The interaction of multiple sclerosis risk loci with Epstein-Barr virus phenotypes implicates the virus in pathogenesis

Translating the findings of genome wide association studies (GWAS) to new therapies requires identification of the relevant immunological contexts to interrogate for genetic effects. In one of the largest GWAS, more than 200 risk loci have been identified for Multiple Sclerosis (MS) susceptibility. Infection with Epstein-Barr virus (EBV) appears to be necessary for the development of Multiple Sclerosis (MS). Many MS risk loci are associated with altered gene expression in EBV infected B cells (LCLs). We have interrogated this immunological context to identify interaction between MS risk loci and EBV DNA copy number, intrinsic growth rate and EBV encoded miRNA expression. The EBV DNA copy number was associated with significantly more risk alleles for MS than for other diseases or traits. EBV miRNAs BART4-3p and BART3-5p were highly associated with EBV DNA copy number and MS risk loci. The poliovirus receptor (PVR) risk SNP was associated with EBV DNA copy number, PVR and miRNA expression. Targeting EBV miRNAs BART4-3p and BART3-5p, and the gene PVR, may provide therapeutic benefit in MS. This study also indicates how immunological context and risk loci interactions can be exploited to validate and develop novel therapeutic approaches. © 2020, The Author(s)

Transcribed B lymphocyte genes and multiple sclerosis risk genes are underrepresented in Epstein–Barr Virus hypomethylated regions

Epstein–Barr Virus (EBV) infection appears to be necessary for the development of Multiple Sclerosis (MS), although the specific mechanisms are unknown. More than 200 single-nucleotide polymorphisms (SNPs) are known to be associated with the risk of developing MS. About a quarter of these are also highly associated with proximal gene expression in B cells infected with EBV (lymphoblastoid cell lines—LCLs). The DNA of LCLs is hypomethylated compared with both uninfected and activated B cells. Since methylation can affect gene expression, and so cell differentiation and immune evasion, we hypothesised that EBV-driven hypomethylation may affect the interaction between EBV infection and MS. We interrogated an existing dataset comprising three individuals with whole-genome bisulfite sequencing data from EBV transformed B cells and CD40L-activated B cells. DNA methylation surrounding MS risk SNPs associated with gene expression in LCLs (LCLeQTL) was less likely to be hypomethylated than randomly selected chromosomal regions. Differential methylation was independent of genomic features such as promoter regions, but genes preferentially expressed in EBV-infected B cells, including the LCLeQTL genes, were underrepresented in the hypomethylated regions. Our data does not indicate MS genetic risk is affected by EBV hypomethylation

The interaction of human and Epstein–Barr virus miRNAs with Multiple Sclerosis risk loci

Although the causes of Multiple Sclerosis (MS) still remain largely unknown, multiple lines of evidence suggest that Epstein–Barr virus (EBV) infection may contribute to the development of MS. Here, we aimed to identify the potential contribution of EBV-encoded and host cellular miRNAs to MS pathogenesis. We identified differentially expressed host miRNAs in EBV infected B cells (LCLs) and putative host/EBV miRNA interactions with MS risk loci. We estimated the genotype effect of MS risk loci on the identified putative miRNA:mRNA interactions in silico. We found that the protective allele of MS risk SNP rs4808760 reduces the expression of hsa-mir-3188-3p. In addition, our analysis suggests that hsa-let-7b-5p may interact with ZC3HAV1 differently in LCLs compared to B cells. In vitro assays indicated that the protective allele of MS risk SNP rs10271373 increases ZC3HAV1 expression in LCLs, but not in B cells. The higher expression for the protective allele in LCLs is consistent with increased IFN response via ZC3HAV1 and so decreased immune evasion by EBV. Taken together, this provides evidence that EBV infection dysregulates the B cell miRNA machinery, including MS risk miRNAs, which may contribute to MS pathogenesis via interaction with MS risk genes either directly or indirectly

Ribosomal protein S6 mRNA is a biomarker upregulated in multiple sclerosis, downregulated by interferon treatment, and affected by season

Background

Aberrant Cell Cycle and Apoptotic Changes Characterise Severe Influenza A Infection – A Meta-Analysis of Genomic Signatures in Circulating Leukocytes

