Дисертації з теми "Tool of expansion"

Dissertation presented to obtain a Master degree in Biotechnology at the Universidade Nova de Lisboa, Faculdade de Ciências e Tecnologia
Human embryonic stem cells (hESCs) are known by their ability to either self-renewal and differentiate into any adult cell type. These properties confer to hESCs a huge applicability for cell therapy, tissue engineering and drug screening. However, successful implementation of hESCs-based technologies requires the production of large numbers of well characterized cells and their efficient long-term storage. In this study, alginate microencapsulation technology was used in order to develop an efficient, scalable and integrated 3D culture system for expansion and cryopreservation of pluripotent hESCs. Three strategies were outlined: microencapsulation of hESCs as single cells, cell aggregates and cells immobilized on microcarriers. Encapsulation of hESCs immobilized on microcarriers was the best strategy to expand and cryopreserve pluripotent hESCs. The culture of encapsulated hESCs-microcarriers in spinner vessels assured an approximately 20-fold increase in cell concentration. Moreover, this strategy improved twice cell survival after cryopreservation by a slow-freezing rate procedure, comparatively with non-encapsulated culture. Microencapsulation also protected hESC aggregates from damage caused by stirring, allowed the control of aggregates size and the maintenance of cells pluripotency for two weeks. This work demonstrates that microencapsulation technology is a powerful tool to enhance growth and post-thawing recovery of pluripotent hESCs. The 3D culture systems developed herein represent a promising vehicle to assist the transition of hESCs to the clinical and industrial fields.
This work was performed in the scope of the project - Integrated strategy for expansion, neuronal differentiation and cryopreservation of human embryonic stem cells (PTDC/BIO/72755/2006) funded by FCT (Fundação para a Ciência e Tecnologia)

Approved for public release; distribution is unlimited
Simulation has overcome critical obstacles to become a valuable method for obtaining insights about the behavior of complex systems. George Boxs famous assessment that all models are wrong, some are useful referred to statistical models, but should now be reimagined to reflect that many simulation models are right enough to aid in decision making for important practical problems. Over the past fifty years, simulation has transformed from its beginnings as a brute-force numerical integration method into an attractive and sophisticated option for decision makers. This is due, in part, to the exponential growth of computing power. Although other analytic approaches also benefit from this trend, keyword searches of several scholarly search engines reveal that the reliance on simulation is increasing more rapidly. A descriptive analysis paints a compelling picture simulation is frequently a researchers preferred method for supporting decision makers and may often be the first resort for complex real world issues.

Recent crisis and economic recession caused in many countries problems with drop in inflation and overall downturn in economic growth. The Central Banks found themselves in so called zero lower bound. This thesis describes the situation of deflation, zero lower bound and liquidity trap. These conditions called for the use of alternative monetary policy tools. The main goal of the thesis is to evaluate the use of foreign exchange rate intervention as unconventional tool in a small open economy with inflation targeting regime represented by the Czech Republic in the analytic part. Thesis examines other non-standard instruments and provides reasons for the Czech National Bank decision. The analysis shows the complexity of the issue and provides the evidence that exchange rate commitment was not displayed to the desired price level. The tool could lead to expected repercussion, but the effect is impacted by factors, which Central Bank cannot control. The effect of the CB way to fight the decreasing inflation will be better shown after the CB exit from the commitment.

Thesis (M. Eng.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 2011.
Cataloged from PDF version of thesis.
Includes bibliographical references (p. 93).
CoolVent, a software design tool for architects, has been improved. The work of Maria- Alejandra Menchaca-B. and colleagues has been improved to include a more robust and intuitive building and window dimensioning scheme, feedback on the validity of user inputs and thermal comfort modeling (custom, ASHRAE and adaptive). These results now allow the architect to understand how their design choices have not only affected the temperature and airflow in each of the zones of their building design but also how their design choices have affected the overall comfort throughout the zones of their building. From this, architect's can now easily understand whether their building design can be successful as a naturally ventilated building and if not, they can use the provided interface to gain insight into how their design can be modified to make their building more sustainable. A user study has been conducted to test the effectiveness of the tool.
by Rebecca E. Rich.
M.Eng.

The Branding Solution & Designing Industry has been seemingly proliferating with the growth inthe Apparel and fashion industry, predominantly. With economic development there has been anincrease in the private consumption and growth in GDP; as the demand from the fashion andready-to-wear industry has increased significantly.Both the global and European markets for branding and design are growing. Brands owners areincreasing their investments in measures intended to contribute to strengthening their brands, inwhich labels, packaging and accessories are important elements.Nilörngruppen is a company in this industry offering complete solutions in branding, design,product development and logistics on a global basis with a clear focus on offering customeruniquesolutions that create added value.To compete for the big branding and design jobs and increase the company business volume it isnecessary to be close to the customers. Developments necessitate Nilörngruppen being present inthe countries where its customers have increased its manufacturing base. This caters the need tomake an entry into new markets through a network of strategic partners. This has motivatedNilörngruppen to establish its part-owned subsidiary as Nilörn India with its own sales andlogistics base.This portrays the need of Nilörngruppen to develop its market through continued optimization ofits business structure and improve return on investments in India. The aim of this thesis report is tomake a Business Strategy development for Nilörn India for its expected market expansion in theIndian market.

Program: Magisterutbildning i Applied Textile Management

Uppsatsnivå: D

This dissertation examines the scope and limitations of port state jurisdiction with respect to the enforcement of international conservation and management measures established under international and national instruments. The current fisheries regulatory regimes rely primarily on flag states to enforce these measures against foreign vessels. The aim of this dissertation is to recommend an expansion of port state enforcement jurisdiction over foreign vessels when fishing in the high seas. The expansion of port state jurisdiction supplements the role of flag states in enforcing the provisions of international conventions and agreements applicable in the high seas and also fills in where flag of convenience fishing vessels have failed to do so. To support this view, the dissertation will compare the issue of illegal unreported unregulated fishing with the issue of marine pollution. The significance of this comparison is to show how provisions in regard to marine pollution, have legitimized the expansion of port state jurisdiction to the extent that port states have enforcement jurisdiction over foreign flagged vessels which violate the provisions of LOSC relating to marine pollution in the high seas.

Biomethane made from the anaerobic digestion of organic waste can provide several economic and environmental benefits such as: the valorisation of waste products, increased resource efficiency, increased retention of nutrients through recycling of biogas digestate (Banks, et al., 2011), reduction of greenhouse gas emissions (Börjesson, et al., 2016) as well as the reduction of nitrogen oxides and particulate matter emissions (Börjesson & Berglund, 2007).To help actors understand when and where biomethane solutions can succeed, including the qualitative and quantitative aspects of a solution, an Early Assessment Method has been developed. The categories included in the assessment are potential, feasibility, economic and environmental performance. The Early Assessment Method was developed using a multi-criteria framework and consists of 15 key areas and 24 key indicators that should be considered when assessing biomethane solutions. Each quantitative indicator can be assessed either with site-specific data or by using generic equations and average values while the qualitative indicators are given a five-grade scale to facilitate the assessment.The potential category focuses on assessing how much raw material there is in the investigated area and how much of the usable products can be produced. The final areas are: biomass potential, biomethane potential and bio-fertilizer potential. In the feasibility assessment, qualitative aspects are assessed using a five-grade scale. The key areas for feasibility include: customer demand, competing applications, strategies for renewable fuels, legislation, economic instruments and infrastructure suitability. Performance is assessed both for economic performance and environmental performance to understand how the biomethane solution would perform if implemented. Economic performance includes both an indicator for cost per unit produced and an indicator for the investment cost for each production step. The key areas included are: biogas generation cost, biogas upgrading cost and biomethane distribution cost. The environmental performance is evaluated to understand how environmental aspects would change if biomethane replaced an alternative fuel on the market in the studied region. Key areas to assess this are: climate impact, air quality and nutrient recycling. These areas highlight some important benefits of using biomethane over fossil fuels, which are the most common fuels for heavy-duty vehicles.A two-part Early Assessment Tool was also developed. The tool is included in the method, but can be used separately if the user has a basic knowledge of biomethane. It assists with information collection, through a questionnaire, and structuring and presenting data, through a spreadsheet. The design of the Early Assessment Tool favours simplicity and usability while striving to maintain relevant information. It is meant to be used both for educational and investigative purposes when providing an early assessment of biomethane solutions within a certain region. The result from the tool can aid when making decisions and help with identifying which local actors to involve and what consultancy work might be needed to realise a biomethane solution.

O planejamento da expansão do sistema elétrico é uma das principais atividades em uma distribuidora de energia elétrica, representando uma grande parcela dos investimentos realizados pelas distribuidoras para atender a demanda dos consumidores e os critérios estabelecidos pela agência reguladora (ANEEL). As empresas buscam o apoio de métodos multicritério no processo decisório de investimento, para otimizar e priorizar, com o intuito de obterem êxito na elaboração de um plano de obras que contemple aspectos técnicos e econômicos. A revisão sistêmica da literatura foi realizada em trabalhos de relevância para o tema em estudo, com auxílio de cinco bases de dados. O referencial teórico, que totaliza 52 publicações, apresenta conceitos teóricos sobre o processo decisório através de métodos multicritério de apoio à decisão, bem como exemplifica, através de aplicações práticas como os métodos estão sendo utilizados na área de energia. Com base nesta revisão foi possível estruturar a aplicação da Teoria da Utilidade Multiatributo (MAUT) em um processo decisório de investimento para fins de planejamento da expansão do sistema de distribuição em uma concessionária distribuidora de energia elétrica. Com a aplicação do método fica evidenciada a importância de um procedimento formal para auxiliar os decisores na hierarquização de forma objetiva dos alimentadores de energia elétrica mais críticos, proporcionando maior clareza e aprendizado em todo o processo de planejamento da expansão do sistema elétrico. Ao final, desenvolveu-se uma ferramenta para tratamento do grande volume de dados, que disponibiliza as informações depuradas para auxiliar na tomada decisão de investimento em ações eficientes, que melhorem a qualidade do fornecimento e atendam o crescimento do sistema. A partir da revisão bibliográfica e com a aplicação do método, oportunidades para estudos futuros foram identificadas.
The expansion planning of the electric system is one of the main activities in an electric energy distributor, representing a large part of the investments made by the distributors to meet the consumer demand and the criteria established by the regulatory agency (ANEEL). The companies seek the support of multi-criteria methods in the investment decision-making process, to optimize and prioritize, in order to succeed in the elaboration of a work plan which contemplates technical and economic aspects. The systemic review of the literature was carried out in current and relevant articles for the subject under study, with the aid of five database sources. The theoretical reference, which totals 52 publications, presents theoretical concepts on the decision process through multicriteria methods of decision support, as well as exemplifies through practical applications how the methods are have been used in the area of energy. Based on this review, it was possible to structure the application of the Multiattribute Utility Theory (MAUT) in an investment decision process for the purpose of planning the expansion of the distribution system in an electric power distribution concessionaire. The application of the method shows the importance of a formal procedure to assist decision makers in the objective hierarchy of the most critical electric power feeders, providing greater clarity and learning throughout the planning process of the expansion of the electric system. In the end, a tool was developed to treat the large volume of data, which provides the purified information to assist in the decision making of investment in assertive actions that improve the quality of supply and meet growth of the system. From the literature review and with the application of the method, opportunities for future studies have been identified.

The expansion of a Gene Regulatory Network (GRN) by finding additional causally-related genes, is of great importance for our knowledge of biological systems and therefore relevant for its biomedical and biotechnological applications. Aim of the thesis work is the development and evaluation of a bioinformatic method for GRN expansion. The method, named PC-IM, is based on the PC algorithm that discovers causal relationships starting from purely observational data. PC-IM adopts an iterative approach that overcomes the limitations of previous applications of PC to GRN discovery. PC-IM takes in input the prior knowledge of a GRN (represented by nodes and relationships) and gene expression data. The output is a list of genes which expands the known GRN. Each gene in the list is ranked depending on the frequency it appears causally relevant, normalized to the number of times it was possible to find it. Since each frequency value is associated with precision and sensitivity values calculated using the prior knowledge of the GRN, the method provides in output those genes that are above the value of frequency that optimize precision and sensitivity (cut-off frequency). In order to investigate the characteristics and the performances of PC-IM, in this thesis work several parameters have been evaluated such as the influence of the type and size of input gene expression data, of the number of iterations and of the type of GRN. A comparative analysis of PC-IM versus another recent expansion method (GENIES) has been also performed. Finally, PC-IM has been applied to expand two real GRNs of the model plant Arabidopsis thaliana

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
This dissertation aims to build a set of tools based on mathematical models to assist a rural electrification cooperative in taking strategic decisions on investing in electrical generation in face of erratic and non-periodic future scenarios. Time series analysis using the Box-Jenkins methods for forecasting was employed to construct the models to predict future energy consumption. Qualitative analysis of future scenarios using Kohler method, that is suited to regional applications, was used. An heuristic approach with hierarchical levels was employed to define the parameters of a mathematical model for the application of integer linear programming at a lower level. This mathematical program was used to optimize the location of photovoltaic solar power plants within a transformer substation area and its branches to minimize disbursements in assets investments, and operations and maintenance costs. The model was tested in a cooperative with six substations, 572 branches, 7,574 cooperative members and a 2,737 km length network. In results obtained was SARIMA models (1,1,1) x (0,1,1) 12. In total, obtained an increase of 1.292 kW for the six substations in the next five years, representing a disbursement R$ 17,170,000.00 if the cooperative to chooses to build a photovoltaic solar power plant to meet this increase of consumption.
A presente dissertação tem por objetivo o desenvolvimento de um modelo de previsão pautando-se em um conjunto de ferramentas com base em modelos matemáticos que auxilie uma cooperativa de eletrificação rural na tomada de decisões estratégicas de investimentos em geração frente a cenários aperiódicos futuros. Como metodologia foi utilizada a análise de séries temporais com métodos de Box-Jenkins para a construção de modelos que foram utilizados na previsão de consumo energético. Análise qualitativa de cenários futuros utilizando a metodologia de Kohler adequada a aplicações regionalizadas. Utilizou-se uma abordagem heurística e em níveis hierárquicos para definição dos parâmetros de um modelo matemático, para aplicação de programação linear inteira. A programação matemática foi usada num nível hierárquico inferior para otimizar a localização de usinas geradoras de energia elétrica por painéis fotovoltaicos em áreas de subestações e ramais visando minimizar desembolsos em geração, manutenção distribuição e operação. O modelo foi testado numa cooperativa com seis subestações, 572 ramais, cerca de 7.574 cooperados e com uma extensão em redes de 2.737 km. Como resultados foram obtidos modelos SARIMA (1,1,1) x (0,1,1) 12. No total foram previstos um aumento de 1.292 kW para as seis subestações nos próximos cinco anos, o que representa um desembolso R$ 17.170.000,00 caso a cooperativa opte na construção de uma usina solar fotovoltaica para suprir este aumento de consumo.

We live in a world where individual wealth and success is sought after by many. Swedish people are more isolated than ever; people feel lonely and mental illnesses is on the rise. This, of course, is caused by many different factors, but we need each other, that is certain. The statistics say that 40% of the households in Sweden are single households, 1 in 3 people over 60 live alone, often as a result of a partner passing away. Used statistics are usually very family- and couple-fixated. It is hard to navigate through the statistics if you’re looking for collectives and other alternative living situations. When having these set standards of SCBs statistics, it is hard to be a visionary. People are leaving their home towns for Umeå due to many different reasons; work and studies at the university are dominant factors. It is quite rough to gain a social network in a new city, and when you’re new somewhere you need a safety net to fall back on when times are rough. But people also need their privacy; their recreational space for healing. People shouldn’t be forced to interact with each other, but they need to get the tools to be able to, when they want it. Imagine a space that celebrates individuality; the neo-liberal way of living we’ve been taught to pursue, but at the same time criticizes it. Imagine quite small isolated dwellings in a bigger enclosed space. As time goes by, the residents will see how bizarre their isolated cocoon homes are, and their activity will bleed out into the collective. The collective space is plain and open for all to use. It is a street within the building that can be adapted to whatever purpose. Eventually, the residents will create a citiness within the building by themselves. They will claim the space outside of their front door. They reclaim the corridor, the elevator, the courtyard, where you usually just nod towards your neighbours. The corridor becomes home, yet it belongs to nobody. They are not forced, but they have been given the tools to discover it themselves; resulting in their homes spilling out into the collective.

We live in a world where individual wealth and success is sought after by many. Swedish peopleare more isolated than ever; people feel lonely and mental illnesses is on the rise. This, of course,is caused by many different factors, but we need each other, that is certain. The statistics say that 40% of the households in Sweden are single households, 1 in 3 people over 60 live alone, often asa result of a partner passing away. Used statistics are usually very family- and couple-fixated. It is hard to navigate through thestatistics if you’re looking for collectives and other alternative living situations. When having theseset standards of SCBs statistics, it is hard to be a visionary. People are leaving their home towns for Umeå due to many different reasons; work and studies atthe university are dominant factors. It is quite rough to gain a social network in a new city, andwhen you’re new somewhere you need a safety net to fall back on when times are rough. But people also need their privacy; their recreational space for healing. People shouldn’t be forced tointeract with each other, but they need to get the tools to be able to, when they want it. Imagine a space that celebrates individuality; the neo-liberal way of living we’ve been taught topursue, but at the same time criticizes it. Imagine quite small isolated dwellings in a biggerenclosed space. As time goes by, the residents will see how bizarre their isolated cocoon homesare, and their activity will bleed out into the collective. The collective space is plain and open for all to use. It is a street within the building that can beadapted to whatever purpose. Eventually, the residents will create a citiness within the building bythemselves. They will claim the space outside of their front door. They reclaim the corridor, theelevator, the courtyard, where you usually just nod towards your neighbours. The corridorbecomes home, yet it belongs to nobody. They are not forced, but they have been given the toolsto discover it themselves; resulting in their homes spilling out into the collective.

Thesis advisor: Abhishek Chatterjee
In the last two decades, unnatural amino acid (UAA) mutagenesis has emerged as a powerful new method to probe and engineer protein structure and function. This technology enables precise incorporation of a rapidly expanding repertoire of UAAs into predefined sites of a target protein expressed in living cells. Owing to the small footprint of these genetically encoded UAAs and the large variety of enabling functionalities they offer, this technology has tremendous potential for deciphering the delicate and complex biology of the mammalian cells. We describe the application of this technology to the modification of adeno-associated virus (AAV) for the first time, enabling the generation of vectors with precisely re-engineered cell-targeting for gene therapy. Our UAA-AAV production platform enables the incorporation of UAAs bearing bio-orthogonal reactive handles into multiple specific sites on the virus capsid and their subsequent functionalization with various labeling molecules. Incorporation of an azido-UAA enabled site-specific attachment of a cyclic-RGD peptide onto the capsid, retargeting the virus to the αv β3 integrin receptors, which are overexpressed in tumor vasculature. This work provides a general chemical approach to introduce various receptor binding agents onto the AAV capsid with site selectivity to generate optimized vectors with engineered infectivity. Next, we used our unique UAA-AAV vector as a tool for the directed evolution of more active UAA incorporation machinery in mammalian cells. It is well known that the efficiency of unnatural amino acid mutagenesis in mammalian cells is limited by the suboptimal activity of the suppressor tRNAs currently in use. The ability to improve their performance through directed evolution can address this limitation, but no suitable selection system was previously available to achieve this. We have developed a novel platform for virus-assisted directed evolution of enhanced suppressor tRNAs (VADER) in live mammalian cells. Our system applies selective pressure for tRNA activity via the nonsense suppression-dependent production of UAA-AAV, and selectivity for the specific incorporation of interest comes from a novel virus purification strategy based on the unique chemistry of the UAA. We demonstrated > 10,000-fold selectivity for active tRNAs out of mock libraries and used this system to evolve libraries generated from the commonly used archaeal pyrrolysyl suppressor tRNA, ultimately identifying a variant which is three times as active as the original tRNA. Finally, we used next-generation sequencing to analyze the fate of every library member over the course of the selection and found that our VADER selection scheme is indeed selective for the enrichment of more active tRNA variants. This work provides a general blueprint for the evolution of better orthogonal suppressor tRNAs in mammalian cells
Thesis (PhD) — Boston College, 2019
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Chemistry

In the context of English youth and community work, this research project investigates digital tools, spaces and places as mediators of youth work practice, and proposes a model formulated through the identification of expansive drivers to guide both professional conduct and curriculum-based practice. The lives of English young people today are shaped by technologies which make interaction in a variety of digital spaces and places possible, yet there are divided views within the youth work community of practice about the place of digital tools, spaces and places as mediators of informal learning in a discipline traditionally focused on association, relationships and critical dialogue. Supported by the conceptual framework of Cultural Historical Activity Theory (CHAT), Developmental Work Research (DWR) techniques have been used to gather data from four English youth and community work practitioners through a workshop-based approach framed by CHAT pre-suppositions and the first three stages of Engestrom’s expansive learning cycle. The data analysis uses the four areas where contradictions can manifest within CHAT activity systems to examine how the use of digital tools, spaces and places aligns with youth work values and principles, and to examine how they can mediate informal learning opportunities with young people. The contribution to knowledge comprises the identification of four ‘spaces’ which are named as safety, production, information and communication, and which form the basis of a model to scaffold the professional use of digital tools, spaces and places as mediators of youth work practice. Expansive drivers, defined as the forces for learning, development and change, are identified within each of the spaces within the model and examined using continuum-based representations portraying professional practice and curriculum-based priorities. Metaphors of digital space and place emerging from within the DWR process are also appraised as a means to situate the work. The model is underpinned firstly by the premise that a youth worker’s choice of digital tool, space or place needs to be based on the needs and input of young people. Secondly, that using digital tools, spaces and places as mediators of youth work practice is most effective as an extension to existing face-to-face youth work where relationships between young people and youth workers have already been formed.

Driven by a number of factors, the electric power industry is expected to undergo a paradigm shift with a considerably increased level of variable energy sources. A significant integration of such sources requires heavy transmission investments over geographically wide and large-scale networks. However, the stochastic nature of such sources, along with the sheer size of network systems, results in problems that may become intractable. Thus, the challenge addressed in this work is to design efficient and reasonably accurate models, strategies and tools that can solve large-scale TEP problems under uncertainty. A long-term stochastic network planning tool is developed, considering a multi-stage decision framework and a high level integration of renewables. Such a tool combines the need for short-term decisions with the evaluation of long-term scenarios, which is the practical essence of a real-world planning. Furthermore, in order to significantly reduce the combinatorial solution search space, a specific heuristic solution strategy is devised. This works by decomposing the original problem into successive optimization phases.One of the modeling challenges addressed in this work is to select the right network model for power flow and congestion evaluation: complex enough to capture the relevant features but simple enough to be computationally fast. Another relevant contribution is a domain-driven clustering process of snapshots which is based on a “moments” technique. Finally, the developed models, methods and solution strategies have been tested on standard and real-life systems. This thesis also presents numerical results of an aggregated 1060-node European network system considering multiple RES development scenarios. Generally, test results show the effectiveness of the proposed TEP model, since—as originally intended—it contributes to a significant reduction in computational effort while fairly maintaining optimality of the solutions.
Driven by several techno-economic, environmental and structural factors, the electric energy industry is expected to undergo a paradigm shift with a considerably increased level of renewables (mainly variable energy sources such as wind and solar), gradually replacing conventional power production sources. The scale and the speed of integrating such sources of energy are of paramount importance to effectively address a multitude of global and local concerns such as climate change, sustainability and energy security. In recent years, wind and solar power have been attracting large-scale investments in many countries, especially in Europe. The favorable agreements of states to curb greenhouse gas emissions and mitigate climate change, along with other driving factors, will further accelerate the renewable integration in power systems. Renewable energy sources (RESs), wind and solar in particular, are abundant almost everywhere, although their energy intensities differ very much from one place to another. Because of this, a significant integration of such energy sources requires heavy investments in transmission infrastructures. In other words, transmission expansion planning (TEP) has to be carried out in geographically wide and large-scale networks. This helps to effectively accommodate the RESs and optimally exploit their benefits while minimizing their side effects. However, the uncertain nature of most of the renewable sources, along with the size of the network systems, results in optimization problems that may become intractable in practice or require a huge computational effort. Thus, the challenge addressed in this work is to design models, strategies and tools that may solve large-scale and uncertain TEP problems, being computationally efficient and reasonably accurate. Of course, the specific definition of the term “reasonably accurate” is the key issue of the thesis work, since it requires a deep understanding of the main cost and technical drivers of adequate TEP investment decisions. A new formulation is proposed in this dissertation for a long-term planning of transmission investments under uncertainty, with a multi-stage decision framework and considering a high level of renewable sources integration. This multi-stage strategy combines the need for short-term decisions with the evaluation of long-term scenarios, which is the practical essence of a real-world planning. The TEP problem is defined as a stochastic mixed-integer linear programming (S-MILP) optimization, an exact solution method. This allows the use of effective off-the-shelf solvers to obtain solutions within a reasonable computational time, enhancing overall problem tractability. Furthermore, in order to significantly reduce the combinatorial solution search (CSS) space, a specific heuristic solution strategy is devised. In this global heuristic strategy, the problem is decomposed into successive optimization phases. Each phase uses more complex optimization models than the previous one, and uses the results of the previous phase so that the combinatorial solution search space is reduced after each phase. Moreover, each optimization phase is defined and solved as an independent problem; thus, allowing the use of specific decomposition techniques, or parallel computation when possible. A relevant feature of the solution strategy is that it combines deterministic and stochastic modeling techniques on a multi-stage modeling framework with a rolling-window planning concept. The planning horizon is divided into two sub-horizons: medium- and long-term, both having multiple decision stages. The first sub-horizon is characterized by a set of investments, which are good enough for all scenarios, in each stage while scenario-dependent decisions are made in the second sub-horizon. One of the first modeling challenges of this work is to select the right network model for power flow and congestion evaluation: complex enough to capture the relevant features but simple enough to be computationally fast. The thesis includes extensive analysis of existing and improved network models such as AC, linearized AC, “DC”, hybrid and pipeline models, both for the existing and the candidate lines. Finally, a DC network model is proposed as the most suitable option. This work also analyzes alternative losses models. Some of them are already available and others are proposed as original contributions of the thesis. These models are evaluated in the context of the target problem, i.e., in finding the right balance between accuracy and computational effort in a large-scale TEP problem subject to significant RES integration. It has to be pointed out that, although losses are usually neglected in TEP studies because of computational limitations, they are critical in network expansion decisions. In fact, using inadequate models may lead not only to cost-estimation errors, but also to technical errors such as the so-called “artificial losses”. Another relevant contribution of this work is a domain-driven clustering process to handle operational states. This allows a more compact and efficient representation of uncertainty with little loss of accuracy. This is relevant because, together with electricity demand and other traditional sources of uncertainty, the integration of variable energy sources introduces an additional operational variability and uncertainty. A substantial part of this uncertainty and variability is often handled by a set of operational states, here referred to as “snapshots”, which are generation-demand patterns of power systems that lead to optimal power flow (OPF) patterns in the transmission network. A large set of snapshots, each one with an estimated probability, is then used to evaluate and optimize the network expansion. In a long-term TEP problem of large networks, the number of operational states must be reduced. Hence, from a methodological perspective, this thesis shows how the snapshot reduction can be achieved by means of clustering, without relevant loss of accuracy, provided that a good selection of classification variables is used in the clustering process. The proposed method relies on two ideas. First, the snapshots are characterized by their OPF patterns (the effects) instead of the generation-demand patterns (the causes). This is simply because the network expansion is the target problem, and losses and congestions are the drivers to network investments. Second, the OPF patterns are classified using a “moments” technique, a well-known approach in Optical Pattern Recognition problems. The developed models, methods and solution strategies have been tested on small-, medium- and large-scale network systems. This thesis also presents numerical results of an aggregated 1060-node European network system obtained considering multiple RES development scenarios. Generally, test results show the effectiveness of the proposed TEP model, since—as originally intended—it contributes to a significant reduction in computational effort while fairly maintaining optimality of the solutions.

QC 20160919

The sugarcane cultivation in Brazil is one of the leading economic pillars, as it is an ethanol precursor, a renewable fuel produced in industrial markets as a substitute for fossil fuels. Brazil produces about 27.44% and 43% of the world production of ethanol and sugar, respectively. São Paulo state has the environmental and logistic conditions for a sugarcane industry, both characteristics turn it the main Brazilian\'s sugarcane production pole, with 63.74% of sugar and 48.23% of ethanol production (RFA, 2017). In São Paulo, the Agro-Environmental Zoning establishes the areas to cultivate sugarcane. However, tools to check the sugarcane industry influences on municipalities\' socioeconomic aspects are superficial. Considering sugarcane industry importance to São Paulo state and Brazil, the Nucleus of Research and Extension on Sustainability and Sanitation initiated different investigations and efforts to study, analyze, and predict the sugarcane industry\'s impacts and sustainability. Within this research\'s general line, the focused was on environmental impacts with emphasis on their accumulation and synergy, climate change scenarios, sustainability concept management among its stakeholders, industry\'s governance, mill unit\'s sustainability evaluation, and so forth. In this context, it appears as a necessary and conclusive step the sustainability assessment tool\'s development, allowing sugarcane industry evaluation, while respecting the individual circumstances. Therefore, this project objective is to develop a sustainability assessment model to sugarcane sector decision-making implemented in an atlas format. The sustainability assessment model includes eighteen indicators about environmental, social, economic, and municipal policies issues. Those indicators describe seven of the eight Gibson\'s principles. It was the principles grouped according to their indicators\' nature in three domains (environmental, socioeconomic, and municipal policies) that finally compose the sustainability index. Some indicators are considered elimination factors to avoid the trade-off between principles and domains, because more than limiting the calculus\' next level, they cut the unsustainable situations by classifying them as such. In the end, the atlas present twelve maps that describe the distribution of principles, domains, and sustainability index across São Paulo state. The results show that the sugarcane ethanol sector still faces new environmental and social impacts, while the Agro-environmental Zoning presents a limited contribution to sustainability. According to the model, environmental issues (Domain A) there are new areas where sugarcane must be forbidden or, at least, increase its requirement for water quality improvement. Nevertheless, half of the state of São Paulo has the environmental condition for sugarcane cultivars. For socioeconomic issues (Domain B), most municipalities presented a moderate performance. In the Domain C few municipalities reached the very high-performance, while the high-performance stood out for being the main one. In both, the Domain B and the Domain C, moderate and high are the significant municipalities\' performances. The atlas format results in a useful instrument, because it is easy to understand, can deliver a full state context and regions contrast, as well it brings a specific outcome for each municipality, and in case of environmental issues it also presents more precise details according to natural limits. Finally, the sensitivity analysis showed that the social indicators explain the results in 19.2%, while the municipal policy indicators influence 15.7% and the economic indicators 5.7%. The environmental indicators correspond to 59.4%, with indicator A3 (water quality) accounting for 19.7%.
O cultivo da cana-de-açúcar no Brasil é um dos principais pilares da economia do país, pois é um precursor de etanol, combustível renovável produzido em quantidades industriais como substituto de combustíveis fósseis. O Brasil produz cerca de 27.44% e 43% da produção mundial de etanol e açúcar, respectivamente. O Estado de São Paulo tem as condições ambientais e logísticas para a indústria da cana-de-açúcar, e ambas as características o tornaram o principal polo de produção no Brasil com 63.74% de açúcar e 48.23% de produções de etanol (RFA, 2017). Em São Paulo, o Zoneamento Agro-Ambiental (AENZ) estabelece as áreas onde a cana-de-açúcar pode ser plantada, considerando critérios ambientais. No entanto, ferramentas para avaliar as influências sobre os aspectos socioeconômicos dos municípios onde as culturas e indústrias de cana-deaçúcar estão inseridas são ainda superficiais. Considerando a importância da indústria da cana-de-açúcar para o Estado de São Paulo e Brasil, o Núcleo de Pesquisa e Extensão de Sustentabilidade e Saneamento iniciou diferentes investigações e esforços para estudar, analisar e prever os impactos e a sustentabilidade da indústria da cana-de-açúcar. Dentro desta linha geral de pesquisa, o foco foi sobre os impactos ambientais com ênfase em sua acumulação e sinergia, cenários de mudança climática, gerenciamento de conceito de sustentabilidade entre os stakeholders, governança do setor, avaliação de sustentabilidade de usinas, etc. Neste contexto, parece ser um passo necessário e conclusivo o desenvolvimento de uma ferramenta de avaliação de sustentabilidade, que permita a avaliação da indústria da cana-de-açúcar, respeitando as circunstâncias particulares de cada região. Portanto, o objetivo deste projeto é desenvolver um modelo de avaliação de sustentabilidade para a tomada de decisão do setor de cana-de-açúcar operacionalizado em um atlas. O modelo de avaliação de sustentabilidade inclui dezoito indicadores sobre questões de políticas municipais, ambientais, sociais e econômicas. Esses indicadores descrevem sete dos oito princípios de Gibson. Foram os princípios agrupados de acordo com a natureza de seus indicadores em três domínios (políticas ambientais, socioeconômicas e municipais) que finalmente compõem um índice de sustentabilidade. Alguns indicadores são considerados fatores de eliminação para evitar o trade-off entre princípios e domínios, porque mais do que limitar o próximo nível do cálculo, eles eliminam as situações insustentáveis, classificando-as como tal. No final, o atlas apresenta doze mapas que descrevem a distribuição de princípios, domínios e índice de sustentabilidade em todo o estado de São Paulo. Os resultados mostram que o setor de etanol de cana ainda enfrenta novos impactos ambientais e sociais, enquanto o Zoneamento Agroambiental apresenta uma contribuição limitada para a sustentabilidade. De acordo com o modelo, em relação às características ambientais (Domínio A), existem novas áreas onde a cana-de-açúcar deve ser proibida ou, pelo menos, se deve aumentar as exigências para a melhoria da qualidade da água. No entanto, metade do estado de São Paulo tem a condição ambiental para as cultivares de cana-de-açúcar. Em questões socioeconômicas (Domínio B), a maioria dos municípios apresentou desempenho moderado. No domínio C, poucos municípios atingiram o muito alto desempenho, enquanto o alto desempenho se destacou por ser o principal. Em ambos, o Domínio B e o Domínio C, moderado e alto são os desempenhos significativos dos municípios. O formato do atlas resulta em um instrumento útil, porque é fácil de entender, pode oferecer um contexto de estado completo e o contraste de regiões, além disso traz um resultado específico para cada município e, em caso de problemas ambientais, também apresenta detalhes mais precisos de acordo com os limites naturais. Finalmente, a análise de sensibilidade mostrou que os indicadores sociais explicam os resultados em 19.2%, enquanto os indicadores da política municipal influenciam 15.7% e os indicadores econômicos 6.7%. Os indicadores ambientais correspondem a 59.4%, com o indicador A3 (qualidade da água) representando 19.7%.

There is a need to investigate and improve upon existing methods to predict response of sensors due to flow-induced vibrations in a pipe flow. The aim was to develop a tool which would enable an engineer to quickly evaluate the suitability of a particular design for a certain pipe flow application, without sacrificing fidelity. The primary methods, found in guides published by the American Society of Mechanical Engineers (ASME), of simple response prediction of sensors were found to be lacking in several key areas, which prompted development of the tool described herein. A particular limitation of the existing guidelines deals with complex stochastic stationary and non-stationary modeling and required much further study, therefore providing direction for the second portion of this body of work. A tool for response prediction of fluid-induced vibrations of sensors was developed which allowed for analysis of low aspect ratio sensors. Results from the tool were compared to experimental lift and drag data, recorded for a range of flow velocities. The model was found to perform well over the majority of the velocity range showing superiority in prediction of response as compared to ASME guidelines. The tool was then applied to a design problem given by an industrial partner, showing several of their designs to be inadequate for the proposed flow regime. This immediate identification of unsuitable designs no doubt saved significant time in the product development process. Work to investigate stochastic modeling in structural dynamics was undertaken to understand the reasons for the limitations found in fluid-structure interaction models. A particular weakness, non-stationary forcing, was found to be the most lacking in terms of use in the design stage of structures. A method was developed using the Karhunen Loeve expansion as its base to close the gap between prohibitively simple (stationary only) models and those which require too much computation time. Models were developed from SDOF through continuous systems and shown to perform well at each stage. Further work is needed in this area to bring this work full circle such that the lessons learned can improve design level turbulent response calculations.
Ph. D.

Abstract This study analyzes an attempt at integration of a pre-school class, a leisure-time center and an elementary school in Sweden. The integration was organized in the form of Vertical Track which implies a successive development of groups comprising children between six and twelve years old, pre-school teachers, recreation pedagogues, and schoolteachers. The integration was prompted by state governed reforms such as the 1992 law allowing six-year olds to start compulsory school. The study is based on cultural-historical activity theory and was carried out as participant observation and action research. The study addresses the question of the potentials and alternative goals for change and development of the present school pedagogy and classroom practice that integration implies. Special attention has been paid to what tools might potentially mediate in processes of integration. A research and educational program, the 5thD, was jointly created between researchers and teachers and located in a Vertical Track. The capacity of this complex tool as a mediator in the multicultural Vertical Track structure was explored. It is argued that the Vertical Track as an instantiation of the integration reform represents an arena for potential expansive transformation. However, in order for integration to have an impact on the pedagogical practice in schools, teacher interactions need to be mediated by communicative and conceptual tools. It is suggested that the 5thD program is an example of such tools. Keywords: Integration, pre-school teacher, recreation pedagogue, schoolteacher, contradiction, expansive learning, mediation, and tool.

Framlagd vid Helsingfors universitet, pedagogiska institutionen.

New modelling tools intended to contribute to the development of components for quieter vehicles are developed. The tools are based on continuum models for wave propagation in poro- and visco-elastic media. By using geometric attributes of the studied components, the computational cost may be radically decreased compared to traditional methods. By assigning known analytical functions for one or two of the spatial directions, the spatial dimension of the remaining numerical problem is reduced. This reduction of spatial dimensions is performed in two di↵erent ways. The first one treats wave propagation in infinitely extended homogeneous and hollowed cylindrical rods, or wave guides, consisting of visco-elastic media. The wave solutions obtained are then used to model rubber vibration isolators of finite length by mode-matching the fields to the radial boundary conditions of interest. The second one is a method for modelling rotationally symmetric multilayered structures consisting of poro-elastic, elastic and fluid domains. By using a harmonic expansion for the azimuthal spatial dependence, the original three-dimensional problem is split up into several, much smaller, two- dimensional ones, radically decreasing the computational load.Moreover, using a mixed measurement/modelling approach, the audible frequency range characteristics of a viscous damper from a truck is studied, illustrating the influence of the rubber bushings by which it is attached to surrounding structures.The modelling approaches presented in this thesis are intended as tools aiding the design process of new vehicles, enabling new technology striving for more sustainable vehicle concepts. More specifically, the tools aim to improve the modelling of sound and vibration properties which are often penalised when seeking new, more sustainable vehicle designs.

Kipunji Rungwecebus kipunji, a Tanzanian endemic and Africa's rarest monkey, was only discovered in 2003. It was subsequently categorised as 'critically endangered' on the IUCN Red List, with 93% of the population found in the degraded Mt Rungwe and Livingstone forests (RL) of the Southern Highlands. Aspects of kipunji ecology and habitat characteristics were investigated for the RL population to inform future evidence-based conservation, and more specifically to look at how range and population expansion can be used as tools to reduce the extinction risk of a 'critically endangered' species. Habitat use models developed for kipunji suggested that they are able to tolerate some forest disturbance, such as a fragmented canopy, as long as this is associated with specific tree communities at mid to lower altitudes. Predictions of habitat suitability suggest there is little room for expansion within forests around the known kipunji range (RL extent of occurrence = 42 km"), although the original habitat in areas south of the current range, now deforested, would have been highly suitable. From these results, improving habitat quality and connectivity inside the forest, and reforesting parts of the former range outside of the forest, would be needed to facilitate range expansion. Twenty three kipunji groups were studied to record demographic data testing a partial count method, used as a response to the problems of estimating age-sex ratios for shy, cryptic and arboreal animals. This method demonstrated potential as a quick and simple way to collect baseline population data. Kipunji demographics indicate a 'healthy' population composition (based on current numbers of adult females to males, females with infants, and proportion of infants per group) that is stable, if not increasing. There is no evidence so far to suggest that kipunji group size changes along a gradient of forest disturbance, although some demographic parameters are inversely correlated with forest disturbance and may be linked to resource availability. The 22-month foraging ecology study demonstrated that kipunji have a wide, diverse and predominantly fruit-rich diet. Fruit consumption was correlated with fruit availability which showed a peak during the wet season, and a period of fruit scarcity in the driest months (August-October). During this period, three fallback foods (unripe fruits, mature leaves and pith) were widely consumed. α diversity and evenness of diet was remarkably similar across months, but there was high β diversity in diets across months at the cusp of wet and dry seasons, and during periods of low fruit availability This suggests considerable dietary adaptability to fluctuating resources, which may act to buffer against further forest disturbance. Tree species associated with relatively undisturbed forest were significantly more important in the diet, especially in the dry season, than those of disturbed forests. Regeneration of key trees appeared healthy except in two important Ficus species. Patterns of home range use showed that temporal and spatial patterns were linked to fruit availability. An expansion of the range occurred with low fruit availability in the dry season, and a longer dry season daily path length was associated with an increase in diversity of fruits in the diet. Activity budgets changed between seasons with a greater proportion of time spent feeding in the dry season. Kipunji exhibited long ranging patterns of home range use, rarely returning to the same site on successive days, which probably facilitated resource monitoring and/or allowed dietary switching as fruit scarcity increased during 'leaner' periods. The main pressures on kipunji in the forest are from logging, charcoal production and hunting. Retributive hunting on the forest edge also occurred in response to crop raiding of maize (and to a lesser extent legumes and potatoes) by kipunji and Moloney's white-collared monkey. This was a localised problem in the wet season months (December to April), and was predicted primarily by the presence of maize, and not habitat measures, suggesting that reforestation schemes at the forest boundary might not necessarily increase the incidence of crop raiding. Mitigation measures should include methods that create physical barriers/buffer zones between maize and the forest edge. The matrix habitat adjacent to the RL forests was dominated by agriculture, interspersed with some small forest patches and single trees, which may be useful as 'links' in the landscape. Matrix habitat immediately bordering the forest was very different from forest within the reserve, and this 'hard edge' means that reforestation to create 'extra' kipunji habitat would basically start from nothing. Kipunji habitat creation which seeks to relieve pressure on the forest and directly benefit communities is likely to be supported as 95% of villagers interviewed were willing to become involved in tree planting/reforestation schemes. Reforesting 800 ha, which may be sufficient for an 'extra' 500 kipunji (almost 50% of the total current population), could cost $491,400 based on current land prices, a relatively modest sum with potentially significant outcomes for a threatened species, but feasibility of such a scheme might be limited by socio-political factors.

New modelling tools intended to contribute to the development of components for quieter vehicles are developed. The tools are based on continuum models for wave propagation in poro– and visco–elastic media. By using geometric attributes of the studied components, the computational cost may be radically decreased compared to traditional methods. By assigning known analytical functions for one or two of the spatial directions, the spatial dimension of the remaining numerical problem is reduced. This reduction of spatial dimensions is performed in two di↵erent ways. The first one treats wave propagation in infinitely extended homogeneous and hollowed cylindrical rods, or wave guides, consisting of visco–elastic media. The wave solutions obtained are then used to model rubber vibration isolators of finite length by mode–matching the fields to the radial boundary conditions of interest. The second one is a method for modelling rotationally symmetric multilayered structures consisting of poro–elastic, elastic and fluid domains. By using a harmonic expansion for the azimuthal spatial dependence, the original three–dimensional problem is split up into several, much smaller, two– dimensional ones, radically decreasing the computational load. Moreover, using a mixed measurement/modelling approach, the audible frequency range characteristics of a viscous damper from a truck is studied, illustrating the influence of the rubber bushings by which it is attached to surrounding structures. The modelling approaches presented in this thesis are intended as tools aiding the design process of new vehicles, enabling new technology striving for more sustainable vehicle concepts. More specifically, the tools aim to improve the modelling of sound and vibration properties which are often penalised when seeking new, more sustainable vehicle designs.

QC 20120522

Centre for Eco2 Vehicle Design

Thesis (Ph.D.)--Boston University
New strategies for treatment and methods of drug delivery are required for patients suffering from cancer-the second leading cause of death worldwide. Current chemotherapeutic treatments frequently suffer from poor water solubility, systemic toxicity, poor accumulation within the target tissues and an inability to eradicate all remaining tumor following resection procedures. Nanoparticles (NPs) are extensively investigated as a means to increase drug solubility, alter biodistribution, target specific sites within the body, and minimize drug side effects and, as such, numerous NP formulations are being investigated as drug delivery devices to assist in the treatment and management of cancer. We have developed a pH-responsive expansile nanoparticle (eNP) that can encapsulate the hydrophobic chemotherapeutic agent Paclitaxel (Pax) (a poorly water soluble, yet potent chemotherapeutic agent), and deliver it specifically to the intracellular compartment of tumor cells. Paclitaxel-loaded-eNPs (Pax-eNPs) localize specifically to regions of intraperitoneal (IP) tumors and, once taken up by tumor cells, undergo a conformational change upon exposure to the mildly acidic cellular endosome that results in eNP swelling and intratumoral drug release. In this work, we describe: 1) the clinical problem and cost (both humanitarian and fmancial) of local cancer recurrence following tumor resection; 2) the eNP delivery system and, specifically, we characterize the swelling of eNPs using microscopy and tunable resistive pulse sensing techniques; 3) the in vitro activity of Pax-eNPs in breast cancer cells; 4) the improved efficacy of Pax- eNPs compared to the standard clinical formulation of Pax (i.e., Pax dissolved in Cremophor/Ethanol) in a murine model of established peritoneal mesothelioma; and, 5) the ability of eNPs to act as intratumoral, intracellular drug concentrating devices. Further investigation of this NP-based drug delivery system will facilitate a greater understanding of the materials and devices used in the delivery of chemotherapeutic agents and may lead to the clinical translation and application of eNPs.
2019-05-01

Thesis (Ph.D.)--Boston University
New strategies for treatment and methods of drug delivery are required for patients suffering from cancer-the second leading cause of death worldwide. Current chemotherapeutic treatments frequently suffer from poor water solubility, systemic toxicity, poor accumulation within the target tissues and an inability to eradicate all remaining tumor following resection procedures. Nanoparticles (NPs) are extensively investigated as a means to increase drug solubility, alter biodistribution, target specific sites within the body, and minimize drug side effects and, as such, numerous NP formulations are being investigated as drug delivery devices to assist in the treatment and management of cancer. We have developed a pH-responsive expansile nanoparticle (eNP) that can encapsulate the hydrophobic chemotherapeutic agent Paclitaxel (Pax) (a poorly water soluble, yet potent chemotherapeutic agent), and deliver it specifically to the intracellular compartment of tumor cells. Paclitaxel-loaded-eNPs (Pax-eNPs) localize specifically to regions of intraperitoneal (IP) tumors and, once taken up by tumor cells, undergo a conformational change upon exposure to the mildly acidic cellular endosome that results in eNP swelling and intratumoral drug release. In this work, we describe: 1) the clinical problem and cost (both humanitarian and fmancial) of local cancer recurrence following tumor resection; 2) the eNP delivery system and, specifically, we characterize the swelling of eNPs using microscopy and tunable resistive pulse sensing techniques; 3) the in vitro activity of Pax-eNPs in breast cancer cells; 4) the improved efficacy of Pax- eNPs compared to the standard clinical formulation of Pax (i.e., Pax dissolved in Cremophor/Ethanol) in a murine model of established peritoneal mesothelioma; and, 5) the ability of eNPs to act as intratumoral, intracellular drug concentrating devices. Further investigation of this NP-based drug delivery system will facilitate a greater understanding of the materials and devices used in the delivery of chemotherapeutic agents and may lead to the clinical translation and application of eNPs.

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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES
This paper discusses the process of urban expansion of Goiânia, under the bias of management tools, from a case study applied to the southeast of the capital. The impacts suffered are analyzed for this region, due to the city metropolization process by conurbation with neighboring municipalities and simultaneously the process of abandonment of the central areas, by the elite. The period studied, the start of structuring the region to the present day (1950-2015), is marked by several phases that sometimes exemplify the history of expansion of Goiânia. It presents reflections on: the role of management tools in the city's expansion preocess, the spatial process and the action of cosial agents producers of the city. It was noticed a pattern of ocupation in the southeast, whose approach was made possible by the application of analytical methodology based on PANERAI (2015), classifying the types of occupation found. The clipping possible to understand the southeast as a whole as well as the current trend of urban expansion undergone by the state of Goiás capital.
Este trabalho discute o processo de expansão urbana de Goiânia, sob o viés dos instrumentos de gestão, a partir de um estudo de caso aplicado à Região Sudeste da capital. São analisados os impactos sofridos por esse região, em decorrência do processo de metropolização da cidade por conurbação com os municípios vizinhos e, simultaneamente, do processo de abandono das áreas centrais, por parte da elite. O período estudado, do início da estruturação da região até os dias atuais (1950-2015), é marcado por várias fases que, por vezes, exemplificam a própria história de expansão de Goiânia. Apresenta reflexões sobre: o papel dos instrumentos de gestão no processo de expansão da cidade, os processos espaciais, bem como a ação dos agentes sociais produtores da cidade. Percebeu-se um padrão de ocupação na região sudeste, cuja abordagem foi possibilitada pela aplicação da metodologia da análise baseada em PANERAI (2015), classificando os tipos de ocupação encontrados. O recorte possibilitou compreender a região sudeste em sua totalidade, bem como a atual tendência de expansão urbana por que passa a capital do estado de Goiás.

This project deals with given safeguard possibilities, both mechanical and electronic. A row house with garden was chosen for being secured. Subsequently, were elaborated two`s proposals of securing and guarding of this object. First, was based on camera`s system and second on common system ESS. Later on they were evaluated and the most considerable benefits were emphasized. A system based on control panel with connected detectors was selected upon specification. Subsequently was created a model of the chosen system, at which the required behaviour was simulated and verified. An outline of an implementation was created in the C language.

A integração do ferramental técnico-científico disponível com os diferentes instrumentos de política e gestão ambiental é essencial para a compatibilização das exigências impostas pelo desenvolvimento com a manutenção ou melhoria da qualidade ambiental e social e, também, para o equacionamento das demandas e dos interesses de cada setor envolvido no processo decisório. Assim, os modelos para a projeção das alterações no uso e ocupação do solo de um determinado território têm sido freqüentemente utilizados. A modelagem propicia a geração e a avaliação das informações para montagem de um panorama das possíveis alterações no uso do solo, considerando que as tendências identificadas para aquele território, num certo instante, sejam mantidas de modo a se desenvolverem de acordo com um determinado cenário projetado. O presente trabalho analisa a possibilidade de aplicação conjunta do método de projeção das alterações no uso e ocupação do solo e instrumentos de política ambiental, levando em conta os aspectos preventivos. Aplicado a uma porção do município de São Carlos (SP), o trabalho apresenta uma projeção para a expansão urbana para os anos de 2012 e 2019, considerando três cenários alternativos de ocupação territorial. Confrontando os resultados obtidos pela modelagem com a capacidade de suporte do meio para a implantação de empreendimentos urbanos - determinada a partir da elaboração de um zoneamento ambiental, verifica-se que, mantidas as tendências atuais, e para os três cenários de ocupação avaliados, a expansão urbana continuará avançando sobre áreas de baixa aptidão para a urbanização, permanecerá exercendo intensa pressão sobre os recursos hídricos e os fragmentos de vegetação nativa, caso não sejam adotadas medidas que modifiquem o atual padrão de ocupação do território.
To compatibilize the demands raised by development with the maintenance or improvement of the social and environmental quality, the integration among technical scientific tools and environmental management instruments is essential to solve the interests of each sector involved at the decision process. On this context are inserted land use and cover change models. The modelling permit the decision-making process to be done evaluating the consequences of possible alterations on land use, which can be identified considering the scenarios projected for the territory under certain circunstances. The presente work analyses the possibility of joint application of this technique and environmental policy tools considering preventive aspects. Allocated to a portion of the São Carlos (SP) municipality, the work projects urban growth for the years 2012 and 2019, considering three alternative scenarios of occupation. Confronting the results obtained by the model with the carrying capacity for the implementation of urban activities - determined from the elaboration of environmental zoning, is showed that, maintained the present tendencies, and for the scenarios evaluated, the urban growth will continue forward and towards the areas with low suitability. In the same way, the pressure over water resources and fragments of native vegetation will remains intense unless measures to modify the standards in occupation can be adopted.

Many engineering parts in industries are assembled by rivets, bolts, pins etc. These joints are more vulnerable to fatigue loadings and a crack is emanated. As structure is in use crack starts propagating over a period of time. Crack propagation can be obstructed by inducing a compressive residual stress zone around the vulnerable parts. Cold expansion hole (CEH) is one of the techniques used to induce compressive stress zone, by inserting a tapered pin or a large diameter ball into an undersized hole. As the oversized object is inserted into the hole, the surrounding material is elastically deformed and when the object comes out from the other side, the expanded material springs back to form tangential compressive residual stress around the hole. In most of the cases the crack origins on the surface, a good surface finish is also an important parameter for increasing the strength at the surface and stop crack emanation. However, good surface finish is not achieved by CEH. A novel technique called rotating tool cold expansion (RTCE) technique is developed where a tapered mandrel is inserted into an undersized hole besides rotating it simultaneously. The tool rotation breaks down the coarse grains into fine grain structure achieving good surface finish. In this method, RTCE is performed with three undersized diameters, namely, 9.2, 9.5 and 9.9 mm diameters to a maximum of 10 mm diameter. The tool material is high speed steel and the work piece material is commercial aluminium. The induced residual stresses are measured using X-ray diffraction method and compared for three different Cold expansion holes. Due to the rotation of the tool, heat is generated because of both friction at the interface and plastic deformation. A 3-D thermo-mechanical analysis is performed in ANSYS FEA for different values of coefficient of friction and plastic deformation rate and validated with experimental results. Compared to the degree of cold expansion through conventional techniques (upto 4%) the proposed technique is capable to produce good results up to 8.69% of cold expansion. Role of heat generated through friction and plastic deformation is critical to attain the best possible result, equal contributions of both are important.

1. Introduction 1.1. Background to the study Advancement in technology have had a immense impact on the e-commerce world, it had transformed the way consumers get connected with brands and empowered them to shop more cost effectively. Driven by the convenience of products getting delivered to your doorstep, ecommerce has now become an integral part of everyday life. (www.Acquire.io) “It’s the first inning. It might even be the first guys up at bat. We’re on the edge of golden age [of AI].” – Jeff Bezos CEO at Amazon From how we live to how we work, AI plays a pivotal role in our day to day schedule. There are numerous examples of AI and the automation tools used are spam filters, voice to text features, smart personal assistants (Such as Siri, Alexa), personalisation of new feeds (www.nibusinessinfo.co.uk). In a research, it was found that 45% of millennials are already using this type of voice activated search for online shopping. Apart from this, Augmented Reality based tools like 3D Try on are the next sensation in E- commerce world. Some are already integrating this features to give their customers better shopping experience. This not only helps the customer but the provider in terms of less churn and high profitability. For the earliest players it has given them competitive advantage over the rivals. Along with this Referrals are playing a major role in attracting and retaining customers. It is a saying that, "Marketing is the most effective when it's not even clear that we are doing any". The best way marketer get their customers is through referral and there is high chances of conversion. A satisfied customer is most likely to recommend product or services to their friends, relatives, acquaintance and they do this not without getting paid. This is the reason why everyone trust their friend's reviews. That means having referral strategy helps the marketer to motivate their satisfied customers to take steps and recommend the products to their friends and relatives might benefit us in terms of expansion and thus revenues. 2 So, in our project we focuses on identifying features which consumers think are important to them and classify them according to their relative importance. This study also includes understanding the perception about the product reviews, referrals and incentives. We have also studied user's perception about Artificial Intelligence and Augmented Reality based tools which could potentially be the next sensation in E-commerce world.
ABSTRACT Now a days, Internet has become one-window for all the internet users in terms of searching for their day-to-day needs due to swift growth in the technology. For their small requirements like shoes to large appliances like refrigerator, they seek it on the internet. The variety or the product and huge number of people seeking them makes competition tighter between the e-commerce providers. In order to attract majority of the customer they have to stand out from their competitors. Referral marketing is another aspect which e-commerce platforms have been using to maximize their reach to prospect customers. They also make use of a technology to replace the offline mode of shopping such as using Augmented Reality based tools which is enhancing the online purchase experience. The study sought to determine the attributes which are important for customers; perception about the product reviews, referrals and incentives; user's perception about Augmented Reality (AR) tools during online purchase experience. For studying the behavior primary data were collected from students of Delhi Technological University and Delhi University. Using convenience sampling technique 200 responses were collected to study their behavior. The primary data for this study was collected via questionnaires. . The quantitative data was analysed by descriptive statistics using SPSS. Factor analysis was done to find the most important factors and later we need Friedman’s Test to find the most important important factors. Cross-tabulation analysis was used to show the relationship among different variables.

碩士
大葉大學
機械工程研究所
89
High-speed machining has become more and more important in recent year. In order to achieve this goal, the high-speed spindles are used. With the increasing rotational speed, the problem of temperature rise occurs. This research uses the Taguchi method to find the optimum parameters for an oil-air lubrication spindle with ceramic bearings. The effects of the design parameters on the temperature rise and the thermal error of the spindle can also be obtained. The results can be used to minimize the temperature rise and the thermal deformation of an oil-air lubrication spindle with ceramic bearings. For the feeding system, this research applies a preload on the screw to compensate the thermal deformation. With varying feed rates and preloads, the temperature rise, the thermal deformation and the positional errors were measured. The thermal deformation and the positional errors are compared. The last part of this research focuses on the thermal errors of a planer-type machining center. The temperature rise and the thermal deformation were measured by using thermocouples and capacitance probes. Multiple-variable regression analysis was used to develop a thermal model. The model is found to greatly improve the accuracy.

The resolution of fluorescence light microscopy was long believed to be limited by the diffraction limit of light of around 200-250 nm described in 1873 by Ernst Abbe. Within the last decade, several approaches, such as structured illumination microscopy (SIM), stimulated emission depletion STED and (direct) stochastic optical reconstruction microscopy (d)STORM have been established to bypass the diffraction limit. However, such super-resolution techniques enabling a resolution <100 nm require specialized and expensive setups as well as expert knowledge in order to avoid artifacts. They are therefore limited to specialized laboratories. Recently, Boyden and colleagues introduced an alternate approach, termed expansion microscopy (ExM). The latter offers the possibility to perform superresolution microscopy on conventional confocal microscopes by embedding the sample into a swellable hydrogel that is isotropically expanded. Since its introduction in 2015, expansion microscopy has developed rapidly offering protocols for 4x, 10x and 20x expansion of proteins and RNA in cells, tissues and human clinical specimens. Mitochondria are double membrane-bound organelles and crucial to the cell by performing numerous tasks, from ATP production through oxidative phosphorylation, production of many important metabolites, cell signaling to the regulation of apoptosis. The inner mitochondrial membrane is strongly folded forming so-called cristae. Besides being the location of the oxidative phosphorylation and therefore energy conversion and ATP production, cristae have been of great interest because changes in morphology have been linked to a plethora of diseases from cancer, diabetes, neurodegenerative diseases, to aging and infection. However, cristae imaging remains challenging as the distance between two individual cristae is often below 100 nm. Within this work, we demonstrate that the mitochondrial creatine kinase MtCK linked to fluorescent protein GFP (MtCK-GFP) can be used as a cristae marker. Upon fourfold expansion, we illustrate that our novel marker enables visualization of cristae morphology and localization of mitochondrial proteins relative to cristae without the need for specialized setups. Furthermore, we show the applicability of expansion microscopy for several bacterial pathogens, such as Chlamydia trachomatis, Simkania negevensis, Neisseria gonorrhoeae and Staphylococcus aureus. Due to differences in bacterial cell walls, we reveal important aspects for the digestion of pathogens for isotropic expansion. We further show that expansion of the intracellular pathogens C. trachomatis and S. negevensis, enables the differentiation between the two distinct developmental forms, catabolic active reticulate bodies (RB) and infectious elementary bodies (EB), on a conventional confocal microscope. We demonstrate the possibility to precisely locate chlamydial effector proteins, such as CPAF or Cdu1, within and outside the chlamydial inclusion. Moreover, we show that expansion microscopy enables the investigation of bacteria, herein S. aureus, within LAMP1 and LC3-II vesicles. With the introduction of the unnatural α-NH2-ω-N3-C6-ceramide, we further present the first approach for the expansion of lipids that may also be suitable for far inaccessible molecule classes like carbohydrates. The efficient accumulation and high labeling density of our functionalized α-NH2-ω-N3-C6-ceramide in both cells and bacteria enables in combination with tenfold expansion nanoscale resolution (10-20 nm) of the interaction of proteins with the plasma membrane, membrane of organelles and bacteria. Ceramide is the central molecule of the sphingolipid metabolism, an important constituent of cellular membranes and regulates many important cellular processes such as differentiation, proliferation and apoptosis. Many studies report about the importance of sphingolipids during infection of various pathogens. While the transport of ceramide to Chlamydia has been reported earlier, one of the unanswered questions remaining was if ceramide forms parts of the outer or inner bacterial membrane. Expansion of α-NH2-ω-N3-C6-ceramide enabled the visualization of ceramide in the inner and outer membrane of C. trachomatis and their distance was determined to be 27.6 ± 7.7 nm
Aufgrund der Beugungseigenschaften des Lichtes wurde bereits 1873 durch Ernst Abbe für die Lichtmikroskopie eine theoretische Auflösungsgrenze von 200-250 nm definiert. Durch die Einführung verschiedener hochauflösender Mikroskopiemethoden, wie beispielsweise SIM-Mikroskopie (structured illumination microscopy), STED-Mikroskopie (stimulated emission depletion) und (d)STORM-Mikroskopie ((direct) stochastic optical reconstruction microscopy), konnte im letzten Jahrzehnt jedoch die Auflösung auf unter 100 nm verbessert werden. Allerdings benötigen solche Hochauflösungstechniken sowohl spezialisierte und kostenintensive Geräte als auch Expertenwissen zur Vermeidung von Artefakten, sodass diese nur in wenigen Laboren angewendet werden können. Ein alternativer Ansatz, die sogenannte Expansionsmikroskopie, wurde kürzlich von der Arbeitsgruppe um Ed Boyden etabliert. Hierbei wird eine Probe mit einem quellfähigen Gel vernetzt, welches daraufhin isotrop expandiert wird, sodass auch an konventionellen konfokalen Mikroskopen Hochauflösung ermöglicht wird. Seit ihrer Einführung im Jahre 2015 hat sich die Expansionsmikroskopie schnell entwickelt und bietet Protokolle für 4-fache, 10-fache oder sogar 20-fache Expansion von Proteinen als auch RNA in Zellen oder sogar komplexen Geweben. Mitochondrien besitzen zwei Membranen und sind für die Zelle von großer Bedeutung, da sie eine Vielzahl wichtiger Aufgaben übernehmen - von der ATP-Produktion durch die oxidative Phosphorylierung über die Produktion vieler wichtiger Metabolite bis hin zur Regulation zellulärer Signalwege. Die innere Mitochondrienmembran ist stark gefaltet und bildet Einstülpungen, die sogenannten Cristae, in welchen die oxidative Phosphorylierung und somit die Energieumwandlung und ATP-Synthese stattfindet. Morphologische Veränderungen der Cristae können sowohl beim Altern von Zellen, als auch bei verschiedenen Infektionen beobachtet werden und können darüber hinaus auch im Rahmen diverser Erkrankungen, wie beispielsweise Krebs, Diabetes oder neurodegenerativen Erkrankungen auftreten. Die Visualisierung der Cristae durch Fluoreszenzmikroskopie ist herausfordernd, da der Abstand zwischen einzelnen Cristae oftmals unter 100 nm beträgt. In der vorliegenden Arbeit wird gezeigt, dass die Expression der mitochondrialen Kreatinkinase gekoppelt an das Fluoreszenzprotein GFP (MtCK-GFP) als Cristaemarker genutzt werden kann. In Kombination mit vierfacher Expansion ermöglicht unser Marker die Untersuchung morphologischer Veränderungen von Cristae, sowie die Lokalisierung mitochondrialer Proteine relativ zu den Cristae. Darüber hinaus wird im Rahmen dieser Arbeit die Anwendbarkeit der Expansionsmikroskopie für mehrere bakterielle Pathogene, und zwar Chlamydia trachomatis, Simkania negevensis, Neisseria gonorrhoeae und Staphylococcus aureus, gezeigt. Hierbei verdeutlichen wir wichtige Aspekte für den vollständigen Verdau unterschiedlicher bakterieller Zellwände und somit isotropen Expansion. Die Expansion der intrazellulären Pathogene C. trachomatis und S. negevensis ermöglichte es uns an konventionellen konfokalen Mikroskopen zwischen den zwei verschiedenen Entwicklungsstadien, der katabolisch aktiven Retikulärkörperchen (RBs) und der infektiösen Elementarkörperchen (EBs), zu unterscheiden. Außerdem konnte die Möglichkeit der präzisen Lokalisierung chlamydialer Proteine wie CPAF und Cdu1 innerhalb und außerhalb der chlamydialen Inklusion gezeigt werden und Bakterien, in diesem Fall S. aureus, in LAMP1 und LC3-II Vesikeln visualisiert werden. Mit der Einführung des unnatürlichen α-NH2-ω-N3-C6-Ceramides, präsentieren wir zudem ein erstes Konzept für die Expansion von Lipiden, welches möglicherweise auch für deutlich unzugänglichere Molekülklassen wie beispielsweise Kohlehydrate geeignet ist. Die effiziente Akkumulierung unseres funktionalisierten α-NH2-ω-N3-C6-Ceramides in Zellen sowie Bakterien ermöglicht in Kombination mit zehnfacher Expansion die Untersuchung der Interaktion von Proteinen mit der Zellmembran, Membranen von Organellen und Bakterien mit einer räumlichen Auflösung von 10-20 nm. Ceramid ist das zentrale Molekül des Sphingolipidstoffwechsels, ein wichtiger Baustein zellulärer Membrane und reguliert viele essentielle Prozesse wie die Zelldifferenzierung, die Proliferation als auch die Apoptose. Viele Studien berichten von der Bedeutung der Sphingolipide während der Infektion verschiedener Pathogene. So wurde beispielsweise zuvor berichtet, dass Ceramide aktiv zu Chlamydien transportiert und in deren Membranen eingebaut werden. Hierbei verblieb allerdings die Frage, ob Ceramide in der äußeren oder inneren bakteriellen Membran lokalisiert sind. Die Expansion unseres α-NH2-ω-N3-C6-Ceramides ermöglichte es uns Ceramide in der inneren und äußeren Membran von C. trachomatis zu visualisieren und den Abstand zwischen beiden Membranen auf 27.6 ± 7.7 nm zu bestimmen

Bolts, rivets and location pins are commonly used in various engineering applications for assembly of components and structures. The holes produced for the assembly is susceptible to cracks due to fatigue caused by tensile loads applied. These cracks can be prevented or its propagation can be prolonged by inducing compressive residual stress in the material around the hole. Cold expansion hole is one of the techniques used to induce compressive stress zone, by inserting a tapered mandrel/pin or ball into an undersized hole. A novel application of the cold expansion and surface modification of walls of the cylindrical hole is presented. Predrilled holes of different diameters in commercially available aluminum and Al- 2014-T6 aluminum alloy plates are cold expanded using a specially fabricated tapered tool that rotates and simultaneously traverses through the hole. The tapered tool expands the hole to the desired diameter and also stirs the internal wall of the hole. In order to understand the role of frictional heating and stirring in the cold expansion of holes three mediums, namely, dry (without cooling and lubricating), metal working fluid (cooling and lubricating) and Al2O3 nanoparticles (lubricating and frictional heating) are used. The residual stress, surface roughness and hardness of the wall of the holes are measured and SEM images are captured. Significant residual stresses are induced in the material around the hole region. Significant hardness improvement with reasonable surface finish is obtained. Moreover the cold expanded holes showed considerable improvement in the fatigue life of the holes. The fatigue life is found to be directly proportional to residual stresses induced around the hole and inversely proportional to surface roughness. Hardness has a negative impact on fatigue life. The rotating tool cold expansion process is compared with conventional cold expansion process and good efficiency of cold expansion is achieved in case of Al-2014-T6 aluminum alloy material using nanoparticles, in terms of fatigue life achieved. It is observed that frictional heating and the plastic deformation have combined effect on the performance of the cold expansion of cylindrical holes.

Dissertação de Mestrado em Biologia Celular e Molecular apresentada à Faculdade de Ciências e Tecnologia
Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3, is a neurodegenerative disorder considered to be the most common form of autosomal dominantly-inherited ataxia in the world. It is a rare disorder, although it has a significative prevalence in some regions of Portugal, especially in the archipelago of Azores. MJD symptoms include a loss of motor coordination and other neurological signs, with the cerebellum being the most affected brain region. MJD arises from an abnormal CAG trinucleotide expansion within the exon 10 of the human ATXN3 gene, which encodes for a protein named ataxin-3 (atxn-3), that bears an aberrant polyglutamine (polyQ) tract in the disease context. The exact biological function of atxn-3 is not fully understood, but it has been described that, when expanded atxn-3 undergoes a toxic gain-of-function that deregulates normal cellular pathways leading to neuronal loss. Recently, it has been suggested that abnormal CAG tracts in mRNA transcripts might also be toxic. As with other polyglutamine diseases, greater numbers of CAG repeats are associated with earlier ages of onset and more severe symptoms.Currently, no therapies capable of delaying or treating the disease are available, and MJD remains a fatal disorder. Many of the therapeutic strategies that have been tested act at a post-transcriptional level, being unable to prevent the putative toxicity of CAG expanded mRNA transcripts. Therefore, new strategies that act at a pre-transcriptional level may be advantageous.However, disease studies can only be robust and feasible when the adequate disease model is used. Yet, the available mouse models used to study MJD either fail to properly mimic the actual genetic context of the disease or are of limited use due to slow and mild symptom progression.In the last decade, the field of gene editing has been thriving. The use of the CRISPR/Cas9 system as a tool for gene editing brought the possibility of performing low-cost, flexible and easy genomic manipulation virtually at any loci. Moreover, CRISPR/Cas9 variants, such as the catalytic inactivated Cas9 (dCas9) have shown promising results regarding gene transcription regulation. In the first part of this work, we planned to establish an in vitro strategy to refine the yeast artificial chromosome (YAC) MJD-Q84.2 mouse, which is the MJD model that best recapitulates the symptoms and the genetic context of the human condition. In this work we proposed to use gene editing tools to overexpand the ATXN3 CAG tract in the exon 10, from 84 to 141 CAG; applying this strategy to the model would be expected to generate a robust mouse model that displayed a more severe phenotype and an earlier disease onset, comparing to the YAC MJD-Q84.2 model. However, the in vitro results here presented, using HEK 293T cells, showed that the strategy used was inefficient at overexpanding the CAG repeats.At the same time, a CRISPR/Cas9-based strategy for correcting the pathogenic ATXN3 gene that could be used to generate isogenic MJD patient-derived cell lines was also tested. The study here presented, using HEK 293T cells, showed that it is possible to integrate a DNA fragment containing 14 CAG repeats plus a selection cassette in the exon 10 of the ATXN3 gene. However, this strategy was not completely infallible, and integration seemed to be independent from Cas9 activity. In the second part of this work, we assessed the effects of dCas9-KRAB as a strategy to pre-transcriptionally silence mutant ATXN3 in a MJD mouse model. In vivo results showed that this approach has a therapeutic potential to improve motor performance in a severely-impaired transgenic mouse model of MJD.
A doença de Machado-Joseph (DMJ), também conhecida por ataxia espinocerebelosa tipo 3, é uma doença neurodegenerativa e a forma mais comum de ataxia hereditária dominante no mundo. É uma doença rara, porém tem uma prevalência significativa em algumas regiões de Portugal, nomeadamente no arquipélago dos Açores. Os sintomas de DMJ incluem perda de coordenação motora bem como outros sinais neurológicos, sendo o cerebelo a região do cérebro mais afetada. A DMJ surge de uma expansão anormal de trinucleótidos CAG no exão 10 do gene ATXN3, que codifica para a proteína ataxina-3 (atxn-3). No contexto da doença, a atxn-3 contém uma sequência de glutaminas (poliQ) anormalmente longa. As funções biológicas da proteína atxn-3 não são totalmente conhecidas, contudo tem sido descrito que a atxn-3 expandida adquire uma função tóxica que desregula o normal funcionamento de diversos sistemas celulares, levando à morte neuronal. Recentemente, tem sido sugerido que tratos CAG anormais presentes em transcritos de mRNA podem também ser tóxicos. Tal como em outras doenças de poliglutaminas, um maior número repetições CAG tem sido associado a sintomas mais severos, com um aparecimento mais precoce.Atualmente, não há terapias capazes de tratar ou atrasar o curso da doença, e, portanto, a DMJ continua a ser fatal. Algumas estratégias terapêuticas que têm sido testadas atuam ao nível pós-transcricional e são por isso incapazes de prevenir os putativos efeitos tóxicos dos transcritos de mRNA que contêm uma cadeia de CAGs expandida. Assim sendo, novas estratégias que atuem a um nível pré-transcricional podem vir a ser vantajosas.O estudo de doenças humanas apenas consegue ser robusto quando é usado um modelo de doença adequado. Porém, os modelos de murganho presentemente usados para estudar a DMJ ou não reproduzem de forma fiel o contexto genético da doença ou apresentam sintomas pouco acentuados e uma progressão lenta que limitam a sua utilização.Na última década, a área da edição genética tem tido desenvolvimentos extraordinários. O uso da CRISPR/Cas9 como uma ferramenta para edição genética trouxe a possibilidade de manipular o genoma virtualmente em qualquer locus, de uma forma barata, fácil e flexível. Além do mais, variantes da CRISPR/Cas9, como é o caso da Cas9 cataliticamente inativa (dCas9), têm mostrado resultados promissores no que diz respeito à regulação da transcrição genética.Na primeira parte deste trabalho pretendemos estabelecer uma estratégia in vitro para aperfeiçoar um modelo de DMJ em murganho designado por yeast artificial chromosome (YAC) MJD-Q84.2, que é considerado como o modelo que melhor recapitula os sintomas e o contexto genético humano em condições de doença. Neste trabalho, utilizámos ferramentas de edição genética para sobreexpandir o trato CAG do exão 10 do gene ATXN3, de 84 para 141 CAGs; ao aplicar esta estratégia ao modelo de murganho seria expectável que se criasse um modelo robusto, com um fenótipo mais severo e em que os sintomas se manifestassem mais cedo em comparação com o já existente modelo YAC MJD-Q84.2. Contudo, os resultados in vitro descritos neste trabalho mostraram que a estratégia usada parece ser ineficiente na sobreexpansão das repetições CAG em células HEK 293T.Paralelamente, usando também a CRISPR/Cas9, foi testada uma estratégia para corrigir o gene ATXN3 mutante, que pudesse ser usada para criar linhas celulares isogénicas derivadas de pacientes de DMJ. O estudo aqui apresentado, usando células HEK 293T, mostrou ser possível integrar um fragmento de DNA contendo 14 repetições do trinucleótido CAG e uma cassete de seleção no exão 10 do gene ATXN3. Contudo, esta abordagem não se mostrou totalmente fiável e que foi detetada integração independente da atividade da Cas9.Na segunda parte deste trabalho foram avaliados os efeitos da dCas9-KRAB como estratégia de silenciamento a nível pré-transcricional do gene humano da ATXN3 num modelo animal de DMJ. Os resultados in vivos mostraram que esta abordagem tem potencial terapêutico, melhorando a performance motora num modelo DJM transgénico severamente afetado.
Outro - This work was funded by the ERDF through the Regional Operational Program Center 2020, Competitiveness Factors Operational Program (COMPETE 2020) and National Funds through FCT (Foundation for Science and Technology) - BrainHealth2020 projects (CENTRO-01-0145-FEDER-000008), ViraVector (CENTRO-01-0145-FEDER-022095), CortaCAGs (PTDC/NEU-NMC/0084/2014|POCI-01-0145-FEDER-016719), SpreadSilencing (POCI-01-0145-FEDER-029716, POCI-01-0145-FEDER-032309) as well as SynSpread, ESMI and ModelPolyQ under the EU Joint Program - Neurodegenerative Disease Research (JPND), the last two co-funded by the European Union H2020 program, GA No.643417; by the National Ataxia Foundation (USA), the American Portuguese Biomedical Research Fund (APBRF) and the Richard Chin and Lily Lock Machado-Joseph Disease Research Fund.

碩士
國立臺灣大學
企業管理碩士專班
107
REFRIA is an OEM manufacturer with over 35 years of experience in making HVAC&R service tools and equipment for many well-known companies from United States, Europe, and Japan. However, REFRIA’s revenue has been stagnant for the past few years. In order to increase sales, REFRIA will need to expand its market. Thus, the purpose of this business plan is to discuss the current position of the company REFRIA, and how the company can further establish itself to expand its market to Taiwan. Therefore, PESTEL analysis, Porter’s 5 forces, and SWOT analysis will be used to analyze REFRIA how itself different from other competitors, and how REFRIA can thrive in this Taiwan market.

碩士
中原大學
機械工程研究所
96
This study mainly developed an error compensation system which can be applied to reduce the thermal expansion error of the spindle of a CNC machine tool. Temperature variations at 5 locations on the spindle were measured by PT-100 thermal sensors and self-designed electric circuit, and the deviations of the spindle in x, y and z directions due to thermal expansion were measured by high precision displacement sensors. Based on the measured temperatures and deviations, a regression mathematic model was calculated and implanted into the PIC chip to form a system for on-line thermal expansion monitoring system. When a machine tool is working, PT100 sensors can on-line measure the temperature variations of the spindle and feedback to the monitoring system to predict the thermal expansion of the spindle. The predicted expansions are then outputted to CNC controller for error compensation through an optical coupling circuit. The experimental results have shown that the system can effectively reduced the thermal expansion error from 40m to less than 10 m.

碩士
國立虎尾科技大學
工業工程與管理研究所
103
This study develops an extended stochastic programming model for the deterministic approach proposed by Chen et al., (2013). Capacity planning which plays a role in the production planning is a challenging problem for semiconductor manufacturing industry. There are three original characteristics of semiconductor industry that caused capacity planning become critical, including (1) fast progress of technology in manufacturing process, (2) high manufacturing cost, and (3) great variability in demand. Therefore, this study dealt with uncertain demands of customer for a foundry industry in Taiwan. Through three scenarios, the stochastic programming model is exploited for solving the optimal medium-term capacity planning problem. To demonstrate the value of our stochastic programming model, the data collected from a real wafer foundry in Taiwan, was treated as a fundamental scenario. The forecast demand variations of other scenarios were complied with a normal distribution, the impact of different probability distribution of demand scenarios on capacity allocation was considered. From the series of capacity planning tests with varying initial customer’s demand, changes in customer order fulfillment rate, or capacity utilization rate were determined. Based on different demand scenarios, the numerical results in this study reveal the concordance for the deterministic model and the proposed stochastic programming model. Furthermore, this stochastic model also expressed the flexible consideration of auxiliary tools and rising number of certified fabrication to capacity planning problem in wafer foundry.

