Functional Characterisation of a Novel Tir-Domain containing Protein in Immune Signalling

Dysregulation of innate immune signalling pathways has been implicated in a host of chronic inflammatory disorders including Multiple Sclerosis, Crohn’s Disease and Rheumatoid Arthritis. As a result, it is critical that there are tight regulatory mechanisms in place to rigidly control such signalling pathways. The IL-17 family of cytokines, which comprises six members in mammals, are potent mediators of inflammation. Produced primarily by CD4+ T helper 17 (Th17) cells, they signal through IL-17 receptor family complexes and protect the host against bacterial infection. Each member of the IL-17R family is composed of an extracellular Fibronectin III-like (FnIII) domain, a single transmembrane domain and an intracellular similar expression to FGF genes (SEF)/IL-17R (SEFIR) domain, which is crucial for IL-17 signalling and is homologous to the TIR domains of Toll-Like Receptors (TLRs). Here, we describe a role for IL-17RD, also known as Sef, the remaining orphan receptor of the family, as a functional regulator of innate immune signalling. Small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) were used to suppress endogenous expression of IL-17RD leading to enhanced activation of NF-κB and NF-κB responsive genes by TLR ligands such as Lipopolysaccharide (LPS) and poyinosinic:polycytidylic acid (Poly I:C). We demonstrate that IL-17RD can differentially regulate the various pathways employed by IL-17A. Neutrophil recruitment, in response to in vivo administration of IL-17A, is abolished in IL-17RD-deficient mice, correlating with reduced IL-17A-induced activation of p38 MAPK and expression of the neutrophil chemokine MIP-2. In contrast, IL-17RD deficiency results in enhanced IL-17A-induced activation of NF-κB and IL-6 and KC expression. IL-17RD disrupts the interaction of Act1 and TRAF6 causing differential regulation of NF-κB and p38 MAPK signalling pathways

Functional Characterisation of a Novel Tir-Domain containing Protein in Immune Signalling

Dysregulation of innate immune signalling pathways has been implicated in a host of chronic inflammatory disorders including Multiple Sclerosis, Crohn’s Disease and Rheumatoid Arthritis. As a result, it is critical that there are tight regulatory mechanisms in place to rigidly control such signalling pathways. The IL-17 family of cytokines, which comprises six members in mammals, are potent mediators of inflammation. Produced primarily by CD4+ T helper 17 (Th17) cells, they signal through IL-17 receptor family complexes and protect the host against bacterial infection. Each member of the IL-17R family is composed of an extracellular Fibronectin III-like (FnIII) domain, a single transmembrane domain and an intracellular similar expression to FGF genes (SEF)/IL-17R (SEFIR) domain, which is crucial for IL-17 signalling and is homologous to the TIR domains of Toll-Like Receptors (TLRs). Here, we describe a role for IL-17RD, also known as Sef, the remaining orphan receptor of the family, as a functional regulator of innate immune signalling. Small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs) were used to suppress endogenous expression of IL-17RD leading to enhanced activation of NF-κB and NF-κB responsive genes by TLR ligands such as Lipopolysaccharide (LPS) and poyinosinic:polycytidylic acid (Poly I:C). We demonstrate that IL-17RD can differentially regulate the various pathways employed by IL-17A. Neutrophil recruitment, in response to in vivo administration of IL-17A, is abolished in IL-17RD-deficient mice, correlating with reduced IL-17A-induced activation of p38 MAPK and expression of the neutrophil chemokine MIP-2. In contrast, IL-17RD deficiency results in enhanced IL-17A-induced activation of NF-κB and IL-6 and KC expression. IL-17RD disrupts the interaction of Act1 and TRAF6 causing differential regulation of NF-κB and p38 MAPK signalling pathways

Regular crabmeat consumers do not show increased urinary cadmium or beta-2-microglobulin levels compared to non-crabmeat consumers

Acknowledgements We acknowledge help from staff at Stromness surgery and Balfour hospital, NHS Orkney who collected and processed samples from the Orkney volunteers. We also gratefully acknowledge the contribution of the all volunteers who participated in the study. Financial Support This study was funded by grants from Orkney Fisherman’s Society Ltd and MacDuff Shellfish Ltd who themselves were awarded a grant from the UK Sea Fish Industry Authority’s (Seafish) Strategic Investment Programme 2015-2018. Neither Seafish, Orkney Fisherman’s Society Ltd nor MacDuff Shellfish Ltd had a role in the design, analysis, or writing of this study. The research of A.A.S. and S.B. is supported by Scottish Government’s Rural and Environment Science and Analytical Services Division (RESAS).Peer reviewedPostprin

Survival outcomes after breast cancer surgery among older women with early invasive breast cancer in England: population-based cohort study

