Les instabilités thermo-acoustiques se rencontrent fréquemment au sein des chambres de combustion de toute taille, de la petite chaudière au moteur de fusée. Ces instabilités sont causées par le couplage entre ondes acoustiques et dégagement de chaleur instationnaire. En effet, le passage d'une onde acoustique au travers d'une flamme va moduler son dégagement de chaleur qui, en retour, va générer de nouvelles ondes acoustiques. Lorsqu'une chambre de combustion entre en instabilité, d'importantes variations de pression sont observées ; ces fluctuations peuvent user prématurément le système ou altérer ses performances. L'étude des instabilités thermo-acoustiques a pour but d'améliorer notre compréhension de ces phénomènes complexes afin de les prévenir. L'objectif de ce travail est d'obtenir et d'intégrer au sein de modèles réduits des descriptions précises de la dissipation acoustique – effet stabilisant - et d'interaction flamme/acoustique – effet déstabilisant. Cette étude se décompose en trois axes : La première partie développe le concept de « modèle acoustique réduit » qui permet de prédire les modes acoustiques d'une chambre de combustion. Pour cela, sont prises en compte les dissipations inhérentes à certaines pièces(diaphragmes, injecteurs, ...) ainsi que le couplage flamme/acoustique. Une fois le modèle établi, il convient d'en chercher les solutions à l'aide d'un solveur numérique spécialement conçu pour cette tâche. Dans une deuxième partie, un banc expérimental est utilisé pour caractériser le lien entre perte de charge et dissipation acoustique. Il est montré de manière théorique et expérimentale que la connaissance des pertes de charge au travers d'un élément permet de prédire son comportement acoustique à basse fréquence. La dernière partie concerne le couplage flamme/acoustique et plus spécifiquement l'influence de la température de l'accroche-flamme :une flamme pauvre pré-mélangée air/méthane est stabilisée sur un cylindre dont la température peut être contrôlée. Ainsi, il est montré que l'influence de la température du cylindre sur la flamme – position d'équilibre, dynamique et stabilité - est remarquable. / From small scale energy systems such as domestic boilers up to rocket motors, combustion chambers are often prone to combustion instabilities. These instabilities stem from the coupling of unsteady heat release rate and acoustic waves. This coupling is two sided: flame front perturbations generate acoustic waves while acoustic waves impinging on flame holders can disturb flames attached on them. Important pressure and velocity oscillations can be reached during unstable regimes, that can alter its efficiency or even damage the entire combustion chamber. One major challenge is to understand, predict, and prevent from these combustion instabilities. The objectives of this thesis are twofold: (1) take into account acoustic dissipation and (2)analyze flame/acoustic coupling to obtain Reduced Order Model (ROM) for combustion instabilities. This work is divided into three parts. First, the concept of ROM that gives the acoustic modes of a combustion chamber is introduced. This modeling strategy is based on the acoustic network theory and may take into account flame/acoustic coupling as well as acoustic dissipation. An efficient numerical algorithm dedicated to solve ROMs was designed on purpose and validated on several academical configurations. Second, an experimental rig was commissioned to study mean and acoustic pressure losses across a diaphragm and two swirl injectors. Results show that these two phenomena are linked and can be simply incorporated into ROMs. Finally, flame/acoustic coupling is investigated by using both direct numerical simulations and experiments: a lean premixed V-shaped laminar flame is anchored on a cylindrical bluff-body and we show that its temperature greatly influences the flame mean shape as well as its dynamics.

Made available in DSpace on 2014-12-17T14:55:58Z (GMT). No. of bitstreams: 1 PauloFB.pdf: 617080 bytes, checksum: 5f9c06266e137d13c8b810163ede788d (MD5) Previous issue date: 2005-08-25 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / Microstrip antennas are widely used in modern telecommunication systems. This is particularly due to the great variety of geometries and because they are easily built and integrated to other high frequency devices and circuits. This work presents a study of the properties of the microstrip antenna with an aperture impressed in the conducting patch. Besides, the analysis is performed for isotropic and anisotropic dielectric substrates. The Multiport Network Model MNM is used in combination with the Segmentation Method and the Greens function technique in the analysis of the considered microstrip antenna geometries. The numerical analysis is performed by using the boundary value problem solution, by considering separately the impedance matrix of the structure segments. The analysis for the complete structure is implemented by choosing properly the number and location of the neighboor element ports. The numerial analysis is performed for the following antenna geometries: resonant cavity, microstrip rectangular patch antenna, and microstrip rectangular patch antenna with aperture. The analysis is firstly developed for microstrip antennas on isotropic substrates, and then extended to the case of microstrip antennas on anisotropic substrates by using a Mapping Method. The experimental work is described and related to the development of several prototypes of rectangular microstrip patch antennas wtih and without rectangular apertures. A good agreement was observed between the simulated and measured results. Thereafter, a good agreement was also observed between the results of this work and those shown in literature for microstrip antennas on isotropic substrates. Furthermore, results are proposed for rectangular microstrip patch antennas wtih rectangular apertures in the conducting patch / As antenas de microfita s?o estruturas muito utilizadas nos sistemas de telecomunica??es atuais. Isto decorre, principalmente, da diversidade de configura??es e da facilidade de constru??o e integra??o dessas antenas com outros dispositivos e circuitos de altas freq??ncias. Neste trabalho, o m?todo de an?lise empregado ? o Modelo de Circuito de M?lti-Porta (Multiport Network Model MNM), que combinado com o M?todo da Segmenta??o e a t?cnica da Fun??o de Green, mostra-se adequado ao estudo da antena de microfita com abertura no patch condutor. A partir do equacionamento do problema do valor de contorno, ? ent?o realizada uma an?lise num?rica que consiste em avaliar a estrutura da antena considerada a partir da integra??o dos elementos em que ela foi dividida. Nessa an?lise, os elementos s?o representados por matrizes de imped?ncia e a integra??o ? implementada atrav?s de portas de circuitos adequadamente escolhidas em n?mero e posicionamento. Na an?lise num?rica, foram consideradas as seguintes estruturas: a cavidade ressonante, a microfita com patch retangular convencional (sem abertura) e a microfita com patch retangular com abertura. A an?lise foi efetuada para substratos isotr?picos e estendida para o caso de antenas com substratos anisotr?picos uniaxiais atrav?s do M?todo do Mapeamento. S?o apresentados resultados para a freq??ncia de resson?ncia e para a imped?ncia de entrada de antenas de microfita. A parte experimental do trabalho consistiu no projeto, constru??o e medi??o de v?rios prot?tipos de antenas de microfita com patches retangulares com e sem abertura. Observou-se que os resultados obtidos, atrav?s da simula??o num?rica, apresentaram uma boa concord?ncia com os das medi??es efetuadas. Os resultados deste trabalho, tamb?m, concordaram com os resultados de outros autores, dispon?veis na literatura

[pt] A compreensão dos mecanismos e fenômenos de transporte relacionados ao fluxo multifásico em meios porosos é de grande relevância para diversas aplicações práticas como captura e sequestro de dióxido de carbono, transporte em células de combustível e recuperação avançada de reservatórios de hidrocarbonetos. A geometria do espaço poroso e as interações dos fluidos com sua parte sólida determinam propriedades macroscópicas como porosidade, permeabilidades relativas e pressão capilar. Porém, a visão em escala microscópica fornece uma melhor descrição e entendimento dos processos físicos e químicos do escoamento de fluidos no espaço poroso. Neste trabalho desenvolvemos um simulador de rede de poros para análise do escoamento bifásico de fluidos imiscíveis tanto para o processo de drenagem quanto para o de embebição. O modelo de rede 240×40 tem capilares com raios médios na ordem de 52.35 micrometro com constrição. Os padrões de escoamento e eficiências de deslocamento foram obtidos para diferentes razões de viscosidade e números de capilaridade. Os resultados encontrados, considerando deslocamento pistão, foram similares a de experimentos realizados previamente, injetando água no meio saturado de óleo. Na drenagem, a saturação residual de óleo cai com o aumento do número de capilaridade. O padrão de escoamento observado é de fingerings viscosos e, a frente de deslocamento torna-se mais estável com o aumento da razão de viscosidade. Na embebição, para números de capilaridade mais baixos, o escoamento foi dominado por fingers capilares. Para números de capilaridade altos, fingers viscosos foram predominantes e, com o aumento da razão de viscosidade, a frente apresentou maior estabilidade. / [en] Understanding the mechanisms and transport phenomena of multiphase flow in porous media has great relevance in several practical applications, such as capture and sequestration of carbon dioxide, transport in fuel cells and enhancement hydrocarbon recovery. The geometry of pore space and the fluid interactions with the solid determine macroscopic properties such as porosity, relative permeabilities and capillary pressure. However, microscopic analysis provides a better description and comprehension of physical and chemical processes of fluid flow in the pore space. In this work, we developed a pore-network simulator to analyze immiscible two-phase flow for both drainage and imbibition processes. The 240×40 pore-network model has constricted capillary channels with radius on the order of 52.35 micrometer. Flow patterns and displacement efficiencies evaluation were obtained at different viscosity ratios and capillary numbers. The results, considering piston-like displacement, were similar to experiments realized previously, injecting water in an oil saturated medium. In the drainage process, the oil saturation reduces with increasing capillary number. The observed flow pattern is viscous fingerings and the front is stable with the higher viscosity ratio. In imbibition, the flow was dominated by capillary fingers at low capillary numbers. At high capillary numbers, viscous fingers were predominant and, with increasing viscosity ratio, the front presented higher stability.

