Structure- and ligand-based drug design approaches for neglected tropical diseases

Drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. Structure( SBDD) and ligand-based drug design (LBDD) approaches bring together the most powerful concepts in modern chemistry and biology, linking medicinal chemistry with structural biology. The definition and assessment of both chemical and biological space have revitalized the importance of exploring the intrinsic complementary nature of experimental and computational methods in drug design. Major challenges in this field include the identification of promising hits and the development of high-quality leads for further development into clinical candidates. It becomes particularly important in the case of neglected tropical diseases (NTDs) that affect disproportionately poor people living in rural and remote regions worldwide, and for which there is an insufficient number of new chemical entities being evaluated owing to the lack of innovation and R&D investment by the pharmaceutical industry. This perspective paper outlines the utility and applications of SBDD and LBDD approaches for the identification and design of new small-molecule agents for NTDs.

Structure- and Ligand-Based Structure-Activity Relationships for a Series of Inhibitors of Aldolase

Aldolase has emerged as a promising molecular target for the treatment of human African trypanosomiasis. Over the last years, due to the increasing number of patients infected with Trypanosoma brucei, there is an urgent need for new drugs to treat this neglected disease. In the present study, two-dimensional fragment-based quantitative-structure activity relationship (QSAR) models were generated for a series of inhibitors of aldolase. Through the application of leave-one-out and leave-many-out cross-validation procedures, significant correlation coefficients were obtained (r(2) = 0.98 and q(2) = 0.77) as an indication of the statistical internal and external consistency of the models. The best model was employed to predict pK(i) values for a series of test set compounds, and the predicted values were in good agreement with the experimental results, showing the power of the model for untested compounds. Moreover, structure-based molecular modeling studies were performed to investigate the binding mode of the inhibitors in the active site of the parasitic target enzyme. The structural and QSAR results provided useful molecular information for the design of new aldolase inhibitors within this structural class.

Quatro Desenhos de Frank Lloyd Wright

O objetivo deste trabalho é discutir aspectos do processo de projeto e sua representação gráfica, num momento em que softwares de projeto 3D vem se tornando hegemônicos na prática do arquiteto e no ensino de arquitetura, em contraponto às práticas de desenho em prancheta. Os motivos e circunstâncias não são objeto do trabalho, cujo foco está numa prática de projeto e representação gráfica 2D, mas que tem muito a contribuir para o debate do quadro acima: os desenhos de projeto de Frank Lloyd Wright. Casos de estudo: quatro pranchas desenhadas por FLLW. É importante notar que, no vasto quadro da historiografia wrightiana, análises e interpretações originais, pioneiras, da arquitetura vem surgindo nas últimas décadas, mas ainda há poucos textos sobre desenhos e representação gráfica do arquiteto. Este constitui uma primeira aproximação do autor acerca de tema que oferece abrangente potencial. São exemplos em que, na relação imagem-objeto, a representação bidimensional constrói o projeto tridimensional. A arquitetura emerge como experimentação sem cair na especulação formal. Demonstram uma prática mais lenta, reflexiva e laboriosa do que a oferecida pelos software 3D atuais – mas onde cada traço, textura e grafismo implica um significado de espaço e materialidade.

Débito cardíaco e fração de ejeção fetal por meio do spatio-temporal image correlation (STIC): comparação entre fetos masculinos e femininos

OBJETIVO: Comparar do débito cardíaco (DC) e a fração de ejeção (FE) do coração de fetos masculinos e femininos obtidos por meio da ultrassonografia tridimensional, utilizando o spatio-temporal image correlation (STIC). MÉTODOS: Realizou-se um estudo de corte transversal com 216 fetos normais, entre 20 a 34 semanas de gestação, sendo 108 masculinos e 108 femininos. Os volumes ventriculares no final da sístole e diástole foram obtidos por meio do STIC, sendo as avaliações volumétricas realizadas pelo virtual organ computer-aided analysis (VOCAL) com rotação de 30º. Para o cálculo do DC utilizou-se a fórmula: DC= volume sistólico/frequência cardíaca fetal, enquanto que para a FE utilizou-se a fórmula: FE= volume sistólico/volume diastólico final. O DC (combinado, feminino e masculino) e a FE (masculina e feminina) foram comparadas utilizando-se o teste t não pareado e ANCOVA. Foram criados gráficos de dispersão com os percentis 5, 50 e 95. RESULTADOS: A média do DC combinado, DC direito, DC esquerdo, FE direita e FE esquerda, para feminino e masculino, foram 240,07 mL/min; 122,67 mL/min; 123,40 mL/min; 72,84%; 67,22%; 270,56 mL/min; 139,22 mL/min; 131,34 mL/min; 70,73% e 64,76%, respectivamente; sem diferença estatística (P> 0,05). CONCLUSÕES: O DC e a FE fetal obtidos por meio da ultrassonografia tridimensional (STIC) não apresentaram diferença significativa em relação ao gênero.

