Differential effects of TR ligands on hormone dissociation rates: Evidence for multiple ligand entry/exit pathways

Some nuclear receptor (NR) ligands promote dissociation of radiolabeled bound hormone from the buried ligand binding cavity (LBC) more rapidly than excess unlabeled hormone itself This result was interpreted to mean that challenger ligands bind allosteric sites on the LBD to induce hormone dissociation, and recent findings indicate that ligands bind weakly to multiple sites on the LBD surface. Here we show, that a large fraction of thyroid hormone receptor (TR) ligands promote rapid dissociation (T(1/2) < 2 h) of , radiolabeled T(3) vs. T(3) (T(1/2), approximate to 5-7 h). We cannot discern relationships between this effect and ligand size, activity or affinity for TR beta. One ligand, GC-24, binds the TR LBC and (weakly) to the TR beta-LBD surface that mediates dimer/heterodimer interaction, but we cannot link this interaction to rapid T(3) dissociation. Instead, several lines of evidence suggest that the challenger ligand must interact with the buried LBC to promote rapid T(3) release. Since previous molecular dynamics simulations suggest that TR ligands leave the LBC by several routes, we propose that a subset of challenger ligands binds and stabilizes a partially unfolded intermediate state of TR that arises during T(3) release and that this effect enhances hormone dissociation. (C) 2009 Elsevier Ltd. All rights reserved.

CoMFA and CoMSIA 3D QSAR Models for a Series of Cyclic Imides with Analgesic Activity

Three-dimensional quantitative structure-activity relationships (3D-QSAR) were performed for a series of analgesic cyclic imides using the CoMFA and CoMSIA methods. Significant correlation coefficients ( CoMFA, r(2) = 0.95 and q(2) = 0.72; CoMSIA, r(2) = 0.96 and q(2) = 0.76) were obtained, and the generated models were externally validated using test sets. The final QSAR models as well as the information gathered from 3D contour maps should be useful for the design of novel cyclic imides having improved analgesic activity.

PK/DB: database for pharmacokinetic properties and predictive in silico ADME models

The study of pharmacokinetic properties (PK) is of great importance in drug discovery and development. In the present work, PK/DB (a new freely available database for PK) was designed with the aim of creating robust databases for pharmacokinetic studies and in silico absorption, distribution, metabolism and excretion (ADME) prediction. Comprehensive, web-based and easy to access, PK/DB manages 1203 compounds which represent 2973 pharmacokinetic measurements, including five models for in silico ADME prediction (human intestinal absorption, human oral bioavailability, plasma protein binding, bloodbrain barrier and water solubility).

Multiple camera people detection and tracking using support integration

This paper proposes a method to locate and track people by combining evidence from multiple cameras using the homography constraint. The proposed method use foreground pixels from simple background subtraction to compute evidence of the location of people on a reference ground plane. The algorithm computes the amount of support that basically corresponds to the ""foreground mass"" above each pixel. Therefore, pixels that correspond to ground points have more support. The support is normalized to compensate for perspective effects and accumulated on the reference plane for all camera views. The detection of people on the reference plane becomes a search for regions of local maxima in the accumulator. Many false positives are filtered by checking the visibility consistency of the detected candidates against all camera views. The remaining candidates are tracked using Kalman filters and appearance models. Experimental results using challenging data from PETS`06 show good performance of the method in the presence of severe occlusion. Ground truth data also confirms the robustness of the method. (C) 2010 Elsevier B.V. All rights reserved.

Measurement error models with a general class of error distribution

In general, the normal distribution is assumed for the surrogate of the true covariates in the classical error model. This paper considers a class of distributions, which includes the normal one, for the variables subject to error. An estimation approach yielding consistent estimators is developed and simulation studies reported.

