A constraint-based genetic algorithm for optimizing neural network architectures for detection of loss of coolant accidents of nuclear power plants

© 2018 Elsevier B.V. The loss of coolant accident (LOCA) of a nuclear power plant (NPP) is a severe accident in the nuclear energy industry. Nowadays, neural networks have been trained on nuclear simulation transient datasets to detect LOCA. This paper proposes a constraint-based genetic algorithm (GA) to find optimised 2-hidden layer network architectures for detecting LOCA of a NPP. The GA uses a proposed constraint satisfaction algorithm called random walk heuristic to create an initial population of neural network architectures of high performance. At each generation, the GA population is split into a sub-population of feature subsets and a sub-population of 2-hidden layer architectures to breed offspring from each sub-population independently in order to generate a wide variety of network architectures. During breeding 2-hidden layer architectures, a constraint-based nearest neighbor search algorithm is proposed to find the nearest neighbors of the offspring population generated by mutation. The results showed that for LOCA detection, the GA-optimised network outperformed a random search, an exhaustive search and a RBF kernel support vector regression (SVR) in terms of generalization performance. For the skillcraft dataset of the UCI machine learning repository, the GA-optimised network has a similar performance to the RBF kernel SVR and outperformed the other approaches

Folding and stability of the extracellular domain of the human amyloid precursor protein

The beta-amyloid peptide (Abeta), the major component of the senile plaques found in the brains of Alzheimer's disease patients, is derived from proteolytic processing of a transmembrane glycoprotein known as the amyloid precursor protein (APP). Human APP exists in various isoforms, of which the major ones contain 695, 751, and 770 amino acids. Proteolytic cleavage of APP by alpha- or beta-secretases releases the extracellular soluble fragments sAPPalpha or sAPPbeta, respectively. Despite the fact that sAPPalpha plays important roles in both physiological and pathological processes in the brain, very little is known about its structure and stability. We have recently presented a structural model of sAPPalpha(695) obtained from small-angle x-ray scattering measurements (Gralle, M., Botelho, M. M., Oliveira, C. L. P., Torriani, I., and Ferreira, S. T. ( 2002) Biophys. J. 83, 3513 - 3524). We now report studies on the folding and stabilities of sAPPalpha(695) and sAPPalpha(770). The combined use of intrinsic fluorescence, 4-4'-Dianilino-1,1' binaphthyl-5,5'-disulfonic acid ( bis-ANS) fluorescence, circular dichroism, differential ultraviolet absorption, and small-angle x-ray scattering measurements of the equilibrium unfolding of sAPPalpha(695) and sAPPalpha(770) by GdnHCl and urea revealed multistep folding pathways for both sAPPalpha isoforms. Such stepwise folding processes may be related to the identification of distinct structural domains in the three-dimensional model of sAPPalpha. Furthermore, the relatively low stability of the native state of sAPPalpha suggests that conformational plasticity may play a role in allowing APP to interact with a number of distinct physiological ligands.27836342593426

Solution studies and structural model of the extracellular domain of the human amyloid precursor protein

The amyloid precursor protein (APP) is the precursor of the beta-amyloid peptide (Abeta), which is centrally related to the genesis of Alzheimer's disease (AD). In addition, APP has been suggested to mediate and/or participate in events that lead to neuronal degeneration in AD. Despite the fact that various aspects of the cell biology of APP have been investigated, little information on the structure of this protein is available. In this work, the solution structure of the soluble extracellular domain of APP (sAPP, composing 89% of the amino acid residues of the whole protein) has been investigated through a combination of size-exclusion chromatography, circular dichroism, and synchrotron radiation small-angle x-ray scattering (SAXS) studies. sAPP is monomeric in solution (65 kDa obtained from SAXS measurements) and exhibits an anisometric molecular shape, with a Stokes radius of 39 or 51 Angstrom calculated from SAXS or chromatographic data, respectively. The radius of gyration and the maximum molecular length obtained by SAXS were 38 Angstrom and 130 Angstrom, respectively. Analysis of SAXS data further allowed building a structural model for sAPP in solution. Circular dichroism data and secondary structure predictions based on the amino acid sequence of APP suggested that a significant fraction of APP (30% of the amino acid residues) is not involved in standard secondary structure elements, which may explain the elongated shape of the molecule recovered in our structural model. Possible implications of the structure of APP in ligand binding and molecular recognition events involved in the biological functions of this protein are discussed.8363513352

Serum leptin and insulin levels in lactating protein-restricted rats: implications for energy balance

The present study analysed the effect of protein restriction on serum insulin and leptin levels and their relationship with energy balance during lactation. Four groups of rats received isocaloric diets containing 170 g protein/kg or 60 g protein/kg from pregnancy until the 14th day of lactation: control non-lactating, control lactating (both fed a control diet), low-protein non-lactating and low-protein lactating. Energy intake, body composition, energy balance. serum insulin and leptin concentrations and the relationship between these hormones and several factors related to obesity were analysed. Low-protein-intake lactating rats exhibited hypoinsulinaemia, hyperleptinaemia, hypophagia and decreased energy expenditure compared with control lactating rats. The protein level in the carcasses was lower in the low-protein lactating group than in the control lactating group, resulting in a higher fat content in the first group compared with the latter. Body fat correlated inversely with serum insulin and positively with serum leptin level. There was a significant negative correlation between serum leptin and energy intake, and a positive relationship between energy intake and serum insulin level in lactating rats and in the combined data from both groups. Energy expenditure was correlated positively with serum insulin and negatively with serum leptin in lactating rats and when data from control non-lactating and lactating rats were pooled. Lactating rats submitted to protein restriction, compared with lactating control rats, showed that maternal reserves were preserved owing to less severe negative energy balance. This metabolic adaptation was obtained, at least in part, by the hypoinsulinaemia that resulted in increased insulin sensitivity favouring enhanced fat deposition, hyperleptinaemia and hypophagia.o TEXTO COMPLETO DESTE ARTIGO, ESTARÁ DISPONÍVEL À PARTIR DE AGOSTO DE 2015.971273

Solution conformation and heparin-induced dimerization of the full-length extracellular domain of the human amyloid precursor protein

Proteolytic cleavage of the amyloid precursor protein (APP) by beta and gamma-secretases gives rise to the beta-amyloid peptide, considered to be a causal factor in Alzheimer's disease. Conversely, the soluble extracellular domain of APP (sAPP alpha), released upon its cleavage by alpha-secretase, plays a number of important physiological functions. Several APP fragments have been structurally characterized at atomic resolution, but the structures of intact APP and of full-length sAPP alpha have not been determined. Here, ab initio reconstruction of molecular models from high-resolution solution X-ray scattering (SAXS) data for the two main isoforms of sAPP alpha (sAPP alpha(695) and sAPP alpha(770)) provided models of sufficiently high resolution to identify distinct structural domains of APP. The fragments for which structures are known at atomic resolution were fitted within the solution models of full-length sAPPa, allowing localization of important functional sites (i.e. glycosylation, protease inhibitory and heparin-binding sites). Furthermore, combined results from SAXS, analytical ultracentrifugation (AUC) and size-exclusion chromatography (SEC) analysis indicate that both sAPP alpha isoforms are monomeric in solution. On the other hand, SEC, bis-ANS fluorescence, AUC and SAXS measurements showed that sAPPa forms a 2:1 complex with heparin. A conformational model for the sAPP alpha:heparin complex was also derived from the SAXS data. Possible implications of such complex formation for the physiological dimerization of APP and biological signaling are discussed in terms of the structural models proposed. (c) 2005 Elsevier Ltd. All rights reserved.357249350