The Behaviour of Both Listeria monocytogenes and Rat Ciliated Ependymal Cells Is Altered during Their Co-Culture

Ciliated ependymal cells line the cerebral ventricles and aqueducts separating the infected CSF from the brain parenchyma in meningitis

Genome-wide imputation identifies novel associations and localises signals in idiopathic inflammatory myopathies.

OBJECTIVES The idiopathic inflammatory myopathies (IIM) are heterogeneous diseases, thought to be initiated by immune activation in genetically predisposed individuals. In this study we imputed variants from the Immunochip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS We analysed 2,565 Caucasian IIM samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically-matched controls. We imputed 1,648,116 variants from the Immunochip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM, and clinical and serological subgroups. RESULTS The human leukocyte antigen (HLA) locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, three in the whole IIM cohort (SDK2 and LINC00924 - both novel, and STAT4), with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM, for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSIONS We report novel and strong associations in IIM and PM, and localise signals to single genes and immune cell types. This article is protected by copyright. All rights reserved

Identification of Novel Associations and Localization of Signals in Idiopathic Inflammatory Myopathies Using Genome-Wide Imputation

OBJECTIVES: The idiopathic inflammatory myopathies (IIM) are heterogeneous diseases, thought to be initiated by immune activation in genetically predisposed individuals. In this study we imputed variants from the Immunochip array using a large reference panel to fine-map associations and identify novel associations in IIM. METHODS: We analysed 2,565 Caucasian IIM samples collected through the Myositis Genetics Consortium (MYOGEN) and 10,260 ethnically-matched controls. We imputed 1,648,116 variants from the Immunochip array using the Haplotype Reference Consortium panel and conducted association analysis on IIM, and clinical and serological subgroups. RESULTS: The human leukocyte antigen (HLA) locus was consistently the most significantly associated region. Four non-HLA regions reached genome-wide significance, three in the whole IIM cohort (SDK2 and LINC00924 - both novel, and STAT4), with evidence of independent variants in STAT4, and NAB1 in the polymyositis (PM) subgroup. We also found suggestive evidence of association with loci previously associated with other autoimmune rheumatic diseases (TEC and LTBR). We identified more significant associations than those previously reported in IIM, for STAT4 and DGKQ in the total cohort, for NAB1 and FAM167A-BLK loci in PM, and CCR5 in inclusion body myositis. We found enrichment of variants among DNase I hypersensitivity sites and histone marks associated with active transcription within blood cells. CONCLUSIONS: We report novel and strong associations in IIM and PM, and localise signals to single genes and immune cell types

Prostaglandin E2 stimulates Fas ligand expression via the EP1 receptor in colon cancer cells

Fas ligand (FasL/CD95L) is a member of the tumour necrosis factor superfamily that triggers apoptosis following crosslinking of the Fas receptor. Despite studies strongly implicating tumour-expressed FasL as a major inhibitor of the anti-tumour immune response, little is known about the mechanisms that regulate FasL expression in tumours. In this study, we show that the cyclooxygenase (COX) signalling pathway, and in particular prostaglandin E2 (PGE2), plays a role in the upregulation of FasL expression in colon cancer. Suppression of either COX-2 or COX-1 by RNA interference in HCA-7 and HT29 colon tumour cells reduced FasL expression at both the mRNA and protein level. Conversely, stimulation with PGE2 increased FasL expression and these cells showed increased cytotoxicity against Fas-sensitive Jurkat T cells. Prostaglandin E2-induced FasL expression was mediated by signalling via the EP1 receptor. Moreover, immunohistochemical analysis using serial sections of human colon adenocarcinomas revealed a strong positive correlation between COX-2 and FasL (r=0.722; P<0.0001) expression, and between EP1 receptor and FasL (r=0.740; P<0.0001) expression, in the tumour cells. Thus, these findings indicate that PGE2 positively regulates FasL expression in colon tumour cells, adding another pro-neoplastic activity to PGE2

Do split and displacement sudden stratospheric warmings have different annular mode signatures?

Sudden stratospheric warmings (SSWs) contribute to intraseasonal tropospheric forecasting skill due to their surface impacts. Recent studies suggest these impacts depend upon whether the polar vortex splits or is displaced during the SSW. We analyse the annular mode signatures of SSWs in a 1000 year IPSL-CM5A-LR simulation. Although small differences in the mean surface Northern Annular Mode (NAM) index following splits and displacements are found, the sign is not consistent for two independent SSW algorithms, and over 50 events are required to distinguish the responses. We use the winter-time correlation between extratropical lower stratospheric wind anomalies and the surface NAM index as a metric for two-way stratosphere-troposphere coupling, and find that the differences between splits and displacements, and between classification methodologies, can be simply understood in terms of their mean stratospheric wind anomalies. Predictability studies should therefore focus on understanding the factors that determine the persistence of these anomalies following SSWs

Hyperhomocysteinemia is independently associated with albuminuria in the population-based CoLaus study

<p>Abstract</p> <p>Background</p> <p>Increased serum levels of homocysteine and uric acid have each been associated with cardiovascular risk. We analyzed whether homocysteine and uric acid were associated with glomerular filtration rate (GFR) and albuminuria independently of each other. We also investigated the association of <it>MTHFR </it>polymorphisms related to homocysteine with albuminuria to get further insight into causality.</p> <p>Methods</p> <p>This was a cross-sectional population-based study in Caucasians (<it>n </it>= 5913). Hyperhomocysteinemia was defined as total serum homocysteine ≥ 15 μmol/L. Albuminuria was defined as urinary albumin-to-creatinine ratio > 30 mg/g.</p> <p>Results</p> <p>Uric acid was associated positively with homocysteine (r = 0.246 in men and r = 0.287 in women, <it>P </it>< 0.001). The prevalence of albuminuria increased across increasing homocysteine categories (from 6.4% to 17.3% in subjects with normal GFR and from 3.5% to 14.5% in those with reduced GFR, <it>P </it>for trend < 0.005). Hyperhomocysteinemia (OR = 2.22, 95% confidence interval: 1.60-3.08, <it>P </it>< 0.001) and elevated serum uric acid (OR = 1.27, 1.08-1.50, per 100 μmol/L, <it>P </it>= 0.004) were significantly associated with albuminuria, independently of hypertension and type 2 diabetes. The 2-fold higher risk of albuminuria associated with hyperhomocysteinemia was similar to the risk associated with hypertension or diabetes. <it>MTHFR </it>alleles related to higher homocysteine were associated with increased risk of albuminuria.</p> <p>Conclusions</p> <p>In the general adult population, elevated serum homocysteine and uric acid were associated with albuminuria independently of each other and of renal function.</p

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

Objectives: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. Methods: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. Results: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9x10(-5). Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28x10(-53) and HLA-DRB1*03:01, p=3.25x10(-9)), anti-PM/Scl (HLA-DQB1*02:01, p=1.47x10(-26)) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40x10(-11)). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92x10(-13)) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09x10(-6)). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47x10(-64)) and position 9 of HLA-B (p=7.03x10(-11)). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. Conclusions: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research

ENIGMA-Sleep:Challenges, opportunities, and the road map

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine