Induction of high-affinity IgE receptor on lung dendritic cells during viral infection leads to mucous cell metaplasia

Respiratory viral infections are associated with an increased risk of asthma, but how acute Th1 antiviral immune responses lead to chronic inflammatory Th2 disease remains undefined. We define a novel pathway that links transient viral infection to chronic lung disease with dendritic cell (DC) expression of the high-affinity IgE receptor (FcεRIα). In a mouse model of virus-induced chronic lung disease, in which Sendai virus triggered a switch to persistent mucous cell metaplasia and airway hyperreactivity after clearance of replicating virus, we found that FceRIa−/− mice no longer developed mucous cell metaplasia. Viral infection induced IgE-independent, type I IFN receptor–dependent expression of FcεRIα on mouse lung DCs. Cross-linking DC FcεRIα resulted in the production of the T cell chemoattractant CCL28. FceRIa−/− mice had decreased CCL28 and recruitment of IL-13–producing CD4+ T cells to the lung after viral infection. Transfer of wild-type DCs to FceRIa−/− mice restored these events, whereas blockade of CCL28 inhibited mucous cell metaplasia. Therefore, lung DC expression of FcεRIα is part of the antiviral response that recruits CD4+ T cells and drives mucous cell metaplasia, thus linking antiviral responses to allergic/asthmatic Th2 responses

Spatial overlaps between the global protected areas network and terrestrial hotspots of evolutionary diversity

AIM : A common approach for prioritizing conservation is to identify concentrations (hotspots) of biodiversity. Such hotspots have traditionally been designated on the basis of species‐level metrics (e.g., species richness, endemism and extinction vulnerability). These approaches do not consider phylogenetics explicitly, although phylogenetic relationships reflect the ecological, evolutionary and biogeographical processes by which biodiversity is generated, distributed and maintained. The aim of this study was to identify hotspots of phylogenetic diversity and compare these with hotspots based on species‐level metrics and with the existing protected areas network. LOCATION : Global. TIME PERIOD : Contemporary. MAJOR TAXA STUDIED : Terrestrial vertebrates (mammals, birds and amphibians) and angiosperms. METHODS : We used comprehensive phylogenies and distribution maps of terrestrial birds, mammals, amphibians and angiosperms to identify areas with high concentrations of phylogenetic diversity, phylogenetic endemism, and evolutionary distinctiveness and global endangerment. We compared the locations of these areas with those included within the current network of protected areas and concentrations of species‐level indices: species richness, species endemism and species threat. RESULTS : We found spatial incongruence among the three evolutionary diversity metrics in each taxonomic group. Spatial patterns of diversity and endemism also differed among taxonomic groups, with some differences between vertebrates and angiosperms. Complementarity analyses of phylogenetic diversity identified the minimal area that encapsulates the full branch lengths for each taxonomic group. The current network of protected areas and species‐level hotspots largely does not overlap with areas of high phylodiversity. MAIN CONCLUSION : Overall, < 10% of hotspot areas were designated as protected areas. Patterns of diversity, endemism and vulnerability differ among taxonomic groups.http://wileyonlinelibrary.com/journal/geb2020-06-01hj2019Plant Production and Soil ScienceZoology and Entomolog

The GATA1s isoform is normally down-regulated during terminal haematopoietic differentiation and over-expression leads to failure to repress MYB, CCND2 and SKI during erythroid differentiation of K562 cells

Background: Although GATA1 is one of the most extensively studied haematopoietic transcription factors little is currently known about the physiological functions of its naturally occurring isoforms GATA1s and GATA1FL in humans—particularly whether the isoforms have distinct roles in different lineages and whether they have non-redundant roles in haematopoietic differentiation. As well as being of general interest to understanding of haematopoiesis, GATA1 isoform biology is important for children with Down syndrome associated acute megakaryoblastic leukaemia (DS-AMKL) where GATA1FL mutations are an essential driver for disease pathogenesis. &lt;p/&gt;Methods: Human primary cells and cell lines were analyzed using GATA1 isoform specific PCR. K562 cells expressing GATA1s or GATA1FL transgenes were used to model the effects of the two isoforms on in vitro haematopoietic differentiation. &lt;p/&gt;Results: We found no evidence for lineage specific use of GATA1 isoforms; however GATA1s transcripts, but not GATA1FL transcripts, are down-regulated during in vitro induction of terminal megakaryocytic and erythroid differentiation in the cell line K562. In addition, transgenic K562-GATA1s and K562-GATA1FL cells have distinct gene expression profiles both in steady state and during terminal erythroid differentiation, with GATA1s expression characterised by lack of repression of MYB, CCND2 and SKI. &lt;p/&gt;Conclusions: These findings support the theory that the GATA1s isoform plays a role in the maintenance of proliferative multipotent megakaryocyte-erythroid precursor cells and must be down-regulated prior to terminal differentiation. In addition our data suggest that SKI may be a potential therapeutic target for the treatment of children with DS-AMKL

