Assessment of Type I Interferon Signaling in Pediatric Inflammatory Disease

International audiencePURPOSE: Increased type I interferon is considered relevant to the pathology of a number of monogenic and complex disorders spanning pediatric rheumatology, neurology, and dermatology. However, no test exists in routine clinical practice to identify enhanced interferon signaling, thus limiting the ability to diagnose and monitor treatment of these diseases. Here, we set out to investigate the use of an assay measuring the expression of a panel of interferon-stimulated genes (ISGs) in children affected by a range of inflammatory diseases. DESIGN, SETTING, AND PARTICIPANTS: A cohort study was conducted between 2011 and 2016 at the University of Manchester, UK, and the Institut Imagine, Paris, France. RNA PAXgene blood samples and clinical data were collected from controls and symptomatic patients with a genetically confirmed or clinically well-defined inflammatory phenotype. The expression of six ISGs was measured by quantitative polymerase chain reaction, and the median fold change was used to calculate an interferon score (IS) for each subject compared to a previously derived panel of 29 controls (where +2 SD of the control data, an IS of \textgreater2.466, is considered as abnormal). Results were correlated with genetic and clinical data. RESULTS: Nine hundred ninety-two samples were analyzed from 630 individuals comprising symptomatic patients across 24 inflammatory genotypes/phenotypes, unaffected heterozygous carriers, and controls. A consistent upregulation of ISG expression was seen in 13 monogenic conditions (455 samples, 265 patients; median IS 10.73, interquartile range (IQR) 5.90-18.41), juvenile systemic lupus erythematosus (78 samples, 55 patients; median IS 10.60, IQR 3.99-17.27), and juvenile dermatomyositis (101 samples, 59 patients; median IS 9.02, IQR 2.51-21.73) compared to controls (78 samples, 65 subjects; median IS 0.688, IQR 0.427-1.196), heterozygous mutation carriers (89 samples, 76 subjects; median IS 0.862, IQR 0.493-1.942), and individuals with non-molecularly defined autoinflammation (89 samples, 69 patients; median IS 1.07, IQR 0.491-3.74). CONCLUSIONS AND RELEVANCE: An assessment of six ISGs can be used to define a spectrum of inflammatory diseases related to enhanced type I interferon signaling. If future studies demonstrate that the IS is a reactive biomarker, this measure may prove useful both in the diagnosis and the assessment of treatment efficacy

Metal-insulator transition in vanadium dioxide nanobeams: probing sub-domain properties of strongly correlated materials

Many strongly correlated electronic materials, including high-temperature superconductors, colossal magnetoresistance and metal-insulator-transition (MIT) materials, are inhomogeneous on a microscopic scale as a result of domain structure or compositional variations. An important potential advantage of nanoscale samples is that they exhibit the homogeneous properties, which can differ greatly from those of the bulk. We demonstrate this principle using vanadium dioxide, which has domain structure associated with its dramatic MIT at 68 degrees C. Our studies of single-domain vanadium dioxide nanobeams reveal new aspects of this famous MIT, including supercooling of the metallic phase by 50 degrees C; an activation energy in the insulating phase consistent with the optical gap; and a connection between the transition and the equilibrium carrier density in the insulating phase. Our devices also provide a nanomechanical method of determining the transition temperature, enable measurements on individual metal-insulator interphase walls, and allow general investigations of a phase transition in quasi-one-dimensional geometry.Comment: 9 pages, 3 figures, original submitted in June 200

Theory of disk accretion onto supermassive black holes

Accretion onto supermassive black holes produces both the dramatic phenomena associated with active galactic nuclei and the underwhelming displays seen in the Galactic Center and most other nearby galaxies. I review selected aspects of the current theoretical understanding of black hole accretion, emphasizing the role of magnetohydrodynamic turbulence and gravitational instabilities in driving the actual accretion and the importance of the efficacy of cooling in determining the structure and observational appearance of the accretion flow. Ongoing investigations into the dynamics of the plunging region, the origin of variability in the accretion process, and the evolution of warped, twisted, or eccentric disks are summarized.Comment: Mostly introductory review, to appear in "Supermassive black holes in the distant Universe", ed. A.J. Barger, Kluwer Academic Publishers, in pres

Innate Immune Sensing of DNA

Discusses efforts to understand how DNA triggers immune responses

Co-Evolution of Primate SAMHD1 and Lentivirus Vpx Leads to the Loss of the vpx Gene in HIV-1 Ancestor