Influenza A infection is a global disease that has been responsible for four pandemics over the last one hundred years. However, it remains poorly understood as to why some infected individuals succumb to life threatening complications whilst others recover and are relatively unaffected. Using gene-expression analysis of circulating leukocytes, here we show that the progression towards severe influenza A infection is characterised by an abnormal transcriptional reprogramming of cell cycle and apoptosis pathways. In severely infected humans, leukocyte gene-expression profiles display opposing cell cycle activities; an increased aberrant DNA replication in the G1/S phase yet delayed progression in the G2/M phase. In mild infection, cell cycle perturbations are fewer and are integrated with an efficient apoptotic program. Importantly, the loss of integration between cell cycle perturbations and apoptosis marks the transition from a mild viral illness to a severe, life threatening infection. Our findings suggest that circulating immune cells may play a significant role in the evolution of the host response. Further study may reveal alternative host response factors previously unrecognized in the current disease model of influenza

The Influence of Coastal Access on Isotope Variation in Icelandic Arctic Foxes

To quantify the ecological effects of predator populations, it is important to evaluate how population-level specializations are dictated by intra- versus inter-individual dietary variation. Coastal habitats contain prey from the terrestrial biome, the marine biome and prey confined to the coastal region. Such habitats have therefore been suggested to better support predator populations compared to habitats without coastal access. We used stable isotope data on a small generalist predator, the arctic fox, to infer dietary strategies between adult and juvenile individuals with and without coastal access on Iceland. Our results suggest that foxes in coastal habitats exhibited a broader isotope niche breadth compared to foxes in inland habitats. This broader niche was related to a greater diversity of individual strategies rather than to a uniform increase in individual niche breadth or by individuals retaining their specialization but increasing their niche differentiation. Juveniles in coastal habitats exhibited a narrower isotope niche breadth compared to both adults and juveniles in inland habitats, and juveniles in inland habitats inhabited a lower proportion of their total isotope niche compared to adults and juveniles from coastal habitats. Juveniles in both habitats exhibited lower intra-individual variation compared to adults. Based on these results, we suggest that foxes in both habitats were highly selective with respect to the resources they used to feed offspring, but that foxes in coastal habitats preferentially utilized marine resources for this purpose. We stress that coastal habitats should be regarded as high priority areas for conservation of generalist predators as they appear to offer a wide variety of dietary options that allow for greater flexibility in dietary strategies

Habitability of the Phoenix landing site

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95488/1/jgre2706.pd

Measurement of neutron-proton capture in the SNO+ water phase

The SNO+ experiment collected data as a low-threshold water Cherenkov detector from September 2017 to July 2019. Measurements of the 2.2-MeV $\gamma$ produced by neutron capture on hydrogen have been made using an Am-Be calibration source, for which a large fraction of emitted neutrons are produced simultaneously with a 4.4-MeV $\gamma$. Analysis of the delayed coincidence between the 4.4-MeV $\gamma$ and the 2.2-MeV capture $\gamma$ revealed a neutron detection efficiency that is centered around 50% and varies at the level of 1% across the inner region of the detector, which to our knowledge is the highest efficiency achieved among pure water Cherenkov detectors. In addition, the neutron capture time constant was measured and converted to a thermal neutron-proton capture cross section of $336.3^{+1.2}_{-1.5}$ mb

Measurement of the 8B solar neutrino flux in SNO+ with very low backgrounds

A measurement of the 8B solar neutrino flux has been made using a 69.2 kt-day dataset acquired with the SNO+ detector during its water commissioning phase. At energies above 6 MeV the dataset is an extremely pure sample of solar neutrino elastic scattering events, owing primarily to the detector’s deep location, allowing an accurate measurement with relatively little exposure. In that energy region the best fit background rate is 0.25+0.09−0.07  events/kt−day, significantly lower than the measured solar neutrino event rate in that energy range, which is 1.03+0.13−0.12  events/kt−day. Also using data below this threshold, down to 5 MeV, fits of the solar neutrino event direction yielded an observed flux of 2.53+0.31−0.28(stat)+0.13−0.10(syst)×106  cm−2 s−1, assuming no neutrino oscillations. This rate is consistent with matter enhanced neutrino oscillations and measurements from other experiments

Search for invisible modes of nucleon decay in water with the SNO+ detector

This paper reports results from a search for nucleon decay through invisible modes, where no visible energy is directly deposited during the decay itself, during the initial water phase of SNO+. However, such decays within the oxygen nucleus would produce an excited daughter that would subsequently deexcite, often emitting detectable gamma rays. A search for such gamma rays yields limits of 2.5×1029  y at 90% Bayesian credibility level (with a prior uniform in rate) for the partial lifetime of the neutron, and 3.6×1029  y for the partial lifetime of the proton, the latter a 70% improvement on the previous limit from SNO. We also present partial lifetime limits for invisible dinucleon modes of 1.3×1028  y for nn, 2.6×1028  y for pn and 4.7×1028  y for pp, an improvement over existing limits by close to 3 orders of magnitude for the latter two