An exploration into identity formation in young people living with a chronic illness

Section A critically reviews relevant theoretical literature and empirical studies exploring the particular impact of chronic illness on identity formation in adolescents. Theoretical conceptualisations of the adolescent period and of the process of identity formation are explored. Following this, empirical literature regarding the impact of chronic illness on the developmental tasks of adolescence and in particular identify formation will be critically examined. A number of clinical implications are discussed to enable clinicians to effectively support young people and future research directions are outlined. Section B reports a narrative analysis of young people's experiences of forming an identity with a diagnosis of an adolescent-onset chronic illness (CI). Identity formation is argued to be one of the key developmental tasks of adolescence. Despite implications for adolescent development, research into CI onset during this period has been notably sparse. This study aimed to explore how diagnosis impacts on the developmental tasks of adolescence, what role adolescent-onset CI plays in identity formation, and how adolescents incorporate the diagnosis into their identity. Individual semi-structured interviews were carried out with 8 young people aged 14-19 who lived with a diagnosis of a CI diagnosed between the ages of 12-16 years. Two illness types were studied; crohn’s disease and juvenile idiopathic arthritis. Interviews were audio-recorded, transcribed and analysed using narrative analysis. Participant narratives contained five core narrative themes: Walking a different path, tolerating contradiction, a changed interface with others, locating power and a fluid relationship. Narratives were considered to have been influenced by factors such as the interview context and dominant social narratives concerning health and illness. Adolescent-onset CI was found to have a significant, though not exclusively negative, impact on developmental tasks. The findings are discussed in relation to existing literature and potential clinical implications. Section C critically appraises the narrative study. A discussion begins with reflections on the research skills developed and insights into the research process. Areas of further learning are identified. Implications of clinical practice are explored and the section concludes with considerations for further research in this area.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Synthesis and evaluation of symmetrical biphenyltetrols as aggregation inhibitors for Alzheimer’s amyloid-β peptide

Inhibiting the aggregation of amyloid-beta peptide (Aβ) is one therapeutic target for the prevention and treatment of Alzheimer’s disease. We have previously demonstrated that biphenyl-3,3′,4,4′-tetrol (3,4-BPT) effectively abrogates Aβ aggregation at stoichiometric concentrations. To investigate molecular architecture and determine how the positioning of the hydroxyl hydrogen-bond donors impacts inhibitor efficacy, we have synthesized four additional symmetrical biphenyltetrols (2,3-, 2,4- 2,5- and 3,5-BPT). We have evaluated these inhibitors by means of Congo red and Thioflavin T dye-binding assays to monitor Aβ aggregation as a function of time and to determine inhibitor IC50 values for reducing equilibrium levels of aggregation. 2,3- and 2,5-BPT were observed to be promising inhibitors of Aβ aggregation: we have qualitatively assessed their IC50 values to be approximately 7X and 3-4X, respectively. In contrast, 2,4- and 3,5-BPT showed little to no inhibition. Thus, 2,5-BPT was the most successful of the four inhibitors evaluated, however; it was not as effective as 3,4-BPT, studied previously (IC50 = 1.0 ± 0.3X). The four isomers we have characterized exhibit a range of IC50 values spanning more than one order of magnitude, likely due to varying abilities to bind to A assemblies. Future work will involve further evaluation of the symmetrical biphenyltetrols, by methods including circular dichroism and transmission electron microscopy, which will afford greater insight into the Aβ assemblies formed in the presence and absence of inhibitors. These results will aid in the rational design of additional small-molecule aggregation inhibitors, including unsymmetrical biphenyltetrols and other architectures bearing hydroxyl substituents in those positions associated with the greatest inhibitory efficacy

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Functional differences exist between TNFα promoters encoding the common -237G SNP and the rarer HLA-B*5701-linked A variant.

A large body of functional and epidemiological evidence have previously illustrated the impact of specific MHC class I subtypes on clinical outcome during HIV-1 infection, and these observations have recently been re-iterated in genome wide association studies (GWAS). Yet because of the complexities surrounding GWAS-based approaches and the lack of knowledge relating to the identity of rarer single nucleotide polymorphism (SNP) variants, it has proved difficult to discover independent causal variants associated with favourable immune control. This is especially true of the candidate variants within the HLA region where many of the recently proposed disease influencing SNPs appear to reflect linkage with 'protective' MHC class I alleles. Yet causal MHC-linked SNPs may exist but remain overlooked owing to the complexities associated with their identification. Here we focus on the ancestral TNFα promoter -237A variant (rs361525), shown historically to be in complete linkage disequilibrium with the 'protective' HLA-B*5701 allele. Many of the ancestral SNPs within the extended TNFα promoter have been associated with both autoimmune conditions and disease outcomes, however, the direct role of these variants on TNFα expression remains controversial. Yet, because of the important role played by TNFα in HIV-1 infection, and given the proximity of the -237 SNP to the core promoter, its location within a putative repressor region previously characterized in mice, and its disruption of a methylation-susceptible CpG dinucleotide motif, we chose to carefully evaluate its impact on TNFα production. Using a variety of approaches we now demonstrate that carriage of the A SNP is associated with lower TNFα production, via a mechanism not readily explained by promoter methylation nor the binding of transcription factors or repressors. We propose that the -237A variant could represent a minor causal SNP that additionally contributes to the HLA-B*5701-mediated 'protective' effect during HIV-1 infection

