Reflections on amyloidosis in Papua New Guinea

The amyloidoses comprise a heterogeneous group of diseases in which 1 out of more than 25 human proteins aggregates into characteristic beta-sheet fibrils with some unique properties. Aggregation is nucleation dependent. Among the known amyloid-forming constituents is the prion protein, well known for its ability to transmit misfolding and disease from one individual to another. There is increasing evidence that other amyloid forms also may be transmissible but only if certain prerequisites are fulfilled. One of these forms is systemic AA-amyloidosis in which an acute-phase reactant, serum AA, is over-expressed and, possibly after cleavage, aggregates into amyloid fibrils, causing disease. In a mouse model, this disorder can easily be transmitted from one animal to another both by intravenous and oral routes. Also, synthetic amyloid-like fibrils made from defined small peptides have this property, indicating a prion-like transmission mechanism. Even some fibrils occurring in the environment can transmit AA-amyloidosis in the murine model. AA-amyloidosis is particularly common in certain areas of Papua New Guinea, probably due to the endemicity of malaria and perhaps genetic predisposition. Now, when kuru is disappearing, more interest should be focused on the potentially lethal systemic AA-amyloidosis

Inactivation of polyketide synthase and related genes results in the loss of complex lipids in Mycobacterium tuberculosis H37Rv

Aims: Phthiocerol dimycocerosate (PDIM) waxes and other lipids are necessary for successful Mycobacterium tuberculosis infection, although the exact role of PDIM in host-pathogen interactions remains unclear. In this study, we investigated the contribution of tesA, drrB, pks6 and pks11 genes in complex lipid biosynthesis in M. tuberculosis. Methods and Results: Four mutants were selected from M. tuberculosis H37Rv transposon mutant library. The transposon insertion sites were confirmed to be within the M. tuberculosis open reading frames for tesA (a probable thioesterase), drrB (predicted ABC transporter), pks11 (putative chalcone synthase) and pks6 (polyketide synthase). The first three of these transposon mutants were unable to generate PDIM and the fourth lacked novel polar lipids. Conclusions: Mycobacterium tuberculosis can be cultivated in vitro without the involvement of certain lipid synthesis genes, which may be necessary for in vivo pathogenicity. Significance and Impact of the Study: The use of transposon mutants is a new functional genomic approach for the eventual definition of the mycobacterial ‘lipidome’

Measurements of Distributed Strain During Impact Pile Driving

This paper reports the use of optical Fibre Bragg Grating (FBG) sensors to monitor the stress waves generated below ground during pile driving, combined with measurements using conventional pile driving analyzer (PDA) sensors mounted at the pile head. Fourteen tubular steel piles with a diameter of 508 mm and embedded length to diameter ratios of 6 to 20 were impact driven at an established chalk test site in Kent, UK. The pile shafts were instrumented with multiple FBG strain gauges and pile head PDA sensors, which monitored the piles’ responses under each hammer blow. A high frequency (5 kHz) fibre optic interrogator allowed a previously unseen resolution of the stress wave propagation along the pile. Estimates of the base soil resistances to driving and distributions of shaft shear resistances were found through signal matching that compared time series of pile head PDA measurements and FBG strains measured below ground surface. Numerical solutions of the one-dimensional wave equation were optimised by taking account of the data from multiple FBG gauges, leading to significant advantages that have potential for widespread application in cases where high resolution strain measurements are made