Structural basis of GC-1 selectivity for thyroid hormone receptor isoforms

Background: Thyroid receptors, TRa and TR beta, are involved in important physiological functions such as metabolism, cholesterol level and heart activities. Whereas metabolism increase and cholesterol level lowering could be achieved by TR beta isoform activation, TRa activation affects heart rates. Therefore, beta-selective thyromimetics have been developed as promising drug-candidates for treatment of obesity and elevated cholesterol level. GC-1 [ 3,5-dimethyl-4-(4'-hydroxy- 3'-isopropylbenzyl)-phenoxy acetic acid] has ability to lower LDL cholesterol with 600-to 1400-fold more potency and approximately two-to threefold more efficacy than atorvastatin (Lipitor(C)) in studies in rats, mice and monkeys. Results: To investigate GC-1 specificity, we solved crystal structures and performed molecular dynamics simulations of both isoforms complexed with GC-1. Crystal structures reveal that, in TRa Arg228 is observed in multiple conformations, an effect triggered by the differences in the interactions between GC-1 and Ser277 or the corresponding asparagine (Asn331) of TR beta. The corresponding Arg282 of TR beta is observed in only one single stable conformation, interacting effectively with the ligand. Molecular dynamics support this model: our simulations show that the multiple conformations can be observed for the Arg228 in TR alpha, in which the ligand interacts either strongly with the ligand or with the Ser277 residue. In contrast, a single stable Arg282 conformation is observed for TR beta, in which it strongly interacts with both GC-1 and the Asn331. Conclusion: Our analysis suggests that the key factors for GC-1 selectivity are the presence of an oxyacetic acid ester oxygen and the absence of the amino group relative to T(3). These results shed light into the beta-selectivity of GC-1 and may assist the development of new compounds with potential as drug candidates to the treatment of hypercholesterolemia and obesity.

Kinematic parameters and membership probabilities of open clusters in the Bordeaux PM2000 catalogue

Aims. We derive lists of proper-motions and kinematic membership probabilities for 49 open clusters and possible open clusters in the zone of the Bordeaux PM2000 proper motion catalogue (+ 11 degrees <= delta <= + 18 degrees). We test different parametrisations of the proper motion and position distribution functions and select the most successful one. In the light of those results, we analyse some objects individually. Methods. We differenciate between cluster and field member stars, and assign membership probabilities, by applying a new and fully automated method based on both parametrisations of the proper motion and position distribution functions, and genetic algorithm optimization heuristics associated with a derivative-based hill climbing algorithm for the likelihood optimization. Results. We present a catalogue comprising kinematic parameters and associated membership probability lists for 49 open clusters and possible open clusters in the Bordeaux PM2000 catalogue region. We note that this is the first determination of proper motions for five open clusters. We confirm the non-existence of two kinematic populations in the region of 15 previously suspected non-existent objects.

Dweller perception using fuzzy logic for slum upgrading

A large number of initiatives in cities in Brazil - including slum clearance and upgrading - have been undertaken over the years in an effort to ameliorate the problems arising from informal occupation; unfortunately, however, little is known about the related performance outcomes. Careful appraisal of the results of such initiatives is thus called for, covering evaluations of dwellers` perceptions of the upgraded environments. Among the available evaluation methods, post-occupancy evaluation (POE) is commonly employed, although it fails adequately to reflect prevailing subjective concepts of quality. The present paper contains the partial findings of a research exercise aimed at developing an original method, using fuzzy logic, for urban environmental quality evaluation in informally occupied areas on the basis of combining quantitative indicators and dweller perception. It combines POE with fuzzy logic in order to develop tools that can better model the uncertain information that emerges from that kind of study. This paper aims to introduce an uncertainty measure used in order to identify the strengths and weaknesses of slum upgrading projects. The results show that it is possible to quantify certainty degrees in the findings and to define if additional information is needed.

