Allelic polymorphism in the T cell receptor and its impact on immune responses

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01 public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2β loop (Gln55→His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55→Ala55) in complex with HLA-B*3501 revealed that the Gln55→His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection

An exploratory randomized control study of combination cytokine and adult autologous bone marrow progenitor cell administration in patients with ischaemic cardiomyopathy: the REGENERATE-IHD clinical trial

This work forms part of the research themes contributing to the translational research portfolio of Barts and the London Cardiovascular Biomedical Research Unit, which is supported and funded by the National Institute of Health Research. This work was funded by unrestricted grants from the Heart Cells Foundation, Barts, and the London Charity and Chugai Pharmaceuticals

Genetic and Structural Basis for Selection of a Ubiquitous T Cell Receptor Deployed in Epstein-Barr Virus Infection

Despite the ∼1018 αβ T cell receptor (TCR) structures that can be randomly manufactured by the human thymus, some surface more frequently than others. The pinnacles of this distortion are public TCRs, which exhibit amino acid-identical structures across different individuals. Public TCRs are thought to result from both recombinatorial bias and antigen-driven selection, but the mechanisms that underlie inter-individual TCR sharing are still largely theoretical. To examine this phenomenon at the atomic level, we solved the co-complex structure of one of the most widespread and numerically frequent public TCRs in the human population. The archetypal AS01 public TCR recognizes an immunodominant BMLF1 peptide, derived from the ubiquitous Epstein-Barr virus, bound to HLA-A*0201. The AS01 TCR was observed to dock in a diagonal fashion, grasping the solvent exposed peptide crest with two sets of complementarity-determining region (CDR) loops, and was fastened to the peptide and HLA-A*0201 platform with residue sets found only within TCR genes biased in the public response. Computer simulations of a random V(D)J recombination process demonstrated that both TCRα and TCRβ amino acid sequences could be manufactured easily, thereby explaining the prevalence of this receptor across different individuals. Interestingly, the AS01 TCR was encoded largely by germline DNA, indicating that the TCR loci already comprise gene segments that specifically recognize this ancient pathogen. Such pattern recognition receptor-like traits within the αβ TCR system further blur the boundaries between the adaptive and innate immune systems

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Effects of Maths on the Move on Children’s Perspectives, Physical Activity, and Maths Performance

YesPurpose To assess the impact of a six-week ‘Maths on the Move’ (MOTM) physically active learning programme on primary school children’s physical activity (PA) levels and maths performance. Method Randomised control trial. Year 5 children’s PA was assessed using accelerometry for five consecutive school days at baseline and during the final intervention week (final sample: n=97, age M=9.61±0.29, 52.6% female). Two maths performance tests were used; one assessing mathematical content taught during MOTM and one assessing math’s fluency (MASSAT). Both tests were conducted at baseline and following the intervention (week seven). Focus groups were conducted in week seven with intervention children (n=12), randomly choosing an even split of children classified with pre-intervention low or high PA levels. Results On average, during a typical 45-49 minutes MOTM lesson, children obtained an additional five minutes of moderate-to-vigorous PA and 5.7 minutes of light PA counteracted by a reduction of 9.5 minutes of time spent sedentary compared to children that remained in the classroom (control condition). The maths attainment test performance significantly improved over time for children in the MOTM compared to the control (+6.1 versus +0.9, p≤0.0001, d=1.507). No significant improvements were found in the MASSAT total score. Seven emerging themes were derived from the child focus groups. Children felt the MOTM sessions resulted in social and environmental improvements, which improved learning during the sessions. Children described the MOTM sessions as enjoyable, fun, engaging and invigorating – resulting in positive associations to learning and activity. Conclusion Collectively, the findings identify the MOTM programme improves pupil’s PA levels, academic outcomes and identifies pupil’s willingness, enjoyment, and engagement

The Daily Mile™ initiative: Exploring physical activity and the acute effects on executive function and academic performance in primary school children

