Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy

We have used various computational methodologies including molecular dynamics, density functional theory, virtual screening, ADMET predictions and molecular interaction field studies to design and analyze four novel potential inhibitors of farnesyltransferase (FTase). Evaluation of two proposals regarding their drug potential as well as lead compounds have indicated them as novel promising FTase inhibitors, with theoretically interesting pharmacotherapeutic profiles, when Compared to the very active and most cited FTase inhibitors that have activity data reported, which are launched drugs or compounds in clinical tests. One of our two proposals appears to be a more promising drug candidate and FTase inhibitor, but both derivative molecules indicate potentially very good pharmacotherapeutic profiles in comparison with Tipifarnib and Lonafarnib, two reference pharmaceuticals. Two other proposals have been selected with virtual screening approaches and investigated by LIS, which suggest novel and alternatives scaffolds to design future potential FTase inhibitors. Such compounds can be explored as promising molecules to initiate a research protocol in order to discover novel anticancer drug candidates targeting farnesyltransferase, in the fight against cancer. (C) 2009 Elsevier Inc. All rights reserved.

Measuring the interaction forces between protein inclusion bodies and an air bubble using an atomic force microscope

Interaction forces between protein inclusion bodies and an air bubble have been quantified using an atomic force microscope (AFM). The inclusion bodies were attached to the AFM tip by covalent bonds. Interaction forces measured in various buffer concentrations varied from 9.7 nN to 25.3 nN (+/- 4-11%) depending on pH. Hydrophobic forces provide a stronger contribution to overall interaction force than electrostatic double layer forces. It also appears that the ionic strength affects the interaction force in a complex way that cannot be directly predicted by DLVO theory. The effects of pH are significantly stronger for the inclusion body compared to the air bubble. This study provides fundamental information that will subsequently facilitate the rational design of flotation recovery system for inclusion bodies. It has also demonstrated the potential of AFM to facilitate the design of such processes from a practical viewpoint.

Molecular View of the Interaction between iota-Carrageenan and a Phospholipid Film and Its Role in Enzyme Immobilization

Proteins incorporated into phospholipid Langmuir-Blodgett (LB) films are a good model system for biomembranes and enzyme immobilization studies. The specific fluidity of biomembranes, an important requisite for enzymatic activity, is naturally controlled by varying phospholipid compositions. In a model system, instead, LB film fluidity may be varied by covering the top layer with different substances able to interact simultaneously with the phospholipid and the protein to be immobilized. In this study, we immobilized a carbohydrate rich Neurospora crassa alkaline phosphatase (NCAP) in monolayers of the sodium salt of dihexadecylphosphoric acid (DHP), a synthetic phospholipid that provides very condensed Langmuir films. The binding of NCAP to DHP Langmuir-Blodgett (LB) films was mediated by the anionic polysaccharide iota-carrageenan (iota-car). Combining results from surface isotherms and the quartz crystal microbalance technique, we concluded that the polysaccharide was essential to promote the interaction between DHP and NCAP and also to increase the fluidity of the film. An estimate of DHP:iota-car ratio within the film also revealed that the polysaccharide binds to DHP LB film in an extended conformation. Furthermore, the investigation of the polysaccharide conformation at molecular level, using sum-frequency vibrational spectroscopy (SFG), indicated a preferential conformation of the carrageenan molecules with the sulfate groups oriented toward the phospholipid monolayer, and both the hydroxyl and ether groups interacting preferentially with the protein. These results demonstrate how interfacial electric fields can reorient and induce conformational changes in macromolecules, which may significantly affect intermolecular interactions at interfaces. This detailed knowledge of the interaction mechanism between the enzyme and the LB film is relevant to design strategies for enzyme immobilization when orientation and fluidity properties of the film provided by the matrix are important to improve enzymatic activity.

A study of the interaction between operator style and machine capability for a hydraulic mining excavator

This paper presents a case study that explores how operator digging style juxtaposes with mechanical capability for a class of hydraulic mining excavators. The relationships between actuator and digging forces are developed and these are used to identify the excavator's capability to apply forces in various directions. Two distinct modes of operation are examined to see how they relate to the mechanical capabilities of the linkage and to establish if one has merit over the other. It is found that one of these styles results in lower loading of the machine.

