Impaired activation of STAT5 upon IL-2 stimulation in Tregs and elevated sIL-2R in Sjögren’s syndrome

Background Interleukin-2 (IL-2) and the high-affinity IL-2 receptor (IL-2R) are essential for the survival of regulatory T cells (Tregs) which are the main players in immune tolerance and prevention of autoimmune diseases. Sjögren’s syndrome (SS) is a chronic autoimmune disease predominantly affecting women and is characterised by sicca symptoms including oral and ocular dryness. The aim of this study was to investigate an association between IL-2R and Treg function in patients with SS of different severity defined by the salivary flow rate. Methods In a cross-sectional study, we determined plasma soluble IL-2R (sIL-2R) levels in women with SS (n=97) and healthy females (n=50) using ELISA. A subset of those (n=51) was screened for Treg function measured by the STAT5 signalling response to IL-2 using phospho-flow cytometry. Results We found that elevated plasma levels of sIL-2R were positively associated with the severity of SS reflected by a pathologically low salivary flow. Phospho-flow analysis revealed that patients with SS have a significantly lower frequency of pSTAT5+ Tregs upon IL-2 stimulation compared with healthy individuals, while the frequency of Tregs and pSTAT5 in conventional T cells remained unchanged. In addition, we observed more pSTAT5+ Tregs at baseline in patients with SS, which is significantly associated with seropositivity and elevated sIL-2R. Conclusions Our data indicates that Tregs have a weakened immunosuppressive function in patients with SS due to impaired IL-2/IL-2R signalling capacity. This could mediate lymphocytic infiltration into salivary glands inducing sicca symptoms. We believe that sIL-2R could act as a useful indicator for SS and disease severity.publishedVersio

Single cell based phosphorylation profiling identifies alterations in toll-like receptor 7 and 9 signaling in patients with primary Sjögren's syndrome

Primary Sjögren's syndrome (pSS) is associated with polymorphisms and mRNA expression profiles that are indicative of an exaggerated innate and type I IFN immune response. Excessive activation potential of signaling pathways may play a role in this profile, but the intracellular signaling profile of the disease is not well characterized. To gain insights into potentially dysfunctional intracellular signaling profiles of pSS patients we conducted an exploratory analysis of MAPK/ERK and JAK/STAT signaling networks in peripheral blood mononuclear cells (PBMC) from 25 female pSS patients and 25 female age-matched healthy donors using phospho-specific flow cytometry. We analyzed unstimulated samples, as well as samples during a 4 h time period following activation of Toll-like receptor (TLR) 7 and 9. Expression levels of MxA, IFI44, OAS1, GBP1, and GBP2 in PBMC were analyzed by real-time PCR. Cytokine levels in plasma were determined using a 25-plex Luminex-assay. Principal component analysis (PCA) showed that basal phosphorylation profiles could be used to differentiate pSS patients from healthy donor samples by stronger intracellular signaling pathway activation in NK and T cells relative to B cells. Stimulation of PBMC with TLR7 and −9 ligands showed significant differences in the phosphorylation profiles between samples from pSS patients and healthy donors. Including clinical parameters such as extraglandular manifestations (EGM), we observed stronger responses of NF-κB and STAT3 S727 in B cells from EGM-negative patients compared to EGM-positive patients and healthy controls. Plasma cytokine levels were correlated to the basal phosphorylation levels in these patients. In addition, 70% of the patients had a positive IFN score. These patients differed from the IFN score negative patients regarding their phosphorylation profiles and their plasma cytokine levels. In conclusion, we here report increased signaling potentials in peripheral B cells of pSS patients in response to TLR7 and −9 stimulation through STAT3 S727 and NF-κB that correlate with a type I IFN signature. Induction of these pathways could contribute to the generation of a type I IFN signature in pSS. Patients displaying elevated potentiation of STAT3 S727 and NF-κB signaling could therefore benefit from therapies targeting these pathways.publishedVersio

Herring roe oil in treatment of psoriasis – influence on immune cells and cytokine network

