Passive monitoring of anisotropy change associated with the Parkfield 2004 earthquake

International audienceWe investigate temporal variations in the polarization of surface waves determined using ambient seismic noise cross-correlations between station pairs at the time of the Mw 6.0 Parkfield earthquake of September 28, 2004. We use data recorded by the High Resolution Seismic Network's 3-component seismometers located along the San Andreas Fault. Our results show strong variations in azimuthal surface wave polarizations, Psi, for the paths containing station VARB, one of the closest stations to the San Andreas Fault, synchronous with the Parkfield earthquake. Concerning the other station pair, only smooth temporal variations of Y are observed. Two principal contributions to these changes in Y are identified and separated. They are: (1) slow and weak variations due to seasonal changes in the incident direction of seismic noise; and (2) strong and rapid rotations synchronous with the Parkfield earthquake for paths containing station VARB. Strong shifts in Y are interpreted in terms of changes in crack-induced anisotropy due to the co-seismic rotation of the stress field. Because these changes are only observed on paths containing station VARB, the anisotropic layer responsible for the changes is most likely localized around VARB in the shallow crust. These results suggest that the polarization of surface waves may be very sensitive to changes in the orientations of distributed cracks and that implementation of our technique on a routine basis may prove useful for monitoring stress changes deep within seismogenic zones. Citation: Durand, S., J. P. Montagner, P. Roux, F. Brenguier, R. M. Nadeau, and Y. Ricard (2011), Passive monitoring of anisotropy change associated with the Parkfield 2004 earthquake, Geophys. Res. Lett., 38, L13303, doi: 10.1029/2011GL047875

On the relationship between residual zonal flows and bump-on tail saturated instabilities

A connection is established between two classical problems: the non linear saturation of a bump-on tail instability in collisionless regime, and the decay of a zonal flow towards a finite amplitude residual. Reasons for this connection are given and commented

Synergetic effects of collisions, turbulence and sawtooth crashes on impurity transport

This paper investigates the interplay of neoclassical, turbulent and MHD processes, which are simultaneously at play when contributing to impurity transport. It is shown that these contributions are not additive, as assumed sometimes. The interaction between turbulence and neoclassical effects leads to less effective thermal screening, i.e. lowers the outward flux due to temperature gradient. This behavior is attributed to poloidal asymmetries of the flow driven by turbulence. Moreover sawtooth crashes play an important role to determine fluxes across the q = 1 surface. It is found that the density profile of a heavy impurity differs significantly in sawtoothing plasmas from the one predicted by neoclassical theory when neglecting MHD events. Sawtooth crashes impede impurity accumulation, but also weaken the impurity outflux due to the temperature gradient when the latter is dominant

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

Large-scale analyses of common and rare variants identify 12 new loci associated with atrial fibrillation

Atrial fibrillation affects more than 33 million people worldwide and increases the risk of stroke, heart failure, and death. Fourteen genetic loci have been associated with atrial fibrillation in European and Asian ancestry groups. To further define the genetic basis of atrial fibrillation, we performed large-scale, trans-ancestry meta-analyses of common and rare variant association studies. The genome-wide association studies (GWAS) included 17,931 individuals with atrial fibrillation and 115,142 referents; the exome-wide association studies (ExWAS) and rare variant association studies (RVAS) involved 22,346 cases and 132,086 referents. We identified 12 new genetic loci that exceeded genome-wide significance, implicating genes involved in cardiac electrical and structural remodeling. Our results nearly double the number of known genetic loci for atrial fibrillation, provide insights into the molecular basis of atrial fibrillation, and may facilitate the identification of new potential targets for drug discovery

Discovery of novel heart rate-associated loci using the Exome Chip

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses. Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods. We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants. Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies

The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies

Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)- production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN- remains unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN- in AGS, and confirmed neurotoxicity of intracerebral IFN- using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN- activated IFNAR signaling within cerebral endothelial cells, caused a distinctive cerebral small vessel disease similarly observed in individuals with AGS. MRI and single-molecule ELISA revealed that central and not peripheral IFN- was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped development of diffuse brain disease and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN- neurotoxicity in AGS, representing an accessible target for therapeutic intervention

Hereditary C1q deficiency is associated with type 1 interferon-pathway activation and a high risk of central nervous system inflammation

Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n=10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα

Hereditary C1q deficiency is associated with type 1 interferon-pathway activation and a high risk of central nervous system inflammation

Hereditary C1q deficiency (C1QDef) is a rare monogenic disorder leading to defective complement pathway activation and systemic lupus erythematosus (SLE)-like manifestations. The link between impairment of the complement cascade and autoimmunity remains incompletely understood. Here, we assessed type 1 interferon pathway activation in patients with C1QDef. Twelve patients with genetically confirmed C1QDef were recruited through an international collaboration. Clinical, biological and radiological data were collected retrospectively. The expression of a standardized panel of interferon stimulated genes (ISGs) in peripheral blood was measured, and the level of interferon alpha (IFNα) protein in cerebrospinal fluid (CSF) determined using SIMOA technology. Central nervous system (encompassing basal ganglia calcification, encephalitis, vasculitis, chronic pachymeningitis), mucocutaneous and renal involvement were present, respectively, in 10, 11 and 2 of 12 patients, and severe infections recorded in 2/12 patients. Elevated ISG expression was observed in all patients tested (n=10/10), and serum and CSF IFNα elevated in 2/2 patients. Three patients were treated with Janus-kinase inhibitors (JAKi), with variable outcome; one displaying an apparently favourable response in respect of cutaneous and neurological features, and two others experiencing persistent disease despite JAKi therapy. To our knowledge, we report the largest original series of genetically confirmed C1QDef yet described. Additionally, we present a review of all previously described genetically confirmed cases of C1QDef. Overall, individuals with C1QDef demonstrate many characteristics of recognized monogenic interferonopathies: particularly, cutaneous involvement (malar rash, acral vasculitic/papular rash, chilblains), SLE-like disease, basal ganglia calcification, increased expression of ISGs in peripheral blood, and elevated levels of CSF IFNα