Tunnelling

Tunnelling has become a fragmented process, excessively influenced by lawyers'notions of confrontational contractual bases. This prevents the pooling of skills, essential to the achievement of the promoters' objectives. Tunnelling: Management by Design seeks the reversal of this trend. After a brief historical treatment of selected developments, t

Mitochondrial content is central to nuclear gene expression: profound implications for human health

We review a recent paper in Genome Research by Guantes et al. showing that nuclear gene expression is influenced by the bioenergetic status of the mitochondria. The amount of energy that mitochondria make available for gene expression varies considerably. It depends on: the energetic demands of the tissue; the mitochondrial DNA (mtDNA) mutant load; the number of mitochondria; stressors present in the cell. Hence, when failing mitochondria place the cell in energy crisis there are major effects on gene expression affecting the risk of degenerative diseases, cancer and ageing. In 2015 the UK parliament approved a change in the regulation of IVF techniques, allowing ‘Mitochondrial replacement therapy’ to become a reproductive choice for women at risk of transmitting mitochondrial disease to their children. This is the first time that this technique will be available. Therefore understanding the interaction between mitochondria and the nucleus has never been more important

Detection of <em>Candida albicans</em> DNA from blood samples using a novel electrochemical assay

The genus Candida contains a number of yeast species which are opportunistic pathogens and are associated with life-threatening infections in immunocompromised individuals. Provision of appropriate therapy relies on the rapid identification of the infecting species, and existing methods of identifying Candida species in clinical samples are time and resource intensive and are not always specific enough to differentiate between drug-susceptible and drug-resistant species. We have previously developed a system for the rapid detection of yeast pathogens in clinical samples using PCR followed by hybridization with a suite of five species-specific, electrochemically labelled DNA probes. The limit of detection of the assay was shown to be 37 fg (∼1 genome) per reaction using extracted genomic DNA. We carried out a study to test the limit of detection of one of the probes, CA PR3, using blood samples from a healthy donor that were spiked with genomic DNA or with C. albicans cells. Our results demonstrated a limit of detection of 37 fg (ml blood)−1 (∼1 genome ml−1) using extracted DNA or 10 c.f.u. (ml blood)−1 using C. albicans cells, indicating that the assay is capable of detecting C. albicans nucleic acid at levels that are encountered in clinical samples.</jats:p

Thyroid Immune Related Adverse Events Following Immune Checkpoint Inhibitor Treatment

The efficacy of immune checkpoint inhibitor (ICI) treatment rivals traditional anti-tumor therapies and in most cases results in significantly less drug related toxicity. However, ICI-use can result in a myriad of immune and inflammatory side effects termed immune related adverse events (irAEs). Thyroid irAEs are the most common endocrine toxicity related to ICI-treatment. In affected patients, permanent thyroid dysfunction can result, necessitating lifelong thyroid hormone replacement and long-term clinical follow-up is required. Prior to this candidature, clinical descriptions of thyroid irAEs were predominately based on small, heterogeneous patient cohorts and little was known about the underlying pathogenesis responsible for their development. This thesis produced a detailed phenotypic report of 1246 patients with melanoma undergoing ICI-treatment. We clearly showed that prevalence of thyroid irAEs was substantially higher than previously reported, and that most patients developed subclinical disease only. We demonstrated that overt thyrotoxicosis had distinct clinical features from other thyroid irAE presentations and was uniquely associated with improvements in survival. We prospectively measured anti-thyroid antibody levels and showed they were highly specific for identifying patients likely to experience a thyroid irAE. Our antibody work was complemented by preclinical studies including development of an animal model to test for autoantibodies against novel thyroid antigens, a genetic study to test for an association with FLT3 gene polymorphism and immunophenotyping peripheral blood to identify key immune cell populations involved in the pathogenesis of thyroid irAEs. In totality, the work in this thesis significantly advances understanding of thyroid irAEs and the mechanisms underpinning their development

