Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor.

The endogenous double-stranded RNA (dsRNA) virus Leishmaniavirus (LRV1) has been implicated as a pathogenicity factor for leishmaniasis in rodent models and human disease, and associated with drug-treatment failures in Leishmania braziliensis and Leishmania guyanensis infections. Thus, methods targeting LRV1 could have therapeutic benefit. Here we screened a panel of antivirals for parasite and LRV1 inhibition, focusing on nucleoside analogs to capitalize on the highly active salvage pathways of Leishmania, which are purine auxotrophs. Applying a capsid flow cytometry assay, we identified two 2'-C-methyladenosine analogs showing selective inhibition of LRV1. Treatment resulted in loss of LRV1 with first-order kinetics, as expected for random virus segregation, and elimination within six cell doublings, consistent with a measured LRV1 copy number of about 15. Viral loss was specific to antiviral nucleoside treatment and not induced by growth inhibitors, in contrast to fungal dsRNA viruses. Comparisons of drug-treated LRV1 <sup>+</sup> and LRV1 <sup>-</sup> lines recapitulated LRV1-dependent pathology and parasite replication in mouse infections, and cytokine secretion in macrophage infections. Agents targeting Totiviridae have not been described previously, nor are there many examples of inhibitors acting against dsRNA viruses more generally. The compounds identified here provide a key proof-of-principle in support of further studies identifying efficacious antivirals for use in in vivo studies of LRV1-mediated virulence

Association of FCGR3A and FCGR3B haplotypes with rheumatoid arthritis and primary Sjögren's syndrome [POSTER PRESENTATION]

Background Rheumatoid arthritis (RA) is an autoimmune disease that is thought to arise from a complex interaction between multiple genetic factors and environmental triggers. We have previously demonstrated an association between a Fc gamma receptor (FcγR) haplotype and RA in a cross-sectional cohort of RA patients. We have sought to confirm this association in an inception cohort of RA patients and matched controls. We also extended our study to investigate a second autoanti-body associated rheumatic disease, primary Sjögren's syndrome (PSS). Methods The FCGR3A-158F/V and FCGR3B-NA1/NA2 functional polymorphisms were examined for association in an inception cohort of RA patients (n = 448), and a well-characterised PSS cohort (n = 83) from the United Kingdom. Pairwise disequilibrium coefficients (D') were calculated in 267 Blood Service healthy controls. The EHPlus program was used to estimate haplotype frequencies for patients and controls and to determine whether significant linkage disequilibrium was present. A likelihood ratio test is performed to test for differences between the haplotype frequencies in cases and controls. A permutation procedure implemented in this program enabled 1000 permutations to be performed on all haplotype associations to assess significance. Results There was significant linkage disequilibrium between FCGR3A and FCGR3B (D' = -0.445, P = 0.001). There was no significant difference in the FCGR3A or FCGR3B allele or genotype frequencies in the RA or PSS patients compared with controls. However, there was a significant difference in the FCGR3A-FCGR3B haplotype distributions with increased homozygosity for the FCGR3A-FCGR3B 158V-NA2 haplotype in both our inception RA cohort (odds ratio = 2.15, 95% confidence interval = 1.1–4.2 P = 0.027) and PSS (odds ratio = 2.83, 95% confidence interval = 1.0–8.2, P = 0.047) compared with controls. The reference group for these analyses comprised individuals who did not possess a copy of the FCGR3A-FCGR3B 158V-NA2 haplotype. Conclusions We have confirmed our original findings of association between the FCGR3A-FCGR3B 158V-NA2 haplotype and RA in a new inception cohort of RA patients. This suggests that there may be an RA-susceptibility gene at this locus. The significant increased frequency of an identical haplotype in PSS suggests the FcγR genetic locus may contribute to the pathogenesis of diverse autoantibody-mediated rheumatic diseases

Vlasov-Maxwell, self-consistent electromagnetic wave emission simulations in the solar corona

1.5D Vlasov-Maxwell simulations are employed to model electromagnetic emission generation in a fully self-consistent plasma kinetic model for the first time in the solar physics context. The simulations mimic the plasma emission mechanism and Larmor drift instability in a plasma thread that connects the Sun to Earth with the spatial scales compressed appropriately. The effects of spatial density gradients on the generation of electromagnetic radiation are investigated. It is shown that 1.5D inhomogeneous plasma with a uniform background magnetic field directed transverse to the density gradient is aperiodically unstable to Larmor-drift instability. The latter results in a novel effect of generation of electromagnetic emission at plasma frequency. When density gradient is removed (i.e. when plasma becomes stable to Larmor-drift instability) and a $low$ density, super-thermal, hot beam is injected along the domain, in the direction perpendicular to the magnetic field, plasma emission mechanism generates non-escaping Langmuir type oscillations which in turn generate escaping electromagnetic radiation. It is found that in the spatial location where the beam is injected, the standing waves, oscillating at the plasma frequency, are excited. These can be used to interpret the horizontal strips observed in some dynamical spectra. Quasilinear theory predictions: (i) the electron free streaming and (ii) the beam long relaxation time, in accord with the analytic expressions, are corroborated via direct, fully-kinetic simulation. Finally, the interplay of Larmor-drift instability and plasma emission mechanism is studied by considering $dense$ electron beam in the Larmor-drift unstable (inhomogeneous) plasma. http://www.maths.qmul.ac.uk/~tsiklauri/movie1.mpg * http://www.maths.qmul.ac.uk/~tsiklauri/movie2.mpg * http://www.maths.qmul.ac.uk/~tsiklauri/movie3.mpgComment: Solar Physics (in press, the final, accepted version

