Kinetic profiling of therapeutic strategies for inhibiting the formation of amyloid oligomers

Protein self-assembly into amyloid fibrils underlies several neurodegenerative conditions, including Alzheimer's and Parkinson's diseases. It has become apparent that the small oligomers formed during this process constitute neurotoxic molecular species associated with amyloid aggregation. Targeting the formation of oligomers represents therefore a possible therapeutic avenue to combat these diseases. However, it remains challenging to establish which microscopic steps should be targeted to suppress most effectively the generation of oligomeric aggregates. Recently, we have developed a kinetic model of oligomer dynamics during amyloid aggregation. Here, we use this approach to derive explicit scaling relationships that reveal how key features of the time evolution of oligomers, including oligomer peak concentration and life-time, are controlled by the different rate parameters. We discuss the therapeutic implications of our framework by predicting changes in oligomer concentrations when the rates of the individual microscopic events are varied. Our results identify the kinetic parameters that control most effectively the generation of oligomers, thus opening the way for the systematic rational design of therapeutic strategies against amyloid-related diseases

Damage and energy absorption behaviour of composite laminates under impact loading using different impactor geometries

The present paper compares the damage and energy absorption behaviour of composites subjected to low-velocity impact using different frontal geometries for the impactor, with the composites possessing a layup of [02/902]2s. In this study, the rigid impactors with either round-nosed or flat-ended frontal geometry are employed to perform drop-weight tests at various impact energies ranging from 10 to 30 J. The measured loading response and energy absorption are analysed and compared. Additionally, the types and extent of impact-induced damage in the composite specimens are assessed via ultrasonic C-scan, optical microscopy (OM) and scanning electron microscopy (SEM) studies. It is shown that the impact energy threshold for damage initiation is greater than 20 J when using the flat-ended impactor but is less than 10 J when using the round-nosed impactor. In both cases, delamination initiates between the plies in the composite laminate. However, for the flat-ended impactor, the damage behaviour of the fibres exhibits kinking fracture, which differs from the pull-out fibre-fracture caused by the round-nosed impactor. These differences in behaviour are attributed to impactor/composite contact geometry effects which leads to different extents of indentation damage, which in turn directly affects the degree of delamination and fibre damage in the composite

Dynamics of oligomer populations formed during the aggregation of Alzheimer's Aβ42 peptide

Oligomeric species populated during the aggregation of the Aβ42 peptide have been identified as potent cytotoxins linked to Alzheimer’s disease, but the fundamental molecular pathways that control their dynamics have yet to be elucidated. By developing a general approach that combines theory, experiment and simulation, we reveal, in molecular detail, the mechanisms of Aβ42 oligomer dynamics during amyloid fibril formation. Even though all mature amyloid fibrils must originate as oligomers, we found that most Aβ42 oligomers dissociate into their monomeric precursors without forming new fibrils. Only a minority of oligomers converts into fibrillar structures. Moreover, the heterogeneous ensemble of oligomeric species interconverts on timescales comparable to those of aggregation. Our results identify fundamentally new steps that could be targeted by therapeutic interventions designed to combat protein misfolding diseases

Experimental investigations on the effects of projectile hardness on the impact response of fibre reinforced composite laminates

This paper presents a detailed experimental investigation on the effects of projectile hardness on the behaviour of thermoplastic composites under impact loading. In this research, gas-gun experiments employ gelatine and high-density polyethylene (HDPE) projectiles, of the same mass and diameter, to impact against woven carbon-fibre reinforced poly (ether-ether ketone) (CF/PEEK) composite specimens. During the experiments, a high-speed camera is employed to capture the deformation of the projectiles and a three-dimensional (3D) Digital Image Correlation (DIC) system is employed to record the major strain and out-of-plane displacement of the thermoplastic composite specimens. Experimental results, including the Digital Image Correlation (DIC) output and the post-impact status, are obtained and compared to show the effects of harder projectiles on increasing the impact damage. The composite specimens, impacted by gelatine and high-density polyethylene (HDPE) projectiles, presented similar major strain and out-of-plane displacement, but the high-density polyethylene (HDPE)-impacted composite specimens show more severe damage than the gelatine-impacted composite specimens

The behaviour of fibre-reinforced composites subjected to a soft impact-loading: An experimental and numerical study

The present paper presents experimental and numerical studies on the behaviour of composite laminates subject to impact loading by soft projectiles. In this research, gas-gun experiments are performed to study woven carbon-fibre reinforced poly (ether-ether ketone) (CF/PEEK) composites subjected to an impact by soft-gelatine projectiles. In addition, woven carbon-fibre reinforced epoxy (CF/epoxy) composite specimens are also evaluated using gelatine projectiles to investigate the effect of the matrix system on the impact response of the composites. A high-speed camera is employed to capture the deformation of the projectiles and a three-dimensional (3D) Digital Image Correlation (DIC) system is used to record the deformation of the impacted composite specimens. A Finite Element (FE) model is developed to simulate the impact by a soft projectile on the composite specimens. Good agreement is shown between the predictions from using the FE model and the experimental results

