau phosphorylation persisted at 24 h following LPS administration in hTau/mTau+/- mice

Investigation of chlorine radical chemistry in the Eyjafjallajkull volcanic plume using observed depletions in non-methane hydrocarbons

As part of the effort to understand volcanic plume composition and chemistry during the eruption of the Icelandic volcano Eyjafjallajkull, the CARIBIC atmospheric observatory was deployed for three special science flights aboard a Lufthansa passenger aircraft. Measurements made during these flights included the collection of whole air samples, which were analyzed for non-methane hydrocarbons (NMHCs). Hydrocarbon concentrations in plume samples were found to be reduced to levels below background, with relative depletions characteristic of reaction with chlorine radicals (Cl). Recent observations of halogen oxides in volcanic plumes provide evidence for halogen radical chemistry, but quantitative data for free halogen radical concentrations in volcanic plumes were absent. Here we present the first observation-based calculations of Cl radical concentrations in volcanic plumes, estimated from observed NMHC depletions. Inferred Cl concentrations were between 1.3 × 10 and 6.6 × 10 Cl cm. The relationship between NMHC variability and local lifetimes was used to investigate the ratio between OH and Cl within the plume, with [OH]/[Cl] estimated to be ∼37. Copyright 2011 by the American Geophysical Union

Effects of Common Ravens on Greater Sage-Grouse in the Great Basin, Region, USA

Anthropogenic modification to ecosystems can result in the redistribution of species at higher trophic levels. Humans have re-organized predator-prey dynamics, namely by removing top predators and subsidizing more generalist mesocarnivore species. As a result, some mid-level predator species have increased in abundance and distribution, often to the detriment of lower-level species that are not adapted to increased predation rates. One example of a native avian predator that has experienced population increase following increased anthropogenic subsidization is the common raven (Corvus corax; hereafter, raven).The raven is an ubiquitous predator within sagebrush ecosystems in the western U.S.,and may contribute to suppressed population growth in greater sage-grouse (Centrocercus urophasianus) through disruptions to lekking behavior and top-down influences on nest success and recruitment. Ravens have expanded in distribution and abundance, in large part due to increased resource subsidies from human infrastructure and land use activities. Concurrently, some sage-grouse populations appear to be in decline where habitat conditions should be promoting species persistence. Using long-term monitoring data on sage-grouse and ravens in the northern Great Basin region, we show that ravens disrupt sage-grouse lekking behavior, increased raven density is associated with reduced sage-grouse nest success, and that negative trends in lek counts may be related to elevated raven occurrence and density. Taken together, these results suggest the need to address a growing problem, as ravens continue to expand their distribution, facilitated by anthropogenic subsidies. These findings are preliminary and provided to meet the need for timely best science

Remote sensing of mangrove forest phenology and its environmental drivers

Mangrove forest phenology at the regional scale have been poorly investigated and its driving factors remain unclear. Multi-temporal remote sensing represents a key tool to investigate vegetation phenology, particularly in environments with limited accessibility and lack of in situ measurements. This paper presents the first characterisation of mangrove forest phenology from the Yucatan Peninsula, south east Mexico. We used 15-year time-series of four vegetation indices (EVI, NDVI, gNDVI and NDWI) derived from MODIS surface reflectance to estimate phenological parameters which were then compared with in situ climatic variables, salinity and litterfall. The Discrete Fourier Transform (DFT) was used to smooth the raw data and four phenological parameters were estimated: start of season (SOS), time of maximum greenness (Max Green), end of season (EOS) and length of season (LOS). Litterfall showed a distinct seasonal pattern with higher rates during the end of the dry season and during the wet season. Litterfall was positively correlated with temperature (r = 0.88, p <0.01) and salinity (r = 0.70, p <0.01). The results revealed that although mangroves are evergreen species the mangrove forest has clear greenness seasonality which is negatively correlated with litterfall and generally lagged behind maximum rainfall. The dates of phenological metrics varied depending on the choice of vegetation indices reflecting the sensitivity of each index to a particular aspect of vegetation growth. NDWI, an index associated to canopy water content and soil moisture had advanced dates of SOS, Max Green and EOS while gNDVI, an index primarily related to canopy chlorophyll content had delayed dates. SOS ranged between day of the year (DOY) 144 (late dry season) and DOY 220 (rainy season) while the EOS occurred between DOY 104 (mid-dry season) to DOY 160 (early rainy season). The length of the growing season ranged between 228 and 264 days. Sites receiving a greater amount of rainfall between January and March showed an advanced SOS and Max Green. This phenological characterisation is useful to understand the mangrove forest dynamics at the landscape scale and to monitor the status of mangrove. In addition the results will serve as a baseline against which to compare future changes in mangrove phenology due to natural or anthropogenic causes