SPH simulations of irradiation-driven warped accretion discs and the long periods in X-ray binaries

We present three dimensional smoothed particle hydrodynamics (SPH) calculations of irradiation-driven warping of accretion discs. Initially unwarped planar discs are unstable to the radiation reaction when the disc is illuminated by a central radiation source. The disc warps and tilts and precesses slowly in a retrograde direction; its shape continuously flexes in response to the changing orientation of the Roche potential. We simulate ten systems: eight X-ray binaries, one cataclysmic variable (CV), and a `generic' low mass X-ray binary (LMXB). We adopt system parameters from observations and tune a single parameter: our model X-ray luminosity ($L_{*}$) to reproduce the observed or inferred super-orbital periods. Without exception, across a wide range of parameter space, we find an astonishingly good match between the observed $L_{X}$ and the model $L_{*}$. We conclude irradiation-driven warping is the mechanism underlying the long periods in X-ray binaries. Our Her X-1 simulation simultaneously reproduces the observed $L_{X}$, the "main-" and "short-high" X-ray states and the orbital inclination. Our simulations of SS 433 give a maximum warp angle of $18.6^{\circ}$, a good match to the cone traced by the jets, but this angle is reached only in the outer disc. In all cases, the overall disc tilt is less than \degrees{13} and the maximum disc warp is less than and or equal to \degrees{21}.Comment: 17 pages, 14 figures, shorter abstract (24 lines limit

Comprehensive simulations of superhumps

(Abridged) We use 3D SPH calculations with higher resolution, as well as with more realistic viscosity and sound-speed prescriptions than previous work to examine the eccentric instability which underlies the superhump phenomenon in semi-detached binaries. We illustrate the importance of the two-armed spiral mode in the generation of superhumps. Differential motions in the fluid disc cause converging flows which lead to strong spiral shocks once each superhump cycle. The dissipation associated with these shocks powers the superhump. We compare 2D and 3D results, and conclude that 3D simulations are necessary to faithfully simulate the disc dynamics. We ran our simulations for unprecedented durations, so that an eccentric equilibrium is established except at high mass ratios where the growth rate of the instability is very low. Our improved simulations give a closer match to the observed relationship between superhump period excess and binary mass ratio than previous numerical work. The observed black hole X-ray transient superhumpers appear to have systematically lower disc precession rates than the cataclysmic variables. This could be due to higher disc temperatures and thicknesses. The modulation in total viscous dissipation on the superhump period is overwhelmingly from the region of the disc within the 3:1 resonance radius. As the eccentric instability develops, the viscous torques are enhanced, and the disc consequently adjusts to a new equilibrium state, as suggested in the thermal-tidal instability model. We quantify this enhancement in the viscosity, which is ~10 per cent for q=0.08. We characterise the eccentricity distributions in our accretion discs, and show that the entire body of the disc partakes in the eccentricity.Comment: 18 pages (mn2e LaTeX), 14 figures, 5 tables, Accepted for publication in MNRA

Three dimensional SPH simulations of radiation-driven warped accretion discs

We present three dimensional smoothed particle hydrodynamics (SPH) calculations of warped accretion discs in X-ray binary systems. Geometrically thin, optically thick accretion discs are illuminated by a central radiation source. This illumination exerts a non-axisymmetric radiation pressure on the surface of the disc resulting in a torque that acts on the disc to induce a twist or warp. Initially planar discs are unstable to warping driven by the radiation torque and in general the warps also precess in a retrograde direction relative to the orbital flow. We simulate a number of X-ray binary systems which have different mass ratios using a number of different luminosities for each. Radiation-driven warping occurs for all systems simulated. For mass ratios q ~ 0.1 a moderate warp occurs in the inner disc while the outer disc remains in the orbital plane (c.f. X 1916-053). For less extreme mass ratios the entire disc tilts out of the orbital plane (c.f. Her X-1). For discs that are tilted out of the orbital plane in which the outer edge material of the disc is precessing in a prograde direction we obtain both positive and negative superhumps simultaneously in the dissipation light curve (c.f. V603 Aql).Comment: 12 pages, 12 figures, paper accepted for publication by MNRA

