SLC19A1 transports immunoreactive cyclic dinucleotides.

The accumulation of DNA in the cytosol serves as a key immunostimulatory signal associated with infections, cancer and genomic damage1,2. Cytosolic DNA triggers immune responses by activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway3. The binding of DNA to cGAS activates its enzymatic activity, leading to the synthesis of a second messenger, cyclic guanosine monophosphate-adenosine monophosphate (2'3'-cGAMP)4-7. This cyclic dinucleotide (CDN) activates STING8, which in turn activates the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), promoting the transcription of genes encoding type I interferons and other cytokines and mediators that stimulate a broader immune response. Exogenous 2'3'-cGAMP produced by malignant cells9 and other CDNs, including those produced by bacteria10-12 and synthetic CDNs used in cancer immunotherapy13,14, must traverse the cell membrane to activate STING in target cells. How these charged CDNs pass through the lipid bilayer is unknown. Here we used a genome-wide CRISPR-interference screen to identify the reduced folate carrier SLC19A1, a folate-organic phosphate antiporter, as the major transporter of CDNs. Depleting SLC19A1 in human cells inhibits CDN uptake and functional responses, and overexpressing SLC19A1 increases both uptake and functional responses. In human cell lines and primary cells ex vivo, CDN uptake is inhibited by folates as well as two medications approved for treatment of inflammatory diseases, sulfasalazine and the antifolate methotrexate. The identification of SLC19A1 as the major transporter of CDNs into cells has implications for the immunotherapeutic treatment of cancer13, host responsiveness to CDN-producing pathogenic microorganisms11 and-potentially-for some inflammatory diseases

Treatment of Late Stage Disease in a Model of Arenaviral Hemorrhagic Fever: T-705 Efficacy and Reduced Toxicity Suggests an Alternative to Ribavirin

A growing number of arenaviruses are known to cause viral hemorrhagic fever (HF), a severe and life-threatening syndrome characterized by fever, malaise, and increased vascular permeability. Ribavirin, the only licensed antiviral indicated for the treatment of certain arenaviral HFs, has had mixed success and significant toxicity. Since severe arenaviral infections initially do not present with distinguishing symptoms and are difficult to clinically diagnose at early stages, it is of utmost importance to identify antiviral therapies effective at later stages of infection. We have previously reported that T-705, a substituted pyrazine derivative currently under development as an anti-influenza drug, is highly active in hamsters infected with Pichinde virus when the drug is administered orally early during the course of infection. Here we demonstrate that T-705 offers significant protection against this lethal arenaviral infection in hamsters when treatment is begun after the animals are ill and the day before the animals begin to succumb to disease. Importantly, this coincides with the time when peak viral loads are present in most organs and considerable tissue damage is evident. We also show that T-705 is as effective as, and less toxic than, ribavirin, as infected T-705-treated hamsters on average maintain their weight better and recover more rapidly than animals treated with ribavirin. Further, there was no added benefit to combination therapy with T-705 and ribavirin. Finally, pharmacokinetic data indicate that plasma T-705 levels following oral administration are markedly reduced during the latter stages of disease, and may contribute to the reduced efficacy seen when treatment is withheld until day 7 of infection. Our findings support further pre-clinical development of T-705 for the treatment of severe arenaviral infections

Connecting With Clients in Later Life: The Use of Telebehavioral Health to Address Older Adults’ Mental Health Needs

Telebehavioral health offers a unique opportunity to expand access to mental health services for older clients by addressing systemic barriers that often render mental health care inaccessible in later life. Although health interventions facilitated by technology, including telebehavioral health approaches, proliferated at the start of the COVID-19 pandemic, little guidance exists for counselors seeking to provide such services to clients in later life. In this manuscript, we describe challenges accessing mental health services, how telebehavioral health services can address these barriers, and practical consideration for delivering telebehavioral health approaches for counselors who work with older clients

Climate Clever Beef : On-farm demonstration of adaptation and mitigation options for climate change in northern Australia

This project engaged with beef producers in five regions of northern Australia to identify management options that improve the performance and resilience of beef businesses. The work was done in the context of increasing the resilience of businesses to current climate variability as well as to projected changes in climate. The project also identified potential synergies and conflicts between improved business performance, climate adaptation practices and greenhouse gas emissions management. Three regions (Qld Gulf, Fitzroy Basin and Victoria River District) evaluated climate adaptation and greenhouse gas mitigation options via a benchmarking and options analysis approach with three “focal” properties. Five indicators of performance were evaluated for each property – profitability, productivity, land condition, climate change risk and greenhouse gas emissions. These detailed business analyses were complemented by demonstration sites in each region. Two other regions (Qld Mitchell grasslands and NT Barkly Tablelands) used on-property demonstration sites to showcase promising climate adaptation practices identified in a previous project. The focal property approach provided a systematic process for assessing current business performance as well as a ready means of estimating the impacts of management changes. For example, over a 15 year period, the Qld Gulf focal property improved its pasture condition dramatically by stocking around the long-term carrying capacity and undertaking wet season spelling. This, combined with herd management improvements, increased profitability and productivity, reduced greenhouse gas emissions by 15%, and improved greenhouse gas emission efficiency by >100%. The demonstration sites in each region effectively promoted and documented the benefits of key grazing practices for improving resilience to both current climate variability and potential climate change. For example, on a 16,118km² property in the Barkly, a paddock demonstration has documented initial land condition recovery at old bores, and the reduced risk of overgrazing around new bores, through best practice stocking rate management and wet season spelling. Qualitative analyses showed that many of the adaptation practices identified for improving resilience are consistent with existing best practice recommendations aimed at improving productivity and sustainability. Furthermore, these adaptation practices appear to have largely neutral implications for greenhouse gas emissions. In contrast, practices and options for reducing greenhouse gas emissions were more likely to create conflicts that leave enterprises more vulnerable to climate change. Examples of the negative consequences of mitigation measures include reduced pasture production associated with increased carbon sequestration in trees (i.e. woody vegetation thickening or regrowth retention) and increased operating costs associated with carbon pricing (if these are not offset with carbon credits). The project demonstration sites and focal property benchmarking process provided a solid base for focussed extension work targeting the drivers of profit, land condition, greenhouse gas emissions intensity and climate adaptation strategies

Comparison of multianalyte proficiency test results by sum of ranking differences, principal component analysis, and hierarchical cluster analysis

Sum of ranking differences (SRD) was applied for comparing multianalyte results obtained by several analytical methods used in one or in different laboratories, i.e., for ranking the overall performances of the methods (or laboratories) in simultaneous determination of the same set of analytes. The data sets for testing of the SRD applicability contained the results reported during one of the proficiency tests (PTs) organized by EU Reference Laboratory for Polycyclic Aromatic Hydrocarbons (EU-RL-PAH). In this way, the SRD was also tested as a discriminant method alternative to existing average performance scores used to compare mutlianalyte PT results. SRD should be used along with the z scores-the most commonly used PT performance statistics. SRD was further developed to handle the same rankings (ties) among laboratories. Two benchmark concentration series were selected as reference: (a) the assigned PAH concentrations (determined precisely beforehand by the EU-RL-PAH) and (b) the averages of all individual PAH concentrations determined by each laboratory. Ranking relative to the assigned values and also to the average (or median) values pointed to the laboratories with the most extreme results, as well as revealed groups of laboratories with similar overall performances. SRD reveals differences between methods or laboratories even if classical test(s) cannot. The ranking was validated using comparison of ranks by random numbers (a randomization test) and using seven folds cross-validation, which highlighted the similarities among the (methods used in) laboratories. Principal component analysis and hierarchical cluster analysis justified the findings based on SRD ranking/grouping. If the PAH-concentrations are row-scaled, (i.e., z scores are analyzed as input for ranking) SRD can still be used for checking the normality of errors. Moreover, cross-validation of SRD on z scores groups the laboratories similarly. The SRD technique is general in nature, i.e., it can be applied to any experimental problem in which multianalyte results obtained either by several analytical procedures, analysts, instruments, or laboratories need to be compared. [Figure not available: see fulltext.] © 2013 Springer-Verlag Berlin Heidelberg

The Relationship between Phytoplankton Distribution and Water Column Characteristics in North West European Shelf Sea Waters

Phytoplankton underpin the marine food web in shelf seas, with some species having properties that are harmful to human health and coastal aquaculture. Pressures such as climate change and anthropogenic nutrient input are hypothesized to influence phytoplankton community composition and distribution. Yet the primary environmental drivers in shelf seas are poorly understood. To begin to address this in North Western European waters, the phytoplankton community composition was assessed in light of measured physical and chemical drivers during the “Ellett Line” cruise of autumn 2001 across the Scottish Continental shelf and into adjacent open Atlantic waters. Spatial variability existed in both phytoplankton and environmental conditions, with clear differences not only between on and off shelf stations but also between different on shelf locations. Temperature/salinity plots demonstrated different water masses existed in the region. In turn, principal component analysis (PCA), of the measured environmental conditions (temperature, salinity, water density and inorganic nutrient concentrations) clearly discriminated between shelf and oceanic stations on the basis of DIN∶DSi ratio that was correlated with both salinity and temperature. Discrimination between shelf stations was also related to this ratio, but also the concentration of DIN and DSi. The phytoplankton community was diatom dominated, with multidimensional scaling (MDS) demonstrating spatial variability in its composition. Redundancy analysis (RDA) was used to investigate the link between environment and the phytoplankton community. This demonstrated a significant relationship between community composition and water mass as indexed by salinity (whole community), and both salinity and DIN∶DSi (diatoms alone). Diatoms of the Pseudo-nitzschia seriata group occurred at densities potentially harmful to shellfish aquaculture, with the potential for toxicity being elevated by the likelihood of DSi limitation of growth at most stations and depths