A cell is a highly complex, ordered, and above all, a robust system. It copes with in-trennel and external uncertainties like heterogeneous stimuli, errors in processing and execution, and changes within and outside the cell. Maintenance of such a system critically depends on a large body of signalling networks and associated regulatory mechanisms. Of the recurrent manoeuvres in cell signalling, protein phosphorylation is the most prominent, and is used as a switch to transmit information and effect-ate various outcomes. It is estimated that 30% of the entire proteome of a typical eukaryotic cell is phosphorylated at one time or another, almost exclusively at the hydroxyl groups of one or more Seer(S)/Thru(T)/Tyr(Y) residues. This phosphorylation is accomplished through the transfer of g-phosphate of ATP in the presence of cations by a superfamily of enzymes called protein kinases, or STY kinases. In accordance with widespread phosphorylation events, STY kinases form a large and diverse superfamily, constituting 2% of the proteins encoded in an eukaryotic genome and about 500 proteins in the human proteome. Distantly related STY kinases share less than 20% sequence identity, phosphorylate specific substrates, bind to dis-tint interaction partners, localise in different cellular compartments and are regulated by different mechanisms. Despite flexibly accommodating these specific attributes, all STY kinases share a conserved 3-dimensional fold and retain the catalytic function. Moreover, all STY kinases can be manipulated by the signalling machinery to be in the “on” (functionally active) or “off” (inactive) state, thereby adding another layer of regulatory control. Such versatility of the STY kinase domain in harbouring specific substrate recognition motifs, binding interfaces, domain architectures and functional states makes it one of the most influential players in cell signalling and a desirable drug target. Despite decades of studies, a comprehensive understanding of the kinase domain, and the features that dictate its catalytic activity and specificity is lacking. This is reflected by the fact that whereas kinases specifically bind and phosphorylate their cognate substrates, most drugs targeted at them are non-specific and beget cross-reactivity. This gap in understanding potentially ensues from an awry outlook of STY kinases from the viewpoint of sequences and structures alone. It is now well established that the function and regulation of a protein molecule, along with its stability and evolution, is closely related to its dynamics. In this premise, this thesis explores the mechanistic and dynamics underpinnings of STY kinases, and interprets them in the light of their multitude of functional responsibilities and specificities In Chapter 1 of the thesis, we broadly discuss the complexity of cell signalling and the pivotal role of STY kinases in it. After a brief introduction to cell signalling in eukaryotes, several signal cascades mediated by different secondary messengers (camp, cGMP, DAG, IP3) are described. In these signal pathways, modularity is identified as a recurrent theme at all levels of hierarchy: within domain, within protein, within signalling pathway and across signalling pathways. One such modular regulation, protein phosphorylation, is discussed in detail and its catalytic enzyme STY kinase is introduced. An overview and historical perspective of the STY kinase superfamily is presented along with the review of literature pertaining to their sequence, structure and catalytic function characteristics. We note that in the active state, all STY kinases adopt a specific spatial conformation characterised by precise positioning of crucial structural motifs, while the inactive state is usually a case of some deviation from these structural constraints. Chapter 2 addresses a fundamental question in the protein dynamics and function paradigm. If mobility and dynamics of a protein is intimately coupled to its function, how does it manifest in STY kinases? Is there a discernible inter-relationship be-tween the mobility of an STY kinase and its functional competence? To answer these questions, we collated 55 crystal structures of 14 STY kinases from diverse groups and families, and subjected their kinase catalytic domains to Gaussian network model (GNM) based normal mode analysis (NMA). GNM models the kinase structure as a 3-dimensional mass-spring system in a coarse-grained fashion, with masses/nodes at Ca atom positions. Proximate Ca nodes, within a 7 A˚ distance cut-off, are con-nested by identical virtual springs, resulting in a simplified network of Ca-Ca bonded and non-bonded interactions modelled as harmonic potentials. Based purely on the topology of mechanical constraints imposed by the springs, GNM analytically deter-mines the isotropic vibrational normal modes available to the kinase structure. This method approximates the energy of the protein structure harmonically, and thus any micro-motion of the kinase can be theoretically described by a linear cSombination of the calculated normal modes. It is known from previous studies that the modes of low frequencies correspond to biologically feasible and meaningful motions like hinge movements, protein folding and catalysis. We note that the multiple crystal structures analysed in each of the 14 STY kinases are identical in sequence and gross structural fold, and vary only in local backbone conformations corresponding to the functional state of the kinase (active/inactive). Upon examining the fluctuations of kinases in the normal mode of the least frequency (or, global mode), we found systematically higher structural fluctuations in the inactive states when compared to the corresponding active states. This observation held true within individual kinases and across all the 14 kinases. Taken together, a more number of residues have higher fluctuations in the inactive states (n = 1095), than those with higher fluctuations in the active states (n = 525; Chi-square test, p value < 0.05). This skewed fluctuation distribution is in corroboration with higher B-factors and con-formational energies of the inactive state crystal structures. Moreover, high fluctuation is observed across the different inactive forms, except a small fraction of DFG-“in” in-active conformations. Interestingly, the regions of differential fluctuation localised to activation loop, catalytic loop, aC-helix and aG-helix, which are implied in kinase function and regulation. Further investigation of 476 crystal structures of kinase com-plexes with other proteins revealed a remarkable correspondence of these regions of differential fluctuation to contact interfaces. We further verified that this differential fluctuation is not a trivial consequence of bound small molecules or mutations, but an inherent attribute of the kinase catalytic domains. In Chapter 3, we verified the accuracy of differential fluctuation observed between the active and inactive STY kinases, as perceived from GNM based NMA, using the more rigorous method of molecular dynamics (MD) simulations. GNM is minimal-is tic in that the STY kinase catalytic domain is coarse-grained and reduced to a 3-dimensional mechanical network of Ca atom nodes. Thus, the role of side chains and their biophysical character, intra-protein interactions, mutations and bound factors are grossly overlooked. In this premise, we conducted all-atom MD simulations using AMBER ff14SB force-field of 6 structural variants of cAMP-dependent protein kinase (PKA) for 1 ms each. We chose 2 crystal structures of active and inactive PKA (PDB IDs 3FJQ and 1SYK respectively) whose kinase domains shared high structural similarity (gRMSD = 2.6 A)˚. They were modified in silico to obtain 6 starting structures for MD simulations: phosphorylated kinase domain in active and inactive states, kinase do-main along with its C-terminal tail in active and inactive states, active kinase domain bound to ATP/2Mg2+, and unphosphorylated inactive kinase domain. In the absence of external domains, the inactive kinase domain conformation elicits higher mobility in terms of Ca RMSD and Ca RMSF than the active kinase domain. Of the 255 residues in PKA, remarkable 198 residues have higher Ca RMSF in the inactive state, with predominant contributions from ATP binding loop, catalytic loop and aG-helix. In the presence of C-terminal tail, the differential mobility of the kinase domain is exaggerated, with 241 out of 255 residues showing higher Ca RMSF in the inactive state. Upon close investigation, we found that in the presence of C-terminal tail, al-though the mobility of residues is generally suppressed in both the functional states, a few functional regions like activation loop and hinge residues experience higher Ca RMSF in the inactive state. This sheds light on the role of C-terminal tail in the dynam-ics of the activation loop, potentially operating through the hinge residues. Absence of phosphorylation in the inactive kinase domain increases the mobility of residues in general, except of those in the aG-helix. When bound to ATP/2Mg2+, active ki-nase domain (active-holo) showed higher mobility than the active-apo and inactive structures, contrary to the previous results and studies. Intrigued, we examined the simulation closely and found a transition of the active-holo structure to another con-formation, named s2, at 450 ns. Upon analysis of the trajectory before the transition, the active-holo form was indeed found to be more stable and less mobile than the inac-tive state(s). Thus, all the inactive variants are found to be consistently more agile and mobile than their active counterparts, in agreement with the results obtained using NMA. Chapter 4 discusses the transition of the active-holo simulation to a new state, named s2, characterises its structural features and explores the possibility of its func-tional relevance. In the previous chapter, while attempting to verify the presence of differential mobility between various active and inactive forms of PKA through MD simulations, we chanced upon the transition of an active PKA state bound to ATP/2Mg2+ (active-holo) to s2 conformation. The s2 state has a Ca RMSD of up to 4.1 A˚ from the initial starting conformations, mainly contributed by the ATP binding loop, abs-helix, act-helix and age-helix, which are implicated in catalysis and substrate recognition. Once formed, s2 was stable and did not revert back to the active-hole starting structure or any other conformation. We calculated all-vs.-all Ca RMSDs of the conformations sampled during the simulation and identified 3 time periods: 0 - 200 ns of initial conformations similar to the starting structure, 201 - 500 ns of transition, and 501 - 1000 ns of s2 conformations. Principle component analysis (PCA) of the Ca spatial positions during the entire trajectory also categorically exposed two energy wells corresponding to the initial and s2 conformations in the first and second PCs (variance = 56%). Upon systematically comparing the conformers sampled in MD with every known kinase structure, no structure hit with Ca RMSD 2 A˚ was found for conformers sampled after 500 ns, deeming s2 as a novel and hitherto unknown conformation. Investigation of persistent intra-protein interactions unique to the s2 state revealed two stabilising interactions: a salt bridge between K73 and E106 in the b-sheet behind the ATP binding cleft and a network of hydrophobic interactions anchoring act-helix to the age-helix. Aside from these defining interactions, s2 is also characterised by a higher density of intra-protein hydrogen bond network, which stabilises it further. PCA of the MD trajectory indicates the transition of active-hole to s2 to be a process with at least 2 steps, the first being the salt bridge formation. Evolutionary conservation analysis shows that the crucial residues involved in the s2-specific interactions are not reliably conserved across PKAs of other organisms. However, convergence to s2 may still be feasible through other courses of stabilising interactions. From a functional perspective, the s2 conformation opens up the age-helix away from the kinase core and mildly rearranges the catalytic cleft, thereby unmasking a hotspot for sub-strata binding that was absent in the initial structure. In an attempt to replicate the s2 conformation, we performed 4 repeat simulations of the same active-hole starting structure for 1 ms each. Although two of these independent simulations achieved the K73-E106 salt bridge, none of them cloned the complete extent of transition and con-mergence to s2. Instead, we sampled another set of novel conformations, s3, in one of the repeat simulations indicating a disposition for the ATP bound PKA to sample different conformations. Comparative analysis suggests a potential role of C-terminal tail in stabilising the active-hole conformation in physiological conditions. Chapter 5 characterises the extent of conservation of structural fluctuations in ho-mologous STY kinases and interprets the observations in the light of their regulatory diversity. Upon establishing that structural fluctuations of STY kinases carry activity-specific information (Chapter 2) and affirming the same using MD simulations (Chap-ter 3), we