Background: Psoriasis is a chronic immune-mediated skin disease with systemic inflammation and comorbidities. Although the disease severity may vary over time, many patients suffer from mild to moderate disease. Often local treatment will be sufficient to control the symptoms, but they may have several side effects. ω-3 polyunsaturated fatty acids have shown promising results in clinical trials with mild-to-moderate psoriasis. Methods: We explored the impact of phospholipid bound docosahexaenoic acid and eicosapentaenoic acid in a 3:1 ratio on immune cells and cytokine networks in peripheral blood of patients with psoriasis. We investigated the inter-relation of plasma cytokine levels and disease severity in 58 patients, and explored the status of circulating immune cell activity in 18 patients with non-severe psoriasis before and during herring roe oil supplementation. Plasma concentration of 22 cytokines was measured by Luminex technology and circulating immune cells were analyzed by multicolor flow cytometry. Results: CCL2 levels decreased over time, and IFN-γR1 increased, possibly related to the action of ω-3 polyunsaturated fatty acids. We observed a shift from naïve to effector CD4+ T cells and decreases of CD38 expression on CD4+ and CD8+ T cells, CD56bright NK cells and CD14+CD16- classical monocytes. Conclusions: These findings support the beneficial effect of herring roe oil supplementation.publishedVersio

Aberrant signaling of immune cells in Sjögren's syndrome patient subgroups upon interferon stimulation

Background: Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, characterized by mononuclear cell infiltrates in the salivary and lacrimal glands, leading to glandular atrophy and dryness. Patient heterogeneity and lack of knowledge regarding its pathogenesis makes pSS a difficult disease to manage. Methods: An exploratory analysis using mass cytometry was conducted of MAPK/ERK and JAK/STAT signaling pathways in peripheral blood mononuclear cells (PBMC) from 16 female medication free pSS patients (8 anti-Sjögren’s syndrome-related antigen A negative/SSA- and 8 SSA+) and 8 female age-matched healthy donors after stimulation with interferons (IFNs). Results: We found significant differences in the frequencies of memory B cells, CD8+ T central and effector memory cells and terminally differentiated CD4+ T cells among the healthy donors and patient subgroups. In addition, we observed an upregulation of HLA-DR and CD38 in many cell subsets in the patients. Upon IFNα2b stimulation, slightly increased signaling through pSTAT1 Y701 was observed in most cell types in pSS patients compared to controls, while phosphorylation of STAT3 Y705 and STAT5 Y694 were slightly reduced. IFNγ stimulation resulted in significantly increased pSTAT1 Y701 induction in conventional dendritic cells (cDCs) and classical and non-classical monocytes in the patients. Most of the observed differences were more prominent in the SSA+ subgroup, indicating greater disease severity in them. Conclusions: Augmented activation status of certain cell types along with potentiated pSTAT1 Y701 signaling and reduced pSTAT3 Y705 and pSTAT5 Y694 induction may predispose pSS patients, especially the SSA+ subgroup, to upregulated expression of IFN-induced genes and production of autoantibodies. These patients may benefit from therapies targeting these pathways.publishedVersio

Advocacy in the tail: Exploring the implications of ‘climategate’ for science journalism and public debate in the digital age

This paper explores the evolving practices of science journalism and public debate in the digital age. The vehicle for this study is the release of digitally stored email correspondence, data and documents from the Climatic Research Unit at the University of East Anglia in the weeks immediately prior to the United Nations Copenhagen Summit (COP-15) in December 2009. Described using the journalistic shorthand of ‘climategate’, and initially promoted through socio-technical networks of bloggers, this episode became a global news story and the subject of several formal reviews. ‘Climategate’ illustrates that media literate critics of anthropogenic explanations of climate change used digital tools to support their cause, making visible selected, newsworthy aspects of scientific information and the practices of scientists. In conclusion, I argue that ‘climategate’ may have profound implications for the production and distribution of science news, and how climate science is represented and debated in the digitally-mediated public sphere

LLAMA : stellar populations in the nuclei of ultra-hard X-ray-selected AGN and matched inactive galaxies

The relation between nuclear (.50 pc) star formation and nuclear galactic activity is still elusive; theoretical models predict a link between the two, but it is unclear whether active galactic nuclei (AGNs) should appear at the same time, before, or after nuclear star formation activity. We present a study of this relation in a complete, volume-limited sample of nine of the most luminous (log L14−195 keV > 1042.5 erg s−1 ) local AGNs (the LLAMA sample), including a sample of 18 inactive control galaxies (six star-forming; 12 passive) that are matched by Hubble type, stellar mass (9.5 . log M?/M . 10.5), inclination, and distance. This allows us to calibrate our methods on the control sample and perform a differential analysis between the AGN and control samples. We performed stellar population synthesis on VLT/X-shooter spectra in an aperture corresponding to a physical radius of ≈150 pc. We find young (.30 Myr) stellar populations in seven out of nine AGNs and in four out of six star-forming control galaxies. In the non-star-forming control population, in contrast, only two out of 12 galaxies show such a population. We further show that these young populations are not indicative of ongoing star formation, providing evidence for models that see AGN activity as a consequence of nuclear star formation. Based on the similar nuclear star formation histories of AGNs and star-forming control galaxies, we speculate that the latter may turn into the former for some fraction of their time. Under this assumption, and making use of the volume completeness of our sample, we infer that the AGN phase lasts for about 5% of the nuclear starburst phase

