An Anglo-Saxon execution cemetery at Walkington Wold, Yorkshire

This paper presents a re-evaluation of a cemetery excavated over 30 years ago at Walkington Wold in east Yorkshire. The cemetery is characterized by careless burial on diverse alignments, and by the fact that most of the skeletons did not have associated crania. The cemetery has been variously described as being the result of an early post-Roman massacre, as providing evidence for a ‘Celtic’ head cult or as an Anglo-Saxon execution cemetery. In order to resolve the matter, radiocarbon dates were acquired and a re-examination of the skeletal remains was undertaken. It was confirmed that the cemetery was an Anglo-Saxon execution cemetery, the only known example from northern England, and the site is set into its wider context in the paper

Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans.

BACKGROUND: The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource - Rare Disease cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n=390) in the cohort. Amino-acid substitutions predicted to be pathogenic were assessed by analysis of structural protein data. Immunophenotyping, immunoblotting and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype co-segregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the non-infective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%) and autoimmune disease (48%), features prior studies correlate with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B lymphocyte differentiation. Detailed assessment of B lymphocyte numbers, phenotype and function identifies the presence of a raised CD21lowB cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID that results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.This study was supported by The National Institute for Health Research England (grant number RG65966), and by the Center of Immunodeficiencies Amsterdam (CIDA). JET is supported by an MRC Clinician Scientist Fellowship (MR/L006197/1). AJT is supported by both the Wellcome Trust (104807/Z/14/Z) and by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. EO receives personal fees from CSL Behring and MSD

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

The fuzzy-boundary arena-a method for constraining an animal's range in spatial experiments without using walls

A method is described for confining an animal within an experimenter-defined area without the use of physical boundaries. The area of exploration is constrained by the presence of an aversive noise, triggered whenever the animal steps across a computer-controlled boundary. The radius of the invisible boundary is constantly reset so that the boundary becomes “fuzzy” and the animal cannot use it as a spatial localizing cue. The effectiveness of this technique is demonstrated both with behavioural data confirming reliable confinement, and also recordings of hippocampal place cells made from rats exploring the arena. The place cell data reveal that indeed, the cells did not appear to be controlled by the fuzzy boundary, in contrast with the strong control normally exerted by fixed boundaries. This technique is thus promising for studies of spatial behaviour in which the strong influence of walls needs to be removed in order to allow the study of more subtle processes such as landmark use and path integration

Evaluation of a CMAQ simulation at high resolution over the UK for the calendar year 2003

A comprehensive ‘operational’ evaluation of the performance of the Community Multiscale Air Quality (CMAQ) modelling system version 4.6 was conducted in support of pollution assessment in the UK for the calendar year 2003. The model was run on multiple grids using one-way nests down to a horizontal resolution as fine as 5 km over the whole of the UK. The model performance was evaluated for pollutants with standards and limit values (e.g. O3, PM10) and species contributing to acidic and nitrogenous deposition (e.g. NH3, SO42-, NO3-, NH4+) against data from operational national monitoring networks. The key performance characteristics of the modelling system were found to be variable according to acceptance criteria and to depend on the type (e.g. urban, rural) and location of the sites, as well as on the time of the year. As regards the techniques that were used for ‘operational’ evaluation, performance generally complied with expected levels and ranged from good (e.g. O3, SO42-) to moderate (e.g. PM10, NO3 e). At a few sites low correlations and large standard deviations for some species (e.g. SO2) suggest that these sites are subject to local factors (e.g. topography, emission sources) that are not well described in the model. Overall, the model tends to over predict O3 and under predict aerosol species (except SO42-). Discrepancies between predicted and observed concentrations may be due to a variety of intertwined factors, which include inaccuracies in meteorological predictions, chemical boundary conditions, temporal variability in emissions, and uncertainties in the treatment of gas and aerosol chemistry. Further work is thus required to investigate the respective contributions of such factors on the predicted concentrations