hypothesised that the mobility of STY kinases is an important consider-action to understand the basis of their regulatory features as well. In that case, one would expect the structural fluctuations to be better conserved in closely related STY kinases than distantly related ones. To test our hypothesis, we collated 73 crystal structures containing an STY kinase domain in the active conformation and subjected them to GNM based NMA as described above. The global mode structural fluctuations of pairs of STY kinases of varying evolutionary divergence (same-protein, within-subfamily, within-family, within-group and across-groups) were analysed. We found that the closely related STY kinase pairs (of same-protein and within-subfamily cate-goriest) have more conserved and better correlated structural fluctuations than those that were distantly related (of within-group and across-group categories). This con-serration of flexibility did not trivially follow from sequence/structure conservation, since a substantial 65.4% of variation in fluctuations was not accounted by variations in sequences and/or structures. Across the 73 active STY kinases belonging to different groups, we identified a conserved flexibility signature defined by low magnitude fluctuations of residues in and around the catalytic loop. Interestingly, we also identified sub-structural residue-specific fluctuation profiles characteristic of kinases of different categories. Specifically, fluctuation patterns that are statistically unique to kinase groups (AGC, TK) and families (PKA, CDK) were recognised. These fluctuation signatures localise in sites known to participate in protein-protein interactions typical of the kinase group and family concerned. Thus, we report for the first time that residues characterised by fluctuations that are differentially conserved within a group/family are involved in interactions specific to the group/family. Upon the validation of structural fluctuation as an indicative tool to understand kinase-specific interactions, we elucidate an application of this understanding. In SC kinase, we identified local regions around the age-helix to be exhibiting conserved differential fluctuations in comparison to its close relatives EGFR and Abl. Following from the learning that specific fluctuations are correlated with specific binding, we propose this as an attractive target for drug design, with minimal cross-reactivity. Overall, this chapter demonstrates the conservation of fluctuation in STY kinases and underscores the importance of consideration of fluctuations, over and above sequence and structural features, in understanding the roles of sites characteristic of kinases. Chapter 6 documents the frequency of substitution of structural fluctuations in STY kinases over the course of divergent evolution. So far, we had established that structural fluctuations are evidently distinct in the varied functional states assumed by a single STY kinase (Chapter 2-3). In addition, fluctuations are differentially conserved within closely related kinases, but systematically vary across families (Chapter 5). In this chapter, we quantify the structural fluctuation variations in all residues of STY kinases put together. In a sense, this is the fluctuation space available for STY kinases across their functional states, binding modes, and regulatory mechanisms. To accomplish this, we systematically compiled all known eukaryotic kinase domain structures solved at resolutions better than 3 A˚. These structures were then divided into wild-type (harbouring no mutations and having typical amino acids at critical functional sites), pseudo-kinase (harbouring no mutations, but having unconventional amino acids at critical functional sites), disease mutant (harbouring mutations that have imp-plications in diseases) and mutant of unknown effect (harbouring mutations whose physiological manifestation is unknown) categories. Global mode structural fluctuations were determined for every kinase catalytic domain structure in each of the 4 enlisted categories. Similar to Benioff and Benioff’s BLOSUM that summarised the probability of all possible amino acid substitutions in homologous proteins, we documented a ma tricks of fluctuation substitution frequency in the conserved regions of wild-type kinases (named FLOSUM). We observe a positive correlation between the mean and variance of structural fluctuations at equivalent residue positions in wild-type kinase structures (Spearman rank order correlation, r = 0.69, p value < 1e 139). This implies that the residues with low flexibility, like catalytic loop, do not adopt diverse fluctuations in different functional states or across kinases. Substitution with any other fluctuation is heavily disfavoured at the lower range of flexibility than at the higher range. While we did not detect apparent differences in the FLOSUMs of wild-type, disease mutant and mutants of unknown effect structures, there is a remarkable distinction in the FLOSUM of pseudo-kinases. Fluctuation substitutions that are traditionally unfavourable in wild-type kinases are freely allowed in pseudo-kinases, thus exhibit-in poor conservative substitution. Over and above the lack of conventional amino acids, poor conservation of structural fluctuations and favourable substitution of de-viand fluctuations could render auxiliary functional character to the kinase domain in pseudo-kinases, despite their structural similarity to STY kinases. Taken together, this study summarises the structural fluctuation landscape of STY kinases in the form of a substitution matrix, which can serve as a model of flexibility substitution during protein evolution. Encouraged by structural fluctuations being differentially conserved in closely re-lasted kinases (Chapter 5) and conservatively substituted across kinases (Chapter 6), we extended this principle to the sequences of STY kinases in Chapter 7. This chapter reports the development of a method to predict the sites of functional specialisation in kinases, which differentiate one kinase from another, and applies it to all known STY kinase families. These are correlates of kinase-specific functional and regulatory attributes like specific protein-protein interactions, cognate substrate recognition and response to specific signals. Two cardinal properties of family-specific functional sites, viz., differential conservation and discriminatory ability, were used to identify them. We systematically compiled a data set of 5488 kinase catalytic domain sequences be-longing to 107 families. After aligning them into a single multiple sequence alignment, we comparatively analysed the amino acid distributions in topologically equivalent positions of different families. Based on 3 different analytical measures, physicochemical property, Shannon’s entropy and random probability, we scored the differential conservation of every alignment position in each family. By maximising the disc rim-inability between the kinase families, we integrated the results of the three measures and devised a single unified scoring scheme called ID score. This integrated scoring method could distinguish the 107 families from one another with an accuracy of 99.2%. Each site in every STY kinase family was given a score in the range 0 to 1, with 0 indicating no functional specialisation and 1 indicating maximum functional spa-canalisation, by the ID score. Several validations of the method were carried out to assess its competence. First, we selected those residue positions which have consistently high ID scores across most families. Using these hotspot alignment positions that render specificity to the kinase, we clustered the kinase sequences into groups and families. We found that the ID score predicted sites clustered the kinases better than the traditional clustering using the entire alignment. Despite reduction in information, the increase in accuracy of clustering is feasible because of efficient filtering of non-discriminatory sites by ID score. Second, a linear discriminant classifier was observed to predict the kinase family, based on the ID score predicted sites, better than traditional methods. Third, family-specific protein-protein interaction sites in CDK and substrate recognising distal sites in MAPK were scored significantly higher than other residues by ID score (Two-tailed unpaired t-test, p value < 0.05). Fourth, family-specific oncogenic driver mutation sites in 8 different kinase families were identified confidently by the ID score. Finally, we demonstrate one feasible application of the ID score method in the prediction of specific protein-protein interaction sites. In summary, we developed an integrated discriminatory method to identify regions of functional specialisation in all known kinases, validated the results for known cases and elucidate a potential application of the method. The learning from the entire thesis work is summarised in Chapter 8, which positions the work in the larger context of functioning of the kinase domain and the use of dynamics to interpret protein functions. The validity of the simple, yet use-full, NMA of proteins and complementary MD simulations to understand basic mechanistic and dynamic properties of proteins is highlighted. Similar to sequence and structure, dynamics is now recognised as a crucial feature holding information about protein function. The main learning of the thesis that the flexibility and mobility of STY kinases is conserved and conservatively substituted at different levels of hierarchy (different functional forms within a kinase, across kinase families and across the entire STY kinase superfamily) is discussed. The contributions of the work in fur-the ring the knowledge of specificity determinants in kinases, which dictate precise regulatory and control mechanisms, are presented. Supplementary information helpful in understanding of the results of individual chapters, but could not be printed in the thesis due to its length, are provided in an optical disk attached to the thesis. The material in the optical disk is referred to in appropriate places in the individual chapters

The global business environment has changed dramatically in recent years, as competition in complex knowledge-based economies has increased. Enterprise Resource Planning (ERP) systems have been viewed as a way to manage increased business complexity, leading to the rapid adoption and implementation of such systems, as ERP can support enterprises to improve their competitiveness. Knowledge management (KM) is crucial for ERP systems implementation, however a highly demanding task. Therefore, the primary concern of this research is to examine the effectiveness of knowledge management activities that would contribute to achieve ERP implementation success. This study adopted mixed methods approach by combining semi-structured interviews and a questionnaire to collect empirical data from ERP professionals in both manufacturing and service sector organisations. In the qualitative phase, it develops the “framework of integrative knowledge” based on empirical evidence, that can improve KM competence for ERP implementation success. Data analysis has been undertaken using a combination of thematic analysis and comparative analysis with respect to 14 ERP implementations in the UK. The framework integrates multiple perspectives in terms of knowledge components to enhance KM competence, including knowledge types, knowledge layers, KM lifecycle and knowledge determinants. It discovered 19 knowledge determinants to drive knowledge management activities during ERP projects, which is another vital contribution to the existing knowledge. Furthermore, the study develops the “knowledge network model” for ERP implementations in order to facilitate the knowledge flows between various stakeholders involved in ERP implementations, which can help to understand the interactions between the knowledge components. Moreover, sub-knowledge types (knowledge elements) under each knowledge type were discovered through empirical evidence. The quantitative phase was adopted to extend the findings of the qualitative phase. The knowledge types and knowledge elements were prioritised using Analytic Hierarchy Process (AHP) method through an online AHP based questionnaire with 77 responses from ERP professionals involved in UK ERP implementations. Furthermore, knowledge prioritisation demonstrates how effectively the framework of integrative knowledge can be used during ERP implementations with the help of prioritised knowledge. In total 4 knowledge types and 21 knowledge elements were ranked based on their contribution to achieve ERP success; four variables of information quality, systems quality, individual impact and organisational impact were used to measure ERP success. This study has number of theoretical contributions including framework of integrative knowledge, knowledge network model for ERP implementations and ERP knowledge prioritisation. Moreover, the framework of integrative knowledge can provide ERP practitioners with useful guidance on what the key knowledge determinants are and how the relationships between knowledge components should be best managed to achieve ERP implementation success in business reality.

