Untangling cosmic magnetic fields: Faraday tomography at metre wavelengths with LOFAR

14 pages, 6 figures. Accepted for publication in "The Power of Faraday Tomography" special issue of GalaxiesThe technique of Faraday tomography is a key tool for the study ofmagnetised plasmas in the new era of broadband radio-polarisation observations. In particular, observations at metre wavelengths provide significantly better Faraday depth accuracies compared to traditional centimetre-wavelength observations. However, the effect of Faraday depolarisationmakes the polarised signal very challenging to detect at metre wavelengths (MHz frequencies). In this work, Faraday tomography is used to characterise the Faraday rotation properties of polarised sources found in data from the LOFAR Two-Metre Sky Survey (LoTSS). Of the 76 extragalactic polarised sources analysed here, we find that all host a radio-loud AGN (Active Galactic Nucleus). The majority of the sources (~64%) are large FRII radio galaxies with a median projected linear size of 710 kpc and median radio luminosity at 144 MHz of 4 × 10 26 W Hz -1 (with ~13% of all sources having a linear size > 1 Mpc). In several cases, both hotspots are detected in polarisation at an angular resolution of ~20'. One such case allowed a study of intergalactic magnetic fields on scales of 3.4 Mpc. Other detected source types include an FRI radio galaxy and at least eight blazars. Most sources display simple Faraday spectra, but we highlight one blazar that displays a complex Faraday spectrum, with two close peaks in the Faraday dispersion function.Peer reviewe

Studies of Relativistic Jets in Active Galactic Nuclei with SKA

Relativistic jets in active galactic nuclei (AGN) are among the most powerful astrophysical objects discovered to date. Indeed, jetted AGN studies have been considered a prominent science case for SKA, and were included in several different chapters of the previous SKA Science Book (Carilli & Rawlings 2004). Most of the fundamental questions about the physics of relativistic jets still remain unanswered, and await high-sensitivity radio instruments such as SKA to solve them. These questions will be addressed specially through analysis of the massive data sets arising from the deep, all-sky surveys (both total and polarimetric flux) from SKA1. Wide-field very-long-baseline-interferometric survey observations involving SKA1 will serve as a unique tool for distinguishing between extragalactic relativistic jets and star forming galaxies via brightness temperature measurements. Subsequent SKA1 studies of relativistic jets at different resolutions will allow for unprecedented cosmological studies of AGN jets up to the epoch of re-ionization, enabling detailed characterization of the jet composition, magnetic field, particle populations, and plasma properties on all scales. SKA will enable us to study the dependence of jet power and star formation on other properties of the AGN system. SKA1 will enable such studies for large samples of jets, while VLBI observations involving SKA1 will provide the sensitivity for pc-scale imaging, and SKA2 (with its extraordinary sensitivity and dynamic range) will allow us for the first time to resolve and model the weakest radio structures in the most powerful radio-loud AGN.Comment: 19 pages, 4 figures; to appear as part of 'Cosmic Magnetism' in Proceedings 'Advancing Astrophysics with the SKA (AASKA14)', PoS(AASKA14_093

Development and validation of a targeted gene sequencing panel for application to disparate cancers

Next generation sequencing has revolutionised genomic studies of cancer, having facilitated the development of precision oncology treatments based on a tumour’s molecular profile. We aimed to develop a targeted gene sequencing panel for application to disparate cancer types with particular focus on tumours of the head and neck, plus test for utility in liquid biopsy. The final panel designed through Roche/Nimblegen combined 451 cancer-associated genes (2.01 Mb target region). 136 patient DNA samples were collected for performance and application testing. Panel sensitivity and precision were measured using well-characterised DNA controls (n = 47), and specificity by Sanger sequencing of the Aryl Hydrocarbon Receptor Interacting Protein (AIP) gene in 89 patients. Assessment of liquid biopsy application employed a pool of synthetic circulating tumour DNA (ctDNA). Library preparation and sequencing were conducted on Illumina-based platforms prior to analysis with our accredited (ISO15189) bioinformatics pipeline. We achieved a mean coverage of 395x, with sensitivity and specificity of >99% and precision of >97%. Liquid biopsy revealed detection to 1.25% variant allele frequency. Application to head and neck tumours/cancers resulted in detection of mutations aligned to published databases. In conclusion, we have developed an analytically-validated panel for application to cancers of disparate types with utility in liquid biopsy