Development of a new error field correction coil (C-coil) for DIII-D

The C-coil recently installed on the DIII-D tokamak was developed to reduce the error fields created by imperfections in the location and geometry of the existing coils used to confine, heat, and shape the plasma. First results from C-coil experiments include stable operation in a 1.6 MA plasma with a density less than 1.0 {times} 10{sup 13} cm{sup {minus}3}, nearly a factor of three lower density than that achievable without the C-coil. The C-coil has also been used in magnetic braking of the plasma rotation and high energy particle confinement experiments. The C-coil system consists of six individual saddle coils, each 60{degree} wide toroidally, spanning the midplane of the vessel with a vertical height of 1.6 m. The coils are located at a major radius of 3.2 m, just outside of the toroidal field coils. The actual shape and geometry of each coil section varied somewhat from the nominal dimensions due to the large number of obstructions to the desired coil path around the already crowded tokamak. Each coil section consists of four turns of 750 MCM insulated copper cable banded with stainless steel straps within the web of a 3 in. x 3 in. stainless steel angle frame. The C-coil structure was designed to resist peak transient radial forces (up to 1,800 Nm) exerted on the coil by the toroidal and ploidal fields. The coil frames were supported from existing poloidal field coil case brackets, coil studs, and various other structures on the tokamak

The composition of the protosolar disk and the formation conditions for comets

Conditions in the protosolar nebula have left their mark in the composition of cometary volatiles, thought to be some of the most pristine material in the solar system. Cometary compositions represent the end point of processing that began in the parent molecular cloud core and continued through the collapse of that core to form the protosun and the solar nebula, and finally during the evolution of the solar nebula itself as the cometary bodies were accreting. Disentangling the effects of the various epochs on the final composition of a comet is complicated. But comets are not the only source of information about the solar nebula. Protostellar disks around young stars similar to the protosun provide a way of investigating the evolution of disks similar to the solar nebula while they are in the process of evolving to form their own solar systems. In this way we can learn about the physical and chemical conditions under which comets formed, and about the types of dynamical processing that shaped the solar system we see today. This paper summarizes some recent contributions to our understanding of both cometary volatiles and the composition, structure and evolution of protostellar disks.Comment: To appear in Space Science Reviews. The final publication is available at Springer via http://dx.doi.org/10.1007/s11214-015-0167-

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

Measurement of the correlation between flow harmonics of different order in lead-lead collisions at √sNN = 2.76 TeV with the ATLAS detector

Correlations between the elliptic or triangular flow coefficients vm (m=2 or 3) and other flow harmonics vn (n=2 to 5) are measured using √sNN=2.76 TeV Pb+Pb collision data collected in 2010 by the ATLAS experiment at the LHC, corresponding to an integrated luminosity of 7 μb−1. The vm−vn correlations are measured in midrapidity as a function of centrality, and, for events within the same centrality interval, as a function of event ellipticity or triangularity defined in a forward rapidity region. For events within the same centrality interval, v3 is found to be anticorrelated with v2 and this anticorrelation is consistent with similar anticorrelations between the corresponding eccentricities, ε2 and ε3. However, it is observed that v4 increases strongly with v2, and v5 increases strongly with both v2 and v3. The trend and strength of the vm−vn correlations for n=4 and 5 are found to disagree with εm−εn correlations predicted by initial-geometry models. Instead, these correlations are found to be consistent with the combined effects of a linear contribution to vn and a nonlinear term that is a function of v22 or of v2v3, as predicted by hydrodynamic models. A simple two-component fit is used to separate these two contributions. The extracted linear and nonlinear contributions to v4 and v5 are found to be consistent with previously measured event-plane correlations

Search for W′→tb→qqbb decays in pp collisions at √s=8 TeV with the ATLAS detector

A search for a massive W′ gauge boson decaying to a top quark and a bottom quark is performed with the ATLAS detector in pp collisions at the LHC. The dataset was taken at a centre-of-mass energy of √s=8 TeV and corresponds to 20.3 fb−1 of integrated luminosity. This analysis is done in the hadronic decay mode of the top quark, where novel jet substructure techniques are used to identify jets from high-momentum top quarks. This allows for a search for high-mass W′ bosons in the range 1.5–3.0 TeV. b-tagging is used to identify jets originating from b-quarks. The data are consistent with Standard Model background-only expectations, and upper limits at 95 % confidence level are set on the W′→tb cross section times branching ratio ranging from 0.16pb to 0.33pb for left-handed W′ bosons, and ranging from 0.10pb to 0.21pb for W′ bosons with purely right-handed couplings. Upper limits at 95 % confidence level are set on the W′-boson coupling to tb as a function of the W′ mass using an effective field theory approach, which is independent of details of particular models predicting a W′boson