YesFor schools to consider physical activity (PA) interventions, improvements must be shown in PA and additional educational benefits such as executive function (EF) and academic performance (AP). Over 8800 schools worldwide have implemented The Daily Mile™ (TDM), without any formal assessments of its impact. Rigorous and high-quality studies are needed to explore TDM's contribution to moderate-to-vigorous PA (MVPA) guidelines and potential impact on EFs and AP. Methods: Children (14 classes, n = 303, age mean = 8.99 ± 0.5) from 11 primary schools already implementing TDM consented. At the individual level, children were randomly assigned using a 4-block process to either TDM or continued academic lessons (TDM n = 158, control n = 145). Children completed pre and post, EF tests (Trail Making Task; Digit Recall; Flanker; Animal Stroop) and a maths fluency test (Maths Addition and Subtraction, Speed and Accuracy Test). Accelerometers assessed MVPA using 15-s-epochs and Evenson cut-points. Results: Using multi-level modelling, TDM revealed significantly greater MVPA (+10.23 min) and reduced sedentary time (−9.28 min) compared to control (p ≤ 0.001, d = 4.92, 3.61 retrospectively). Maths fluency interacted with condition and time (p = 0.031, d = 0.25); post hocs revealed no significances over time (p > 0.05). No differences in EFs (all p > 0.05). Conclusions: This study is the first assessing the acute effects of TDM compared to continued academic lessons. TDM revealed no significant improvements in maths fluency or EF. These findings question justifying the widespread adoption of TDM based on enhanced cognition claims. Nonetheless, TDM may provide 10 min of MVPA, achieving a third of the daily in school recommendations to meet overall daily recommendations

Identification of key residues involved in adrenomedullin binding to the AM 1 receptor

BACKGROUND AND PURPOSE:Adrenomedullin (AM) is a peptide hormone whose receptors are members of the class B GPCR family. They comprise a heteromer between the GPCR, the calcitonin receptor-like receptor and one of the receptor activity-modifying proteins 1-3. AM plays a significant role in angiogenesis and its antagonist fragment AM22-52 can inhibit blood vessel and tumour growth. The mechanism by which AM interacts with its receptors is unknown.EXPERIMENTAL APPROACH:We determined the AM22-52 binding epitope for the AM1 receptor extracellular domain using biophysical techniques, heteronuclear magnetic resonance spectroscopy and alanine scanning.KEY RESULTS:Chemical shift perturbation experiments located the main binding epitope for AM22-52 at the AM1 receptor to the C-terminal 8 amino acids. Isothermal titration calorimetry of AM22-52 alanine-substituted peptides indicated that Y52, G51 and I47 are essential for AM1 receptor binding and that K46 and P49 and R44 have a smaller role to play. Characterization of these peptides at the full-length AM receptors was assessed in Cos7 cells by cAMP assay. This confirmed the essential role of Y52, G51 and I47 in binding to the AM1 receptor, with their substitution resulting in ≥100-fold reduction in antagonist potency compared with AM22-52 . R44A, K46A, S48A and P49A AM22-52 decreased antagonist potency by approximately 10-fold.CONCLUSIONS AND IMPLICATIONS:This study localizes the main binding epitope of AM22-52 to its C-terminal amino acids and distinguishes essential residues involved in this binding. This will inform the development of improved AM receptor antagonists

SNARE-ing the structures of Sec1/Munc18 proteins

Membrane fusion is essential for cellular transport in eukaryotes. Abnormalities contribute to a wide range of diseases including diabetes and neurological disorders. A key regulator of SNARE-mediated membrane fusion is the Sec1/Munc18 (SM) protein family. Universal structural features of SM proteins have been identified that affect the way these interact with their partner Syntaxin SNARE proteins. Whilst the molecular basis for SM-regulated SNARE complex formation has been extensively studied, it remains poorly understood. Recent crystal structures of SM proteins alone or in complex have provided new insight. Here we examine the available structural information on SM proteins for clues to how these enigmatic proteins might regulate SNARE complex assembly and membrane fusion