Background: This study assessed the influence of age, co-morbidity and frailty on 5-year survival outcomes after breast conservation surgery (BCS) with radiotherapy (RT) versus mastectomy (with or without RT) in women with early invasive breast cancer. Methods: Women aged over 50 years with early invasive breast cancer diagnosed in England (2014–2019) who had breast surgery were identified from Cancer Registry data. Survival estimates were calculated from a flexible parametric survival model. A competing risk approach was used for breast cancer–specific survival (BCSS). Standardized survival probabilities and cumulative incidence functions for breast cancer death were calculated for each treatment by age. Results: Among 101 654 women, 72.2% received BCS + RT and 27.8% received mastectomy. Age, co-morbidity and frailty were associated with overall survival (OS), but only age and co-morbidity were associated with BCSS. Survival probabilities for OS were greater for BCS + RT (90.3%) versus mastectomy (87.0%), and the difference between treatments varied by age (50 years: 1.9% versus 80 years: 6.5%). Cumulative incidence functions for breast cancer death were higher after mastectomy (5.1%) versus BCS + RT (3.9%), but there was little change in the difference by age (50 years: 0.9% versus 80 years: 1.2%). The results highlight the change in baseline mortality risk by age for OS compared to the stable baseline for BCSS. Conclusion: For OS, the difference in survival probabilities for BCS + RT and mastectomy increased slightly with age. The difference in cumulative incidence functions for breast cancer death by surgery type was small regardless of age. Evidence on real-world survival outcomes among older populations with breast cancer is informative for treatment decision-making

Higher total faecal short chain fatty concentrations correlate with increasing proportions of butyrate and decreasing proportions of branched chain fatty acids across multiple human studies

The Rowett Institute (University of Aberdeen) receives financial support from the Scottish Government Rural and Environmental Sciences and Analytical Services (RESAS). Studies 779 and 780 were supported by a grant from the World Cancer Research Fund.Peer reviewedPublisher PD

Analysis of lesion localisation at colonoscopy: outcomes from a multi-centre U.K. study

Background: Colonoscopy is currently the gold standard for detection of colorectal lesions, but may be limited in anatomically localising lesions. This audit aimed to determine the accuracy of colonoscopy lesion localisation, any subsequent changes in surgical management and any potentially influencing factors. Methods: Patients undergoing colonoscopy prior to elective curative surgery for colorectal lesion/s were included from 8 registered U.K. sites (2012–2014). Three sets of data were recorded: patient factors (age, sex, BMI, screener vs. symptomatic, previous abdominal surgery); colonoscopy factors (caecal intubation, scope guide used, colonoscopist accreditation) and imaging modality. Lesion localisation was standardised with intra-operative location taken as the gold standard. Changes to surgical management were recorded. Results: 364 cases were included; majority of lesions were colonic, solitary, malignant and in symptomatic referrals. 82% patients had their lesion/s correctly located at colonoscopy. Pre-operative CT visualised lesion/s in only 73% of cases with a reduction in screening patients (64 vs. 77%; p = 0.008). 5.2% incorrectly located cases at colonoscopy underwent altered surgical management, including conversion to open. Univariate analysis found colonoscopy accreditation, scope guide use, incomplete colonoscopy and previous abdominal surgery significantly influenced lesion localisation. On multi-variate analysis, caecal intubation and scope guide use remained significant (HR 0.35, 0.20–0.60 95% CI and 0.47; 0.25–0.88, respectively). Conclusion: Lesion localisation at colonoscopy is incorrect in 18% of cases leading to potentially significant surgical management alterations. As part of accreditation, colonoscopists need lesion localisation training and awareness of when inaccuracies can occur

Higher total faecal short-chain fatty acid concentrations correlate with increasing proportions of butyrate and decreasing proportions of branched-chain fatty acids across multiple human studies

Metabolites produced by microbial fermentation in the human intestine, especially short-chain fatty acids (SCFAs), are known to play important roles in colonic and systemic health. Our aim here was to advance our understanding of how and why their concentrations and proportions vary between individuals. We have analysed faecal concentrations of microbial fermentation acids from 10 human volunteer studies, involving 163 subjects, conducted at the Rowett Institute, Aberdeen, UK over a 7-year period. In baseline samples, the % butyrate was significantly higher, whilst % iso-butyrate and % iso-valerate were significantly lower, with increasing total SCFA concentration. The decreasing proportions of iso-butyrate and iso-valerate, derived from amino acid fermentation, suggest that fibre intake was mainly responsible for increased SCFA concentrations. We propose that the increase in % butyrate among faecal SCFA is largely driven by a decrease in colonic pH resulting from higher SCFA concentrations. Consistent with this, both total SCFA and % butyrate increased significantly with decreasing pH across five studies for which faecal pH measurements were available. Colonic pH influences butyrate production through altering the stoichiometry of butyrate formation by butyrate-producing species, resulting in increased acetate uptake and butyrate formation, and facilitating increased relative abundance of butyrate-producing species (notably Roseburia and Eubacterium rectale).The Rowett Institute (University of Aberdeen) receives financial support from the Scottish Government Rural and Environmental Sciences and Analytical Services (RESAS). Studies 779 and 780 were supported by a grant from the World Cancer Research Fund.Peer reviewe