Polymeric micelles and molecular modeling applied to the development of radiopharmaceuticals

Micelles composed of amphiphilic copolymers linked to a radioactive element are used in nuclear medicine predominantly as a diagnostic application. A relevant advantage of polymeric micelles in aqueous solution is their resulting particle size, which can vary from 10 to 100 nm in diameter. In this review, polymeric micelles labeled with radioisotopes including technetium (99mTc) and indium (111In), and their clinical applications for several diagnostic techniques, such as single photon emission computed tomography (SPECT), gamma-scintigraphy, and nuclear magnetic resonance (NMR), were discussed. Also, micelle use primarily for the diagnosis of lymphatic ducts and sentinel lymph nodes received special attention. Notably, the employment of these diagnostic techniques can be considered a significant tool for functionally exploring body systems as well as investigating molecular pathways involved in the disease process. The use of molecular modeling methodologies and computer-aided drug design strategies can also yield valuable information for the rational design and development of novel radiopharmaceuticals.

Collision free region determination by modified polygonal Boolean operations

Cutting and packing problems are found in numerous industries such as garment, wood and shipbuilding. The collision free region concept is presented, as it represents all the translations possible for an item to be inserted into a container with already placed items. The often adopted nofit polygon concept and its analogous concept inner fit polygon are used to determine the collision free region. Boolean operations involving nofit polygons and inner fit polygons are used to determine the collision free region. New robust non-regularized Boolean operations algorithm is proposed to determine the collision free region. The algorithm is capable of dealing with degenerated boundaries. This capability is important because degenerated boundaries often represent local optimal placements. A parallelized version of the algorithm is also proposed and tests are performed in order to determine the execution times of both the serial and parallel versions of the algorithm.

A contribution for developing more efficient dynamic modelling algorithms of parallel robots

Parallel kinematic structures are considered very adequate architectures for positioning and orienti ng the tools of robotic mechanisms. However, developing dynamic models for this kind of systems is sometimes a difficult task. In fact, the direct application of traditional methods of robotics, for modelling and analysing such systems, usually does not lead to efficient and systematic algorithms. This work addre sses this issue: to present a modular approach to generate the dynamic model and through some convenient modifications, how we can make these methods more applicable to parallel structures as well. Kane’s formulati on to obtain the dynamic equations is shown to be one of the easiest ways to deal with redundant coordinates and kinematic constraints, so that a suitable c hoice of a set of coordinates allows the remaining of the modelling procedure to be computer aided. The advantages of this approach are discussed in the modelling of a 3-dof parallel asymmetric mechanisms.

A representação gráfica na Revista Projeto & Design.

Esta pesquisa inicia-se pelo estudo das diferentes maneiras de representação de um projeto arquitetônico: desenhos analógicos e digitais, desenhos naturais e técnicos, desenhos auxiliados por computador, maquetes físicas e modelos digitais. Teve como objetivo analisar a representação gráfica utilizada nas publicações de obras arquitetônicas em mídias impressas especializadas, tendo sido selecionada a Revista Projeto & Design como estudo de caso. Com este estudo foi possível, por meio de bibliometria gráfica, verificar as contribuições das representações na compreensão e leitura dos projetos arquitetônicos, elencando-se e exemplificando-se as tipologias de imagens utilizadas nas últimas décadas, bem como relacionar os resultados com o momento histórico em que foram projetadas ou publicadas.

A subpixel edge detector applied to aortic dissection detection

[EN] The aortic dissection is a disease that can cause a deadly situation, even with a correct treatment. It consists in a rupture of a layer of the aortic artery wall, causing a blood flow inside this rupture, called dissection. The aim of this paper is to contribute to its diagnosis, detecting the dissection edges inside the aorta. A subpixel accuracy edge detector based on the hypothesis of partial volume effect is used, where the intensity of an edge pixel is the sum of the contribution of each color weighted by its relative area inside the pixel. The method uses a floating window centred on the edge pixel and computes the edge features. The accuracy of our method is evaluated on synthetic images of different hickness and noise levels, obtaining an edge detection with a maximal mean error lower than 16 percent of a pixel.