Preparative and spectroscopic studies of some phosphorus (V) chloride and bromide derivatives

Further preparative and Raman spectroscopic investigations of products derived from reactions of phosphorus (III) halides, boron trihalides and halogens have been made. A new compound of empirical formula P2BCl13 has been formulated as [equations] and may be considered as the parent of a series involving the [equations] cations. The structural implications of the proposed single halide anions and the relationship of the compounds to metastable PCl5 (Phase III) is discussed; changes which occur on heating have been monitored by Raman and magic angle rotation NMR spectroscopy. A further compound analogous to P2Cl9Br has been reported. The compounds MePCl4, Me2PCl3 and Me3PCl2 were prepared and 31Raman and P magic angle rotation NMR measurements support ionicformulations containing single halide ions. Complexes of these withLewis acids were made and the characteristic shifts associated withthe presence of single halide ions in the Raman spectra of the phosphonium cations were observed. Mixed chlorobromo cations ofthese methylphosphoranes were prepared and their Raman spectrapartially assigned. Conventional matrix isolation as well as low temperature sublimation experiments were performed on the vapours above PCl5, PBr5 and MePCl4. Monomeric species were observed for both PCI5 and MePCl4 but decomposition occurred with PBr5. In these studies Raman spectra were monitored from 15K to ambient temperatures and the conversion of covalent to ionic species was observed.<p

Dietary supplementation with vitamin E modulates avian intestinal immunity

The effect of dietary vitamin E on immunoglobulin A (IgA) antibody production, which acts as the first line of defence at the intestinal mucosa, has not been evaluated in chickens. In the present study the impact of the inclusion of supplementary levels of vitamin E to the diet, on total and antigen-specific IgA antibody titres, T-cell subsets and Ia+ cells, was assessed. From hatching, chickens received a maize-based diet which was supplemented with either 25, 250, 2500 or 5000 mg dl-alpha-tocopherol acetate/kg. Primary immunisation with tetanus toxoid (T. toxoid) emulsified in a vegetable oil-in-water adjuvant was administered by the intraperitoneal route at 21 d of age. At 35 d of age all birds received an oral booster vaccination of T. toxoid. Significantly higher total IgA antibody titres were present in the day 42 intestinal scrapings of birds receiving the 5000 mg/kg vitamin E-supplemented diet (VESD) (P=0.05) and a notable increase was observed in birds receiving the 250 mg/kg VESD (P=0.06). At days 21 and 42 total serum IgA antibody titres of birds receiving the 250 mg/kg VESD was significantly higher (

Maternal obesity-induced decreases in plasma, hepatic and uterine polyunsaturated fatty acids during labour is reversed through improved nutrition at conception

Maternal obesity is associated with prolonged and dysfunctional labour, potentially through decreased synthesis of prostaglandins that stimulate myometrial contractions. We assessed the impact of maternal obesity on concentrations of precursor fatty acids (FA) for prostaglandin synthesis and whether any changes could be reversed by improved nutrition post-conception. Wistar rats were fed control (CON) or High-Fat, High-cholesterol (HFHC) diets 6 weeks before mating. At conception half the dams switched diets providing 4 dietary groups: (1) CON, (2) HFHC, (3) CON-HFHC or (4) HFHC-CON. During parturition rats were euthanized and FA composition of plasma, liver and uterus determined. Visceral fat was doubled in rats exposed to the HFHC diet prior to and/or during pregnancy compared to CON. HFHC diet increased MUFAs but decreased omega-3 and omega-6 PUFAs in plasma and liver. Uterine omega-3 FA concentrations were halved in HFHC versus CON rats, but all other FAs were similar. Switching from HFHC to CON diet at conception restored all FA profles to those seen in CON rats. The increased MUFA and decreased PUFA concentrations in obese HFHC dams may contribute to aberrant prostaglandin synthesis and dysfunctional myometrial activity and it may be possible to reverse these changes, and potentially improve labour outcomes, by improving nutrition at conception