Simulations of spectral lines from an eccentric precessing accretion disc

Two dimensional SPH simulations of a precessing accretion disc in a q=0.1 binary system (such as XTE J1118+480) reveal complex and continuously varying shape, kinematics, and dissipation. The stream-disc impact region and disc spiral density waves are prominent sources of energy dissipation.The dissipated energy is modulated on the period P_{sh} = ({P_{orb}}^{-1}-{P_{prec}}^{-1}^{-1} with which the orientation of the disc relative to the mass donor repeats. This superhump modulation in dissipation energy has a variation in amplitude of ~10% relative to the total dissipation energy and evolves, repeating exactly only after a full disc precession cycle. A sharp component in the light curve is associated with centrifugally expelled material falling back and impacting the disc. Synthetic trailed spectrograms reveal two distinct "S-wave" features, produced respectively by the stream gas and the disc gas at the stream-disc impact shock. These S-waves are non-sinusoidal, and evolve with disc precession phase. We identify the spiral density wave emission in the trailed spectrogram. Instantaneous Doppler maps show how the stream impact moves in velocity space during an orbit. In our maximum entropy Doppler tomogram the stream impact region emission is distorted, and the spiral density wave emission is uppressed. A significant radial velocity modulation of the whole line profile occurs on the disc precession period. We compare our SPH simulation with a simple 3D model: the former is appropriate for comparison with emission lines while the latter is preferable for skewed absorption lines from precessing discs.Comment: See http://physics.open.ac.uk/FHMR/ for associated movie (avi) files. The full paper is in MNRAS press. Limited disk space limit of 650k, hence low resolution figure file

Impact of fluoroquinolones and aminoglycosides on P. aeruginosa virulence factor production and cytotoxicity.

The opportunistic pathogen Pseudomonas aeruginosa is one of leading causes of disability and mortality worldwide and the world health organisation has listed it with the highest priority for the need of new antimicrobial therapies. P. aeruginosa strains responsible for the poorest clinical outcomes express either ExoS or ExoU, which are injected into target host cells via the type III secretion system (T3SS). ExoS is a bifunctional cytotoxin that promotes intracellular survival of invasive P. aeruginosa by preventing targeting of the bacteria to acidified intracellular compartments. ExoU is a phospholipase which causes destruction of host cell plasma membranes, leading to acute tissue damage and bacterial dissemination. Fluoroquinolones are usually employed as a first line of therapy as they have been shown to be more active against P. aeruginosain vitro than other antimicrobial classes. Their overuse over the past decade, however, has resulted in the emergence of antibiotic resistance. In certain clinical situations, aminoglycosides have been shown to be more effective then fluoroquinolones, despite their reduced potency towards P. aeruginosa in vitro. In this study, we evaluated the effects of fluoroquinolones (moxifloxacin and ciprofloxacin) and aminoglycosides (tobramycin and gentamycin) on T3SS expression and toxicity, in corneal epithelial cell infection models. We discovered that tobramycin disrupted T3SS expression and reduced both ExoS and ExoU mediated cytotoxicity, protecting infected HCE-t cells at concentrations below the minimal inhibitory concentration (MIC). The fluoroquinolones moxifloxacin and ciprofloxacin, however, upregulated the T3SS and did not inhibit and may have increased the cytotoxic effects of ExoS and ExoU

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Post hoc Analysis for Detecting Individual Rare Variant Risk Associations Using Probit Regression Bayesian Variable Selection Methods in Case-Control Sequencing Studies