Some restriction tests in a new class of regression models for proportions

The main purpose of this work is to study the behaviour of Skovgaard`s [Skovgaard, I.M., 2001. Likelihood asymptotics. Scandinavian journal of Statistics 28, 3-32] adjusted likelihood ratio statistic in testing simple hypothesis in a new class of regression models proposed here. The proposed class of regression models considers Dirichlet distributed observations, and the parameters that index the Dirichlet distributions are related to covariates and unknown regression coefficients. This class is useful for modelling data consisting of multivariate positive observations summing to one and generalizes the beta regression model described in Vasconcellos and Cribari-Neto [Vasconcellos, K.L.P., Cribari-Neto, F., 2005. Improved maximum likelihood estimation in a new class of beta regression models. Brazilian journal of Probability and Statistics 19,13-31]. We show that, for our model, Skovgaard`s adjusted likelihood ratio statistics have a simple compact form that can be easily implemented in standard statistical software. The adjusted statistic is approximately chi-squared distributed with a high degree of accuracy. Some numerical simulations show that the modified test is more reliable in finite samples than the usual likelihood ratio procedure. An empirical application is also presented and discussed. (C) 2009 Elsevier B.V. All rights reserved.

Multiple stages of detergent-erythrocyte membrane interaction-A spin label study

The various stages of the interaction between the detergent Triton X-100 (TTX-100) and membranes of whole red blood cells (RBC) were investigated in a broad range of detergent concentrations. The interaction was monitored by RBC hemolysis-assessed by release of intracellular hemoglobin (Hb) and inorganic phosphate- and by analysis of EPR spectra of a fatty acid spin probe intercalated in whole RBC suspensions, as well as pellets and supernatants obtained upon centrifugation of detergent-treated cells. Hemolysis finished at ca. 0.9 mM TTX-100. Spectral analysis and calculation of order parameters (S) indicated that a complex sequence of events takes place, and allowed the characterization of various structures formed in the different stages of detergent-membrane interaction. Upon reaching the end of cell lysis, essentially no pellet was detected, the remaining EPR signal being found almost entirely in the supernatants. Calculated order parameters revealed that whole RBC suspensions, pellets, and supernatants possessed a similar degree of molecular packing, which decreased to a small extent up to 2.5 mM detergent. Between 3.2 and 10 mM TTX-100, a steep decrease in S was observed for both whole RBC suspensions and supernatants. Above 10 mM detergent, S decreased in a less pronounced manner and the EPR spectra approached that of pure TTX-100 micelles. The data were interpreted in terms of the following events: at the lower detergent concentrations, an increase in membrane permeability occurs: the end of hemolysis coincides with the lack of pellet upon centrifugation. Up to 2.5 mM TTX-100 the supernatants consist of a (very likely) heterogeneous population of membrane fragments with molecular packing similar to that of whole cells. As the detergent concentration increases, mixed micelles are formed containing lipid and/or protein, approaching the packing found in pure TTX-100 micelles. This analysis is in agreement with the models proposed by Lasch (Biochim. Biophys Acta 1241 (1995) 269-292) and by Le Maire and coworkers (Biochim. Biophys. Acta 1508 (2000) 86-111). (C) 2010 Elsevier B.V. All rights reserved.

Methodological issues in applying Location Models to Rural areas

Location Models are usedfor planning the location of multiple service centers in order to serve a geographicallydistributed population. A cornerstone of such models is the measure of distancebetween the service center and a set of demand points, viz, the location of thepopulation (customers, pupils, patients and so on). Theoretical as well asempirical evidence support the current practice of using the Euclidian distancein metropolitan areas. In this paper, we argue and provide empirical evidencethat such a measure is misleading once the Location Models are applied to ruralareas with heterogeneous transport networks. This paper stems from the problemof finding an optimal allocation of a pre-specified number of hospitals in alarge Swedish region with a low population density. We conclude that the Euclidianand the network distances based on a homogenous network (equal travel costs inthe whole network) give approximately the same optimums. However networkdistances calculated from a heterogeneous network (different travel costs indifferent parts of the network) give widely different optimums when the numberof hospitals increases.  In terms ofaccessibility we find that the recent closure of hospitals and the in-optimallocation of the remaining ones has increased the average travel distance by 75%for the population. Finally, aggregation the population misplaces the hospitalsby on average 10 km.