Transition metal alloys are an important class of materials in heterogeneous catalysis due in no small part to the often greatly enhanced activity and selectivity they exhibit compared to their monometallic constituents. A host of experimental and theoretical studies have demonstrated that, in many cases, these synergistic effects can be attributed to atomic-scale features of the catalyst surface. Realizing the goal of designing -- rather than serendipitously discovering -- new alloy catalysts thus depends on our ability to predict their atomic configuration under technologically relevant conditions. This dissertation presents original research into the development and use of computational tools to accomplish this objective. These tools are all based on a similar strategy: For each of the alloy systems examined, cluster expansion (CE) Hamiltonians were constructed from the results of density functional theory (DFT) calculations, and then used in Metropolis Monte Carlo (MC) simulations to predict properties of interest. Following a detailed description of the DFT+CE+MC simulation scheme, results for the AuPd/Pd(111) and AuPt/Pt(111) surface alloys are presented. These two systems exhibit considerably different trends in their atomic arrangement, which are explicable in terms of their interatomic interactions. In AuPd, a preference for heteronuclear, Au-Pd interactions results in the preferential formation of Pd monomers and other small ensembles, while in AuPt, a preference for homonuclear interactions results in the opposite. AuPd/Pd(100) and AuPt/Pt(100) were similarly examined, revealing not only the effects of the same heteronuclear/homonuclear preferences in this facet, but also a propensity for the formation of second nearest-neighbor pairs of Pd monomers, in close agreement with experiment. Subsequent simulations of the AuPd/Pd(100) surface suggest the application of biaxial compressive strain as a means increasing the population of this catalytically important ensemble of atoms. A method to incorporate the effects of subsurface atomic configuration is also presented, using AuPd as an example. This method represents several improvements over others previously reported in the literature, especially in terms of its simplicity. Finally, we introduce the dimensionless scaled pair interaction, whereby the finite-temperature atomic configuration of any bimetallic surface alloy may be predicted from a small number of relatively inexpensive calculations.
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Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2016
In Friedreich’s ataxia (FRDA), abnormal GAA repeat expansions in intron 1 of the frataxin gene (FXN) cause epigenetic changes and reduce FXN mRNA levels in averaged cell samples though a poorly understood mechanism. Dissecting the silencing mechanism in FRDA in situ is crucial to improve our understanding of the disease. Here, I use novel FRDA human cell models suitable for screening compounds able to upregulate FXN expression and to analyse the link between FXN nuclear localisation and expression in single cells. FXN-Luc, FXN-GAA-Luc, FXN-MS2-Luc and FXN-GAA-MS2-Luc stable human clones carry a site-specific integration of a single copy of the whole FXN locus with either 6 (FXN-Luc and FXN-MS2-Luc) or ~310 (FXN-GAA-Luc and FXN-GAA-MS2-Luc) GAA repeats in intron 1. To fluorescently label the transgenic FXN mRNA, I inserted MS2 binding sites into exon 2 of FXN-MS2-Luc and FXN-GAA-MS2-Luc transgenes by homologous recombination. The ~310 GAA repeats recapitulate the characteristic FXN gene repression and epigenetic changes seen in FRDA. I report a single-cell analysis of FXN repression in which I identify the nuclear lamina (NL) as a novel and key player in FXN transcriptional impairment and silencing. Using a multidisciplinary approach, including analysis in both fixed and living single cells, I show that expanded GAA repeats increase FXN positioning at the NL, leading to decreased numbers of FXN mRNA molecules and slower transcription kinetics in the FXN-GAA-MS2 cell model. Restoring histone acetylation reverses NL positioning. I observe the same abnormal repositioning to the NL in carrier and FRDA patient cells and show that this tightly correlates with a marked decrease in the number of actively expressing FXN alleles. Furthermore, I show that those few active expanded FXN alleles located at the NL express at a significantly lower level than the alleles located in the interior of the nucleus. Finally, I demonstrate that expanded GAA repeats predominantly disrupt FXN transcription initiation. Collectively, these results suggest repressive epigenetic modifications at the expanded GAA-FXN locus may lead to NL relocation, where further repression may occur. The mechanisms described may extend to other genetic diseases mediated by repeat expansions within regions of non-coding DNA.
Na Ataxia de Friedreich (FRDA), uma expansão de repetições trinucleotídicas GAA, presentes no intrão 1 do gene que codifica a proteína frataxina (FXN), causa mudanças epigenéticas e reduz os níveis médios de RNA do gene FXN em amostras celulares através de um mecanismo pouco conhecido. Com o intuito de melhor perceber a patogénese inerente à doença e, em última análise, desenvolver terapias eficientes para a FRDA, é importante criar modelos celulares que traduzam as características repressivas da doença ao mesmo tempo que permitem quantificar eficientemente os níveis de expressão do gene FXN. As linhas celulares reporter FXN-GAA-Luc, FXN-Luc, FXN-GAA-MS2-Luc e FXNMS2-Luc, descritas nesta Tese, foram especificamente criadas de modo a permitir a comparação directa entre o efeito das repetições GAA normais e expandidas na expressão do gene FXN. Para o efeito usei: (i) todo o locus FXN com o seu promotor, intrões e exões originais e todos os elementos necessários para a expressão fisiológica do transgene, com inserção do gene luciferase no final do exão 5a; e (ii) uma única cópia de cada BAC integrado num sítio FRT especificamente localizado no cromossoma 1 de células HEK FRT, de modo a excluir efeitos contraditórios na expressão do gene FXN devido a integração de ambos os vectores em sítios diferentes. Análise das modificações das histonas no promoter do gene FXN e regiões que ladeiam as repetições GAA a montante e a jusante revelou um decréscimo da acetilação de H3K9 e H4K8 e um aumento da metilação de H3K9me2 e H3K9me3 nas três regiões nas células FXN-GAA-Luc. Adicionalmente, as regiões a montante e a jusante das repetições GAA das células FXN-GAA-Luc apresentam um aumento da metilação do DNA em CpG específicos. As células FXN-GAA-Luc foram usadas num rastreio de compostos terapêuticos e permitiram identificar uma molécula capaz de aumentar a expressão do gene FXN-GAA-Luc para níveis similares aos das células FXN-Luc. A análise usando a técnica de imunoprecipitação da cromatina em células derivadas de pacientes depois de tratadas com esta molécula revelou o restauro para níveis normais de acetilação de H3K9 e H4K8 nas regiões que ladeiam as repetições GAA. Estes resultados sugerem que as repetições GAA induzem a repressão do gene FXN nas células FXN-GAA-Luc através da alteração da estrutura da cromatina no transgene, fazendo com que estas células sejam consideradas excelentes para o rastreio de moléculas capazes de aumentar a expressão do gene FXN. No entanto, o modelo FXN-GAA-Luc apenas apresenta o estado provável do gene FXN visto que os resultados provêm de experiências onde se efectuam medições médias resultantes de amostras contento milhões de células. Consequentemente, o modelo FXNGAA-MS2-Luc foi criado para dissecar o mecanismo repressivo de FRDA in situ, permitindo a visualisação e análise da localização e repressão de FXN em células fixas e vivas usando o sistema MS2. Neste trabalho, desenvolvi um modelo celular humano para analisar a associação entre a localização e a expressão do gene FXN ao nível da célula. Os clones celulares estáveis FXN-MS2-Luc e FXN-GAA-MS2-Luc foram gerados por integração dos transgenes num local específico e contêm todo o locus FXN de 80 kb, o gene repórter luciferase no exão 5a e seis repetições ou uma expansão de ~310 tripletos GAA no intrão 1, respectivamente. Para efectuar uma marcação fluorescente do mRNA FXN transgénico e quantificar o efeito da expansão de tripletos GAA na transcrição do gene, inseri 24 repetições de locais de ligação da proteína MS2 (MBS) no exão 2 por recombinação homóloga. A expansão de ~310 GAA na linha celular FXN-GAA-MS2-Luc traduz as características repressivas do gene FXN em FRDA. A localização do transgene FXN nas linhas FXN-MS2-Luc e FXN-GAA-MS2-Luc foi determinado por Immuno-FISH. FXN contactou com a lâmina nuclear (NL) em ~44% das células FXN-GAA-MS2-Luc quando comparado com apenas ~10% das células FXNMS2-Luc. Após tratamento das células com inibidores das desacetilases de histonas, apenas o transgene FXN-GAA-MS2-Luc se reposicionou longe da NL. No entanto, ocorreu um aumento da expressão do mRNA FXN transgénico nas duas linhas celulares, sugerindo que existe uma associação complexa entre repressão do gene FXN e a sua localização intranuclear. Para aprofundar o conhecimento sobre a repressão do gene FXN, analisei o output de transcrição de alelos FXN transgénicos individuais nas células FXN-MS2-Luc e FXN-GAA-MS2-Luc por RNA FISH e recuperação de fluorescência após a fotodegradação (FRAP). As células FXN-GAA-MS2-Luc contêm ~5 ± 2 mRNAs por célula e as células FXN-MS2-Luc cells contêm ~9 ± 4 mRNA por célula, indicando que ~310 tripletos GAA reduzem o número de moléculas de mRNA em 44% ao nível celular. As curvas FRAP mostram que o tempo necessário para a recuperação completa da fluorescência após a fotodegradação é diferente nas duas linhas celulares. O transgene FXN-MS2-Luc apresentou um tempo total de recuperação de 120 segundos, enquanto o transgene FXNGAA-MS2-Luc apresentou uma cinética mais lenta com recuperação total de 260 segundos. Devido ao facto de a estabilidade do mRNA de FXN não apresentar diferenças entre as células FXN-GAA-MS2-Luc e FXN-GAA-MS2-Luc, os resultados de RNA FISH e FRAP indicam que a expansão de GAA diminui a quantidade de moléculas de mRNA de FXNGAA-MS2-Luc através do impedimento da iniciação e/ou elongação da transcrição por parte da polimerase de RNA II. De modo a elucidar a relação entre a localização e repressão do gene FXN, analisei a intensidade fluorescente de transgene activos em células FXN-MS2-Luc e FXN-GAA-MS2-Luc vivas. A intensidade fluorescente de locais de transcrição foi significativamente menor quando os transgenes estavam a expressar na periferia nuclear comparando com o nucleoplasma em células FXN-MS2-Luc e FXN-GAAMS2-Luc. Estes dados indicam que os dois transgenes expressam quando localizados na periferia nuclear, embora o façam em quantidades mais pequenas. Quando comparados com transgenes FXN-MS2-Luc activos, a intensidade dos locais de transcrição dos transgenes FXN-MS2-GAA-Luc foi significativamente mais baixa apenas no interior do núcleo. No seu conjunto, estes resultados sugerem que a expansão de GAA aumenta a localização do transgene FXN-GAA-MS2-Luc na NL, onde os níveis de expressão são reduzidos quando comparados com o interior nuclear ou com os níveis de expressão do transgene FXN-MS2-Luc. Em seguida, analisei a localização do gene no seu ambiente genómico natural em células derivadas de pessoas saudáveis, de portadores heterozigóticos de um alelo FXN mutante e de pacientes. Em células derivadas de portadores heterozigóticos, o alelo FXN contendo a expansão de GAA localiza-se preferencialmente mais próximo da periferia nuclear do que o alelo normal e contacta mais vezes com a NL. Quando se compara a localização do gene FXN em células saudáveis com células derivadas de pacientes, os resultados indicam que a expansão de GAA aumenta a probabilidade de um alelo se encontrar associado à NL e consequentemente a probabilidade de estar silenciado. Adicionalmente, quando os alelos FXN expandidos se encontravam a expressar, os níveis de expressão eram significativamente reduzidos quando se encontram no nucleoplasma, mas especialmente quando localizados na periferia nuclear. Estes resultados indicam uma relação directa entre o posicionamento do gene FXN na NL e a repressão da transcrição mediada pela expansão de GAA. A realização de uma quantificação ao nível celular mostrou ainda que a expansão das repetições de GAA induz um défice na expressão maioritariamente ao nível da iniciação da transcrição do gene FXN, mas também induz um pequeno bloqueio na elongação da polimerase de RNA II. No seu conjunto, estes resultados sugerem que as modificações epigenéticas repressivas no locus FXN expandido podem induzir a relocalização do gene para a NL, onde uma repressão adicional pode ocorrer. O efeito combinado da presença da expansão de GAA e relocalização do gene para a NL resultam numa redução catastrófica dos níveis de transcrição, levando à redução dos níveis da proteína frataxina e, em última análise, à manisfestação de FRDA. O trabalho descrito nesta Tese apresenta novos conhecimentos sobre as causas moleculares subjacentes à FRDA e poderá ser aplicável a outras doenças genéticas causadas por expansões de nucleótidos em regiões não codificantes do DNA.

Dynamic Traffic Assignment (DTA) is gaining wider acceptance among agencies and practitioners because it serves as a more realistic representation of real-world traffic phenomena than static traffic assignment. Many metropolitan planning organizations and transportation departments are beginning to utilize DTA to predict traffic flows within their networks when conducting traffic analysis or evaluating management measures. To analyze DTA-based optimization applications, it is critical to obtain the dual (or gradient) information as dual information can typically be employed as a search direction in algorithmic design. However, very limited number of approaches can be used to estimate network-wide dual information while maintaining the potential to scale. This dissertation investigates the theoretical/practical aspects of DTA-based dual approximation techniques and explores DTA applications in the context of various transportation models, such as transportation network design, off-line DTA capacity calibration and dynamic congestion pricing. Each of the later entities is formulated as bi-level programs. Transportation Network Design Problem (NDP) aims to determine the optimal network expansion policy under a given budget constraint. NDP is bi-level by nature and can be considered a static case of a Stackelberg game, in which transportation planners (leaders) attempt to optimize the overall transportation system while road users (followers) attempt to achieve their own maximal benefit. The first part of this dissertation attempts to study NDP by combining a decomposition-based algorithmic structure with dual variable approximation techniques derived from linear programming theory. One of the critical elements in considering any real-time traffic management strategy requires assessing network traffic dynamics. Traffic is inherently dynamic, since it features congestion patterns that evolve over time and queues that form and dissipate over a planning horizon. It is therefore imperative to calibrate the DTA model such that it can accurately reproduce field observations and avoid erroneous flow predictions when evaluating traffic management strategies. Satisfactory calibration of the DTA model is an onerous task due to the large number of variables that can be modified and the intensive computational resources required. In this dissertation, the off-line DTA capacity calibration problem is studied in an attempt to devise a systematic approach for effective model calibration. Congestion pricing has increasingly been seen as a powerful tool for both managing congestion and generating revenue for infrastructure maintenance and sustainable development. By carefully levying tolls on roadways, a more efficient and optimal network flow pattern can be generated. Furthermore, congestion pricing acts as an effective travel demand management strategy that reduces peak period vehicle trips by encouraging people to shift to more efficient modes such as transit. Recently, with the increase in the number of highway Build-Operate-Transfer (B-O-T) projects, tolling has been interpreted as an effective way to generate revenue to offset the construction and maintenance costs of infrastructure. To maximize the benefits of congestion pricing, a careful analysis based on dynamic traffic conditions has to be conducted before determining tolls, since sub-optimal tolls can significantly worsen the system performance. Combining a network-wide time-varying toll analysis together with an efficient solution-building approach will be one of the main contributions of this dissertation. The problems mentioned above are typically framed as bi-level programs, which pose considerable challenges in theory and as well as in application. Due to the non-convex solution space and inherent NP-complete complexity, a majority of recent research efforts have focused on tackling bi-level programs using meta-heuristics. These approaches allow for the efficient exploration of complex solution spaces and the identification of potential global optima. Accordingly, this dissertation also attempts to present and compare several meta-heuristics through extensive numerical experiments to determine the most effective and efficient meta-heuristic, as a means of better investigating realistic network scenarios.
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While decision-making under uncertainty is a major universal problem, its implications in the field of transportation systems are especially enormous; where the benefits of right decisions are tremendous, the consequences of wrong ones are potentially disastrous. In the realm of highway systems, decisions related to the highway configuration (number of lanes, right of way, etc.) need to incorporate both the traffic demand and land price uncertainties. In the literature, these uncertainties have generally been modeled using the Geometric Brownian Motion (GBM) process, which has been used extensively in modeling many other real life phenomena. But few scholars, including those who used the GBM in highway configuration decisions, have offered any rigorous justification for the use of this model. This thesis attempts to offer a detailed analysis of various aspects of transportation systems in relation to decision-making. It reveals some general insights as well as a new concept that extends the notion of opportunity cost to situations where wrong decisions could be made. Claiming deficiency of the GBM model, it also introduces a new formulation that utilizes a large and flexible parametric family of jump models (i.e., Lévy processes). To validate this claim, data related to traffic demand and land prices were collected and analyzed to reveal that their distributions, heavy-tailed and asymmetric, do not match well with the GBM model. As a remedy, this research used the Merton, Kou, and negative inverse Gaussian Lévy processes as possible alternatives. Though the results show indifference in relation to final decisions among the models, mathematically, they improve the precision of uncertainty models and the decision-making process. This furthers the quest for optimality in highway projects and beyond.