Impacts of climate change on harmful algal blooms

High biomass Harmful Algal Blooms (HABs) such as Karenia mikimotoi and shellfish toxin producing HAB species continue to be observed in UK and Republic of Ireland waters. Regional differences continue to be seen in the distribution of HABs in UK and RoI waters with impacts mainly observed in the south and west coast of Ireland and regions in the UK with a strong Atlantic influence, e.g. Regions 1, 3, 4, 6 and 7. There is little monitoring aside from the continuous plankton recorder (CPR) in Region 8. The impacts from HABs in Wales, Northern Ireland and the Isle of Man are generally low. Since the last MCCIP report card was issued, blooms of Karenia mikimotoi have caused problems in Ayrshire, Scotland, and also in the north-west coast of Ireland where concerns about the quantity of dead wild fish washing on shore during an event in Ireland in 2012 resulted in two beaches being closed to the public. No clear trend that can be attributed to climate change can be observed in the incidence of shellfish toxin producing HABs since the last report card was issued. During the last two years the incidence of some shellfish toxins has continued to decrease (e.g. paralytic shellfish poisoning toxins in Scotland). High concentrations of yessotoxins (YTX) and azaspiracids (AZAs) have been recorded for the first time in Scotland. Northern Ireland enforced its first shellfish harvesting closure for high concentrations of domoic acid (the toxin responsible for amnesic shellfish poisoning, ASP) in 2012. A recent survey in Scottish waters (Regions 1, 6 and 7) has revealed the presence of domoic acid in the urine and faeces of harbour seals (Phoca vitulina). The impacts of these toxins on the health of marine mammals are unknown and a more detailed study is currently being undertaken. Many of the future impacts of climate change are unknown. Increasing sea surface temperatures as a result of climate change may increase the potential for blooms of species that are not currently found in UK and RoI waters through range expansion or human mediated introduction. There is evidence that no new HAB species have become established during the last two years. An increase in the duration of stratification of the water column may influence the abundance of HABs in UK and RoI waters. This is particularly relevant in shelf areas and Region 8, an area where offshore high biomass K. mikimotoi blooms have been hypothesized to initiate and impact coastal areas along the west of Ireland and Regions 6, 7 and 1. Conversely, an increase in wind speed and duration may reduce the duration of stratification in the water column. This may result in a decrease of some HAB dinoflagellate species and an increase in HAB diatom species. Little is known about the impacts of ocean acidification or changes in offshore circulation on the incidence of HABs. The role of offshore blooms in seeding coastal blooms (e.g. of K. mikimotoi) remains unknown and the lack of monitoring in Region 8 and on the shelf edge compounds this knowledge gap

MoonLITE programmatic and technological update

MoonLITE is a proposed four penetrator lunar mission. Following a US/UK working group assessment, a science assessment and the first UK impact trials, a full mission-level phase A study has begun. A technological and programmatic update of the mission is given

Tightrope walkers and solidarity sisters: critical workplace educators in the garment industry

Abstract: This article focuses on the complex negotiations of critical workplace educators positioned amongst contradictory agendas and discourses in the workplace. While philosophically aligned with critical pedagogical agendas of transformation and collective action for workplace change, these educators perform an array of pedagogic articulations in everyday practice to secure their continued presence in the workplace. What becomes evident in these seemingly opposing articulations are various strategic political positionings of educators alongside their juggling of demands, attachments and inter-identifications with both learners and managers. The pedagogy that emerges challenges conventional binaries of ‘transformative’ and ‘reproductive’ learning. Dynamics of transformation and liberation as well as reproduction and subjugation appear to be interlinked, along with expanding nets of social relations that blur power hierarchies and spatial boundaries, in a pedagogy that ultimately appears to mobilise hope and agency among workers. The workplace educator works a delicate balance of these dynamics to survive. The argument is based on a case study of a garment factory in Canada in which an adult education programme managed to thrive for 17 years: both workers and educators were interviewed in depth