Non-coding RNA and transcriptional regulation in CD4 T cell lineages

CD4 T cell lineage choice epitomises the ability of the immune system to become tailored to a specific threat and provides a framework for understanding the mechanisms behind cell specification. The differentiation of T effectors from naïve cells gives rise to pro-inflammatory lineages including T helper 1 (Th1) and Th2 and anti-inflammatory regulatory T cells (Treg). An additional lineage of Treg also exits the thymus in parallel to naïve T cells and together these Treg are required for prevention of autoimmunity. These T cell lineages are distinct in terms of their cytokine production and functional effects but also through their differences in gene expression and its regulation, which are orchestrated by the presence of lineage-specifying transcription factors specific for each lineage. In addition, post-translational modification of histones also provide insights into this transcriptional regulation and more recently the pervasive and tissue-specific transcription of multiple classes of RNA species without protein coding capacity, non-coding RNA (ncRNA), has been found to play a role in cell differentiation and function. In this thesis I identify several ncRNAs with differential expression different T cell lineages. This includes ncRNAs upregulated Treg compared to T responders. The characterisation of these, including their expression in the autoimmune context of systemic lupus erythematosus (SLE), is presented and their possible biological functions are examined. The relevance of histone modifications for influencing Treg identity in SLE is also investigated. An additional class of ncRNAs that originate from gene enhancer regions, eRNA, is also investigated in the context of Th1 versus Th2 lineage choice. This enhancer transcription is increased genome-wide in Th1 cells at enhancers with high density T-bet binding in, termed ‘super-enhancers’. The functional relevance of these eRNAs, including at the super-enhancer upstream of the Th1 signature cytokine gene, IFNG, is also investigated in knockdown experiments

Tubulointerstitial nephritis in primary Sjögren syndrome: clinical manifestations and response to treatment

BACKGROUND: Primary Sjögren syndrome (pSS) is a common autoimmune condition which primarily affects epithelial tissue, often including the kidney causing either tubulointerstitial nephritis (TIN) or more rarely, an immune complex related glomerulonephritis. METHODS: We describe the clinical, biochemical and histological characteristics of 12 patients with pSS related TIN and their response to treatment with antiproliferative agents. All 12 patients were investigated and treated at the UCL Centre for Nephrology in London. RESULTS: All patients had TIN demonstrated via needle biopsy; immunophenotyping showed that the interstitial infiltrate was predominantly a CD4+ T-cell infiltrate. Urinary acidification testing demonstrated distal renal tubular acidosis in 8 patients. Proximal tubular dysfunction was present in 5 patients. All but 1 patient were treated with antiproliferative agents and most also with a reducing course of steroids. In the treated patients, there was a significant improvement in the serum creatinine and measured GFR. CONCLUSION: Patients with pSS TIN have significant renal impairment and other functional tubular defects. There is a mononuclear lymphocytic infiltrate on renal biopsy and this appears to be mainly a CD4+ T-cell infiltrate. Treatment with mycophenolate (and corticosteroids) improves the renal function in patients with pSS TIN

Same-sex sexual behaviour as a dominance display

Same-sex sexual behaviour (SSB) is widespread across taxa. One adaptive hypothesis to explain the occurrence and maintenance of SSB is that it acts to intensify or diminish aggression by providing males with a means to reinforce or resolve dominance. However, evidence for this hypothesis is very limited across taxa and the possibility that SSB acts as an extension of intrasexual competition remains contentious. We investigated the role of SSB in intensifying or diminishing aggression in the broad-horned flour beetle, Gnatocerus cornutus. We tested the hypothesis that SSB is an extension of male-male competition by observing how the occurrence of SSB and the stability of SSB courtship roles (i.e. whether males switched between mounting and being mounted) influenced levels of aggression within pairs. We found that, typically, males rapidly establish fixed SSB roles and moreover that the occurrence of SSB and the stability of SSB roles had a highly significant effect on levels of aggression observed within pairs. Pairs in which one male consistently mounted the other showed significantly lower levels of aggression than pairs in which neither male exhibited SSB or in which males continuously switched SSB roles and attempted to mount each other. Furthermore, males that were consistently on the receiving end of SSB demonstrated lower propensity to court females and had a lower mating success than active males. This pattern was analogous to that found in loser males as a result of fighting. Males that lost fights also courted less and had lower mating success than males that won fights. Our findings provide the first empirical support for the hypothesis that SSB is an extension of male-male competition. Furthermore, our results suggest that SSB may act as a display, allowing males to resolve dominance hierarchies without escalating into an injurious fight