Decision making in fuzzy environment and multicriteria power engineering problems

This paper presents results of research into the use of the Bellman-Zadeh approach to decision making in a fuzzy environment for solving multicriteria power engineering problems. The application of the approach conforms to the principle of guaranteed result and provides constructive lines in computationally effective obtaining harmonious solutions on the basis of solving associated maxmin problems. The presented results are universally applicable and are already being used to solve diverse classes of power engineering problems. It is illustrated by considering problems of power and energy shortage allocation, power system operation, optimization of network configuration in distribution systems, and energetically effective voltage control in distribution systems. (c) 2011 Elsevier Ltd. All rights reserved.

A calibration approach based on Takagi-Sugeno fuzzy inference system for digital electronic compasses

Recently, the development of industrial processes brought on the outbreak of technologically complex systems. This development generated the necessity of research relative to the mathematical techniques that have the capacity to deal with project complexities and validation. Fuzzy models have been receiving particular attention in the area of nonlinear systems identification and analysis due to it is capacity to approximate nonlinear behavior and deal with uncertainty. A fuzzy rule-based model suitable for the approximation of many systems and functions is the Takagi-Sugeno (TS) fuzzy model. IS fuzzy models are nonlinear systems described by a set of if then rules which gives local linear representations of an underlying system. Such models can approximate a wide class of nonlinear systems. In this paper a performance analysis of a system based on IS fuzzy inference system for the calibration of electronic compass devices is considered. The contribution of the evaluated IS fuzzy inference system is to reduce the error obtained in data acquisition from a digital electronic compass. For the reliable operation of the TS fuzzy inference system, adequate error measurements must be taken. The error noise must be filtered before the application of the IS fuzzy inference system. The proposed method demonstrated an effectiveness of 57% at reducing the total error based on considered tests. (C) 2011 Elsevier Ltd. All rights reserved.

Modal functions of future tenses in French

The paper disputes two influential claims in the Romance Linguistics literature. The first is that the synthetic future tenses in spoken Western Romance are now rivalled, if not supplanted, as temporal functors by the more recently developed GO futures. The second is that these synthetic futures now have modal rather than temporal meanings in spoken Romance. These claims are seen as reflecting a universal cycle of diachronic change, in which verb forms originally expressing modal (or aspectual) values take on future temporal reference, becoming tenses. The new modal meanings supplant the temporal, which are then taken up by new forms. Challenges to this theory for French are raised on the basis of empirical evidence of two sorts. Positively, future tenses in spoken Romance continue to be used with temporal meaning. Negatively, evidence of modal meaning for these forms is lacking. The evidence comes froma corpora of spoken French, native speaker judgements and verb data from a daily broadsheet. Cumulatively, it points to the reverse of the claims noted above: the synthetic future in spoken French has temporal but little modal meaning.

Protein fold recognition without Boltzmann statistics or explicit physical basis

We present a fast method for finding optimal parameters for a low-resolution (threading) force field intended to distinguish correct from incorrect folds for a given protein sequence. In contrast to other methods, the parameterization uses information from >10(7) misfolded structures as well as a set of native sequence-structure pairs. In addition to testing the resulting force field's performance on the protein sequence threading problem, results are shown that characterize the number of parameters necessary for effective structure recognition.

Group theory and quasiprobability integrals of Wigner functions

The integral of the Wigner function of a quantum-mechanical system over a region or its boundary in the classical phase plane, is called a quasiprobability integral. Unlike a true probability integral, its value may lie outside the interval [0, 1]. It is characterized by a corresponding selfadjoint operator, to be called a region or contour operator as appropriate, which is determined by the characteristic function of that region or contour. The spectral problem is studied for commuting families of region and contour operators associated with concentric discs and circles of given radius a. Their respective eigenvalues are determined as functions of a, in terms of the Gauss-Laguerre polynomials. These polynomials provide a basis of vectors in a Hilbert space carrying the positive discrete series representation of the algebra su(1, 1) approximate to so(2, 1). The explicit relation between the spectra of operators associated with discs and circles with proportional radii, is given in terms of the discrete variable Meixner polynomials.