Circulating pancreatic polypeptide concentrations predict visceral and liver fat content

CONTEXT AND OBJECTIVE: No current biomarker can reliably predict visceral and liver fat content, both of which are risk factors for cardiovascular disease. Vagal tone has been suggested to influence regional fat deposition. Pancreatic polypeptide (PP) is secreted from the endocrine pancreas under vagal control. We investigated the utility of PP in predicting visceral and liver fat. PATIENTS AND METHODS: Fasting plasma PP concentrations were measured in 104 overweight and obese subjects (46 men and 58 women). In the same subjects, total and regional adipose tissue, including total visceral adipose tissue (VAT) and total subcutaneous adipose tissue (TSAT), were measured using whole-body magnetic resonance imaging. Intrahepatocellular lipid content (IHCL) was quantified by proton magnetic resonance spectroscopy. RESULTS: Fasting plasma PP concentrations positively and significantly correlated with both VAT (r = 0.57, P < .001) and IHCL (r = 0.51, P < .001), but not with TSAT (r = 0.02, P = .88). Fasting PP concentrations independently predicted VAT after controlling for age and sex. Fasting PP concentrations independently predicted IHCL after controlling for age, sex, body mass index (BMI), waist-to-hip ratio, homeostatic model assessment 2-insulin resistance, (HOMA2-IR) and serum concentrations of triglyceride (TG), total cholesterol (TC), and alanine aminotransferase (ALT). Fasting PP concentrations were associated with serum ALT, TG, TC, low- and high-density lipoprotein cholesterol, and blood pressure (P < .05). These associations were mediated by IHCL and/or VAT. Fasting PP and HOMA2-IR were independently significantly associated with hepatic steatosis (P < .01). CONCLUSIONS: Pancreatic polypeptide is a novel predictor of visceral and liver fat content, and thus a potential biomarker for cardiovascular risk stratification and targeted treatment of patients with ectopic fat deposition

The Second Transmembrane Domain of P2X7 Contributes to Dilated Pore Formation

Activation of the purinergic receptor P2X7 leads to the cellular permeability of low molecular weight cations. To determine which domains of P2X7 are necessary for this permeability, we exchanged either the C-terminus or portions of the second transmembrane domain (TM2) with those in P2X1 or P2X4. Replacement of the C-terminus of P2X7 with either P2X1 or P2X4 prevented surface expression of the chimeric receptor. Similarly, chimeric P2X7 containing TM2 from P2X1 or P2X4 had reduced surface expression and no permeability to cationic dyes. Exchanging the N-terminal 10 residues or C-terminal 14 residues of the P2X7 TM2 with the corresponding region of P2X1 TM2 partially restored surface expression and limited pore permeability. To further probe TM2 structure, we replaced single residues in P2X7 TM2 with those in P2X1 or P2X4. We identified multiple substitutions that drastically changed pore permeability without altering surface expression. Three substitutions (Q332P, Y336T, and Y343L) individually reduced pore formation as indicated by decreased dye uptake and also reduced membrane blebbing in response to ATP exposure. Three others substitutions, V335T, S342G, and S342A each enhanced dye uptake, membrane blebbing and cell death. Our results demonstrate a critical role for the TM2 domain of P2X7 in receptor function, and provide a structural basis for differences between purinergic receptors. © 2013 Sun et al

Invasive species differ in key functional traits from native and non‐invasive alien plant species