Multi-scale interaction of flow and the artery wall

We discuss, from the perspective of basic science, the physical and biological processes which underlie atherosclerotic (plaque) initiation at the vascular endothelium, identifying their widely separated spatial and temporal scales which participate. We draw on current, related models of vessel wall evolution, paying particular attention to the role of flow, and proceed to propose, then validate (in practical, qualitative terms, at least) a multiply coupled, multi-scale modeling strategy, which, eventually, aims at a quantitative, patient-specific understanding of the coupling between the flow and the endothelial state

Metabolic Biomarkers for Monitoring in Situ Anaerobic Hydrocarbon Degradation

During the past 15 years researchers have made great strides in understanding the metabolism of hydrocarbons by anaerobic bacteria. Organisms capable of utilizing benzene, toluene, ethylbenzene, xylenes, alkanes, and polycyclic aromatic hydrocarbons have been isolated and described. In addition, the mechanisms of degradation for these compounds have been elucidated. This basic research has led to the development of methods for detecting in situ biodegradation of petroleum-related pollutants in anoxic groundwater. Knowledge of the metabolic pathways used by anaerobic bacteria to break down hydrocarbons has allowed us to identify unique intermediate compounds that can be used as biomarkers for in situ activity. One of these unique intermediates is 2-methylbenzylsuccinate, the product of fumarate addition to o-xylene by the enzyme responsible for toluene utilization. We have carried out laboratory studies to show that this compound can be used as a reliable indicator of anaerobic toluene degradation. Field studies confirmed that the biomarker is detectable in field samples and its distribution corresponds to areas where active biodegradation is predicted. For naphthalene, three biomarkers were identified [2-naphthoic acid (2-NA), tetrahydro-2-NA, and hexahydro-2-NA] that can be used in the field to identify areas of active in situ degradation

The Use of Unregulated Staff: Time for Regulation?

Internationally, shortages in the nursing workforce, escalating patient demands, and financial constraints within the health system have led to the growth of unlicensed nursing support workers. Recently, in relation to the largest publicly funded health system (National Health Service), it was reported that extensive substitution of registered nurses with unskilled nursing support workers resulted in inadequate patient care, increased morbidity and mortality rates, and negative nurse outcomes. We argue that it is timely to consider regulation of nursing support workers with their role and scope of practice clearly defined. Further, the addition of these workers in a complementary model of care (rather than substitutive model) should also be explored in future research, in terms of impact on patient and nurse outcomes. © The Author(s) 2014 Reprints and permissions:]br]sagepub.co.uk/journalsPermissions.nav

Effect of warm intravenous and irrigating fluids on body temperature during transurethral resection of the prostate gland

<p>Abstract</p> <p>Background</p> <p>Transurethral resection of the prostate gland with irrigation fluid at room temperature leads to perioperative hypothermia which could give rise to adverse cardiovascular events in the perioperative period. The use of isothermic irrigation fluid reduces but does not eliminate this risk. Routine use of warm intravenous fluids along with isothermic irrigation had not been documented. This study set out to investigate the effect of the use of warm intravenous fluid together with isothermic irrigation fluid on the body temperature in patients undergoing transurethral resection of the prostate gland.</p> <p>Methods</p> <p>One hundred and twenty consented patients with obstructing benign prostatic hyperplasia were randomly assigned to one of 3 groups. Group 1 received irrigation and intravenous fluids at room temperature, group 2 received warmed irrigation fluid at 38°C along with intravenous fluid at room temperature while group 3 patients received warmed irrigation fluid and warmed intravenous fluids at 38°C. Their perioperative body temperature changes were monitored, analyzed and compared.</p> <p>Results</p> <p>The mean decrease in body temperature at the end of the procedure was significantly greater in group 1 (0.98 ± 0.56°C) than in group 2 (0.42 ± .21°C) (p < 0.001). Significantly more patients in group 1 also experienced shivering. However, in group 3, there was no significant change in the mean body temperature (p > 0.05) and none of them felt cold or shivered.</p> <p>Conclusion</p> <p>It is concluded that the use of isothermic irrigation fluid together with warm intravenous fluids during TURP prevents the occurrence of perioperative hypothermia.</p> <p>Trial registration number</p> <p>CCT-NAPN-15944</p