A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus

The innate immune system is critical in the response to infection by pathogens and it is activated by pattern recognition receptors (PRRs) binding to pathogen associated molecular patterns (PAMPs). During viral infection, the direct recognition of the viral nucleic acids, such as the genomes of DNA viruses, is very important for activation of innate immunity. Recently, DNA-dependent protein kinase (DNA-PK), a heterotrimeric complex consisting of the Ku70/Ku80 heterodimer and the catalytic subunit DNA-PKcs was identified as a cytoplasmic PRR for DNA that is important for the innate immune response to intracellular DNA and DNA virus infection. Here we show that vaccinia virus (VACV) has evolved to inhibit this function of DNA-PK by expression of a highly conserved protein called C16, which was known to contribute to virulence but by an unknown mechanism. Data presented show that C16 binds directly to the Ku heterodimer and thereby inhibits the innate immune response to DNA in fibroblasts, characterised by the decreased production of cytokines and chemokines. Mechanistically, C16 acts by blocking DNA-PK binding to DNA, which correlates with reduced DNA-PK-dependent DNA sensing. The C-terminal region of C16 is sufficient for binding Ku and this activity is conserved in the variola virus (VARV) orthologue of C16. In contrast, deletion of 5 amino acids in this domain is enough to knockout this function from the attenuated vaccine strain modified vaccinia virus Ankara (MVA). In vivo a VACV mutant lacking C16 induced higher levels of cytokines and chemokines early after infection compared to control viruses, confirming the role of this virulence factor in attenuating the innate immune response. Overall this study describes the inhibition of DNA-PK-dependent DNA sensing by a poxvirus protein, adding to the evidence that DNA-PK is a critical component of innate immunity to DNA viruses

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Euclid preparation XXVIII. Forecasts for ten different higher-order weak lensing statistics

Recent cosmic shear studies have shown that higher-order statistics (HOS) developed by independent teams now outperform standard two-point estimators in terms of statistical precision thanks to their sensitivity to the non-Gaussian features of large-scale structure. The aim of the Higher-Order Weak Lensing Statistics (HOWLS) project is to assess, compare, and combine the constraining power of ten different HOS on a common set of Euclid-like mocks, derived from N-body simulations. In this first paper of the HOWLS series, we computed the nontomographic (Ωm, σ8) Fisher information for the one-point probability distribution function, peak counts, Minkowski functionals, Betti numbers, persistent homology Betti numbers and heatmap, and scattering transform coefficients, and we compare them to the shear and convergence two-point correlation functions in the absence of any systematic bias. We also include forecasts for three implementations of higher-order moments, but these cannot be robustly interpreted as the Gaussian likelihood assumption breaks down for these statistics. Taken individually, we find that each HOS outperforms the two-point statistics by a factor of around two in the precision of the forecasts with some variations across statistics and cosmological parameters. When combining all the HOS, this increases to a 4.5 times improvement, highlighting the immense potential of HOS for cosmic shear cosmological analyses with Euclid. The data used in this analysis are publicly released with the paper

Euclid preparation. TBD. Forecast impact of super-sample covariance on 3x2pt analysis with Euclid

Deviations from Gaussianity in the distribution of the fields probed by large-scale structure surveys generate additional terms in the data covariance matrix, increasing the uncertainties in the measurement of the cosmological parameters. Super-sample covariance (SSC) is among the largest of these non-Gaussian contributions, with the potential to significantly degrade constraints on some of the parameters of the cosmological model under study -- especially for weak lensing cosmic shear. We compute and validate the impact of SSC on the forecast uncertainties on the cosmological parameters for the Euclid photometric survey, obtained with a Fisher matrix analysis, both considering the Gaussian covariance alone and adding the SSC term -- computed through the public code PySSC. The photometric probes are considered in isolation and combined in the `3$\times$2pt' analysis. We find the SSC impact to be non-negligible -- halving the Figure of Merit of the dark energy parameters ($w_0$, $w_a$) in the 3$\times$2pt case and substantially increasing the uncertainties on $\Omega_{{\rm m},0}, w_0$, and $\sigma_8$ for cosmic shear; photometric galaxy clustering, on the other hand, is less affected due to the lower probe response. The relative impact of SSC does not show significant changes under variations of the redshift binning scheme, while it is smaller for weak lensing when marginalising over the multiplicative shear bias nuisance parameters, which also leads to poorer constraints on the cosmological parameters. Finally, we explore how the use of prior information on the shear and galaxy bias changes the SSC impact. Improving shear bias priors does not have a significant impact, while galaxy bias must be calibrated to sub-percent level to increase the Figure of Merit by the large amount needed to achieve the value when SSC is not included.Comment: 22 pages, 13 figure