Clinical quantification of the integrin αvβ6 by [18F]FB-A20FMDV2 positron emission tomography in healthy and fibrotic human lung (PETAL Study)

© 2019, The Author(s). Purpose: The RGD-integrin, αvβ6, plays a role in the pathogenesis of pulmonary fibrosis through activation of transforming growth factor beta (TGFβ). This study sought to quantify expression of αvβ6 in the lungs of healthy humans and subjects with pulmonary fibrosis using the αvβ6-selective [18F]FB-A20FMDV2 PET ligand. Methods: [18F]FB-A20FMDV2 PET/CT scans were performed in healthy subjects and those with fibrotic lung disease. Standard uptake values (SUV) and volume of distribution (VT) were used to quantify αvβ6 expression. In subjects with fibrotic lung disease, qualitative assessment of the relationship between αvβ6 expression and the distribution of fibrosis on high resolution computed tomography was conducted. Results: A total of 15 participants (6 healthy, 7 with idiopathic pulmonary fibrosis (IPF) and 2 with connective tissue disease (CTD) associated PF) were enrolled. VT and SUV of [18F]FB-A20FMDV2 were increased in the lungs of subjects with pulmonary fibrosis (PF) compared with healthy subjects. Geometric mean VT (95% CI) was 0.88 (0.60, 1.29) mL/cm3 for healthy subjects, and 1.40 (1.22, 1.61) mL/cm3 for subjects with IPF; and SUV was 0.54 (0.36, 0.81) g/mL for healthy subjects and 1.03 (0.86, 1.22) g/mL for subjects with IPF. The IPF/healthy VT ratio (geometric mean, (95% CI of ratio)) was 1.59 (1.09, 2.32) (probability ratio > 1 = 0.988)) and the SUV ratio was 1.91 (1.27, 2.87) (probability ratio > 1 = 0.996). Increased uptake of [18F]FB-A20FMDV2 in PF was predominantly confined to fibrotic areas. [18F]FB-A20FMDV2 measurements were reproducible at an interval of 2 weeks. [18F]FB-A20FMDV2 was safe and well tolerated. Conclusions: Lung uptake of [18F]FB-A20FMDV2, a measure of expression of the integrin αvβ6, was markedly increased in subjects with PF compared with healthy subjects

Observational constraints on the stellar recycled gas in active galactic nuclei feeding

Near-infrared long-slit spectroscopy has been used to study the stellar population (SP) of the low luminosity active galactic nuclei (AGNs) and matched analogues (LLAMA) sample. To perform the SP fits we have employed the X-shooter simple stellar population models together with the STARLIGHT code. Our main conclusions are: The star formation history of the AGNs is very complex, presenting many episodes of star formation during their lifetimes. In general, AGN hosts have higher fractions of intermediate-age SP (light-weighted mean ages, L ≲ 4.5 Gyr) when compared with their analogues ( L ≲ 8.0 Gyr). AGNs are more affected by reddening and require significant fractions of featureless continuum and hot dust components. The ratio between the AGN radiated energy and the gravitational potential energy of the molecular gas (ERad/EPG) for the AGN is compared with the L and a possible anticorrelation is observed. This suggests that the AGN is affecting the star formation in these galaxies, in the sense that more energetic AGN [log(ERad/EPG) ≳ 3] tend to host nuclear younger SP ( L ≲4 Gyr). We found that the recent (t <2 Gyr) returned (recycled) stellar mass is higher in AGN than in the controls. We also provide evidence that the mass-loss of stars would be enough to feed the AGN, thus providing observational constraints for models that predict that AGN feeding is partially due to the recycled gas from dying stars

MYBA From Blueberry (Vaccinium Section Cyanococcus) Is a Subgroup 6 Type R2R3MYB Transcription Factor That Activates Anthocyanin Production

