Investigating the role of HLA class I derived peptide in alloreactivity.

The peptide complexed with human leukocyte antigen (HLA) can be said to have a significant role in the generation of alloresponses, both in terms of cellular and humoral alloresponses. Previous researchers have identified minor histocompatibility antigen (mHAG) derived peptides such as HA-1, and their contribution to alloresponses. However, little research has been performed regarding the contribution of peptides, which are themselves derived from HLA molecules. To redress this, this thesis focused upon identifying and assessing the function of endogenous peptides, in particular peptides which are themselves derived from HLA class I molecules, which may have a role in the alloresponses, within the context of clinical transplantation.This research describes the creation of a database of HLA class I derived peptides predicted to bind to HLA-A*02 molecules, and then utilises this database to identify HLA class I derived peptides which are bound by the HLA-A*02 molecule, present upon the surface of the monocytic THP-1 cell line. This process identified two peptides, which were derived from one HLA class I molecule and presented by another (HLA-A*02). One of the identified peptides (VMAPRTLIL) belongs to a group of peptides, known as leader peptides, which have functions in both innate and adaptive immune responses. A clinical audit was performed to assess the effect of mismatching the HLA class I derived leader peptides within the context of renal transplantation and identified a correlation with a poorer functioning allograft at 12 months post transplant, when the donor and recipient have 3 leader peptide mismatches (p=< 0.05).Further experimental work attempted to determine a functional role of the endogenous peptides. In particular seeking to establish if variation within peptides bound by the same HLA molecule can influence the subsequent binding of HLA specific antibodies, and if so, seek to elucidate the mechanisms involved. Using a T2 cell line peptide binding assay, as a target for a HLA-A*02 specific antibody, a variation between the ability of the antibody to bind when alternative peptides were bound was observed. Through the use of structural modelling it was demonstrated that changes within HLA class I bound peptides can induce conformational changes to epitopes,which were previously described for HLA class I molecules as being the targets of HLA class I specific antibodies.These findings suggest an important role for HLA class I derived leader peptides in the outcome of renal transplantation, which requires further study within a validating cohort of patients. While the observation that peptides can induce conformational variation within identified epitopes provides further insight into the complex nature of alloantibody binding, and aides the understanding of this process

Ba4Ru3O10.2(OH)1.8 : a new member of the layered hexagonal perovskite family crystallised from water

A new barium ruthenium oxyhydroxide Ba4Ru3O10.2(OH)1.8 crystallises under hydrothermal conditions at 200 °C: powder neutron diffraction data show it adopts an 8H hexagonal perovskite structure with a new stacking sequence, while high resolution electron microscopy reveals regions of ordered layers of vacant Ru sites, and magnetometry shows antiferromagnetism with TN = 200(5) K

Risk Factors for 1-Year Mortality and Hospital Utilization Patterns in Critical Care Survivors

OBJECTIVES: Clear understanding of the long-term consequences of critical care survivorship is essential. We investigated the care process and individual factors associated with long-term mortality among ICU survivors and explored hospital use in this group. DESIGN: Population-based data linkage study using the Secure Anonymised Information Linkage databank. SETTING: All ICUs between 2006 and 2013 in Wales, United Kingdom. PATIENTS: We identified 40,631 patients discharged alive from Welsh adult ICUs. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was 365-day survival. The secondary outcomes were 30- and 90-day survival and hospital utilization in the 365 days following ICU discharge. Kaplan-Meier curves were plotted to compare survival rates. Cox proportional hazards regression models were used to determine risk factors of mortality. Seven-thousand eight-hundred eighty-three patients (19.4%) died during the 1-year follow-up period. In the multivariable Cox regression analysis, advanced age and comorbidities were significant determinants of long-term mortality. Expedited discharge due to ICU bed shortage was associated with higher risk. The rate of hospitalization in the year prior to the critical care admission was 28 hospitalized days/1,000 d; post critical care was 88 hospitalized days/1,000 d for those who were still alive; and 57 hospitalized days/1,000 d and 412 hospitalized days/1,000 d for those who died by the end of the study, respectively. CONCLUSIONS: One in five ICU survivors die within 1 year, with advanced age and comorbidity being significant predictors of outcome, leading to high resource use. Care process factors indicating high system stress were associated with increased risk. More detailed understanding is needed on the effects of the potentially modifiable factors to optimize service delivery and improve long-term outcomes of the critically ill

New software for statistical analysis of Cambridge Structural Database data

A new piece of software for statistical analysis of geometrical, chemical and crystallographic data within the Cambridge Structural Database System is described. This software has been written specifically to deal with chemical structure data and crucially provides simultaneous visualization of the three-dimensional structural information

Binding of human SLBP on the 3′-UTR of histone precursor H4-12 mRNA induces structural rearrangements that enable U7 snRNA anchoring

In metazoans, cell-cycle-dependent histones are produced from poly(A)-lacking mRNAs. The 3′ end of histone mRNAs is formed by an endonucleolytic cleavage of longer precursors between a conserved stem–loop structure and a purine-rich histone downstream element (HDE). The cleavage requires at least two trans-acting factors: the stem–loop binding protein (SLBP), which binds to the stem–loop and the U7 snRNP, which anchors to histone pre-mRNAs by annealing to the HDE. Using RNA structure-probing techniques, we determined the secondary structure of the 3′-untranslated region (3′-UTR) of mouse histone pre-mRNAs H4–12, H1t and H2a–614. Surprisingly, the HDE is embedded in hairpin structures and is therefore not easily accessible for U7 snRNP anchoring. Probing of the 3′-UTR in complex with SLBP revealed structural rearrangements leading to an overall opening of the structure especially at the level of the HDE. Electrophoretic mobility shift assays demonstrated that the SLBP-induced opening of HDE actually facilitates U7 snRNA anchoring on the histone H4–12 pre-mRNAs 3′ end. These results suggest that initial binding of the SLBP functions in making the HDE more accessible for U7 snRNA anchoring

Large-scale associations between the leukocyte transcriptome and BOLD responses to speech differ in autism early language outcome subtypes.

Heterogeneity in early language development in autism spectrum disorder (ASD) is clinically important and may reflect neurobiologically distinct subtypes. Here, we identified a large-scale association between multiple coordinated blood leukocyte gene coexpression modules and the multivariate functional neuroimaging (fMRI) response to speech. Gene coexpression modules associated with the multivariate fMRI response to speech were different for all pairwise comparisons between typically developing toddlers and toddlers with ASD and poor versus good early language outcome. Associated coexpression modules were enriched in genes that are broadly expressed in the brain and many other tissues. These coexpression modules were also enriched in ASD-associated, prenatal, human-specific, and language-relevant genes. This work highlights distinctive neurobiology in ASD subtypes with different early language outcomes that is present well before such outcomes are known. Associations between neuroimaging measures and gene expression levels in blood leukocytes may offer a unique in vivo window into identifying brain-relevant molecular mechanisms in ASD

Deleterious Heteroplasmic Mitochondrial Mutations are associated With an increased Risk of Overall and Cancer-Specific Mortality

Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia