Design and synthesis of novel quinolones directed to the Plasmodium falciparum bc1 protein complex

Tese de Doutoramento, Química, Especialização em Química Orgânica, Faculdade de Ciências e Tecnologia, Universidade do Algarve, 2016

Development of a novel platform for high-throughput gene design and artificial gene synthesis to produce large libraries of recombinant venom peptides for drug discovery

Tese de Doutoramento em Ciências Veterinárias na Especialidade de Ciências Biológicas e Biomédicas

Design gráfico para televisão

Dissertação para obtenção do grau de Mestre em Design de Comunicação apresentada na Universidade de Lisboa - Faculdade de Arquitetura.

Design of composites for thermal management: Aluminum reinforced with diamond-containing bimodal particle mixtures

A new design route is proposed in order to fabricate aluminum matrix diamond-containing composite materials with optimized values of thermal conductivity (TC) for thermal management applications. The proper size ratio and proportions of particulate diamond–diamond and diamond–SiC bimodal mixtures are selected based on calculations with predictive schemes, which combine two main issues: (i) the volume fraction of the packed particulate mixtures, and (ii) the influence of different types of particulates (with intrinsically different metal/reinforcement interfacial thermal conductances) on the overall thermal conductivity of the composite material. The calculated results are validated by comparison with measurements on composites fabricated by gas pressure infiltration of aluminum into preforms of selected compositions of particle mixtures. Despite the relatively low quality (low price) of the diamond particles used in this work, outstanding values of TC are encountered: a maximum of 770 W/m K for Al/diamond–diamond and values up to 690 W/m K for Al/diamond–SiC.

Interrelated product design activities sequencing with efficient tabu search algorithms

This paper proposes and investigates a metaheuristic tabu search algorithm (TSA) that generates optimal or near optimal solutions sequences for the feedback length minimization problem (FLMP) associated to a design structure matrix (DSM). The FLMP is a non-linear combinatorial optimization problem, belonging to the NP-hard class, and therefore finding an exact optimal solution is very hard and time consuming, especially on medium and large problem instances. First, we introduce the subject and provide a review of the related literature and problem definitions. Using the tabu search method (TSM) paradigm, this paper presents a new tabu search algorithm that generates optimal or sub-optimal solutions for the feedback length minimization problem, using two different neighborhoods based on swaps of two activities and shifting an activity to a different position. Furthermore, this paper includes numerical results for analyzing the performance of the proposed TSA and for fixing the proper values of its parameters. Then we compare our results on benchmarked problems with those already published in the literature. We conclude that the proposed tabu search algorithm is very promising because it outperforms the existing methods, and because no other tabu search method for the FLMP is reported in the literature. The proposed tabu search algorithm applied to the process layer of the multidimensional design structure matrices proves to be a key optimization method for an optimal product development.

Interrelated product design activities sequencing with efficient tabu search algorithms

This paper proposes and investigates a metaheuristic tabu search algorithm (TSA) that generates optimal or near optimal solutions sequences for the feedback length minimization problem (FLMP) associated to a design structure matrix (DSM). The FLMP is a non-linear combinatorial optimization problem, belonging to the NP-hard class, and therefore finding an exact optimal solution is very hard and time consuming, especially on medium and large problem instances. First, we introduce the subject and provide a review of the related literature and problem definitions. Using the tabu search method (TSM) paradigm, this paper presents a new tabu search algorithm that generates optimal or sub-optimal solutions for the feedback length minimization problem, using two different neighborhoods based on swaps of two activities and shifting an activity to a different position. Furthermore, this paper includes numerical results for analyzing the performance of the proposed TSA and for fixing the proper values of its parameters. Then we compare our results on benchmarked problems with those already published in the literature. We conclude that the proposed tabu search algorithm is very promising because it outperforms the existing methods, and because no other tabu search method for the FLMP is reported in the literature. The proposed tabu search algorithm applied to the process layer of the multidimensional design structure matrices proves to be a key optimization method for an optimal product development.

Using Research Methods in Human Computer Interaction to Design Technology for Resilience

Research in human computer interaction (HCI) covers both technological and human behavioural concerns. As a consequence, the contributions made in HCI research tend to be aware to either engineering or the social sciences. In HCI the purpose of practical research contributions is to reveal unknown insights about human behaviour and its relationship to technology. Practical research methods normally used in HCI include formal experiments, field experiments, field studies, interviews, focus groups, surveys, usability tests, case studies, diary studies, ethnography, contextual inquiry, experience sampling, and automated data collection. In this paper, we report on our experience using the evaluation methods focus groups, surveys and interviews and how we adopted these methods to develop artefacts: either interface’s design or information and technological systems. Four projects are examples of the different methods application to gather information about user’s wants, habits, practices, concerns and preferences. The goal was to build an understanding of the attitudes and satisfaction of the people who might interact with a technological artefact or information system. Conversely, we intended to design for information systems and technological applications, to promote resilience in organisations (a set of routines that allow to recover from obstacles) and user’s experiences. Organisations can here also be viewed within a system approach, which means that the system perturbations even failures could be characterized and improved. The term resilience has been applied to everything from the real estate, to the economy, sports, events, business, psychology, and more. In this study, we highlight that resilience is also made up of a number of different skills and abilities (self-awareness, creating meaning from other experiences, self-efficacy, optimism, and building strong relationships) that are a few foundational ingredients, which people should use along with the process of enhancing an organisation’s resilience. Resilience enhances knowledge of resources available to people confronting existing problems.

The Academic-enterprise experiences framework as a guide for design education

The establishment of support platforms for the development of a new culture in design education, in order to achieve both research exploitation and its results, as an approach to the industrial community, challenges higher education institutions to rethink their functioning, divided between investigation on their own initiative or on demand, and its usefulness / practical application. At the same time, through design education, how can they be the engine that aggregates all these frequently antagonistic interests? Polytechnic institutes are predisposed to collaboration and interdisciplinarity. In our course of Technology and Design of Furniture, the availability of a production unit, testing laboratories, and expertise in engineering, design and marketing, encourage the development of a holistic project. In order to develop such knowledge, we adapt three important ways of thinking in designing interactions influenced by the traditional approach, namely, 1) identifying and understanding a design problem, i.e. a market need, 2) defining the design process and knowing what can be used for design education, i.e. opportunities for design education, and 3) sustainability of this framework and design projects' alignment with education in the same field. We explain our approach by arguing from the academicenterprise experiences perspective. This concept is proposed as a way to achieve those three ways of thinking in design education. Then, a set of interaction attributes is defined to explain how engineering and product design education can enhance meaningful relations with manufacturers, stakeholders and society in general. A final discussion is presented with the implications and benefits of this approach. The results suggest that through academic-enterprise partnerships in design, several goals such as students' motivation, product design innovation and potential for knowledge transfer to industries can be achieved.

Design of products to honor people post mortem

The cemeterial units, are places of social practices of everyday life and worship and the tomb where nostalgia can be externalized and the memory of the deceased revered. In Western societies we can find a category of artifacts meant to evoke the memory or honor the dead. In this paper we we mention three examples of products that enabled a reflection on the concepts that gave rise to their ways, and that risks to fit them into a new "material culture", in that it may have created a break with the traditional system codes and standards shared by companies, and its manifestations in relation to the physical creation of this category of products. This work offers a reflection on the Design Products.What probably makes it special is the field where it is located: the design of products in one post mortem memory. Usually made of granite rock or marble, have the form of plate or tablet, open book or rolled sheet. On one side have a photograph of the person who intend to honor and inscriptions. The thought of inherent design of this work put on one side the intricate set of emotions that this type of product can generate, and other components more affordable, and concerning the form, function and object interactions with users and with use environments. In the definition of the problem it was regarded as mandatory requirements: differentiation, added value and durability as key objectives.The first two should be manifested in the various components / product attributes. The aesthetic and material/structural durability of product necessarily imply the introduction of qualifying terms and quantitative weights, which positively influence the generation and evaluation of concepts based on the set of 10 principles for the project that originated a matrix as a tool to aid designing products. The concrete definition of a target audience was equally important. At this stage, the collaboration of other experts in the fields of psychology and sociology as disciplines with particular ability to understand individuals and social phenomena respectively was crucial. It was concluded that a product design to honor someone post mortem, should abandon the more traditional habits and customs to focus on identifying new audiences. Although at present it can be considered a niche market, it is believed that in the future may grow as well as their interest in this type of products.

An Analysis of the Early Prediction of Highway Construction Project Completion using the Contract Status Report

History has shown that projects move in and out of poor status through the life of the project. Predicting the success or failure of a project to complete on time because of its recent history on the contract status report could provide our project managers another tool for monitoring contract progress. In many instances, poor contract progress results in the loss of contract time and late completion of projects. This research evaluates the combinations of work type, point in time physical work begins, recent poor status, and contract bid amount as indicators of late project completion.

Internal Improvements to SCDOT Project Delivery for Construction Projects

The purpose of this research project is to investigate project delivery as it relates to construction projects to help support the Department of Transportation's vision. The project delivery goals of the Agency as it relates to this research include: Fifty percent of construction projects are completed on schedule ; Ninety-five percent of projects are closed out within 270 days ; Seventy-five percent of construction projects are authorized on schedule. The goals of this project are to determine what factors contribute to unsuccessful project delivery and determine how these factors can be improved. This project will mainly investigate Construction roles during the Preconstruction phase of the project as well as examine the project during construction and identify areas that prohibit effective and timely project delvery.

