Role of death receptor 3 in health and disease

Death receptor 3 (DR3) is a death domain-containing type I transmembrane protein. It can bring about a wide range of responses from apoptosis to proliferation through association with intracellular signaling molecules. The only accepted ligand for DR3 is TNF-like protein 1A (TL1A). An important role for DR3 in inflammatory disease states is emerging with links being made with inflammatory bowel disease (IBD), Rheumatoid Arthritis, atherosclerosis, allergic lung inflammation and in renal inflammation. The project undertaken in this thesis investigated the role of DR3 in a murine model for rheumatoid arthritis, namely antigen-induced arthritis (AIA), using mice genetically deficient in DR3. A further aim of this project was to generate reagents for use in DR3 research through the employment of DR3 gene cloning strategies. DR3 deficient animals displayed a high degree of protection from mAIA in terms of resolution of joint swelling and the pathological degenerative alterations occurring within the joint. At day 21 post-arthritis induction, a time-point when maximal structural damage would likely be observed, DR37 animals showed a significant reduction in all histopathological parameters including a complete absence of bone erosion. This effect was shown to be DR3 specific through the administration of TL1A to control animals. Mice receiving increasing concentrations of TL1A showed a dose-dependent increase in synovial hyperplasia and bone erosion. DR3 deficient mice also displayed protection from cartilage depletion following induction of AIA. In an attempt to dissect a mechanism for this reduced disease severity, an analysis of osteoclast numbers and F4/80+ osteoclast precursor cell numbers within the joints was undertaken. DR3 sufficient mice displayed significantly more osteoclasts at sites of focal bone erosion which could not be attributed to differences in F4/80+ precursor cell numbers. The results presented here identify a potentially novel target for the treatment of human inflammatory joint disease.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Role of death receptor 3 in health and disease

Death receptor 3 (DR3) is a death domain-containing type I transmembrane protein. It can bring about a wide range of responses from apoptosis to proliferation through association with intracellular signaling molecules. The only accepted ligand for DR3 is TNF-like protein 1A (TL1A). An important role for DR3 in inflammatory disease states is emerging with links being made with inflammatory bowel disease (IBD), Rheumatoid Arthritis, atherosclerosis, allergic lung inflammation and in renal inflammation. The project undertaken in this thesis investigated the role of DR3 in a murine model for rheumatoid arthritis, namely antigen-induced arthritis (AIA), using mice genetically deficient in DR3. A further aim of this project was to generate reagents for use in DR3 research through the employment of DR3 gene cloning strategies. DR3 deficient animals displayed a high degree of protection from mAIA in terms of resolution of joint swelling and the pathological degenerative alterations occurring within the joint. At day 21 post-arthritis induction, a time-point when maximal structural damage would likely be observed, DR37 animals showed a significant reduction in all histopathological parameters including a complete absence of bone erosion. This effect was shown to be DR3 specific through the administration of TL1A to control animals. Mice receiving increasing concentrations of TL1A showed a dose-dependent increase in synovial hyperplasia and bone erosion. DR3 deficient mice also displayed protection from cartilage depletion following induction of AIA. In an attempt to dissect a mechanism for this reduced disease severity, an analysis of osteoclast numbers and F4/80+ osteoclast precursor cell numbers within the joints was undertaken. DR3 sufficient mice displayed significantly more osteoclasts at sites of focal bone erosion which could not be attributed to differences in F4/80+ precursor cell numbers. The results presented here identify a potentially novel target for the treatment of human inflammatory joint disease

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

The Death Receptor 3/TNF-like protein 1A pathway drives adverse bone pathology in inflammatory arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints that is associated with cartilage and bone destruction. Death Receptor 3 (DR3), a tumor necrosis factor (TNF) receptor superfamily member, has recently been associated with the pathogenesis of RA. We demonstrate that absence of DR3 confers resistance to the development of adverse bone pathology in experimental antigen-induced arthritis (AIA). DR3ko mice exhibited a reduction in all histopathological hallmarks of AIA but, in particular, failed to develop subchondral bone erosions and were completely protected from this characteristic of AIA. In contrast, TNF-like protein 1A (TL1A), the ligand for DR3, exacerbated disease in a dose- and DR3-dependent fashion. Analysis of osteoclast number within AIA joint revealed a reduction in areas susceptible to bone erosion in DR3ko mice, whereas in vitro osteoclastogenesis assays showed that TL1A could directly promote osteoclastogenesis in mouse and man. Treatment with antagonistic anti-TL1A mAb protected animals in a systemic model of RA disease collagen-induced arthritis. We therefore conclude that the DR3–TL1A pathway regulates joint destruction in two murine models of arthritis and represents a potential novel target for therapeutic intervention in inflammatory joint diseas

Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatory actions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19. Methods: In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospital with COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients were randomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatment groups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment and were twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants and local study staff were not masked to the allocated treatment, but all others involved in the trial were masked to the outcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) were eligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was 65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomly allocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall, 561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days (rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median 10 days [IQR 5 to &gt;28] vs 11 days [5 to &gt;28]) or the proportion of patients discharged from hospital alive within 28 days (rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, no significant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilation or death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24). Interpretation: In patients admitted to hospital with COVID-19, azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research