Rare variants (RVs) have been shown to be significant contributors to complex disease risk. By definition, these variants have very low minor allele frequencies and traditional single-marker methods for statistical analysis are underpowered for typical sequencing study sample sizes. Multimarker burden-type approaches attempt to identify aggregation of RVs across case-control status by analyzing relatively small partitions of the genome, such as genes. However, it is generally the case that the aggregative measure would be a mixture of causal and neutral variants, and these omnibus tests do not directly provide any indication of which RVs may be driving a given association. Recently, Bayesian variable selection approaches have been proposed to identify RV associations from a large set of RVs under consideration. Although these approaches have been shown to be powerful at detecting associations at the RV level, there are often computational limitations on the total quantity of RVs under consideration and compromises are necessary for large-scale application. Here, we propose a computationally efficient alternative formulation of this method using a probit regression approach specifically capable of simultaneously analyzing hundreds to thousands of RVs. We evaluate our approach to detect causal variation on simulated data and examine sensitivity and specificity in instances of high RV dimensionality as well as apply it to pathway-level RV analysis results from a prostate cancer (PC) risk case-control sequencing study. Finally, we discuss potential extensions and future directions of this work

Clique-Finding for Heterogeneity and Multidimensionality in Biomarker Epidemiology Research: The CHAMBER Algorithm

Commonly-occurring disease etiology may involve complex combinations of genes and exposures resulting in etiologic heterogeneity. We present a computational algorithm that employs clique-finding for heterogeneity and multidimensionality in biomedical and epidemiological research (the "CHAMBER" algorithm).This algorithm uses graph-building to (1) identify genetic variants that influence disease risk and (2) predict individuals at risk for disease based on inherited genotype. We use a set-covering algorithm to identify optimal cliques and a Boolean function that identifies etiologically heterogeneous groups of individuals. We evaluated this approach using simulated case-control genotype-disease associations involving two- and four-gene patterns. The CHAMBER algorithm correctly identified these simulated etiologies. We also used two population-based case-control studies of breast and endometrial cancer in African American and Caucasian women considering data on genotypes involved in steroid hormone metabolism. We identified novel patterns in both cancer sites that involved genes that sulfate or glucuronidate estrogens or catecholestrogens. These associations were consistent with the hypothesized biological functions of these genes. We also identified cliques representing the joint effect of multiple candidate genes in all groups, suggesting the existence of biologically plausible combinations of hormone metabolism genes in both breast and endometrial cancer in both races.The CHAMBER algorithm may have utility in exploring the multifactorial etiology and etiologic heterogeneity in complex disease

REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants

Supplemental Data Supplemental Data include one figure and five tables and can be found with this article online at http://dx.doi.org/10.1016/j.ajhg.2016.08.016. Supplemental Data Document S1. Figure S1 and Tables S1–S5 Download Document S2. Article plus Supplemental Data Download Web Resources ClinVar, https://www.ncbi.nlm.nih.gov/clinvar/ dbNSFP, https://sites.google.com/site/jpopgen/dbNSFP Human Gene Mutation Database, http://www.hgmd.cf.ac.uk/ REVEL, https://sites.google.com/site/revelgenomics/ SwissVar, http://swissvar.expasy.org/ The vast majority of coding variants are rare, and assessment of the contribution of rare variants to complex traits is hampered by low statistical power and limited functional data. Improved methods for predicting the pathogenicity of rare coding variants are needed to facilitate the discovery of disease variants from exome sequencing studies. We developed REVEL (rare exome variant ensemble learner), an ensemble method for predicting the pathogenicity of missense variants on the basis of individual tools: MutPred, FATHMM, VEST, PolyPhen, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP, SiPhy, phyloP, and phastCons. REVEL was trained with recently discovered pathogenic and rare neutral missense variants, excluding those previously used to train its constituent tools. When applied to two independent test sets, REVEL had the best overall performance (p < 10−12) as compared to any individual tool and seven ensemble methods: MetaSVM, MetaLR, KGGSeq, Condel, CADD, DANN, and Eigen. Importantly, REVEL also had the best performance for distinguishing pathogenic from rare neutral variants with allele frequencies <0.5%. The area under the receiver operating characteristic curve (AUC) for REVEL was 0.046–0.182 higher in an independent test set of 935 recent SwissVar disease variants and 123,935 putatively neutral exome sequencing variants and 0.027–0.143 higher in an independent test set of 1,953 pathogenic and 2,406 benign variants recently reported in ClinVar than the AUCs for other ensemble methods. We provide pre-computed REVEL scores for all possible human missense variants to facilitate the identification of pathogenic variants in the sea of rare variants discovered as sequencing studies expand in scale