Administrative Law Through a Regulatory Lens: Situating Judicial Adjudication Within a Wider Accountability Framework

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AB0176 increased toll-like receptor 5 signalling and IL-6 production in monocytes from patients with systemic lupus erythematosus

Background The innate immune system contributes to the pathogenesis of SLE, in part through the activity of Toll-like receptors (TLRs), a family of pattern-recognition receptors. Nucleic acid containing immune-complexes, which are characteristic of SLE, activate the RNA and DNA sensing TLRs 7 and 9, resulting in interferon production [1]. Although a role for interferon is well established in SLE, other cytokines such as interleukin (IL)-6 have also been shown to correlate with disease activity, with an anti-IL-6 receptor antibody (Tocilizumab) demonstrating some early success in clinical trials [2][3]. Objectives TLR-7 and 9 are primarily considered drivers of IFN production, but in this study, our aim was to explore the biology of other key TLR's (4, 5 and 8) in SLE in vitro, specifically the role of these TLR's in the induction of interleukin-6 production by monocytes. Methods Freshly-obtained peripheral blood monocytes from patients with known SLE (satisfying standard diagnostic and seroplogical criteria) were studied, contemporaneously with cells from healthy volunteers. TLR expression was evaluated by flow cytometry. Monocyte IL-6 production was measured by ELISA, and evaluation of mRNA levels, before and after in vitro stimulation with flagellin. Results An increase in TLR5 expression (p<0.001; 30 patients and controls) and TLR5-induced IL-6 production was observed in SLE monocytes: (HC mean 0.311ng/ml; SLE mean 2.26ng/ml), p=0.0447; 31 patients, 19 controls). Additionally, downstream regulators of TLR5 signalling were also found to be dysregulated at the mRNA level in the patient samples, showing a direct correlation with TLR5 induced IL-6 production (p=0.0005, r2=0.515). Conclusions These data suggest that there is altered expression and function of TLR5 in SLE patient monocytes. Our results indicate that this may be a factor contributing to incresaed IL-6 levels in the paient group, with potential pathogenic implications. With further charactertisation this pathway may be amenable to therapeutic modification in the future

Genome sequences of 12 isolates of the EU1 lineage of Phytophthora ramorum, a fungus-like pathogen that causes extensive damage and mortality to a wide range of trees and other plants

Here we present genome sequences for twelve isolates of the invasive pathogen Phytophthora ramorum EU1. The assembled genome sequences and raw sequence data are available via BioProject accession number PRJNA177509. These data will be useful in developing molecular tools for specific detection and identification of this pathogen

Correction: Studholme et al., Draft Genome Sequences of Xanthomonas sacchari and Two Banana-Associated Xanthomonads Reveal Insights into the Xanthomonas Group 1 clade. Genes 2011, 2, 1050-1065

Following publication of our article [1], we found errors in analyses performed by the corresponding author (DJS) related to the phylogenetic relationship between Xylella species and the other xanthomonads. These errors do not make any difference to the main findings and conclusions reported in our paper. For example, the phylogenetic positions of NCPPB1131, NCPPB1132 and NCPPB4393 within the Group 1 Xanthomonas species are unaffected. However, we wish to apologize to the authors of a previous work [2] for creating any negative impression on the quality of their phylogenetic analyses and to take this opportunity to rectify the errors. [...]

Genome Sequencing of Xanthomonas vasicola Pathovar vasculorum Reveals Variation in Plasmids and Genes Encoding Lipopolysaccharide Synthesis, Type-IV Pilus and Type-III Secretion Effectors

