Biochemical and structural characterisation of membrane-containing icosahedral dsDNA bacteriophages infecting thermophilic Thermus thermophilus

AbstractIcosahedral dsDNA viruses isolated from hot springs and proposed to belong to the Tectiviridae family infect the Gram-negative thermophilic Thermus thermophilus bacterium. Seven such viruses were obtained from the Promega Corporation collection. The structural protein patterns of three of these viruses, growing to a high titer, appeared very similar but not identical. The most stable virus, P23-77, was chosen for more detailed studies. Analysis of highly purified P23-77 by thin layer chromatography for neutral lipids showed lipid association with the virion. Cryo-EM based three-dimensional image reconstruction of P23-77 to 1.4 nm resolution revealed an icosahedrally-ordered protein coat, with spikes on the vertices, and an internal membrane. The capsid architecture of P23-77 is most similar to that of the archaeal virus SH1. These findings further complicate the grouping of icosahedrally-symmetric viruses containing an inner membrane. We propose a single superfamily or order with members in several viral families

Disease and pharmacologic risk factors for first and subsequent episodes of equine laminitis: a cohort study of free-text electronic medical records

Electronic medical records from first opinion equine veterinary practice may represent a unique resource for epidemiologic research. The appropriateness of this resource for risk factor analyses was explored as part of an investigation into clinical and pharmacologic risk factors for laminitis. Amalgamated medical records from seven UK practices were subjected to text mining to identify laminitis episodes, systemic or intra-synovial corticosteroid prescription, diseases known to affect laminitis risk and clinical signs or syndromes likely to lead to corticosteroid use. Cox proportional hazard models and Prentice, Williams, Peterson models for repeated events were used to estimate associations with time to first, or subsequent laminitis episodes, respectively. Over seventy percent of horses that were diagnosed with laminitis suf- fered at least one recurrence. Risk factors for first and subsequent laminitis episodes were found to vary. Corticosteroid use (prednisolone only) was only significantly associated with subsequent, and not ini- tial laminitis episodes. Electronic medical record use for such analyses is plausible and offers important advantages over more traditional data sources. It does, however, pose challenges and limitations that must be taken into account, and requires a conceptual change to disease diagnosis which should be considered carefully

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