Teoricamente, o Alinhamento Estratégico pode ser obtido com um bom Gerenciamento de Processos de Negócio (BPM na sigla em inglês), porém a relação entre esses temas é, na maioria das vezes, assumida implicitamente e pouco elaborada, tornando-se difícil a visualização e vínculo entre as estratégias e os modelos de processos detalhados, sendo necessário empreender pesquisas na direção de uma união efetiva dos dois temas. O presente trabalho desenvolveu um metamodelo multinível, para ligar os objetivos estratégicos com os processos de negócio da organização através da modelagem de processos de negócio. O trabalho conceitual foi acrescido por uma ferramenta de suporte à modelagem que permite a geração de modelos com base no metamodelo multinível e também a representação dos modelos em diferentes formas de abstração. A abordagem foi aplicada em uma grande multinacional e posteriormente foi conduzida uma avaliação experimental no qual foram realizadas entrevistas com funcionários de diferentes níveis hierárquicos para validar a eficiência e eficácia do trabalho desenvolvido. Como resultado foi possível constatar não apenas a efetividade em alcançar os objetivos propostos como também a facilidade na utilização e compreensão da abordagem em níveis devido a simplicidade na representação dos elementos e seus possíveis relacionamentos / Theoretically, the Strategic Alignment can be accomplished with a good Business Process Management, but the relationship between these themes is, most often, implicitly assumed and little developed, making it difficult to visualize and link between the strategies and the models of detailed processes, being necessary to undertake research towards an effective union of the two themes. This study developed a multilevel metamodel for connecting strategic objectives with organizational business processes through modeling of business processes. The conceptual work was increased by a support tool for modeling that allows the generation of models based on multilevel metamodel and also the representation of models in different forms of abstraction. The approach was applied in a large multinational and was subsequently conducted an experimental evaluation in which interviews with employees from different hierarchical levels were performed to validate the efficiency and effectiveness of their work. As a result it was possible to not only the effectiveness in achieving the proposed objectives as well as the ease of use and understanding of the tiered approach because of the simplicity in the representation of the elements and their possible relationships

Teoricamente, o Alinhamento Estratégico pode ser obtido com um bom Gerenciamento de Processos de Negócio (BPM na sigla em inglês), porém a relação entre esses temas é, na maioria das vezes, assumida implicitamente e pouco elaborada, tornando-se difícil a visualização e vínculo entre as estratégias e os modelos de processos detalhados, sendo necessário empreender pesquisas na direção de uma união efetiva dos dois temas. O presente trabalho desenvolveu um metamodelo multinível, para ligar os objetivos estratégicos com os processos de negócio da organização através da modelagem de processos de negócio. O trabalho conceitual foi acrescido por uma ferramenta de suporte à modelagem que permite a geração de modelos com base no metamodelo multinível e também a representação dos modelos em diferentes formas de abstração. A abordagem foi aplicada em uma grande multinacional e posteriormente foi conduzida uma avaliação experimental no qual foram realizadas entrevistas com funcionários de diferentes níveis hierárquicos para validar a eficiência e eficácia do trabalho desenvolvido. Como resultado foi possível constatar não apenas a efetividade em alcançar os objetivos propostos como também a facilidade na utilização e compreensão da abordagem em níveis devido a simplicidade na representação dos elementos e seus possíveis relacionamentos / Theoretically, the Strategic Alignment can be accomplished with a good Business Process Management, but the relationship between these themes is, most often, implicitly assumed and little developed, making it difficult to visualize and link between the strategies and the models of detailed processes, being necessary to undertake research towards an effective union of the two themes. This study developed a multilevel metamodel for connecting strategic objectives with organizational business processes through modeling of business processes. The conceptual work was increased by a support tool for modeling that allows the generation of models based on multilevel metamodel and also the representation of models in different forms of abstraction. The approach was applied in a large multinational and was subsequently conducted an experimental evaluation in which interviews with employees from different hierarchical levels were performed to validate the efficiency and effectiveness of their work. As a result it was possible to not only the effectiveness in achieving the proposed objectives as well as the ease of use and understanding of the tiered approach because of the simplicity in the representation of the elements and their possible relationships