Euclid preparation TBD. The effect of baryons on the Halo Mass Function

The Euclid photometric survey of galaxy clusters stands as a powerful cosmological tool, with the capacity to significantly propel our understanding of the Universe. Despite being sub-dominant to dark matter and dark energy, the baryonic component in our Universe holds substantial influence over the structure and mass of galaxy clusters. This paper presents a novel model to precisely quantify the impact of baryons on galaxy cluster virial halo masses, using the baryon fraction within a cluster as proxy for their effect. Constructed on the premise of quasi-adiabaticity, the model includes two parameters calibrated using non-radiative cosmological hydrodynamical simulations and a single large-scale simulation from the Magneticum set, which includes the physical processes driving galaxy formation. As a main result of our analysis, we demonstrate that this model delivers a remarkable one percent relative accuracy in determining the virial dark matter-only equivalent mass of galaxy clusters, starting from the corresponding total cluster mass and baryon fraction measured in hydrodynamical simulations. Furthermore, we demonstrate that this result is robust against changes in cosmological parameters and against varying the numerical implementation of the sub-resolution physical processes included in the simulations. Our work substantiates previous claims about the impact of baryons on cluster cosmology studies. In particular, we show how neglecting these effects would lead to biased cosmological constraints for a Euclid-like cluster abundance analysis. Importantly, we demonstrate that uncertainties associated with our model, arising from baryonic corrections to cluster masses, are sub-dominant when compared to the precision with which mass-observable relations will be calibrated using Euclid, as well as our current understanding of the baryon fraction within galaxy clusters.Comment: 18 pages, 10 figures, 4 tables, 1 appendix, abstract abridged for arXiv submissio

Binary and Millisecond Pulsars

We review the main properties, demographics and applications of binary and millisecond radio pulsars. Our knowledge of these exciting objects has greatly increased in recent years, mainly due to successful surveys which have brought the known pulsar population to over 1700. There are now 80 binary and millisecond pulsars associated with the disk of our Galaxy, and a further 103 pulsars in 24 of the Galactic globular clusters. Recent highlights have been the discovery of the first ever double pulsar system and a recent flurry of discoveries in globular clusters, in particular Terzan 5.Comment: 77 pages, 30 figures, available on-line at http://www.livingreviews.org/lrr-2005-

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study

Background Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75–1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58–1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91–1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70–1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50–0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38–0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45–0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Panitumumab added to docetaxel, cisplatin and fluoropyrimidine in oesophagogastric cancer: ATTAX3 phase II trial

BACKGROUND: This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer. METHODS: Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy. RESULTS: A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34-64%) in the chemotherapy arm and 58% (95% CI 42-72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively. CONCLUSIONS: Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities

Charnockite formation at Ponmudi in Southern India

Charnockites, constituents of most Precambrian high-grade terrains 1,2, are essential for understanding the evolution of the early continental crust. The arrested development of charnockite in shear veins at Kabbaldurga3, in the state of Karnataka in India, suggests flow of CO2-rich water-deficient fluids through deep-seated rocks as a mechanism of granulite grade metamorphism4,5. We report here an occurrence of arrested charnockite formation well south of Kabbaldurga, in the khondalite belt of southern Kerala, where rocks with amphibolite facies give way to the vast southern India-Sri Lanka charnockite terrain, indicating that metamorphism due to CO2-rich fluids (carbonic metamorphism) may have operated over a large area in southern India. If such localities prove to be widespread, the present level of exposure throughout much of the high-grade terrain probably does not extend far beyond an isofacial surface marking the boundary between upper and lower crust in the late Archaean. © 1985 Nature Publishing Group