Xanthomonas vasicola pathovar vasculorum (Xvv) is the bacterial agent causing gumming disease in sugarcane. Here, we compare complete genome sequences for five isolates of Xvv originating from sugarcane and one from maize. This identified two distinct types of lipopolysaccharide synthesis gene clusters among Xvv isolates: one is similar to that of Xanthomonas axonopodis pathovar citri (Xac) and is probably the ancestral type, while the other is similar to those of the sugarcane-inhabiting species, Xanthomonas sacchari. Four of six Xvv isolates harboured sequences similar to the Xac plasmid, pXAC47, and showed a distinct Type-IV pilus (T4P) sequence type, whereas the T4P locus of the other two isolates resembled that of the closely related banana pathogen, Xanthomonas campestris pathovar musacearum (Xcm). The Xvv isolate from maize has lost a gene encoding a homologue of the virulence effector, xopAF, which was present in all five of the sugarcane isolates, while xopL contained a premature stop codon in four out of six isolates. These findings shed new light on evolutionary events since the divergence of Xvv and Xcm, as well as further elucidating the relationships between the two closely related pathogens

Comparative genome analysis provides insights into the evolution and adaptation of Pseudomonas syringae pv. aesculi on Aesculus hippocastanum.

A recently emerging bleeding canker disease, caused by Pseudomonas syringae pathovar aesculi (Pae), is threatening European horse chestnut in northwest Europe. Very little is known about the origin and biology of this new disease. We used the nucleotide sequences of seven commonly used marker genes to investigate the phylogeny of three strains isolated recently from bleeding stem cankers on European horse chestnut in Britain (E-Pae). On the basis of these sequences alone, the E-Pae strains were identical to the Pae type-strain (I-Pae), isolated from leaf spots on Indian horse chestnut in India in 1969. The phylogenetic analyses also showed that Pae belongs to a distinct clade of P. syringae pathovars adapted to woody hosts. We generated genome-wide Illumina sequence data from the three E-Pae strains and one strain of I-Pae. Comparative genomic analyses revealed pathovar-specific genomic regions in Pae potentially implicated in virulence on a tree host, including genes for the catabolism of plant-derived aromatic compounds and enterobactin synthesis. Several gene clusters displayed intra-pathovar variation, including those encoding type IV secretion, a novel fatty acid biosynthesis pathway and a sucrose uptake pathway. Rates of single nucleotide polymorphisms in the four Pae genomes indicate that the three E-Pae strains diverged from each other much more recently than they diverged from I-Pae. The very low genetic diversity among the three geographically distinct E-Pae strains suggests that they originate from a single, recent introduction into Britain, thus highlighting the serious environmental risks posed by the spread of an exotic plant pathogenic bacterium to a new geographic location. The genomic regions in Pae that are absent from other P. syringae pathovars that infect herbaceous hosts may represent candidate genetic adaptations to infection of the woody parts of the tree

Long term health outcomes in people with diabetes 12 months after hospitalisation with COVID-19 in the UK: a prospective cohort study

Background: People with diabetes are at increased risk of hospitalisation, morbidity, and mortality following SARS-CoV-2 infection. Long-term outcomes for people with diabetes previously hospitalised with COVID-19 are, however, unknown. This study aimed to determine the longer-term physical and mental health effects of COVID-19 in people with and without diabetes. Methods: The PHOSP-COVID study is a multicentre, long-term follow-up study of adults discharged from hospital between 1 February 2020 and 31 March 2021 in the UK following COVID-19, involving detailed assessment at 5 and 12 months after discharge. The association between diabetes status and outcomes were explored using multivariable linear and logistic regressions. Findings: People with diabetes who survived hospital admission with COVID-19 display worse physical outcomes compared to those without diabetes at 5- and 12-month follow-up. People with diabetes displayed higher fatigue (only at 5 months), frailty, lower physical performance, and health-related quality of life and poorer cognitive function. Differences in outcomes between diabetes status groups were largely consistent from 5 to 12-months. In regression models, differences at 5 and 12 months were attenuated after adjustment for BMI and presence of other long-term conditions. Interpretation: People with diabetes reported worse physical outcomes up to 12 months after hospital discharge with COVID-19 compared to those without diabetes. These data support the need to reduce inequalities in long-term physical and mental health effects of SARS-CoV-2 infection in people with diabetes. Funding: UK Research and Innovation and National Institute for Health Research. The study was approved by the Leeds West Research Ethics Committee (20/YH/0225) and is registered on the ISRCTN Registry (ISRCTN10980107)