Parameterization Of Turbulence Models Using 3DVAR Data Assimilation

In this research the 3DVAR data assimilation scheme is implemented in the numerical model DIVAST in order to optimize the performance of the numerical model by selecting an appropriate turbulence scheme and tuning its parameters. Two turbulence closure schemes: the Prandtl mixing length model and the two-equation k-ε model were incorporated into DIVAST and examined with respect to their universality of application, complexity of solutions, computational efficiency and numerical stability. A square harbour with one symmetrical entrance subject to tide-induced flows was selected to investigate the structure of turbulent flows. The experimental part of the research was conducted in a tidal basin. A significant advantage of such laboratory experiment is a fully controlled environment where domain setup and forcing are user-defined. The research shows that the Prandtl mixing length model and the two-equation k-ε model, with default parameterization predefined according to literature recommendations, overestimate eddy viscosity which in turn results in a significant underestimation of velocity magnitudes in the harbour. The data assimilation of the model-predicted velocity and laboratory observations significantly improves model predictions for both turbulence models by adjusting modelled flows in the harbour to match de-errored observations. 3DVAR allows also to identify and quantify shortcomings of the numerical model. Such comprehensive analysis gives an optimal solution based on which numerical model parameters can be estimated. The process of turbulence model optimization by reparameterization and tuning towards optimal state led to new constants that may be potentially applied to complex turbulent flows, such as rapidly developing flows or recirculating flows.

Analysis Of Semi-Distributed And Global Hydrological Models In The Central Tropical Basins Of The Gulf Of Mexico To The Effects Of Extreme Hydrometeorological Phenomena

In the last years extreme hydrometeorological phenomena have increased in number and intensity affecting the inhabitants of various regions, an example of these effects are the central basins of the Gulf of Mexico (CBGM) that they have been affected by 55.2% with floods and especially the state of Veracruz (1999-2013), leaving economic, social and environmental losses. Mexico currently lacks sufficient hydrological studies for the measurement of volumes in rivers, since is convenient to create a hydrological model (HM) suited to the quality and quantity of the geographic and climatic information that is reliable and affordable. Therefore this research compares the semi-distributed hydrological model (SHM) and the global hydrological model (GHM), with respect to the volumes of runoff and achieve to predict flood areas, furthermore, were analyzed extreme hydrometeorological phenomena in the CBGM, by modeling the Hydrologic Modeling System (HEC-HMS) which is a SHM and the Modèle Hydrologique Simplifié à I'Extrême (MOHYSE) which is a GHM, to evaluate the results and compare which model is suitable for tropical conditions to propose public policies for integrated basins management and flood prevention. Thus it was determined the temporal and spatial framework of the analyzed basins according to hurricanes and floods. It were developed the SHM and GHM models, which were calibrated, validated and compared the results to identify the sensitivity to the real model. It was concluded that both models conform to tropical conditions of the CBGM, having MOHYSE further approximation to the real model. Worth mentioning that in Mexico there is not enough information, besides there are no records of MOHYSE use in Mexico, so it can be a useful tool for determining runoff volumes. Finally, with the SHM and the GHM were generated climate change scenarios to develop risk studies creating a risk map for urban planning, agro-hydrological and territorial organization.

Leakage Detection And Localization Method Based On A Hybrid Inverse/Direct Modelling Approach Suitable For Handling Multiple-Leak Scenarios

When an accurate hydraulic network model is available, direct modeling techniques are very straightforward and reliable for on-line leakage detection and localization applied to large class of water distribution networks. In general, this type of techniques based on analytical models can be seen as an application of the well-known fault detection and isolation theory for complex industrial systems. Nonetheless, the assumption of single leak scenarios is usually made considering a certain leak size pattern which may not hold in real applications. Upgrading a leak detection and localization method based on a direct modeling approach to handle multiple-leak scenarios can be, on one hand, quite straightforward but, on the other hand, highly computational demanding for large class of water distribution networks given the huge number of potential water loss hotspots. This paper presents a leakage detection and localization method suitable for multiple-leak scenarios and large class of water distribution networks. This method can be seen as an upgrade of the above mentioned method based on a direct modeling approach in which a global search method based on genetic algorithms has been integrated in order to estimate those network water loss hotspots and the size of the leaks. This is an inverse / direct modeling method which tries to take benefit from both approaches: on one hand, the exploration capability of genetic algorithms to estimate network water loss hotspots and the size of the leaks and on the other hand, the straightforwardness and reliability offered by the availability of an accurate hydraulic model to assess those close network areas around the estimated hotspots. The application of the resulting method in a DMA of the Barcelona water distribution network is provided and discussed. The obtained results show that leakage detection and localization under multiple-leak scenarios may be performed efficiently following an easy procedure.

Managing Dual Enrollment Programs: Review of Program Models, Operations, and Outcomes

Universities that offer dual enrollment programs for high school students must manage increasing student demand in the face of changing state legislation. This brief examines how institutions finance their dual enrollment programs, and how they ensure academic rigor as their programs continue to grow. The report also considers how dual enrollment programs ensure that students can transfer credits, and what strategies they use to encourage DE students to matriculate as undergraduates.

A Framework supporting collaboration on the distributed design of integrated systems

The work described in this thesis aims to support the distributed design of integrated systems and considers specifically the need for collaborative interaction among designers. Particular emphasis was given to issues which were only marginally considered in previous approaches, such as the abstraction of the distribution of design automation resources over the network, the possibility of both synchronous and asynchronous interaction among designers and the support for extensible design data models. Such issues demand a rather complex software infrastructure, as possible solutions must encompass a wide range of software modules: from user interfaces to middleware to databases. To build such structure, several engineering techniques were employed and some original solutions were devised. The core of the proposed solution is based in the joint application of two homonymic technologies: CAD Frameworks and object-oriented frameworks. The former concept was coined in the late 80's within the electronic design automation community and comprehends a layered software environment which aims to support CAD tool developers, CAD administrators/integrators and designers. The latter, developed during the last decade by the software engineering community, is a software architecture model to build extensible and reusable object-oriented software subsystems. In this work, we proposed to create an object-oriented framework which includes extensible sets of design data primitives and design tool building blocks. Such object-oriented framework is included within a CAD Framework, where it plays important roles on typical CAD Framework services such as design data representation and management, versioning, user interfaces, design management and tool integration. The implemented CAD Framework - named Cave2 - followed the classical layered architecture presented by Barnes, Harrison, Newton and Spickelmier, but the possibilities granted by the use of the object-oriented framework foundations allowed a series of improvements which were not available in previous approaches: - object-oriented frameworks are extensible by design, thus this should be also true regarding the implemented sets of design data primitives and design tool building blocks. This means that both the design representation model and the software modules dealing with it can be upgraded or adapted to a particular design methodology, and that such extensions and adaptations will still inherit the architectural and functional aspects implemented in the object-oriented framework foundation; - the design semantics and the design visualization are both part of the object-oriented framework, but in clearly separated models. This allows for different visualization strategies for a given design data set, which gives collaborating parties the flexibility to choose individual visualization settings; - the control of the consistency between semantics and visualization - a particularly important issue in a design environment with multiple views of a single design - is also included in the foundations of the object-oriented framework. Such mechanism is generic enough to be also used by further extensions of the design data model, as it is based on the inversion of control between view and semantics. The view receives the user input and propagates such event to the semantic model, which evaluates if a state change is possible. If positive, it triggers the change of state of both semantics and view. Our approach took advantage of such inversion of control and included an layer between semantics and view to take into account the possibility of multi-view consistency; - to optimize the consistency control mechanism between views and semantics, we propose an event-based approach that captures each discrete interaction of a designer with his/her respective design views. The information about each interaction is encapsulated inside an event object, which may be propagated to the design semantics - and thus to other possible views - according to the consistency policy which is being used. Furthermore, the use of event pools allows for a late synchronization between view and semantics in case of unavailability of a network connection between them; - the use of proxy objects raised significantly the abstraction of the integration of design automation resources, as either remote or local tools and services are accessed through method calls in a local object. The connection to remote tools and services using a look-up protocol also abstracted completely the network location of such resources, allowing for resource addition and removal during runtime; - the implemented CAD Framework is completely based on Java technology, so it relies on the Java Virtual Machine as the layer which grants the independence between the CAD Framework and the operating system. All such improvements contributed to a higher abstraction on the distribution of design automation resources and also introduced a new paradigm for the remote interaction between designers. The resulting CAD Framework is able to support fine-grained collaboration based on events, so every single design update performed by a designer can be propagated to the rest of the design team regardless of their location in the distributed environment. This can increase the group awareness and allow a richer transfer of experiences among them, improving significantly the collaboration potential when compared to previously proposed file-based or record-based approaches. Three different case studies were conducted to validate the proposed approach, each one focusing one a subset of the contributions of this thesis. The first one uses the proxy-based resource distribution architecture to implement a prototyping platform using reconfigurable hardware modules. The second one extends the foundations of the implemented object-oriented framework to support interface-based design. Such extensions - design representation primitives and tool blocks - are used to implement a design entry tool named IBlaDe, which allows the collaborative creation of functional and structural models of integrated systems. The third case study regards the possibility of integration of multimedia metadata to the design data model. Such possibility is explored in the frame of an online educational and training platform.