Coronary CT angiography using 64 detector rows: methods and design of the multi-centre trial CORE-64

Multislice computed tomography (MSCT) for the noninvasive detection of coronary artery stenoses is a promising candidate for widespread clinical application because of its non-invasive nature and high sensitivity and negative predictive value as found in several previous studies using 16 to 64 simultaneous detector rows. A multi-centre study of CT coronary angiography using 16 simultaneous detector rows has shown that 16-slice CT is limited by a high number of nondiagnostic cases and a high false-positive rate. A recent meta-analysis indicated a significant interaction between the size of the study sample and the diagnostic odds ratios suggestive of small study bias, highlighting the importance of evaluating MSCT using 64 simultaneous detector rows in a multi-centre approach with a larger sample size. In this manuscript we detail the objectives and methods of the prospective ""CORE-64"" trial (""Coronary Evaluation Using Multidetector Spiral Computed Tomography Angiography using 64 Detectors""). This multi-centre trial was unique in that it assessed the diagnostic performance of 64-slice CT coronary angiography in nine centres worldwide in comparison to conventional coronary angiography. In conclusion, the multi-centre, multi-institutional and multi-continental trial CORE-64 has great potential to ultimately assess the per-patient diagnostic performance of coronary CT angiography using 64 simultaneous detector rows.

Contribution towards a reflection about methodological strategies in design education and the function of drawing in design

This work presents a reflection on Design education and specifically on the role of Drawing in this area. As a subject, Design has expanded its field of action expanding into new areas such as Experience Design or Service Design. It became necessary for the designer to have more than an education based on technological knowledge or know-how. Many authors like Meredith Davis, Don Norman or Jamie Hobson point out the urgency to review the curricula of Design courses because nowadays “… design is more than appearance, design is about interaction, about strategy and about services. Designers change social behavior” (Norman 2011). When shifting from a product-centered design to a person-centered design (in a structure, a service or in a relationship) what should the function of drawing in a design course be? What should its curriculum be? Our work methodology will be to confront today’s perspectives on design theory and practice in an attempt to add to the discussion on the methodological strategies in design teaching in the contemporary context.

Contributo para uma reflexão sobre estratégias metodológicas no ensino do Design e a função do Desenho em Design

Neste trabalho apresentaremos uma reflexão sobre o ensino do Design e, especificamente, sobre a função do Desenho nessa área disciplinar. O Design, enquanto disciplina, alargou a sua área de actuação diversificando-se em novos campos como o Design de Experiência ou o Design de Serviço, não bastando ao designer uma formação ligada ao conhecimento tecnológico, ou ao “saber-fazer”. Diversos autores, como Meredith Davis, Don Norman ou Jamie Hobson, alertam para a urgência de uma reflexão aprofundada sobre as estruturas curriculares dos cursos de Design, já que na actualidade “(…) design is more than appearance, design is about interaction, about strategy and about services. Designers change social behavior” (Norman, 2011). Na passagem de um design centrado na forma, para um design centrado na pessoa (numa estrutura, num serviço, ou numa relação) qual deverá ser a função do desenho num curso de design? Qual deverá ser a sua estrutura programática? Como metodologia de trabalho iremos confrontar perspectivas actuais da teoria e da prática do design que equacionam esta problemática procurando, deste modo, contribuir para a reflexão de estratégias metodológicas no ensino do design no contexto contemporâneo.

Contribution towards a reflection about methodological strategies in Design Education and the function of Drawing in Design

This work presents a reflection on Design education and specifically on the role of Drawing in this area. As a subject, Design has expanded its field of action expanding into new areas such as Experience Design or Service Design. It became necessary for the designer to have more than an education based on technological knowledge or know-how. Many authors like Meredith Davis, Don Norman or Jamie Hobson point out the urgency to review the curricula of Design courses because nowadays “ … design is more than appearance, design is about interaction, about strategy and about services. Designers change social behavior” (Norman, 2011) When shifting from a product-centered design to a person-centered design (in a structure, a service or in a relationship) what should the function of drawing in a design course be? What should its curriculum be? Our work methodology will be to confront today’s perspectives on design theory and practice in an attempt to add to the discussion on the methodological strategies in design teaching in the contemporary context.