Temporal constraints in large optical flow estimation

[EN] The aim of this work is to propose a model for computing the optical flow in a sequence of images. We introduce a new temporal regularizer that is suitable for large displacements. We propose to decouple the spatial and temporal regularizations to avoid an incongruous formulation. For the spatial regularization we use the Nagel-Enkelmann operator and a newly designed temporal regularization. Our model is based on an energy functional that yields a partial differential equation (PDE). This PDE is embedded into a multipyramidal strategy to recover large displacements. A gradient descent technique is applied at each scale to reach the minimum.

3D reconstruction from a vascular tree model

[EN] In this paper, we present a vascular tree model made with synthetic materials and which allows us to obtain images to make a 3D reconstruction.We have used PVC tubes of several diameters and lengths that will let us evaluate the accuracy of our 3D reconstruction. In order to calibrate the camera we have used a corner detector. Also we have used Optical Flow techniques to follow the points through the images going and going back. We describe two general techniques to extract a sequence of corresponding points from multiple views of an object. The resulting sequence of points will be used later to reconstruct a set of 3D points representing the object surfaces on the scene. We have made the 3D reconstruction choosing by chance a couple of images and we have calculated the projection error. After several repetitions, we have found the best 3D location for the point.

Models and methods for power monolithic microwave integrated circuits

Computer aided design of Monolithic Microwave Integrated Circuits (MMICs) depends critically on active device models that are accurate, computationally efficient, and easily extracted from measurements or device simulators. Empirical models of active electron devices, which are based on actual device measurements, do not provide a detailed description of the electron device physics. However they are numerically efficient and quite accurate. These characteristics make them very suitable for MMIC design in the framework of commercially available CAD tools. In the empirical model formulation it is very important to separate linear memory effects (parasitic effects) from the nonlinear effects (intrinsic effects). Thus an empirical active device model is generally described by an extrinsic linear part which accounts for the parasitic passive structures connecting the nonlinear intrinsic electron device to the external world. An important task circuit designers deal with is evaluating the ultimate potential of a device for specific applications. In fact once the technology has been selected, the designer would choose the best device for the particular application and the best device for the different blocks composing the overall MMIC. Thus in order to accurately reproducing the behaviour of different-in-size devices, good scalability properties of the model are necessarily required. Another important aspect of empirical modelling of electron devices is the mathematical (or equivalent circuit) description of the nonlinearities inherently associated with the intrinsic device. Once the model has been defined, the proper measurements for the characterization of the device are performed in order to identify the model. Hence, the correct measurement of the device nonlinear characteristics (in the device characterization phase) and their reconstruction (in the identification or even simulation phase) are two of the more important aspects of empirical modelling. This thesis presents an original contribution to nonlinear electron device empirical modelling treating the issues of model scalability and reconstruction of the device nonlinear characteristics. The scalability of an empirical model strictly depends on the scalability of the linear extrinsic parasitic network, which should possibly maintain the link between technological process parameters and the corresponding device electrical response. Since lumped parasitic networks, together with simple linear scaling rules, cannot provide accurate scalable models, either complicate technology-dependent scaling rules or computationally inefficient distributed models are available in literature. This thesis shows how the above mentioned problems can be avoided through the use of commercially available electromagnetic (EM) simulators. They enable the actual device geometry and material stratification, as well as losses in the dielectrics and electrodes, to be taken into account for any given device structure and size, providing an accurate description of the parasitic effects which occur in the device passive structure. It is shown how the electron device behaviour can be described as an equivalent two-port intrinsic nonlinear block connected to a linear distributed four-port passive parasitic network, which is identified by means of the EM simulation of the device layout, allowing for better frequency extrapolation and scalability properties than conventional empirical models. Concerning the issue of the reconstruction of the nonlinear electron device characteristics, a data approximation algorithm has been developed for the exploitation in the framework of empirical table look-up nonlinear models. Such an approach is based on the strong analogy between timedomain signal reconstruction from a set of samples and the continuous approximation of device nonlinear characteristics on the basis of a finite grid of measurements. According to this criterion, nonlinear empirical device modelling can be carried out by using, in the sampled voltage domain, typical methods of the time-domain sampling theory.

