Population of nonnative states of lysozyme variants drives amyloid fibril formation.

The propensity of protein molecules to self-assemble into highly ordered, fibrillar aggregates lies at the heart of understanding many disorders ranging from Alzheimer's disease to systemic lysozyme amyloidosis. In this paper we use highly accurate kinetic measurements of amyloid fibril growth in combination with spectroscopic tools to quantify the effect of modifications in solution conditions and in the amino acid sequence of human lysozyme on its propensity to form amyloid fibrils under acidic conditions. We elucidate and quantify the correlation between the rate of amyloid growth and the population of nonnative states, and we show that changes in amyloidogenicity are almost entirely due to alterations in the stability of the native state, while other regions of the global free-energy surface remain largely unmodified. These results provide insight into the complex dynamics of a macromolecule on a multidimensional energy landscape and point the way for a better understanding of amyloid diseases.

Multi-dimensional conditional moment closure modelling applied to a heavy-duty common-rail diesel engine

A multi-dimensional combustion code implementing the Conditional Moment Closure turbulent combustion model interfaced with a well-established RANS two- phase flow field solver has been employed to study a broad range of operating conditions for a heavy duty direct-injection common-rail Diesel engine. These conditions include different loads (25%, 50%, 75% and full load) and engine speeds (1250 and 1830 RPM) and, with respect to the fuel path, different injection timings and rail pressures. A total of nine cases have been simulated. Excellent agreement with experimental data has been found for the pressure traces and the heat release rates, without adjusting any model constants. The chemical mechanism used contains a detailed NOx sub-mechanism. The predicted emissions agree reasonably well with the experimental data considering the range of operating points and given no adjustments of any rate constants have been employed. In an effort to identify CPU cost reduction potential, various dimensionality reduction strategies have been assessed. Furthermore, the sensitivity of the predictions with respect to resolution in particular relating to the CMC grid has been investigated. Overall, the results suggest that the presented modelling strategy has considerable predictive capability concerning Diesel engine combustion without requiring model constant calibration based on experimental data. This is true particularly for the heat release rates predictions and, to a lesser extent, for NOx emissions where further progress is still necessary. © 2009 SAE International.