[pt] A injeção de soluções poliméricas tem sido utilizada em muitas aplicações para aumentar a viscosidade da fase aquosa e, por conseguinte, reduzir a elevada razão de mobilidade durante o deslocamento de óleo num meio poroso. Evidências experimentais mostraram também que o comportamento viscoelástico de algumas soluções poliméricas pode contribuir para um melhor deslocamento do óleo na escala de poros, reduzindo assim, a saturação de óleo residual. Este comportamento na escala de poros não é claramente compreendido já que a modelagem de um fluxo viscoelástico de uma solução polimérica em meios porosos é extremamente desafiadora. O comportamento do escoamento em escala macroscópica está diretamente associado com o fluxo extensional dominante através das gargantas e poros que formam o meio poroso. Muitos modelos têm sido desenvolvidos com o objetivo de descrever o efeito extensional observados no fluxo de soluções poliméricas de elevado peso molecular. O modelo desenvolvido neste trabalho baseia-se na relação entre a vazão e a queda de pressão do escoamento de soluções poliméricas através de capilares com garganta que servem como um modelo simples da geometria das gargantas de poro. Um modelo de rede de capilares bidimensional foi desenvolvido para obter os parâmetros macroscópicos do escoamento a partir do entendimento do comportamento microscópico. No modelo monofásico, os resultados apresentam efeitos de diferentes parâmetros reológicos no comportamento macroscópico do escoamento. Para estudar o escoamento bifásico, um modelo de rede dinâmico foi desenvolvido. Os resultados obtidos fornecem uma descrição mais detalhada do processo de deslocamento de óleo pela fase aquosa. / [en] Injection of a polymer solution is used in many applications to increase the viscosity of the water phase and therefore reduce the high mobility ratio during oil displacement in porous media. Experimental evidence has shown that the viscoelastic behavior of some polymer solutions may contribute to a better oil displacement at the pore-level, reducing the residual oil saturation. This pore-level behavior is not clearly understood. Modeling viscoelastic flow of polymeric solutions in porous media is extremely challenging. The macroscopic flow behavior is directly associated with the extensional dominant flow through pore throats that form the porous media. Accurate models should be able to describe the extensional thickening effect observed in the flow of dilute high molecular weight polymer solutions. The model developed in this work is based on the flow rate-pressure drop relationship of polymer solution flow through constricted capillaries that serves as a simple model of the geometry of pore throats. A two-dimensional capillary network model is constructed in order to obtain macroscopic parameters from upscaling of the microscopic behavior. In single-phase flow, results show the effect of different rheological parameters on the macroscopic flow behavior. To study a two-phase flow, a dynamic network model was developed. The results obtained provide a more detailed description of the oil displacement by the water phase.

<p>Doktorskom disertacijom je dokazano da postojeće metode detekcije i identifikacije loših podataka nisu primenjive na distributivne mreže usled njihovih specifičnosti u stepenu redundanse merenja i broja pseudo merenja. Dodatno, razvijeni su algoritmi detekcije loših oblasti primenom dekuplovanog Hi-kvadrat testa, identifikacije loših merenja primenom novo definisanih izbeljenih reziduala, estimacije fazne konektivnosti primenom uslovnih ograničenja u estimatoru stanja, i korekcije pseudo merenja primenom informacija sa pametnih brojila. Navedeni algoritmi su specijalizovani za distributivne mreže i verifikovani primenom na dva test sistema.</p> / <p>The doctoral dissertation has demonstrated that conventional bad data detection and<br />identification methods cannot be efficiently applied in distribution networks, due to<br />their characteristics such as low measurement redundancy, number of pseudo<br />measurements and level of measurements correlation. In addition, the doctoral<br />dissertation described newly developed algorithms for bad area detection based on<br />decoupled Chi-squares test, bad data identification using newly defined whitened<br />residuals, estimation of phase connectivity by extension of state estimation with<br />conditional constraints and correction of pseudo measurements using AMI data. The<br />mentioned algorithms are specialized for distribution networks and verified through<br />simulation on two test systems.</p>

This dissertation is related to mathematical modelling of the spread of respiratory syncytial virus (RSV) in Valencia and is still causing a large number of hospitalizations of children in this community. A mathematical model based on a system of nonlinear differential equations of first order has been built. This model considers the population divided into two age groups to pay particular attention to children under one year who are the most affected by this disease. This model has been fitted with hospitalizations data of Valencia and has been used to perform a cost analysis of a potential vaccination strategy. We also propose a complete network model to study the seasonal evolution of RSV epidemics in which seasonal parameters were fitted with the previous continuous model. Both developments are contrasted. On the complete network model we propose a strategy for vaccination of children based on the administration of three doses, and develop a cost-effectiveness study for different vaccination rates. Finally we have defined a SIRS model for RSV epidemics on a random social network of contacts among individuals. In this model has not forced the seasonality. The seasonality arises naturally for certain values of the duration of immunity of a patient recovered, the number of contacts and the likelihood of infection from a contact in a day. In this social network model only a narrow range of parameters can support RSV epidemic seasons. / Moraño Fernández, JA. (2010). Mathematical modelling of Respiratory Syncytial Virus spread in the Spanish region of Valencia. Preventive applications [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/8638 / Palancia

This work deals with simulation of the urban distribution network reliability. For the evaluation of these networks are used indicators of reliability which are described in the first part. Next methods of analysis and posibilities for capabilities reliability simulation of distribution network are described. The third part deals with the real value of the reliability of electricity distribution in Italy. These values are presented in tables and graphs. The last part is a simulation of the urban network. Effect of different configurations on the reliability of electricity supply are studied. Sensitivity analysis is done for failure rate and proportional of the number of sampling points; the simulated values are fiven in tables and graphically.

Optimized fiber utilization is crucial to the process efficiency and profitability in paper and board making. The fibers can be developed in a refining process in order to reach a desired quality level. Refining causes a variety of simultaneous structural changes to the fibers such as internal fibrillation, external fibrillation and fines formation that contribute in different ways to improve the sheet consolidation and enforce bonding between fibers. This increases the strength, which is one of the quality parameters of paper. Three grades of refining are studied. Microscopy of the pulps shows that the fines are not a homogeneous fraction. However, in analyzing SEM images of the handsheet surfaces, fibrillar fines and their bundles are observed to form links between neighboring fibers which can reinforce the network and the bond regions. The fiber characterization method by FiberLab only captures trends in changed fines content in the pulps and these are underestimations since the instruments optical resolution is limited in characterizing fibrillar fines. SEM images of the cross sections of the sheets along with thickness measurements show that increased grade of refining causes a densification of the sheets. Tensile tests show that refining results in a significant increase in tensile strength and stiffness but a more modest increase in strain at break. A 3D fiber network model is built with a deposition technique according to experimental results. Introducing fines in the same way as fibers and increasing the amount of fibrillar fines does not affect the thickness significantly. The densification is instead captured either by changing the width-to-height ratio of the fiber cross sections or by changing the flexibility of the fibers through the so-called interface angle, both having a large impact on the thickness. But SEM images suggest that the width-height-ratio did not reveal a significant change between the three grades of refining. The effect of refining on the mechanical properties is studied numerically using micromechanical simulations which assist interpretation of experimental results. The FE network simulations show that the thickness change alone cannot explain the increased stiffness observed in physical experiments. The addition of fines fraction modelled to capture the fibrillar fines observed in SEM images proved to have a large impact on stiffness comparable to that of experiments. Thus the increased stiffness is partly due to increased number of contacts after densification and partly due to the addition of fines. / Optimerad användning av fibrerna är avgörande för processeffektivitet och lönsamhet i tillverkningen av papper och kartong. Fibrerna kan vidareutvecklas genom ytterligare mekanisk malning för att nå önskad fiberkvalitet. Malning leder till en mängd simultana strukturförändringar av fibrerna såsom inre fibrillering, yttre fibrillering och bildning av så kallade fines, finare partiklar, som på olika sätt bidrar till att förbättra pappersarkens sammansättning och förstärka bindningen mellan fibrer. Detta förbättrar pappersstyrkan vilken är en av kvalitetsparametrarna hos papper. Tre malgrader har studerats. Mikroskopbilder av pappersmassan visar att de finare partiklarna inte är en homogen sammansättning. Men i analysen av SEM bilder av pappersarkens ytor så kan fibriller och grupper av fibriller observeras bilda länkar mellan angränsande fibrer vilka kan förstärka fibernätverket och fibrernas bindningsregioner. Fiberkarakteriseringsmetoden utförd av FiberLab kan bara fånga trender i mängden fines i pappersmassorna och dessa är underskattningar eftersom instrumentets optiska upplösning är begränsad i karakteriseringen av fibriller. SEM bilder av arkens tvärsnitt tillsammans med tjockleksmätningar visar på att ökad malgrad resulterar i en förtätning av arken. Dragprov visar att ökad malgrad leder till en märkbar ökad styrka och styvhet men en något blygsammare ökning i töjningsgräns. En 3D fibernätverksmodell skapas med en depositionsteknik enligt experimentella resultat. Genom att introducera fines på samma sätt som fibrer och öka antalet visade sig inte ha någon signifikant inverkan på nätverkets tjocklek. Istället fångas förtätningen av arken på två andra sätt i genereringen av fibernätverket, antingen genom ändring av bredd-höjd kvoten av fibrernas tvärsnitt eller genom förändring av fibrernas flexibilitet med användandet av den så kallade interfacevinkeln, vilka båda har stor inverkan på tjockleken. Men SEM bilder av tvärsnitten visade ingen stor skillnad hos bredd-höjd kvoten mellan de tre malgraderna. Malgradens påverkan på de mekaniska egenskaperna studeras numeriskt genom mikromekaniska simuleringar, vilka jämförs med experimentella resultat. Finita element simuleringarna visar att tjockleksändringen inte ensamt kan förklara den ökade styvheten som observerats i dragproven. Tillägget av fines modellerade att fånga fibrillernas egenskaper observerade i SEM bilder visade sig ha en stor inverkan på styvheten, jämförbar med dragproven. Alltså, den ökade styvheten beror dels på ökat antal kontaktpunkter efter förtätning av arken och dels på innehållet av fines.