An investigation into the role of Bcl-3 in toll-like receptor signalling

Through the recognition of potentially harmful stimuli, Toll-like receptors (TLRs) initiate the innate immune response and induce the expression of hundreds of immune and pro-inflammatory genes. TLRs are critical in mounting a defence against invading pathogens however, strict control of TLR signalling is vital to prevent host damage from excessive or prolonged immune activation. In this thesis the role of the IκB protein Bcl (B-cell lymphoma)-3 in the regulation of TLR signalling is investigated. Bcl3-/- mice and cells are hyper responsive to TLR stimulation and are defective in LPS tolerance. Bcl-3 interacts with and blocks the ubiquitination of homodimers of the NF-κB subunit, p50. Through stabilisation of inhibitory p50 homodimers, Bcl-3 negatively regulates NF-κB dependent inflammatory gene transcription following TLR activation. Firstly, we investigated the nature of the interaction between Bcl-3 and p50 and using peptide array technology. Key amino acids required for the formation of the p50:Bcl-3 immunosuppressor complex were identified. Furthermore, we demonstrate for the first time that interaction between Bcl-3 and p50 is necessary and sufficient for the anti-inflammatory properties of Bcl-3. Using the data generated from peptide array analysis we then generated cell permeable peptides designed to mimic Bcl-3 function and stabilise p50 homodimers. These Bcl-3 derived peptides are potent inhibitors of NF-κB dependent transcription activity in vitro and provide a solid basis for the development of novel gene-specific approaches in the treatment of inflammatory diseases. Secondly, we demonstrate that Bcl-3 mediated regulation of TLR signalling is not limited to NF-κB and identify the MAK3K Tumour Progression Locus (Tpl)-2 as a new binding partner of Bcl-3. Our data establishes role for Bcl-3 as a negative regulator of the MAPK-ERK pathway.

Analysis of species hyper-diversity in the tropical rain forests of Indonesia: the problem of non-observance

The main interest in the assessment of forest species diversity for conservation purposes is in the rare species. The main problem in the tropical rain forests is that most of the species are rare. Assessment of species diversity in the tropical rain forests is therefore often concerned with estimating that which is not observed in recorded samples. Statistical methodology is therefore required to try to estimate the truncated tail of the species frequency distribution, or to estimate the asymptote of species/diversity-area curves. A Horvitz-Thompson estimator of the number of unobserved (“virtual”) species in each species intensity class is proposed. The approach allows a definition of an extended definition of diversity, ( or generalised Renyi entropy). The paper presents a case study from data collected in Jambi, Sumatra, and the “extended diversity measure” is used on the species data.

A last resort

Considers the situations in which the presumption of advancement should apply to gifts given to family members and how this relates to the presumption of a resulting trust, whereby the law presumes that gifts are to be held for the benefit of the donor unless expressed otherwise, with reference to the Privy Council ruling in Antoni v Antoni. Highlights the bias inherent in the presumption of advancement where it operates for gifts given by husbands to wives, but not the other way round. [From Legal Journals Index]

Venetian time and the meander

Argues that the past is necessary to architectural modernity for its self-definition. Goes on to look at Le Corbusier and the past in relation to his revolutionary architectural manifesto, 'Vers une architecture' (1923), and his and Tafuri's views on Venice. Also considers Le Corbusier's 'law of meander' as a strategy for urbanism and his Venice Hospital project