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

An experimental methodology to characterise post-necking behaviour and quantify ductile damage accumulation in isotropic materials

The development of ductile damage, that occurs beyond the point of necking in a tensile test, can be difficult to quantify. An experimental methodology has been developed to accurately characterise the post-necking deformation response of a material through continuous monitoring of the specimens shape up until rupture. By studying the evolution of the neck geometry, the correct values of the local stress and strain have been determined in samples of grade 304L stainless steel and C110 copper. Notched bar specimens of various notch acuities were examined enabling the effects of stress triaxiality on ductile fracture to be determined. The methodology developed has provided a robust framework for macroscopic measurements of ductile damage during the necking process. To characterise the material degradation process, the elastic modulus reduction method was employed on hourglass-shaped specimens of the same materials. Stiffness degradation was measured using a small gauge extensometer during uninterrupted tensile tests with partial elastic unloadings. A metallographic study was conducted on progressively damaged specimens in order to validate the macroscopic damage measurements. A new non-linear ductile damage accumulation law has been developed and calibrated, which provides an advanced representation of the experimental results, and a significant improvement compared to linear accumulation models frequently employed. This realistic modelling approach considers the degradation of the material when it has undergone severe plastic deformation, and provides a more accurate representation of the near failure behaviour by considering the effects of stress triaxiality. The methodology provides accurate data for damage model development and calibration, to improve the predictions of remnant life from ductile damage in engineering components

Fluctuating awareness of treatment goals amongst patients and their caregivers: a longitudinal study of a dynamic process

Background: Because increasing numbers of people now survive for months or years with advanced cancer, communication between patients, service providers, and family caregivers often continues over long periods. Hence, understanding of the goals of medical treatment may develop and change as time elapses and disease progresses. This understanding is closely related to the "awareness of dying," which has been studied in both qualitative and quantitative research. However, when both a patient and family caregiver are involved, the question of "awareness" becomes more complex. A recent longitudinal study reported on patient and caregiver knowledge of treatment goals, but no comparison of such knowledge using matched interview schedules and paired data analysis has been provided. This report examines patterns of awareness and factors associated with these patterns. Materials and methods: One hundred sixty-three patients with incurable cancer and their nominated principal family caregivers (136) were recruited from The Canberra Hospital Oncology Services. Participants' understanding of the treatment goals were measured by interview questions at weeks 1 and 12. Results: One-third of both patients and caregivers understood that the treatment goal was not curative; however, not all patient and caregiver pairs had the same understanding. In 15% of pairs, both patient and caregiver believed that the goal of treatment was curative, while another 13% said that they did not know the aim of the treatment. Thirty-nine percent of pairs registered incongruent responses in which only one member of the pair understood that the treatment was not intended to cure the disease. Over time, a few respondents changed their perception of the treatment goals toward accurate clarification. Bivariate analysis using an awareness variable, constructed for the purpose, showed that in 6 months before death, at least one person in 89% of pairs understood that the treatment was noncurative. Time-to-death, gender, and place of residence were also important predictors of knowledge. Conclusions: Discrepancies between patients and their caregivers may complicate the delivery of effective care when patients are seriously ill. Misunderstanding or uncertainty about treatment goals will obstruct proper informed consent. Health professionals providing care for families dealing with advanced cancer must recognize that the discussion of treatment goals is a dynamic process, which may require them to extend their communication skills

Combined modelling and experimental studies of failure in thick laminates under out-of-plane shear

A multi-scale model validated with out-of-plane shear testing is presented to analyse thick composite structural failure. Key features of this multi-scale analysis approach are inclusion of shear non linearity and modelling the response at a sub-laminate level whilst the structural failure is predicted at a ply level. Based on this multi-scale approach, a user-defined FORTRAN subroutine (VUMAT) has been written for ABAQUS/EXPLICIT solver and is used to model the shear nonlinearity and intra-laminar failure. In addition, a cohesive zone model is used to predict the inter-laminar delamination. The modelling has been employed to predict the failure processes for Iosipescu shear test specimens with different fibre orientations. The results show that both the failure mode and the load-displacement trace for finite element simulations agree closely with the experimental findings. This demonstrates the validity of this multi-scale, nonlinear, three-dimensional model for thick laminates. In particular, for the Iosepescu shear test, the effect of the fibres being aligned along the length of the specimen or out-of-plane is investigated as well as different dimensions of the specimen. These simulations are validated by experiments using Digital Image Correlation (DIC)