QUESTIONS : Invasive species establish either by possessing traits, or trait trade‐offs similar to native species, suggesting pre‐adaptation to local conditions; or by having a different suite of traits and trait trade‐offs, which allow them to occupy unfilled niches. The trait differences between invasives and non‐invasives can inform on which traits confer invasibility. Here, we ask: (a) are invasive species functionally different or similar to native species? (b) which traits of invasives differ from traits of non‐invasive aliens and thus confer invasibility? and (c) do results from the sub‐Antarctic region, where this study was conducted, differ from findings from other regions? LOCATION : Sub‐Antarctic Marion Island. METHODS : We measured 13 traits of all terrestrial native, invasive and non‐invasive alien plant species. Using principal components analysis and phylogenetic generalized least‐squares models, we tested for differences in traits between invasive (widespread alien species) and native species. Bivariate trait relationships between invasive and native species were compared using standardized major axis regressions to test for differences in trait trade‐offs between the two groups. Second, using the same methods, we compared the traits of invasive species to non‐invasive aliens (alien species that have not spread). RESULTS : Between invasive and native species, most traits differed, suggesting that the success of invasive species is mediated by being functionally different to native species. Additionally, most bivariate trait relationships differed either in terms of their y‐intercept or their position on the axes, highlighting that plants are positioned differently along a spectrum of shared trait trade‐offs. Compared to non‐invasive aliens, invasive species had lower plant height, smaller leaf area, lower frost tolerance, and higher specific leaf area, suggesting that these traits are associated with invasiveness. The findings for the sub‐Antarctic corresponded to those of other regions, except lower plant height which provides a competitive advantage to invaders in the windy sub‐Antarctic context. CONCLUSION : Our findings support the expectation that trait complexes of invasive species are predominantly different to those of coexisting native species, and that high resource acquisition and low defence investment are characteristic of invasive plant species.Supplementary information : Raw data, tables and figures of results from trait comparisons between native, invasive and non‐invasive alien species of Marion Island Appendix S1. A list of all vascular plants surveyed on Marion Island Appendix S2. Residence time of alien vascular plants species on Marion Island Appendix S3. Map of Marion Island and sampling localities Appendix S4. Terrestrial habitats of Marion Island Appendix S5. Sampling design Appendix S6. Sampling data Appendix S7. Trait data Appendix S8. Literature sources Appendix S9. Trait data from literature sources Appendix S10. Descriptions of traits used Appendix S11. Trait processing Appendix S12. Multivariate analysis (principal component analysis) Appendix S13. Phylogenetic tree of all study species Appendix S14. Univariate analysis (phylogenetic generalized least‐squares models) Appendix S15. Trait data of vascular plant species common in the coastal areas of Marion Island Appendix S16. Bivariate trait analysis (standardized major axis) Appendix S17. Ordination of invasive and non‐invasive vascular plant species Appendix S18. Trait differences between native and invasive species common in the coastal areas of Marion Island Appendix S19. Results of standardized major axis regression analysis for vascular plant species on Marion IslandThe South African National Research Foundationhttp://wileyonlinelibrary.com/journal/jvs2020-09-01hj2019Plant Production and Soil Scienc

Hsp90 orchestrates transcriptional regulation by Hsf1 and cell wall remodelling by MAPK signalling during thermal adaptation in a pathogenic yeast

Acknowledgments We thank Rebecca Shapiro for creating CaLC1819, CaLC1855 and CaLC1875, Gillian Milne for help with EM, Aaron Mitchell for generously providing the transposon insertion mutant library, Jesus Pla for generously providing the hog1 hst7 mutant, and Cathy Collins for technical assistance.Peer reviewedPublisher PD

Modulation of enhancer looping and differential gene targeting by Epstein-Barr virus transcription factors directs cellular reprogramming

Epstein-Barr virus (EBV) epigenetically reprogrammes B-lymphocytes to drive immortalization and facilitate viral persistence. Host-cell transcription is perturbed principally through the actions of EBV EBNA 2, 3A, 3B and 3C, with cellular genes deregulated by specific combinations of these EBNAs through unknown mechanisms. Comparing human genome binding by these viral transcription factors, we discovered that 25% of binding sites were shared by EBNA 2 and the EBNA 3s and were located predominantly in enhancers. Moreover, 80% of potential EBNA 3A, 3B or 3C target genes were also targeted by EBNA 2, implicating extensive interplay between EBNA 2 and 3 proteins in cellular reprogramming. Investigating shared enhancer sites neighbouring two new targets (WEE1 and CTBP2) we discovered that EBNA 3 proteins repress transcription by modulating enhancer-promoter loop formation to establish repressive chromatin hubs or prevent assembly of active hubs. Re-ChIP analysis revealed that EBNA 2 and 3 proteins do not bind simultaneously at shared sites but compete for binding thereby modulating enhancer-promoter interactions. At an EBNA 3-only intergenic enhancer site between ADAM28 and ADAMDEC1 EBNA 3C was also able to independently direct epigenetic repression of both genes through enhancer-promoter looping. Significantly, studying shared or unique EBNA 3 binding sites at WEE1, CTBP2, ITGAL (LFA-1 alpha chain), BCL2L11 (Bim) and the ADAMs, we also discovered that different sets of EBNA 3 proteins bind regulatory elements in a gene and cell-type specific manner. Binding profiles correlated with the effects of individual EBNA 3 proteins on the expression of these genes, providing a molecular basis for the targeting of different sets of cellular genes by the EBNA 3s. Our results therefore highlight the influence of the genomic and cellular context in determining the specificity of gene deregulation by EBV and provide a paradigm for host-cell reprogramming through modulation of enhancer-promoter interactions by viral transcription factors