SIDT1 localizes to endolysosomes and mediates double-stranded RNA transport into the cytoplasm

dsRNA is a common by-product of viral replication and acts as a potent trigger of antiviral immunity. SIDT1 and SIDT2 are closely related members of the SID-1 transmembrane family. SIDT2 functions as a dsRNA transporter and is required to traffic internalized dsRNA from endocytic compartments into the cytosol for innate immune activation, but the role of SIDT1 in dsRNA transport and in the innate immune response to viral infection is unclear. In this study, we show that Sidt1 expression is upregulated in response to dsRNA and type I IFN exposure and that SIDT1 interacts with SIDT2. Moreover, similar to SIDT2, SIDT1 localizes to the endolysosomal compartment, interacts with the long dsRNA analog poly(I:C), and, when overexpressed, enhances endosomal escape of poly(I:C) in vitro. To elucidate the role of SIDT1 in vivo, we generated SIDT1-deficient mice. Similar to Sidt2/ mice, SIDT1-deficient mice produced significantly less type I IFN following infection with HSV type 1. In contrast to Sidt2/ mice, however, SIDT1-deficient animals showed no impairment in survival postinfection with either HSV type 1 or encephalomyocarditis virus. Consistent with this, we observed that, unlike SIDT2, tissue expression of SIDT1 was relatively restricted, suggesting that, whereas SIDT1 can transport extracellular dsRNA into the cytoplasm following endocytosis in vitro, the transport activity of SIDT2 is likely to be functionally dominant in vivo

DNA methylation abrogates the activity of both SNP variant TNFα promoters but does not readily explain their functional differences.

<p>(a) Reporter luciferase genes under the control of TNFα promoters carrying either the −237A or G variant were methylated, or demethylated prior to transfection into Jurkat cells. Following 24 hours the cells were stimulated with PMA (for a further 4 hours) prior to the evaluation of luciferase activity. Fold changes (stimulated/non-stimulated) in TNFα production for unmethylated promoters are noted in parentheses (b) Outline of the proximal TNFα promoter adapted from previous reports <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040100#pone.0040100-Falvo1" target="_blank">[10]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0040100#pone.0040100-Barthel1" target="_blank">[43]</a>, illustrating the various transcription factors known to bind in this region. CpG dinucleotides including those which encompass the −237 and −1030 SNPs are noted as black strips, and their positioning relative to the Transcription Start Site (TSS) is displayed numerically (in red). (c) DNA isolated from −237 AA homozygous, −237GG homozygous and GA heterozygous BCLs was bisulfite converted, PCR amplified and sequenced to assess the methylation status of TNFα promoter sequences. A representative sequencing screen encompassing the −1030 SNP denotes the frequency of methylated cytidines (noted as black circles) within individual templates sequenced for a single donor, with a tabular version of summary data for a selection of BCL lines denoting the percentage of methylation at each CpG dinucleotide motif. (d) Three BCL lines encoding different combinations of the TNFα promoter −237 SNP variants (GG, GA and AA) were either left untreated or pre-incubated for 48 hours with 5-Azacytidine prior to PMA stimulation for 4 hours. sTNFα was subsequently measured by ELISA, and both absolute (bar chart) and sTNFα fold increase compared to their respective non-drug treated, PMA stimulated backgrounds (embedded values) are reported. Two biological and technical replicates were analysed per experiment, and median TNFα production plus SEM is reported.</p

Reduced sTNFα production on a−237A SNP background following LPS-activation of PBMCs.

<p>1 million PBMCs isolated from healthy −237GG (n = 9) homozygous or GA heterozygous (n = 9) donors were either left untreated, or stimulated for 4 hours with LPS, following which TNFα levels were estimated by ELISA. sTNFα datasets were evaluated relative to the number of CD14 positive monocytes present in each sample, and TNFα levels were adjusted to represent TNFα production per 1million CD14+ cells. (a) Absolute sTNFα production (stimulated minus non-stimulated) and (b) fold induction (stimulated/non-stimulated) were compared. Wilcoxon-Mann-Whitney tests were used for statistical comparisons, and two-tailed P values are indicated.</p