Towards in silico IBV vaccine design: defining the role of polymorphism in viral attenuation

The gammacoronavirus, Infectious Bronchitis Virus (IBV), is a respiratory pathogen of chickens. IBV is a constant threat to poultry production as established vaccines are often ineffective against emerging strains. This requires constant and rapid vaccine production by a process of viral attenuation by egg passage, but the essential forces leading to attenuation in the virus have not yet been characterised. Knowledge of these factors will lead to the development of more effective, rationally attenuated, live vaccines and reduction of the mortality and morbidity caused by this pathogen. M41 CK strain was egg passaged four times many years ago at Houghton Poultry Research Station and stored as M41-CK EP4 (stock virus at The Pirbright Institute since 1992). It was the first egg passage to have its genome pyrosequenced and was therefore used as the baseline reference. The overall aim of this project was to analyse deep sequence data obtained from four IBV isolates (called A, A1, C and D) each originating from the common M41-CK EP4 (ep4) and independently passaged multiple times in embryonated chicken eggs (figure 1.1). Highly polymorphic encoding regions of the IBV genome were then identified which are likely involved in the attenuation process through the formation of independent SNPs and/or SNP clusters. This was then used to direct targeted investigation of SNPs during the attenuation process of the four IBV passages. A previously generated deep sequence dataset was used as a preliminary map of attenuation for one virulent strain of IBV. This investigation showed the nucleocapsid and spike as two highly polymorphic encoding regions within the IBV genome with the highest proportion of SNPs compared to encoding region size. This analysis then led to more focussed studies of the nucleocapsid and spike encoding region with the ultimate aim of mapping key attenuating regions and nucleotide positions. The 454 pyrosequencing data and further investigation of nucleocapsid and spike encoding regions have identified the SNPs present at the same nucleotide positions within analysed A, A1, C and D isolates. These SNPs probably play a crucial role in viral attenuation and universal vaccine production but it is not clear if independent SNPs are also involved in loss of virulence. The majority of SNPs accumulated at different nucleotide positions without further continuation in Sanger sequenced egg passages presenting S2 subunit (spike) and nucleocapsid as polymorphic encoding regions which in nature remain highly conserved.

Product/Brand co-creation methodology crossing marketing, design thinking, creativity and management: ideas(r)evolution

This thesis introduce a new innovation methodology called IDEAS(R)EVOLUTION that was developed according to an on-going experimental research project started in 2007. This new approach to innovation has initial based on Design thinking for innovation theory and practice. The concept of design thinking for innovation has received much attention in recent years. This innovation approach has climbed from the design and designers knowledge field towards other knowledge areas, mainly business management and marketing. Human centered approach, radical collaboration, creativity and breakthrough thinking are the main founding principles of Design thinking that were adapted by those knowledge areas due to their assertively and fitness to the business context and market complexity evolution. Also Open innovation, User-centered innovation and later on Living Labs models emerge as answers to the market and consumers pressure and desire for new products, new services or new business models. Innovation became the principal business management focus and strategic orientation. All this changes had an impact also in the marketing theory. It is possible now to have better strategies, communications plans and continuous dialogue systems with the target audience, incorporating their insights and promoting them to the main dissemination ambassadors of our innovations in the market. Drawing upon data from five case studies, the empirical findings in this dissertation suggest that companies need to shift from Design thinking for innovation approach to an holistic, multidimensional and integrated innovation system. The innovation context it is complex, companies need deeper systems then the success formulas that “commercial “Design thinking for innovation “preaches”. They need to learn how to change their organization culture, how to empower their workforce and collaborators, how to incorporate external stakeholders in their innovation processes, hoe to measure and create key performance indicators throughout the innovation process to give them better decision making data, how to integrate meaning and purpose in their innovation philosophy. Finally they need to understand that the strategic innovation effort it is not a “one shot” story it is about creating a continuous flow of interaction and dialogue with their clients within a “value creation chain“ mindset; RESUMO: Metodologia de co-criação de um produto/marca cruzando Marketing, Design Thinking, Criativity and Management - IDEAS(R)EVOLUTION. Esta dissertação apresenta uma nova metodologia de inovação chamada IDEAS(R)EVOLUTION, que foi desenvolvida segundo um projecto de investigação experimental contínuo que teve o seu início em 2007. Esta nova abordagem baseou-se, inicialmente, na teoria e na práctica do Design thinking para a inovação. Actualmente o conceito do Design Thinking para a inovação “saiu” do dominio da area de conhecimento do Design e dos Designers, tendo despertado muito interesse noutras áreas como a Gestão e o Marketing. Uma abordagem centrada na Pessoa, a colaboração radical, a criatividade e o pensamento disruptivo são principios fundadores do movimento do Design thinking que têm sido adaptados por essas novas áreas de conhecimento devido assertividade e adaptabilidade ao contexto dos negócios e à evolução e complexidade do Mercado. Também os modelos de Inovação Aberta, a inovação centrada no utilizador e mais tarde os Living Labs, emergem como possiveis soluções para o Mercado e para a pressão e desejo dos consumidores para novos productos, serviços ou modelos de negócio. A inovação passou a ser o principal foco e orientação estratégica na Gestão. Todas estas mudanças também tiveram impacto na teoria do Marketing. Hoje é possivel criar melhores estratégias, planos de comunicação e sistemas continuos de diálogo com o público alvo, incorporando os seus insights e promovendo os consumidores como embaixadores na disseminação da inovação das empresas no Mercado Os resultados empiricos desta tese, construídos com a informação obtida nos cinco casos realizados, sugerem que as empresas precisam de se re-orientar do paradigma do Design thinking para a inovação, para um sistema de inovação mais holistico, multidimensional e integrado. O contexto da Inovação é complexo, por isso as empresas precisam de sistemas mais profundos e não apenas de “fórmulas comerciais” como o Design thinking para a inovação advoga. As Empresas precisam de aprender como mudar a sua cultura organizacional, como capacitar sua força de trabalho e colaboradores, como incorporar os públicos externos no processo de inovação, como medir o processo de inovação criando indicadores chave de performance e obter dados para um tomada de decisão mais informada, como integrar significado e propósito na sua filosofia de inovação. Por fim, precisam de perceber que uma estratégia de inovação não passa por ter “sucesso uma vez”, mas sim por criar um fluxo contínuo de interação e diálogo com os seus clientes com uma mentalidade de “cadeia de criação de valor”