A Bayesian approach to fuzzy hypotheses testing for the estimation of optimal age for vaccination against measles

Fuzzy Bayesian tests were performed to evaluate whether the mother`s seroprevalence and children`s seroconversion to measles vaccine could be considered as ""high"" or ""low"". The results of the tests were aggregated into a fuzzy rule-based model structure, which would allow an expert to influence the model results. The linguistic model was developed considering four input variables. As the model output, we obtain the recommended age-specific vaccine coverage. The inputs of the fuzzy rules are fuzzy sets and the outputs are constant functions, performing the simplest Takagi-Sugeno-Kang model. This fuzzy approach is compared to a classical one, where the classical Bayes test was performed. Although the fuzzy and classical performances were similar, the fuzzy approach was more detailed and revealed important differences. In addition to taking into account subjective information in the form of fuzzy hypotheses it can be intuitively grasped by the decision maker. Finally, we show that the Bayesian test of fuzzy hypotheses is an interesting approach from the theoretical point of view, in the sense that it combines two complementary areas of investigation, normally seen as competitive. (C) 2007 IMACS. Published by Elsevier B.V. All rights reserved.

Supervisory control of wastewater treatment plants by combining principal component analysis and fuzzy c-means clustering

In this paper a methodology for integrated multivariate monitoring and control of biological wastewater treatment plants during extreme events is presented. To monitor the process, on-line dynamic principal component analysis (PCA) is performed on the process data to extract the principal components that represent the underlying mechanisms of the process. Fuzzy c-means (FCM) clustering is used to classify the operational state. Performing clustering on scores from PCA solves computational problems as well as increases robustness due to noise attenuation. The class-membership information from FCM is used to derive adequate control set points for the local control loops. The methodology is illustrated by a simulation study of a biological wastewater treatment plant, on which disturbances of various types are imposed. The results show that the methodology can be used to determine and co-ordinate control actions in order to shift the control objective and improve the effluent quality.

Adapted Gaussian basis sets for atoms from Li through Xe generated with the generator coordinate Hartree-Fock method

Utiliza-se o método coordenada geradora Hartree-Fock para gerar bases Gaussianas adaptadas para os átomos de Li (Z=3) até Xe (Z=54). Neste método, integram-se as equações de Griffin-Hill-Wheeler-Hartree-Fock através da técnica de discretização integral. Comparam-se as funções de ondas geradas neste trabalho com as funções de ondas Roothaan-Hartree-Fock de Clementi e Roetti (1974) e com outros conjuntos de bases relatados na literatura. Para os átomos estudados aqui, os erros em nossas energias totais relativos aos limites numéricos Hartree-Fock são sempre menores que 7,426 milihartree.

Utilização da lógica fuzzy na geração de zonas de manejo

Este trabalho teve como objetivo utilizar a lógica fuzzy para geração de zonas de manejo, na área agrária e ambiental. Uma das aplicações consistiu da utilização do método fuzzy C-means, para geração de zonas de manejo para a cultura do mamoeiro, em um plantio comercial localizado em São Mateus-ES, com base em determinações realizadas através de amostragens e análises químicas do solo, considerando os atributos: P, K, Ca, Mg, e Saturação por bases (V%). Aplicou-se também a lógica fuzzy para desenvolver e executar um procedimento para dar suporte ao processo de tomada de decisões, envolvendo análise multicritério, gerando mapas de adequabilidade ao uso público e a conservação no Parque Estadual da Cachoeira da Fumaça, no município de Alegre-ES, considerando como fatores a localização da cachoeira, o uso do solo, os recursos hídricos, as trilhas, os locais de acessos, a infraestrutura, a declividade da área, e utilizando a abordagem de Sistema de Informações Geográficas para análise e combinação da base de dados. A partir das zonas de manejo geradas, foi possível explicar a variabilidade espacial dos atributos do solo na área de estudo da cultura do mamoeiro, e observa-se que as similaridades entre as zonas geradas, a partir de diferentes atributos, mostrou variação, mas observa-se uma influência nos dados, principalmente pelos atributos P e V. A partir do zoneamento da Unidade de Conservação foi possível selecionar áreas mais aptas ao ecoturismo, sendo encontradas próximas da cachoeira, trilhas em zonas de reflorestamento e de Mata Atlântica. Quanto às áreas propensas a medidas de conservação localizam-se próximas à cachoeira e às estruturas do parque, devido à maior pressão antrópica exercida nesses locais. Outras áreas que se destacaram, foram as áreas de pastagem, por estarem em estágio de regeneração natural. Os resultados indicam áreas de mesmo potencial de produção do mamoeiro, ou quando aplicado à área ambiental, áreas que devem receber maior cuidado para utilização por ecoturismo e para preservação e servem de base para a tomada de decisões, visando melhor aproveitamento da área.

