Amyloid fibrillation has been intensively studied because of its association with various neurological disorders. While extensive time-dependent fibrillation experimental data are available and appear similar, few mechanistic models have been developed to unify those results. The aim of this work was to interpret these experimental results via a rigorous mathematical model that incorporates the physical chemistry of nucleation and fibril growth dynamics. A three-stage mechanism consisting of protein misfolding, nucleation, and fibril elongation is proposed and supported by the features of homogeneous fibrillation responses. Estimated by nonlinear least-squares algorithms, the rate constants for nucleation were approximately 10,000,000 times smaller than those for fibril growth. These results, coupled with the positive feedback characteristics of the elongation process, account for the typical sigmoidal behavior during fibrillation. In addition, experiments with different proteins, various initial concentrations, seeding versus nonseeding, and several agitation rates were analyzed with respect to fibrillation using our new model. The wide applicability of the model confirms that fibrillation kinetics may be fairly similar among amyloid proteins and for different environmental factors. Recommendations on further experiments and on the possible use of molecular simulations to determine the desired properties of potential fibrillation inhibitors are offered.

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Abstract.A new method for parametric uncertainty analysis of nu.merical geophysical models is presented. It approximates model response surfaces, which are functions of model input parameters, using orthogonal polynomials, whose weighting functions are the probabilistic density functions (PDFs) of the input uncertain parameters. This approach has been applied to the uncertainty analysis of an analytical model of the direct radiative forcing by anthropogenic sulfate aerosols which has nine uncertain parameters. This method is shown to generate PDFs of the radiative forcing which are very similar to the exact analytical PDF. Compared with the Monte Carlo method for this problem, the new method is a factor of 25 to 60 times faster, depending on the error tolerance, and exhibits an exponential decrease of error with increasing order of the approximation.

This paper describes a computation al implementation of the Fourie rAmp litude Sensitivity Test (FAST) and illustrates its use with a sampl e problem.The FAST procedure i s ideally su ited to t he · i. :ask of determining the global sensitivity of nonl i near ma thematical mode ls subjected to var i ations of arbitrary size in either the system parame ters or initial condition s . A FORTRAN computer program, capable of pe d ormi ng sensitivity analyse s of either algebraic or differential equati on systems i s desc ribed.*Department of Chemical Engineering The computer program presented here provides a general framework for implementation of the FAST method. When combined with a user supplied subroutine for the specific system of interest, the FAST program computes the sen si tivities of the system outputs to the parameter variations specified by the user. The method is illustrated ~ an example involving a simple autocatalytic reaction mechanism.-3-

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▪ Abstract  The environment has emerged as an important determinant of the performance of the modern chemical industry. This paper reviews approaches for incorporating environmental issues into the design of new processes and manufacturing facilities. The organizational framework is the design process itself, which includes framing the problem and generating, analyzing, and evaluating alternatives. A historical perspective on the chemical process synthesis problem illustrates how both performance objectives and the context of the design have evolved to the point where environmental issues must be considered throughout the production chain. In particular, the review illustrates the need to view environmental issues as part of the design objectives rather than as constraints on operations. A concluding section identifies gaps in the literature and opportunities for additional research.

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