A simple strategy for defining polynomial spline spaces over hierarchical T-meses

[EN]We present a new strategy for constructing spline spaces over hierarchical T-meshes with quad- and octree subdivision scheme. The proposed technique includes some simple rules for inferring local knot vectors to define C 2 -continuous cubic tensor product spline blending functions. Our conjecture is that these rules allow to obtain, for a given T-mesh, a set of linearly independent spline functions with the property that spaces spanned by nested T-meshes are also nested, and therefore, the functions can reproduce cubic polynomials. In order to span spaces with these properties applying the proposed rules, the T-mesh should fulfill the only requirement of being a 0- balanced mesh...

New functional and biomechanical assessments for the improvement of the surgical navigation systems for joint replacement in the human lower limb

In case of severe osteoarthritis at the knee causing pain, deformity, and loss of stability and mobility, the clinicians consider that the substitution of these surfaces by means of joint prostheses. The objectives to be pursued by this surgery are: complete pain elimination, restoration of the normal physiological mobility and joint stability, correction of all deformities and, thus, of limping. The knee surgical navigation systems have bee developed in computer-aided surgery in order to improve the surgical final outcome in total knee arthroplasty. These systems provide the surgeon with quantitative and real-time information about each surgical action, like bone cut executions and prosthesis component alignment, by mean of tracking tools rigidly fixed onto the femur and the tibia. Nevertheless, there is still a margin of error due to the incorrect surgical procedures and to the still limited number of kinematic information provided by the current systems. Particularly, patello-femoral joint kinematics is not considered in knee surgical navigation. It is also unclear and, thus, a source of misunderstanding, what the most appropriate methodology is to study the patellar motion. In addition, also the knee ligamentous apparatus is superficially considered in navigated total knee arthroplasty, without taking into account how their physiological behavior is altered by this surgery. The aim of the present research work was to provide new functional and biomechanical assessments for the improvement of the surgical navigation systems for joint replacement in the human lower limb. This was mainly realized by means of the identification and development of new techniques that allow a thorough comprehension of the functioning of the knee joint, with particular attention to the patello-femoral joint and to the main knee soft tissues. A knee surgical navigation system with active markers was used in all research activities presented in this research work. Particularly, preliminary test were performed in order to assess the system accuracy and the robustness of a number of navigation procedures. Four studies were performed in-vivo on patients requiring total knee arthroplasty and randomly implanted by means of traditional and navigated procedures in order to check for the real efficacy of the latter with respect to the former. In order to cope with assessment of patello-femoral joint kinematics in the intact and replaced knees, twenty in-vitro tests were performed by using a prototypal tracking tool also for the patella. In addition to standard anatomical and articular recommendations, original proposals for defining the patellar anatomical-based reference frame and for studying the patello-femoral joint kinematics were reported and used in these tests. These definitions were applied to two further in-vitro tests in which, for the first time, also the implant of patellar component insert was fully navigated. In addition, an original technique to analyze the main knee soft tissues by means of anatomical-based fiber mappings was also reported and used in the same tests. The preliminary instrumental tests revealed a system accuracy within the millimeter and a good inter- and intra-observer repeatability in defining all anatomical reference frames. In in-vivo studies, the general alignments of femoral and tibial prosthesis components and of the lower limb mechanical axis, as measured on radiographs, was more satisfactory, i.e. within ±3°, in those patient in which total knee arthroplasty was performed by navigated procedures. As for in-vitro tests, consistent patello-femoral joint kinematic patterns were observed over specimens throughout the knee flexion arc. Generally, the physiological intact knee patellar motion was not restored after the implant. This restoration was successfully achieved in the two further tests where all component implants, included the patellar insert, were fully navigated, i.e. by means of intra-operative assessment of also patellar component positioning and general tibio-femoral and patello-femoral joint assessment. The tests for assessing the behavior of the main knee ligaments revealed the complexity of the latter and the different functional roles played by the several sub-bundles compounding each ligament. Also in this case, total knee arthroplasty altered the physiological behavior of these knee soft tissues. These results reveal in-vitro the relevance and the feasibility of the applications of new techniques for accurate knee soft tissues monitoring, patellar tracking assessment and navigated patellar resurfacing intra-operatively in the contest of the most modern operative techniques. This present research work gives a contribution to the much controversial knowledge on the normal and replaced of knee kinematics by testing the reported new methodologies. The consistence of these results provides fundamental information for the comprehension and improvements of knee orthopedic treatments. In the future, the reported new techniques can be safely applied in-vivo and also adopted in other joint replacements.