On the extent of fracture toughness transfer from 1D/2D nanomodified epoxy matrices to glass fibre composites

In this study, the effects of adding nanofillers to an epoxy resin (EP) used as a matrix in glass fibre-reinforced plastic (GFRP) composites have been investigated. Both 1D and 2D nanofillers were used, specifically (1) carbon nanotubes (CNTs), (2) few-layer graphene nanoplatelets (GNPs), as well as hybrid combinations of (3) CNTs and boron nitride nanosheets, and (4) GNPs and boron nitride nanotubes (BNNTs). Tensile tests have shown improvements in the transverse stiffness normal to the fibre direction of up to about 25% for the GFRPs using the ‘EP + CNT’ and the ‘EP + BNNT + GNP’ matrices, compared to the composites with the unmodified epoxy (‘EP’). Mode I and mode II fracture toughness tests were conducted using double cantilever beam (DCB) and end-notched flexure (ENF) tests, respectively. In the quasi-static mode I tests, the values of the initiation interlaminar fracture toughness, GCIC, of the GFRP composites showed that the transfer of matrix toughness to the corresponding GFRP composite is greatest for the GFRP composite with the GNPs in the matrix. Here, a coefficient of toughness transfer (CTT), defined as the ratio of mode I initiation interlaminar toughness for the composite to the bulk polymer matrix toughness, of 0.68 was recorded. The highest absolute values of the mode I interlaminar fracture toughness at crack initiation were achieved for the GFRP composites with the epoxy matrix modified with the hybrid combinations of nanofillers. The highest value of the CTT during steady-state crack propagation was ~ 2 for all the different types of GFRPs. Fractographic analysis of the composite surfaces from the DCB and ENF specimens showed that failure was by a combination of cohesive (through the matrix) and interfacial (along the fibre/matrix interface) modes, depending on the type of nanofillers used

Mutation at the Evi1 locus in Junbo mice causes susceptibility to otitis media

Otitis media ( OM), inflammation of the middle ear, remains the most common cause of hearing impairment in children. It is also the most common cause of surgery in children in the developed world. There is evidence from studies of the human population and mouse models that there is a significant genetic component predisposing to OM, yet nothing is known about the underlying genetic pathways involved in humans. We identified an N-ethyl-N-nitrosourea-induced dominant mouse mutant Junbo with hearing loss due to chronic suppurative OM and otorrhea. This develops from acute OM that arises spontaneously in the postnatal period, with the age of onset and early severity dependent on the microbiological status of the mice and their air quality. We have identified the causal mutation, a missense change in the C-terminal zinc finger region of the transcription factor Evi1. This protein is expressed in middle ear basal epithelial cells, fibroblasts, and neutrophil leukocytes at postnatal day 13 and 21 when inflammatory changes are underway. The identification and characterization of the Junbo mutant elaborates a novel role for Evi1 in mammalian disease and implicates a new pathway in genetic predisposition to OM

Modelling the effects of patch-plug configuration on the impact performance of patch-repaired composite laminates

The patch-plug configuration has been widely used to repair composite structures and restore the structural integrity of damaged composites. In the present research, single-sided CFRP patch-repaired panels, with different patch-plug configurations, are prepared. This is where a circular-shaped damaged area has been removed and a CFRP patch has been adhesively-bonded onto the panel. In some cases, a CFRP plug is inserted into the hole, caused by removal of the damaged area, before the patch is applied. Such patch-repaired panels, and the pristine CFRP panel, are subjected to a low-velocity impact at an energy of 7.5 J. These impacted pristine and repaired panels are then examined using ultrasonic C-scan and optical microscopy to inspect the impact-associated permanent indentation, interlaminar and intralaminar damage. A finite element analysis (FEA) model, which significantly extends a previously validated elastic-plastic (E-P) numerical damage model, has been developed to predict the impact behaviour of the pristine CFRP panel and the various designs of patch-repaired CFRP panels. The comparison between the experimental and numerical results for all the studied cases shows the maximum deviations for the loading response and the damage area are 12% and 15%, respectively. The good agreement between the experimentally-measured impact properties and those predicted using the numerical model demonstrates that the model is a useful design tool

The ‘Hothaps’ programme for assessing climate change impacts on occupational health and productivity: an invitation to carry out field studies

The ‘high occupational temperature health and productivity suppression’ programme (Hothaps) is a multi-centre health research and prevention programme aimed at quantifying the extent to which working people are affected by, or adapt to, heat exposure while working, and how global heating during climate change may increase such effects. The programme will produce essential new evidence for local, national and global assessment of negative impacts of climate change that have largely been overlooked. It will also identify and evaluate preventive interventions in different social and economic settings