The Vaccinium genus in the family Ericaceae comprises many species, including the fruit-bearing blueberry, bilberry, cranberry, huckleberry, and lingonberry. Commercially, the most important are the blueberries (Vaccinium section Cyanococcus), such as Vaccinium corymbosum (northern highbush blueberry), Vaccinium virgatum (rabbiteye blueberry), and Vaccinium angustifolium (lowbush blueberry). The rising popularity of blueberries can partly be attributed to their “superfood” status, with an increasing body of evidence around human health benefits resulting from the fruit metabolites, particularly products of the phenylpropanoid pathway such as anthocyanins. Activation of anthocyanin production by R2R3-MYB transcription factors (TFs) has been characterized in many species, but despite recent studies on blueberry, cranberry, and bilberry, no MYB anthocyanin regulators have been reported for Vaccinium. Indeed, there has been conjecture that at least in bilberry, MYB TFs divergent to the usual type are involved. We report identification of MYBA from blueberry, and show through sequence analysis and functional studies that it is homologous to known anthocyanin-promoting R2R3-MYBs of subgroup 6 of the MYB superfamily. In transient assays, MYBA complemented an anthocyanin MYB mutant of Antirrhinum majus and, together with a heterologous bHLH anthocyanin regulator, activated anthocyanin production in Nicotiana benthamiana. Furthermore anthocyanin accumulation and anthocyanin structural gene expression (assayed by qPCR and RNA-seq analyses) correlated with MYBA expression, and MYBA was able to transactivate the DFR promoter from blueberry and other species. The RNA-seq data also revealed a range of other candidate genes involved in the regulation of anthocyanin production in blueberry fruit. The identification of MYBA will help to resolve the regulatory mechanism for anthocyanin pigmentation in the Vaccinium genus. The sequence information should also prove useful in developing tools for the accelerated breeding of new Vaccinium cultivars

Crop Updates 2010 - Genetically Modified Crops, Nutrition and Soils

GENETICALLY MODIFIED CROPS 1. Evaluation of the environmental and economic impact of Roundup Ready® canola in the Western Australian crop production system, James Fisher and Désirée Futures, York, Western Australia, Peter Tozer, PRT Consulting, Armidale NSW 2. Controlling wild radish (Raphanus raphanistrum) in Roundup Ready®1 Canola: Outcomes from the Nufarm 2009 Roundup Ready small plot trial Program, Mike Jackson, Nufarm Australia Limited 3. Weed strategies for glyphosate tolerant crops, John Moore, Department of Agriculture and Food 4. Results of the 2009 Western Australia Roundup Ready® canola trials, Dr James Neilsen, Canola Systems Specialist, Monsanto Australia NUTRITION 5. Modelling P runoff losses from agricultural systems, Geoff Anderson1, Wen Chen1, 2, Richard Bell2 and Ross Brennan1, 1Department of Agriculture and Food, 2School of Environmental Science, Murdoch University 6. Evaluation of deep banded biochars or biochar-mineral complex for increasing wheat yield or replacing fertiliser, Paul Blackwell, Allan Herbert and Stephen Davies, Department of Agriculture and Food 7. Improving fertiliser management: Redefining soil test-crop response relationships for canola in Western Australia, Wen Chen1, 2, Ross Brennan2, Richard Bell1, Mike Bolland2 and Geoff Anderson2, 1School of Environmental Science, Murdoch University, 2Department of Agriculture and Food 8. Phosphorus placement for wheat and lupins in WA cropping systems, 1School of Environmental Science, Murdoch University, 2Department of Agriculture and Food 9. The benefits of fertilising pastures for following crops, James Easton, Ryan Guthrie and Rowan Maddern, CSBP 10. Good nutrition produces high quality wheat in the high rainfall zone of Western Australia, Darren Hughes, Adveco Fertilisers; Wagga Wagga, Robert Belford, Curtin University of Technology, Wal Anderson, Department of Agriculture and Food, and Ian Edwards, Edstar Genetics, Perth 11. Lime to get maximum benefit from soil phosphorus, Reg Lunt and Bill Bowden, Department of Agriculture and Food 12. Variable rate top up N – Is it worth the trouble? Nigel Metz, South East Premium Wheat Growers Association (SEPWA) SOILS 13. Impact of soil inversion, soil dilution and claying on non-wetting sandplain soils, Stephen Davies, Peter Newman and Breanne Best, Department of Agriculture and Food 14. Long term effects of lime application on soil p, crop yields and annual ryegrass competition, Chris Gazey, Department of Agriculture and Food, Joel Andrew, Precision SoilTech, Belmont, Western Australi