Cross-species transmission and adaptation of simian immunodeficiency viruses (SIVs) to humans have given rise to human immunodeficiency viruses (HIVs). HIV type 1 (HIV-1) and type 2 (HIV-2) were derived from SIVs that infected chimpanzee (SIVcpz) and sooty mangabey (SIVsm), respectively. The HIV-1 restriction factor SAMHD1 inhibits HIV-1 infection in human myeloid cells and can be counteracted by the Vpx protein of HIV-2 and the SIVsm lineage. However, HIV-1 and its ancestor SIVcpz do not encode a Vpx protein and HIV-1 has not evolved a mechanism to overcome SAMHD1-mediated restriction. Here we show that the co-evolution of primate SAMHD1 and lentivirus Vpx leads to the loss of the vpx gene in SIVcpz and HIV-1. We found evidence for positive selection of SAMHD1 in orangutan, gibbon, rhesus macaque, and marmoset, but not in human, chimpanzee and gorilla that are natural hosts of Vpx-negative HIV-1, SIVcpz and SIVgor, respectively, indicating that vpx drives the evolution of primate SAMHD1. Ancestral host state reconstruction and temporal dynamic analyses suggest that the most recent common ancestor of SIVrcm, SIVmnd, SIVcpz, SIVgor and HIV-1 was a SIV that had a vpx gene; however, the vpx gene of SIVcpz was lost approximately 3643 to 2969 years ago during the infection of chimpanzees. Thus, HIV-1 could not inherit the lost vpx gene from its ancestor SIVcpz. The lack of Vpx in HIV-1 results in restricted infection in myeloid cells that are important for antiviral immunity, which could contribute to the AIDS pandemic by escaping the immune responses

Environmentally induced changes in antioxidant phenolic compounds levels in wild plants

[EN] Different adverse environmental conditions cause oxidative stress in plants by generation of reactive oxygen species (ROS). Accordingly, a general response to abiotic stress is the activation of enzymatic and non-enzymatic antioxidant systems. Many phenolic compounds, especially flavonoids, are known antioxidants and efficient ROS scavengers in vitro, but their exact role in plant stress responses in nature is still under debate. The aim of our work is to investigate this role by correlating the degree of environmental stress with phenolic and flavonoid levels in stress-tolerant plants. Total phenolic and antioxidant flavonoid contents were determined in 19 wild species. Meteorological data and plant and soil samples were collected in three successive seasons from four Mediterranean ecosystems: salt marsh, dune, semiarid and gypsum habitats. Changes in phenolic and flavonoid levels were correlated with the environmental conditions of the plants and were found to depend on both the taxonomy and ecology of the investigated species. Despite species-specific differences, principal component analyses of the results established a positive correlation between plant phenolics and several environmental parameters, such as altitude, and those related to water stress: temperature, evapotranspiration, and soil water deficit. The correlation with salt stress was, however, very weak. The joint analysis of all the species showed the lowest phenolic and flavonoid levels in the halophytes from the salt marsh. This finding supports previous data indicating that the halophytes analysed here do not undergo oxidative stress in their natural habitat and therefore do not need to activate antioxidant systems as a defence against salinity.This work has been funded by the Spanish Ministry of Science and Innovation (Project CGL2008-00438/BOS), with contribution from the European Regional Development Fund. Thanks to Dr. Rafael Herrera for critical reading of the manuscript.Bautista, I.; Boscaiu, M.; Lidón, A.; Llinares Palacios, JV.; Lull, C.; Donat-Torres, MP.; Mayoral García-Berlanga, O.... (2016). Environmentally induced changes in antioxidant phenolic compounds levels in wild plants. Acta Physiologiae Plantarum. 38(1):1-15. https://doi.org/10.1007/s11738-015-2025-2S115381Agati G, Biricolti S, Guidi L, Ferrini F, Fini A, Tattini M (2011) The biosynthesis of flavonoids is enhanced similarly by UV radiation and root zone salinity in L. vulgare leaves. 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dSETDB1 and SU(VAR)3–9 Sequentially Function during Germline-Stem Cell Differentiation in Drosophila melanogaster

Germline-stem cells (GSCs) produce gametes and are thus true “immortal stem cells”. In Drosophila ovaries, GSCs divide asymmetrically to produce daughter GSCs and cystoblasts, and the latter differentiate into germline cysts. Here we show that the histone-lysine methyltransferase dSETDB1, located in pericentric heterochromatin, catalyzes H3-K9 trimethylation in GSCs and their immediate descendants. As germline cysts differentiate into egg chambers, the dSETDB1 function is gradually taken over by another H3-K9-specific methyltransferase, SU(VAR)3–9. Loss-of-function mutations in dsetdb1 or Su(var)3–9 abolish both H3K9me3 and heterochromatin protein-1 (HP1) signals from the anterior germarium and the developing egg chambers, respectively, and cause localization of H3K9me3 away from DNA-dense regions in most posterior germarium cells. These results indicate that dSETDB1 and SU(VAR)3–9 act together with distinct roles during oogenesis, with dsetdb1 being of particular importance due to its GSC-specific function and more severe mutant phenotype