No description available.

No description available.

The adrenal gland is a highly dynamic organ with the ability to respond to changes in its environment with rapid changes in hormone production, and dramatic remodelling of its structure. Our understanding of the role of the melanocortin peptides in this process has been mostly restricted to the anterior pituitary hormone ACTH, via the melanocortin 2 receptor MC2R. The presence of additional melanocortin receptors and their antagonists has been demonstrated in rat and bovine adrenals, but the role of these in humans has not been well explored. An intensive clinical and biochemical work-up of a single patient with ACTH-independent Cushing's syndrome and a gastrointestinal stromal tumour (GIST) was performed. The data presented are consistent with the possibility that her disease was caused by release of some bioactive molecule released from the GIST. We propose that alpha-MSH is a possible candidate for this molecule, on the basis that the GIST immuno-stained for alpha- MSH but not ACTH, that alpha-MSH but not ACTH was present in supernatant from a primary culture, and that alpha-MSH has the potential to stimulate cortisol production from adrenal cells. The precise mechanism for alpha-MSH secretion from the tumour is not fully elucidated, and further work is required to corroborate this hypothesis. The patient had both pigmented skin and pigmented adrenal nodules, and we further demonstrated the presence of the alpha-MSH receptor MC1R was demonstrated with her excised adrenal gland. The pigment was identified as melanin, and we went on to show that same pattern in primary pigmented nodular adrenal disease, and to demonstrate that the zona reticularis in normal adrenal gland contains melanin, and has additional features in common with melanocytic tissues elsewhere in the body. The role of alpha-MSH in normal adrenal function, and the possibility that melanin is also playing an important role, perhaps for its antioxidant properties, is an exciting area for future study.

published_or_final_version / Anatomy / Master / Master of Philosophy

Section 1 (Introduction) provides a short history of pigment development through selected examples. It also details some of the requirements which have to be considered during the formulation of new coloured materials. A brief outline of some synthetic routes towards arylated amino acids and substituted 2,5-dioxopiperazines is also described with the aim of including some of these ideas into the project. Section 2 (Results and Discussion) develops some of the ideas outlined in Section 1. This Section is split into two parts, namely synthetic approaches to some arylated amino acids and some 3,6-disubstituted-2,5-dioxopiperazines. The former part covers the possible routes towards the desired amino acids and deals with the search for a suitable N-protecting group for glycine ethyl ester. It was shown that the propensity for the arylated amino acids either to polymerise or decarboxylate greatly hindered the removal of the various protecting groups examined. The second part covers the search for a suitable N-acyl protecting group to allow the coupling of the 1,4-diprotected-2,5-dioxopiperazine with an aromatic heterocycle. Synthesis of 3,6-bis(benzoxazol-2-yl)-1,4-dibenzyl-2,5-dioxopiperazine was successful; however all attempts at debenzylation failed. The synthesis of 3-(1-t-butoxycarbonyl- benzimidazol-2-yl)-2,5-dioxopiperazine gave rise to some very interesting spectroscopic data which are discussed in this Section. Section 3 (Experimental) details the synthetic procedures used and this is then followed by the Bibliography.

The oxidation of dopamine in aqueous solutions deposits thin conformal films on a wide variety of material surfaces. These films consist of a material known as polydopamine (PDA), and they exhibit chemical and structural similarities to melanin pigments and adhesive proteins secreted by mussels. The facile synthesis and versatile adhesion of PDA enable the functional modification of numerous material surfaces for applications in biomedical devices, energy storage, and water purification. This thesis details fundamental investigations into the deposition, oxidation, and adhesive mechanisms of PDA films. Depositing PDA films on substrates with different controlled chemistries revealed the importance of solution pH and initial deposition rates on the morphology of the films. The deposition of PDA molecules with increasing pH depends on two competing factors: increased generation rate of PDA molecules versus increased solubility due to catechol ionization. The areal density and coverage of three-dimensional PDA islands is influenced by the surface charge and hydrophobicity of the substrate in aqueous solutions. Spectroscopic and electrochemical characterization of PDA films revealed that redox-inactive metal cations can accelerate the oxidation of PDA. The generation of radicals of 5,6-dihydroxyindole were monitored in situ via ultraviolet-visible spectroscopy as a function of cation concentration and pH. The extent of oxidation was quantified by cyclic voltammetry. The resulting oxidation modifies the metal sorption properties of PDA by generating more carboxylic acid groups and enhancing the iron chelation of the films. The adhesive stability of PDA films was characterized by delamination kinetics of films on SiO2 and indium tin oxide (ITO). PDA film adhesion is a substrate, salt, and oxidation-dependent phenomenon. Long-term adhesive stability of PDA films can be promoted by use of higher dopamine concentrations during synthesis, incorporation of multivalent cations, and avoiding alkaline conditions and strongly oxidizing electrical bias. Elastic moduli of PDA films were quantified by compressive thin film wrinkling, and the measured value of 2.0 ± 0.9 GPA agrees with simulations of PDA based on an oligomeric aggregate model. This thesis helps develop a framework for understanding the synthesis, composition, microstructure, and stability of PDA films.

Cryptococcus neoformans is a basidiomycetous yeast capable of causing fatal meningoencephalitis in immunocompromised individuals. Naturally found worldwide in association with pigeon droppings, C. neoformans produces melanin pigments that play a protective role in both natural and physiological settings. Significant variation in the level of melanin production has been observed among natural populations of C. neoformans, although the factors behind this phenotypic variation remain unclear. In my project, I quantified the level of melanin production in 54 strains of C. neoformans and characterized the change in melanin response to three common stressors encountered by C. neoformans in natural and clinical environments: thermal, oxidative and nitrosative stresses. Using this data, I assessed the contribution of genetic factors, environmental factors and genotype-environmental interactions to the observed variance in melanin. The analysis revealed that over 50% of the variance in melanin was attributable to genetic differences among the strains. I identified three single nucleotide polymorphisms (SNPs) in the LAC1 gene, which is essential for melanin synthesis, to be significantly associated with melanin production in thermal and oxidative stresses. One of the SNPs is predicted to cause an amino acid change (P182A/T) in a putative catalytic domain of the Lac1 protein. The genotype-environment interactions were also found to contribute to a significant proportion of the variance in phenotype. In the majority of tested stress conditions, environmental factors only contributed to a small amount of variance ranging from 5-15%. These results highlight the complex interplay of genetic, environmental and interaction factors that contribute to an observable phenotype. C. neoformans is a model fungal pathogen whose ability to produce melanin is a well-established virulence factor. The results from this project contribute to our understanding of the evolutionary trajectory and regulation of melanin production in C. neoformans. / Thesis / Master of Science (MSc) / The yeast, Cryptococcus neoformans, is naturally found worldwide in soil and pigeon droppings, and causes fatal infections in people with a weakened immune system. It produces dark melanin pigments that aid the yeast in neutralizing the immune response of the infected host. My project sought to characterize the variation in melanin levels found among natural populations of C. neoformans and to determine the factors that contribute to this variation. I identified genetic differences between the strains to be the biggest cause of variation in melanin levels. Changes in the LAC1 gene which is essential for melanin synthesis, were found to shape the melanin production significantly when the yeast is exposed to stressful conditions. Interactions between genes and the environment were also revealed to be a significant contribution to the observed differences in melanin levels. These results highlight the complex interplay of factors that shape the expression of observable traits.

Thesis (M.Sc.(Physiological Chemistry)--University of the Witwatersrand, Faculty of Science, 1954.

No description available.

Universiẗat, Diss., 2005--Würzburg.