Software defined utility: A step towards a flexible, reliable and low-cost smart grid

The Smart Grid relies in Information and Communication Technologies (ICT) but usually there is still a lack of integration in their deployment. They are designed as separated systems and managed that way too. In addition, the changes in the electric network are so complex and dependable on a very rigid hardware architecture. Based on the work done in the European project FINESCE, this paper presents the “Software Defined Utility “(SDU) concept, which advocates the migration of the utility infrastructure to software systems instead of relying on complex and rigid hardware based systems. This new approach provides a prospective view on the evolution of power systems that will benefit from software systems and high-speed data network infrastructures. More concretely, as a first SDU building block, the paper proposes a data storage and management system based on a hybrid cloud infrastructure to meet the storage requirements of electric utilities. In this regard, the following dimensions have been analysed: the most appropriate methodology to select where data resources should be allocated; security requirements and threads taking into account its deployment in a critical infrastructure like a Smart Grid

The influence of age, comorbidity and frailty on treatment with surgery and systemic therapy in older women with operable triple negative breast cancer (TNBC) in England: A population-based cohort study.

BACKGROUND: Surgery and chemotherapy use were studied among older women with early stage triple negative breast cancer (TNBC) in a population-based cohort. METHODS: Women aged ≥50 years with unilateral early (stage 1-3a) TNBC diagnosed in 2014-2017 were identified from English cancer registration data. Information on surgery and chemotherapy was from linked Hospital Episode Statistics and Systemic Anti-Cancer Therapy datasets, respectively. Logistic regression was used to investigate the influences of patient age, comorbidity and frailty on uptake of surgery and chemotherapy. RESULTS: There were 7094 women with early stage TNBC. Overall rate of surgery was 94%, which only decreased among women aged ≥85 years (74%) and among the most frail. Among the 6681 women receiving surgery, 16% had neoadjuvant and 42% had adjuvant chemotherapy; the use of both decreased with age. More comorbidities and greater frailty were associated with lower rates of chemotherapy. There were differences in the uptake of chemotherapy across geographical regions and in the neoadjuvant and adjuvant chemotherapy regimens between age groups. CONCLUSION: Majority of older women with early TNBC had surgery, although some physically fit older women did not. Chemotherapy use varied by age and fitness

A grape seed and bilberry extract reduces blood pressure in individuals at risk of developing type 2 diabetes: the PRECISE study, a double-blind placebo-controlled cross-over intervention study

BackgroundType 2 Diabetes Mellitus (T2DM) is a major risk factor for the development of cardiometabolic diseases. T2DM prevention is largely based on weight-loss and whole diet changes, but intervention with dietary plant bioactives may also improve metabolic health.ObjectiveTo assess whether supplementation with bilberry and grape seed extract for 12 weeks improves cardiometabolic outcomes in individuals at risk of developing T2DM, and to determine whether individual treatment response is associated with differences in gut microbiota composition and levels of phenolic metabolites in blood and feces.MethodsIn the randomized, double-blind, placebo-controlled, cross-over PRECISE intervention study, 14 participants, aged ≥45 years, with a BMI >28 kg/m2, and having an increased risk of T2DM, received a supplement containing 250 mg of bilberry plus 300 mg of grape seed extract, or 550 mg of a control extract, per day, for 12 weeks each. Blood samples were obtained for the assessment of HbA1c, fasting glucose, oral glucose tolerance tests, insulin, glucagon levels, total, LDL and HDL cholesterol, and phenolic acids. We also assessed advanced glycation end products in the skin, ambulatory 24 hours blood pressure, 7-day dietary intake by weighed food diaries, fecal levels of phenolic metabolites using LC–MS/MS and gut microbiota composition using 16S rRNA gene sequencing analysis.ResultsThe combined bilberry and grape seed extract did not affect glucose and cholesterol outcomes, but it decreased systolic and diastolic ambulatory blood pressure by 4.7 (p < 0.001) and 2.3 (p = 0.0009) mmHg, respectively. Eight out of fourteen participants were identified as blood pressure ‘responders’. These responders had higher levels of phenylpropionic and phenyllactic acids in their fecal samples, and a higher proportional abundance of Fusicatenibacter-related bacteria (p < 0.01) in their baseline stool samples.ConclusionLong-term supplementation with bilberry and grape seed extract can improve systolic and diastolic blood pressure in individuals at risk of T2DM. Individual responsiveness was correlated with the presence of certain fecal bacterial strains, and an ability to metabolize (epi)catechin into smaller phenolic metabolites.Clinical trial registry number: Research Registry (number 4084)