Penalty fuzzy function for derivative-free optimization

Penalty and Barrier methods are normally used to solve Nonlinear Optimization Problems constrained problems. The problems appear in areas such as engineering and are often characterised by the fact that involved functions (objective and constraints) are non-smooth and/or their derivatives are not know. This means that optimization methods based on derivatives cannot net used. A Java based API was implemented, including only derivative-free optimizationmethods, to solve both constrained and unconstrained problems, which includes Penalty and Barriers methods. In this work a new penalty function, based on Fuzzy Logic, is presented. This function imposes a progressive penalization to solutions that violate the constraints. This means that the function imposes a low penalization when the violation of the constraints is low and a heavy penalisation when the violation is high. The value of the penalization is not known in beforehand, it is the outcome of a fuzzy inference engine. Numerical results comparing the proposed function with two of the classic penalty/barrier functions are presented. Regarding the presented results one can conclude that the prosed penalty function besides being very robust also exhibits a very good performance.

Optimal fuzzy PID control tuned with genetic algorithms

Fuzzy logic controllers (FLC) are intelligent systems, based on heuristic knowledge, that have been largely applied in numerous areas of everyday life. They can be used to describe a linear or nonlinear system and are suitable when a real system is not known or too difficult to find their model. FLC provide a formal methodology for representing, manipulating and implementing a human heuristic knowledge on how to control a system. These controllers can be seen as artificial decision makers that operate in a closed-loop system, in real time. The main aim of this work was to develop a single optimal fuzzy controller, easily adaptable to a wide range of systems – simple to complex, linear to nonlinear – and able to control all these systems. Due to their efficiency in searching and finding optimal solution for high complexity problems, GAs were used to perform the FLC tuning by finding the best parameters to obtain the best responses. The work was performed using the MATLAB/SIMULINK software. This is a very useful tool that provides an easy way to test and analyse the FLC, the PID and the GAs in the same environment. Therefore, it was proposed a Fuzzy PID controller (FL-PID) type namely, the Fuzzy PD+I. For that, the controller was compared with the classical PID controller tuned with, the heuristic Ziegler-Nichols tuning method, the optimal Zhuang-Atherton tuning method and the GA method itself. The IAE, ISE, ITAE and ITSE criteria, used as the GA fitness functions, were applied to compare the controllers performance used in this work. Overall, and for most systems, the FL-PID results tuned with GAs were very satisfactory. Moreover, in some cases the results were substantially better than for the other PID controllers. The best system responses were obtained with the IAE and ITAE criteria used to tune the FL-PID and PID controllers.

Natural and amyloid self-assembly of S100 proteins: structural basis of functional diversity

The S100 proteins are 10-12 kDa EF-hand proteins that act as central regulators in a multitude of cellular processes including cell survival, proliferation, differentiation and motility. Consequently, many S100 proteins are implicated and display marked changes in their expression levels in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases. The structure and function of S100 proteins are modulated by metal ions via Ca2+ binding through EF-hand motifs and binding of Zn2+ and Cu2+ at additional sites, usually at the homodimer interfaces. Ca2+ binding modulates S100 conformational opening and thus promotes and affects the interaction with p53, the receptor for advanced glycation endproducts and Toll-like receptor 4, among many others. Structural plasticity also occurs at the quaternary level, where several S100 proteins self-assemble into multiple oligomeric states, many being functionally relevant. Recently, we have found that the S100A8/A9 proteins are involved in amyloidogenic processes in corpora amylacea of prostate cancer patients, and undergo metal-mediated amyloid oligomerization and fibrillation in vitro. Here we review the unique chemical and structural properties of S100 proteins that underlie the conformational changes resulting in their oligomerization upon metal ion binding and ultimately in functional control. The possibility that S100 proteins have intrinsic amyloid-forming capacity is also addressed, as well as the hypothesis that amyloid self-assemblies may, under particular physiological conditions, affect the S100 functions within the cellular milieu.