Heranças patrimonialistas, (dis)funções burocráticas, práticas gerenciais e os novos arranjos do estado em rede: entendendo a configuração atual da administração pública brasileira

O objetivo do trabalho é compreender a configuração atual da administração pública brasileira a partir da identificação dos seus atributos caracterizadores, tomando como ponto de partida a rejeição da ideia de modelos rígidos e de ruptura entre esses modelos. Os caminhos teóricos percorridos, e que culminaram com a construção de um quadro teórico preliminar, contemplaram inicialmente: a análise histórico-conceitual das relações entre sociedade, Estado e administração pública; a análise da formação do Estado brasileiro desde o período colonial até os dias atuais; a apresentação das configurações da administração pública brasileira, consagradas pela literatura e seus respectivos atributos. Em seguida, foram resgatadas as bases teóricas da administração pública patrimonial, desde a ideia weberiana de dominação patrimonial até as contribuições de alguns interpretes do pensamento social brasileiro à luz da experiência nacional. Foram apresentadas as bases teóricas da administração pública burocrática, desde o tipo ideal weberiano de dominação racional-legal até a releitura do seu processo de implementação e desenvolvimento no Brasil. Também foram expostas as bases teóricas da administração pública gerencial, desde sua origem a nível mundial até os efeitos de seu marco inaugural no Brasil, o Plano Diretor da Reforma do Aparelho do Estado. A pesquisa, predominantemente qualitativa, assumiu três tipologias: bibliográfica, documental e de campo, permitindo o emprego da triangulação. A pesquisa de campo processou-se por meio de nove entrevistas, com roteiro semi-estruturado, com experts em administração pública brasileira. Para a pesquisa documental, foram selecionadas, primordialmente fontes primárias, com ênfase em documentos oficiais, mas também matérias e reportagens em sites, jornais e revistas. Após a análise do conteúdo das entrevistas e dos documentos, chegou-se a quatro eixos temáticos, cada qual com suas respectivas unidades de significado, que permitiram identificar os atributos presentes na administração pública brasileira e definir sua configuração, são eles: a) heranças patrimonialistas, sendo elas o mandonismo (a personalização do poder), o clientelismo, o favoritismo e a cultura da corrupção; b) (dis)funções burocráticas, sendo elas o formalismo, a hierarquia de cargos e funções, a profissionalização do quadro administrativo e a (im)pessoalidade); c) práticas gerenciais, sendo elas a busca da efetividade, as técnicas do management, a governança e a gestão transparente e participativa; e d) novos arranjos do Estado em rede, sendo elas o Estado Global, a cultura da virtualidade, a lógica das redes e o governo eletrônico. Esses eixos permitiram a construção de um quadro final de interpretações que demonstra a presença de atributos patrimonialistas, burocráticos e gerenciais na administração pública brasileira, e também atributos do que se chama de administração pública em rede, principal achado da pesquisa, o que explica a sua configuração múltipla.

Evaluating the existence of structural change in the brazilian term structure of interest: evidence based on cointegration models with structural break

This paper investigates whether there is evidence of structural change in the Brazilian term structure of interest rates. Multivariate cointegration techniques are used to verify this evidence. Two econometrics models are estimated. The rst one is a Vector Autoregressive Model with Error Correction Mechanism (VECM) with smooth transition in the deterministic coe¢ cients (Ripatti and Saikkonen [25]). The second one is a VECM with abrupt structural change formulated by Hansen [13]. Two datasets were analysed. The rst one contains a nominal interest rate with maturity up to three years. The second data set focuses on maturity up to one year. The rst data set focuses on a sample period from 1995 to 2010 and the second from 1998 to 2010. The frequency is monthly. The estimated models suggest the existence of structural change in the Brazilian term structure. It was possible to document the existence of multiple regimes using both techniques for both databases. The risk premium for di¤erent spreads varied considerably during the earliest period of both samples and seemed to converge to stable and lower values at the end of the sample period. Long-term risk premiums seemed to converge to inter-national standards, although the Brazilian term structure is still subject to liquidity problems for longer maturities.