Reflexão sobre estratégias metodológicas no ensino do design e a função do desenho em design

Neste trabalho apresentaremos uma reflexão sobre o ensino do Design e, especificamente, sobre a função do Desenho nessa área disciplinar. O Design, enquanto disciplina, alargou a sua área de actuação diversificando-se em novos campos como o Design de Experiência ou o Design de Serviço, não bastando ao designer uma formação ligada ao conhecimento tecnológico, ou ao “saber-fazer”. Diversos autores, como Meredith Davis, Don Norman ou Jamie Hobson, alertam para a urgência de uma reflexão aprofundada sobre as estruturas curriculares dos cursos de Design, já que na actualidade “(…) design is more than appearance, design is about interaction, about strategy and about services. Designers change social behavior” (Norman, 2011). Na passagem de um design centrado na forma, para um design centrado na pessoa (numa estrutura, num serviço, ou numa relação) qual deverá ser a função do desenho num curso de design? Qual deverá ser a sua estrutura programática? Como metodologia de trabalho iremos confrontar perspectivas actuais da teoria e da prática do design que equacionam esta problemática procurando, deste modo, contribuir para a reflexão de estratégias metodológicas no ensino do design no contexto contemporâneo.

Reflexão sobre Estratégias Metodológicas no Ensino do Design e a Função do Desenho em Design

Somos habitantes de um mundo que sofre constantes transformações estruturais em qualquer área. As tecnologias, a globalização e a política dos mercados, deslocam tudo e todos da sua zona de conforto, exigindo constantes adaptações a novos vocabulários e hábitos para os quais não temos antecedentes. Novas competências devem ser adquiridas face às novas exigências, e no ensino, base de uma preparação (pessoal e profissional), impõe-se uma constante revisão de estratégias metodológicas de aquisição e partilha de conhecimento. Neste trabalho apresentaremos uma reflexão sobre o ensino do Design e, especificamente, sobre a função do Desenho nessa área disciplinar. O Design, enquanto disciplina, alargou a sua área de actuação diversificando-se em novos campos como o Design de Experiência ou o Design de Serviço, não bastando ao designer uma formação ligada ao conhecimento tecnológico, ou ao “saber-fazer”. Diversos autores, como Meredith Davis, Don Norman ou Jamie Hobson, alertam para a urgência de uma reflexão aprofundada sobre as estruturas curriculares dos cursos de Design, já que na actualidade “(…) design is more than appearance, design is about interaction, about strategy and about services. Designers change social behavior.” Na passagem de um design centrado na forma, para um design centrado na pessoa (numa estrutura, num serviço, ou numa relação) qual deverá ser a função do desenho num curso de design? Qual deverá ser a sua estrutura programática? Como metodologia de trabalho iremos confrontar perspectivas actuais da teoria e da prática do design que equacionam esta problemática procurando, deste modo, contribuir para a reflexão de estratégias metodológicas no ensino do design no contexto contemporâneo.

CoS: a new perspective of operating systems design for the cyber-physical world

Our day-to-day life is dependent on several embedded devices, and in the near future, many more objects will have computation and communication capabilities enabling an Internet of Things. Correspondingly, with an increase in the interaction of these devices around us, developing novel applications is set to become challenging with current software infrastructures. In this paper, we argue that a new paradigm for operating systems needs to be conceptualized to provide aconducive base for application development on Cyber-physical systems. We demonstrate its need and importance using a few use-case scenarios and provide the design principles behind, and an architecture of a co-operating system or CoS that can serve as an example of this new paradigm.

Smart object for 3D interaction

This paper reports on the creation of an interface for 3D virtual environments, computer-aided design applications or computer games. Standard computer interfaces are bound to 2D surfaces, e.g., computer mouses, keyboards, touch pads or touch screens. The Smart Object is intended to provide the user with a 3D interface by using sensors that register movement (inertial measurement unit), touch (touch screen) and voice (microphone). The design and development process as well as the tests and results are presented in this paper. The Smart Object was developed by a team of four third-year engineering students from diverse scientific backgrounds and nationalities during one semester.

Visualization and interaction in a simulation system for flood emergencies

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Engenharia Informática