DISC1 regulates N-methyl-D-aspartate receptor dynamics:abnormalities induced by a Disc1 mutation modelling a translocation linked to major mental illness

Abstract The neuromodulatory gene DISC1 is disrupted by a t(1;11) translocation that is highly penetrant for schizophrenia and affective disorders, but how this translocation affects DISC1 function is incompletely understood. N-methyl-D-aspartate receptors (NMDAR) play a central role in synaptic plasticity and cognition, and are implicated in the pathophysiology of schizophrenia through genetic and functional studies. We show that the NMDAR subunit GluN2B complexes with DISC1-associated trafficking factor TRAK1, while DISC1 interacts with the GluN1 subunit and regulates dendritic NMDAR motility in cultured mouse neurons. Moreover, in the first mutant mouse that models DISC1 disruption by the translocation, the pool of NMDAR transport vesicles and surface/synaptic NMDAR expression are increased. Since NMDAR cell surface/synaptic expression is tightly regulated to ensure correct function, these changes in the mutant mouse are likely to affect NMDAR signalling and synaptic plasticity. Consistent with these observations, RNASeq analysis of the translocation carrier-derived human neurons indicates abnormalities of excitatory synapses and vesicle dynamics. RNASeq analysis of the human neurons also identifies many differentially expressed genes previously highlighted as putative schizophrenia and/or depression risk factors through large-scale genome-wide association and copy number variant studies, indicating that the translocation triggers common disease pathways that are shared with unrelated psychiatric patients. Altogether, our findings suggest that translocation-induced disease mechanisms are likely to be relevant to mental illness in general, and that such disease mechanisms include altered NMDAR dynamics and excitatory synapse function. This could contribute to the cognitive disorders displayed by translocation carriers

The Rapid ASKAP Continuum Survey III: Spectra and Polarisation In Cutouts of Extragalactic Sources (SPICE-RACS) First Data Release

The Australian SKA Pathfinder (ASKAP) radio telescope has carried out a survey of the entire Southern Sky at 887.5MHz. The wide area, high angular resolution, and broad bandwidth provided by the low-band Rapid ASKAP Continuum Survey (RACS-low) allow the production of a next-generation rotation measure (RM) grid across the entire Southern Sky. Here we introduce this project as Spectral and Polarisation in Cutouts of Extragalactic sources from RACS (SPICE-RACS). In our first data release, we image 30 RACS-low fields in Stokes $I$, $Q$, $U$ at 25'' angular resolution, across 744 to 1032MHz with 1MHz spectral resolution. Using a bespoke, highly parallelised, software pipeline we are able to rapidly process wide-area spectro-polarimetric ASKAP observations. Notably, we use 'postage stamp' cutouts to assess the polarisation properties of \ncomponents\ radio components detected in total intensity. We find that our Stokes $Q$ and $U$ images have an rms noise of ~80$\mu$Jy/PSF, and our correction for instrumental polarisation leakage allows us to characterise components with >1% polarisation fraction over most of the field of view. We produce a broadband polarised radio component catalogue that contains \nrms\ RM measurements over an area of ~1300deg^2 with an average error in RM of 1.6+1.1-1.0rad/m^2, and an average linear polarisation fraction 3.4+3.0-1.6%. We determine this subset of components using the conditions that the polarised signal-to-noise ratio is $>8$, the polarisation fraction is above our estimated polarised leakage, and the Stokes $I$ spectrum has a reliable model. Our catalogue provides an areal density of $4\pm2$ RMs/deg^2; an increase of $\sim4$ times over the previous state-of-the-art (Taylor et al. 2009). Meaning that, having used just 3% of the RACS-low sky area, we have produced the 3rd largest RM catalogue to date. This catalogue has broad applications for studying...Comment: 42 pages, 24 figures, 6 tables. Accepted for publications in PAS

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, PAM, 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 pArg1931* 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

Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO): a randomised controlled trial

We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978. Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50–72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88–1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90. Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19. US National Institutes of Health and Operation Warp Spee