Characteristics and outcome of infants with candiduria in neonatal intensive care - a Paediatric Investigators Collaborative Network on Infections in Canada (PICNIC) study

<p>Abstract</p> <p>Background</p> <p>There is limited information in the literature on the presentation and prognosis of candidal urinary tract infection (UTI) in infants in the neonatal intensive care unit (NICU).</p> <p>Methods</p> <p>This was a prospective cohort study performed in 13 Canadian NICUs. Infants with candidal UTI without extra-renal candidal infection at presentation were enrolled.</p> <p>Results</p> <p>Thirty infants fit the study criteria. Median birth weight and gestational age were 2595 grams (range 575-4255) and 35 weeks (range 24-41) with 10 infants being < 30 weeks gestation. The most common primary underlying diagnosis was congenital heart disease (n = 10). The median age at initial diagnosis was 16 days (range 6-84 days). Renal ultrasonography findings were compatible with possible fungal disease in 15 of the 26 infants (58%) in whom it was performed. Treatment was variable, but fluconazole and either amphotericin B deoxycholate or lipid-based amphotericin B in combination or sequentially were used most frequently. Extra-renal candidiasis subsequently developed in 4 infants. In 2 of these 4 infants, dissemination happened during prolonged courses of anti-fungal therapy. Three of 9 deaths were considered to be related to candidal infection. No recurrences of candiduria or episodes of invasive candidiasis following treatment were documented.</p> <p>Conclusion</p> <p>Candidal UTI in the NICU population occurs both in term infants with congenital abnormalities and in preterm infants, and is associated with renal parenchymal disease and extra-renal dissemination. A wide variation in clinical approach was documented in this multicenter study. The overall mortality rate in these infants was significant (30%). In one third of the deaths, <it>Candida </it>infection was deemed to be a contributing factor, suggesting the need for antifungal therapy with repeat evaluation for dissemination in infants who are slow to respond to therapy.</p

Increased incidence of glucose disorders during pregnancy is not explained by pre-pregnancy obesity in London, Canada

<p>Abstract</p> <p>Background</p> <p>The increasing incidence of impaired glucose tolerance (IGT), gestational diabetes (GDM) and type 2 diabetes (T2D) during pregnancy was hypothesized to be associated with increases in pre-pregnancy body mass index (BMI). The aims were to 1) determine the prevalence of IGT/GDM/T2 D over a 10 year period; 2) examine the relationship between maternal overweight/obesity and IGT/GDM/T2D; and 3) examine the extent to which maternal metabolic complications impact maternal and fetal pregnancy outcomes.</p> <p>Methods</p> <p>Data arose from a perinatal database which contains maternal characteristics and perinatal outcome for all singleton infants born in London, Canada between January 1, 2000 and December 31, 2009. Univariable and multivariable odds ratios (OR) were estimated using logistic regression with IGT/GDM/T2 D being the outcome of interest.</p> <p>Results</p> <p>A total of 36,597 women were included in the analyses. Population incidence of IGT, GDM and T2 D rose from 0.7%, 2.9% and 0.5% in 2000 to 1.2%, 4.2% and 0.9% in 2009. The univariable OR for IGT, GDM and T2 D were 1.65, 1.52 and 2.06, respectively, over the ten year period. After controlling for maternal age, parity and pre-pregnancy BMI the OR did not decrease. Although there was a positive relationship between pre-pregnancy BMI and prevalence of IGT/GDM/T2 D, this did not explain the time trends in the latter. Diagnosis of IGT/GDM/T2 D increased the risk of having an Apgar score <7 at 5 minutes, which was partially explained by gestational hypertension, high placental ratio, gestational age and large for gestational age babies.</p> <p>Conclusions</p> <p>We found a significant increase in the incidence of IGT/GDM/T2 D for the decade between 2000-2009 which was not explained by rising prevalence of maternal overweight/obesity.</p