Ca2+ is a universal and versatile intracellular messenger, regulating a vast array of biological processes due to variations in the frequency, amplitude, spatial and temporal dynamics of Ca2+ signals. Increases in cytosolic free Ca2+ concentration ([Ca2+]c) are due to influx from either an infinite extracellular Ca2+ pool or from the more limited intracellular Ca2+ stores. Stimulation of the endogenous muscarinic (M3) receptors of human embryonic kidney (HEK) cells with carbachol results in the activation of phospholipase C (PLC) and formation of inositol 1,4,5-trisphosphate (IP3), activation of IP3 receptors (IP3Rs), release of Ca2+ from the endoplasmic reticulum (ER), and activation of store-operated Ca2+ entry (SOCE). Lysosomes are the core digestive compartments of the cell, but their importance as signalling organelles is also now widely appreciated. Accumulating evidence indicates that lysosomal Ca2+ is important for their physiological functions. Lysosomal Ca2+ release triggers fusion during membrane trafficking and, through calmodulin, it regulates lysosome size. Luminal Ca2+ is critical for regulation of lysosomal biogenesis and autophagy during starvation through the transcription factor, TFEB. Furthermore, aberrant lysosomal Ca2+ is associated with some lysosomal storage diseases. Lysosomes in mammalian cells have long been suggested to accumulate Ca2+ via a low-affinity Ca2+-H+ exchanger (CAX). This is consistent with evidence that dissipating the lysosomal H+ gradient increased [Ca2+]c and decreased lysosomal free [Ca2+], and with the observation that lysosomal Ca2+ uptake was followed by an increase in pHly. Furthermore, heterologous expression of Xenopus CAX in mammalian cells attenuated carbachol-evoked Ca2+ signals. However, there is no known CAX in mammalian cells, and so the identity of the lysosomal Ca2+ uptake pathway in mammalian cells is unresolved. Using mammalian cells loaded with a fluorescent Ca2+ indicator, I show that dissipating the pHly gradient pharmacologically or by siRNA-mediated knockdown of an essential subunit of the H+ pump, increases the amplitude of IP3-evoked cytosolic Ca2+ signals without affecting those evoked by SOCE. A genetically encoded low-affinity Ca2+ sensor expressed on the lysosome surface reports larger increases in [Ca2+]c than the cytosolic sensor, but only when the Ca2+ signals are evoked by IP3R rather than SOCE. Using cells expressing single IP3R subtypes, I demonstrate that each of the three IP3R subtypes can deliver Ca2+ to lysosomes. I conclude that IP3Rs release Ca2+ within near-lysosome microdomains that fuel a low-affinity lysosomal Ca2+ uptake system. The temporal relationship between the increase in pHly and reduced Ca2+ sequestration suggests that pHly affects the organization of the microdomain rather than the Ca2+ uptake mechanism. I show that abrogation of the lysosome H+ gradient does not acutely prevent uptake of Ca2+ into lysosomes, but disrupts junctions with the ER where the exchange of Ca2+ occurs. The dipeptide, glycyl-L-phenylalanine 2-naphthylamide (L-GPN), is much used to disrupt lysosomes and release Ca2+ from them. The mechanism is widely assumed to require cleavage of GPN by cathepsin C, causing accumulation of amino acid residues, and osmotic lysis of lysosomal membranes. I show, using LysoTracker Red and Oregon Green-dextran to report pHly, that L-GPN is effective in HEK cells lacking functional cathepsin C, following CRISPR-Cas9-mediated gene disruption. Furthermore, D-GPN, which is resistant to cleavage by cathepsin C, is as effective as L-GPN at increasing pHly, and it is similarly effective in cells with and without cathepsin C. L-GPN and D-GPN increase cytosolic pH, and the effect is similar when the lysosomal V-ATPase is inhibited with bafilomycin A1. This is not consistent with GPN releasing the acidic contents of lysosomes. I conclude that the effects of GPN on lysosomes are not mediated by cathepsin C. Both L-GPN and D-GPN evoke Ca2+ release, the response is unaffected by inhibition or knock-out of cathepsin C, but it requires Ca2+ within the ER. GPN-evoked increases in [Ca2+]c require Ca2+ within the ER, but they are not mediated by ER Ca2+ channels amplifying Ca2+ release from lysosomes. GPN increases [Ca2+]c by increasing pHcyt, which then directly stimulates Ca2+ release from the ER. I conclude that physiologically relevant increases in pHcyt stimulate Ca2+ release from the ER independent of IP3 and ryanodine receptors, and that GPN does not selectively target lysosomes. I conclude that all three IP3R subtypes selectively deliver Ca2+ to lysosomes, and that the low pH within lysosomes is required to maintain the junctions between ER and lysosomes, but not for lysosomal Ca2+ uptake. I suggest that GPN lacks the specificity required to allow selective release of Ca2+ from lysosomes.

Ο σκοπός της παρούσας εργασίας αφορά ένα αντικείμενο που έχει ιδιαίτερο ενδιαφέρον στην οικονομική αγορά, την τεχνολογική εξέλιξη και τα Διεθνή Δίκτυα Παραγωγής. Το πρώτο μέρος της εργασίας αφορά στο θεωρητικό πλαίσιο ώστε να γίνει κατανοητός ο όρος Διεθνών Δικτύων Παραγωγής και γενικότερα τα χαρακτηριστικά, τα πλεονεκτήματα και τα επιμέρους τμήματα που τα αποτελούν. Επίσης αναφέρεται η άμεση σχέση των δικτύων με το Κράτος , το ανθρώπινο δυναμικό καθώς και οι άμεσες επιπτώσεις από την ανάπτυξη των δικτύων δηλαδή την διάχυση της τεχνολογίας και της γνώσης. Τέλος, η μελέτη ολοκληρώνεται με την αναφορά μιας μελέτης περίπτωσης για το κλάδο της αυτοκινητοβιομηχανίας γενικότερα, και ειδικότερα στην Ταϊλάνδη. / The purpose of this work it refers to a subject that has a particular interest in the financial market, technological progress and Global Production Networks. The first part of this project concerns the theoretical framework to understand the term of Global Production Networks and general characteristics, advantages and the individual parts that a network includes. Also, the networks are directly connected with the State, the human resources and the direct impact of the development of networks in the diffusion of technology and knowledge. Finally, the study concludes with a report of a case study for the automotive industry in general and particularly in Thailand.

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