Towards the pathogenesis of autoimmune liver disease

There have been recent improvements in the clinical understanding and definition of the major types of autoimmune liver disease. However, still lacking is knowledge of their prevalence and pathogenesis. Three areas of study are in progress in our laboratory. First, in type 1 autoimmune hepatitis, the search continues to identify a liver/disease-specific autoantigenic reactant. Using hepatocyte membrane preparations, immunoblotting has underlined the problem of distinguishing, among multiple reactants, those that may be causally rather than consequentially related to hepatocellular damage. Second, in primary biliary cirrhosis (PBC), the need for population screening to ascertain prevalence and detect preclinical cases can be met by a rapid automated procedure for detection, by specific enzyme inhibition in microtitre wells, of antibody (anti-M2) to the pyruvate dehydrogenase complex E2 subunit (PDC-E2). Third, the structure of the conformational epitope within the inner lipoyl domain of PDC-E2 is being investigated by screening random phage-displayed peptide libraries using PBC sera. This has yielded phage clones in which the sequence of the peptide insert portrays the structure of this epitope, as judged by clustering of PBC-derived sequences to particular branches of a guide-tree that shows relatedness of peptides, and by reactivity of selected phage clones with anti-PDC-E2. Thus phage display identifies a peptide 'mimotope' of the antibody epitope in the inner lipoyl domain of PDC-E2.

Multiple alignment and sorting of peptides derived from phage-displayed random peptide libraries with polyclonal sera allows discrimination of relevant phagotopes

Biopanning of phage-displayed random peptide libraries is a powerful technique for identifying peptides that mimic epitopes (mimotopes) for monoclonal antibodies (mAbs). However, peptides derived using polyclonal antisera may represent epitopes for a diverse range of antibodies. Hence following screening of phage libraries with polyclonal antisera, including autoimmune disease sera, a procedure is required to distinguish relevant from irrelevant phagotopes. We therefore applied the multiple sequence alignment algorithm PILEUP together with a matrix for scoring amino acid substitutions based on physicochemical properties to generate guide trees depicting relatedness of selected peptides. A random heptapeptide library was biopanned nine times using no selecting antibodies, immunoglobulin G (IgG) from sera of subjects with autoimmune diseases (primary biliary cirrhosis (PBC) and type 1 diabetes) and three murine ascites fluids that contained mAbs to overlapping epitope(s) on the Ross River Virus envelope protein 2. Peptides randomly sampled from the library were distributed throughout the guide tree of the total set of peptides whilst many of the peptides derived in the absence of selecting antibody aligned to a single cluster. Moreover peptides selected by different sources of IgG aligned to separate clusters, each with a different amino acid motif. These alignments were validated by testing all of the 53 phagotopes derived using IgG from PBC sera for reactivity by capture ELISA with antibodies affinity purified on the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), the major autoantigen in PBC: only those phagotopes that aligned to PBC-associated clusters were reactive. Hence the multiple sequence alignment procedure discriminates relevant from irrelevant phagotopes and thus a major difficulty with biopanning phage-displayed random peptide libraries with polyclonal antibodies is surmounted.

Insurance contract disclosure – an uncertain balance

This article canvasses recent case law adjudicating the uneasy disclosure balance between the interests of the insurer and the insured in the process of transacting an insurance contract. It examines also the consequences of non-disclosure and misrepresentation and whether the avowed legislative intent — that the liability of the insurer in respect of a claim is to be reduced to the amount that would place the insurer in the position it would have been had the non-disclosure or misrepresentation not occurred — is being achieved in practice. As there is no doubt as to who bears the onus of proof as to non-disclosure or misrepresentation it is surprising that insurers continue to flounder in this regard in relation to underwriting guidelines and adherence to them. The article reviews recent case law in this context and stresses that an insurer wishing to preserve its capacity to avoid liability on the basis that it would not have entered into a contract at all had the true situation been known to it must maintain detailed underwriting guidelines supported by consistent adherence to those guidelines. Recent case law also emphasises that the insurer must provide clear and cogent admissible evidence from appropriate personnel and officers of the company to discharge its onus.

The Murmur of Surfaces: An art collection in perspective exhibition

The Murmur of Surfaces presents the creative outcomes of my PhD research Thesis, Surface Materials and Aspects of Care. As a perspective exhibition at Caboolture Regional Gallery, it also provided me the opportunity to evaluate this more recent body of work alongside earlier work that was formally distinct, highlighting in some ways, a shift from the primacy of form to the agency of matter. The installation of works led the discussion of surfaces to one of space.

CYP19A1 fine-mapping and Mendelian randomization: Estradiol is causal for endometrial cancer

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8x10(-11)). SNP rs727479 was also among those most strongly associated with circulating E2 concentrations in 2767 post-menopausal controls (P=7.4x10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (Pinteraction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.

Selling surf, sun and fitness: Queensland's mass-market fashion

How two powerhouse brands, Billabong and Lorna Jane, took the quintessential Queensland lifestyle to the world stage.

Twitter as a first draft of the present – and the challenges of preserving it for the future

This paper provides a framework for understanding Twitter as a historical source. We address digital humanities scholars to enable the transfer of concepts from traditional source criticism to new media formats, and to encourage the preservation of Twitter as a cultural artifact. Twitter has established itself as a key social media platform which plays an important role in public, real-time conversation. Twitter is also unique as its content is being archived by a public institution (the Library of Congress). In this paper we will show that we still have to assume that much of the contextual information beyond the pure tweet texts is already lost, and propose additional objectives for preservation.