The Proces of Curriculum and Module Design

The outcome of the inductive decision -making process of the leading project management group (PMG) was the proposal to develop three modules, Human Resource Management and Knowledge Management, Quality Management and Intercultural management, each for 10 ECTS credits. As a result of the theoretical and organisational framework and analytical phase of the project, four strategies informed the development and implemen- tation of the modules: 1. Collaboration as a principle stemming from EU collaborative policy and receiving it’s expression on all implementation levels (designing the modules, modes of learning, delivering the modules, evaluation process). 2. Building on the Bologna process masters level framework to assure ap- propriate academic level of outputs. 3. Development of value -based leadership of students through transforma- tional learning in a cross -cultural setting and continual reflection of theory in practice. 4. Continual evaluation and feedback among teachers and students as a strategy to achieve a high quality programme. In the first phase of designing the modules the collaborative strategy in particular was applied, as each module was led by one university, but members from all other universities participated in the discussions and development of the mod- ules. The Bologna process masters level framework and related standards and guidelines informed the form and method of designing the modules.

Design and Synthesis of Novel Kinase Inhibitors for the Treatment of Chronic Respiratory Diseases

In 2017, Chronic Respiratory Diseases accounted for almost four million deaths worldwide. Unfortunately, current treatments are not definitive for such diseases. This unmet medical need forces the scientific community to increase efforts in the identification of new therapeutic solutions. PI3K delta plays a key role in mechanisms that promote airway chronic inflammation underlying Asthma and COPD. The first part of this project was dedicated to the identification of novel PI3K delta inhibitors. A first SAR expansion of a Hit, previously identified by a HTS campaign, was carried out. A library of 43 analogues was synthesised taking advantage of an efficient synthetic approach. This allowed the identification of an improved Hit of nanomolar enzymatic potency and moderate selectivity for PI3K delta over other PI3K isoforms. However, this compound exhibited low potency in cell-based assays. Low cellular potency was related to sub optimal phys-chem and ADME properties. The analysis of the X-ray crystal structure of this compound in human PI3K delta guided a second tailored SAR expansion that led to improved cellular potency and solubility. The second part of the thesis was focused on the rational design and synthesis of new macrocyclic Rho-associated protein kinases (ROCKs) inhibitors. Inhibition of these kinases has been associated with vasodilating effects. Therefore, ROCKs could represent attractive targets for the treatment of pulmonary arterial hypertension (PAH). Known ROCK inhibitors suffer from low selectivity across the kinome. The design of macrocyclic inhibitors was considered a promising strategy to obtain improved selectivity. Known inhibitors from literature were evaluated for opportunities of macrocyclization using a knowledge-based approach supported by Computer Aided Drug Design (CADD). The identification of a macrocyclic ROCK inhibitor with enzymatic activity in the low micro molar range against ROCK II represented a promising result that validated this innovative approach in the design of new ROCKs inhibitors.