I dagens hårda konkurrenssituation krävs det mer och mer av företags informations-system. Detta gör att fler och fler företag väljer att implementera ett integrerat affärs-system. Integreringen gör att företag får en enhetlig systemmiljö för hela företagets informationsbehandling. Implementeringen är dock en kostsam och tidskrävande process (Ekstrand, 1998). Mitt arbete behandlar frågeställningarna om varför företag väljer att implementera ett affärssystem, hur implementeringen förlöpte samt hur affärssystemet fungerar när implementeringen är färdig. Bland de företag jag vände mig till så var den främsta anledningen till att företag installerar ett affärssystem att systemen är omfattande och integrerade. Jag kom även till slutsatsen att det nästan är omöjligt att genomföra en implementering av ett affärssystem helt smärtfritt. Problemen beror dock inte alltid på affärssystemet utan på t.ex. dålig beredskap från företagens sida. Sammanfattningsvis fick jag intrycket att de flesta företag är nöjda med sitt val av system och de som inte ännu såg nyttan med systemen trodde att de inom kort skulle göra det.

This thesis, which focuses on sleep disturbance in people with neurodevelopmental disabilities, is divided into three sections. Paper one is a systematic review of the extant literature on objective studies of sleep in neurodevelopmental genetic disorders. Twenty papers met inclusion criteria and were subject to quality assessment, of which five were found to be high-quality, thirteen were medium-quality and two were low-quality. Studies were grouped by disorder and although there was some disparity across investigations, generally there was agreement about specific sleep difficulties in each disorder which seem to be part of the behavioural phenotypes. Overall a lack of total sleep, diminished REM sleep, and fragmented, less efficient sleep are prevalent across the disorders. Paper two is an empirical study which employed actigraphy to assess sleep in children with mucopolysaccharidosis type III (MPS III) and typically developing children. Parents completed a sleep diary, a sleep questionnaire and took saliva samples from their child. Actigraphic findings showed that MPS III patients had lengthened sleep onset latencies and greater daytime sleep than controls, but night-time sleep duration was within the normal range. In the MPS III group, some sleep problems correlated with age and progression of the disorder. Analysis of saliva samples revealed that children with MPS III had abnormal melatonin concentrations. Questionnaire responses demonstrated that children with MPS III had more sleep difficulties in all domains compared to controls. Implications for the management of sleep difficulties are discussed. Paper three is a critical appraisal of the research process which includes personal reflections on designing and conducting this research and a discussion of the principal issues which arose. Strengths and limitations of the research, ideas for further research and implications for clinical practice are considered.

JetBrains MPS is a language workbench focusing on domain-specific languages. Unlike many other language workbenches and IDEs, it uses a projectional editor for code. The developer directly manipulates the program in its tree form (AST) and not by editing a text source code. This brings many advantages, but on the other hand requires time-consuming and complicated MPS language definition. The thesis elaborates on the possibility of automating the process of creating MPS language definition from its grammar description. It introduces the MPS editor, evaluates approaches of related projects and describes author's efforts to implement an MPS plugin that allows this import. The chosen approach and the selection of tools used for implementation are justified in the thesis. We point out important problems that any similar project might deal with and we introduce some possible solutions. Furthermore, the thesis contains examples of imported languages, showing the potency of the chosen approach. The thesis also aims to lay groundwork for future extensions and suggest possible improvements.

Kyoto University (京都大学) / 0048 / 新制・課程博士 / 博士(工学) / 甲第15613号 / 工博第3302号 / 新制||工||1498(附属図書館) / 28140 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 伊藤 紳三郎, 教授 赤木 和夫, 教授 辻井 敬亘 / 学位規則第4条第1項該当

There is an unmet need to develop and test treatments for rare lysosomal disease (LD). Most LDs are present in childhood and do not currently have approved therapies. Rare diseases individually are uncommon but taken together account for a population prevalence of 3.5-5.9% worldwide. Due to their rarity, it often takes significant time and effort to diagnose rare diseases. New diagnostic tools, especially for early detection, will offer an advantage in avoiding this diagnostic odyssey. This dissertation is focused on investigating novel diagnostic and treatment methods in vitro for two neurodegenerative LDs: Gaucher disease (GD) and mucopolysaccharidosis IIIB (MPS IIIB). Mutations in NAGLU and GBA1, the genes that encode for lysosomal hydrolases required for degradation of heparan sulfate and glucocerebrosides, lead to the observed pathogenesis in MPS IIIB and GD, respectively. Since many LDs, including MPS IIIB and some forms of GD, are neurodegenerative, cell and gene-based therapeutic strategies are of significant interest. Therapeutics that offer some symptom mitigation in other LDs, such as enzyme replacement or substrate reduction therapies, do not offer appreciable disease mitigation in MPS IIIB or neurodegenerative GD. Here, a novel compound heterozygous mutation, NAGLUY140C/R297X, that results in approximately 50% residual NAGLU protein and 0.6% NAGLU enzyme activity is reported in NAGLU. Furthermore, a RFLP and site-directed mutagenesis strategy was developed to identify the presence of the relatively common p.R297X mutation in patient cell samples, in addition to two other novel molecular assays for the detection of the p.E153K mutation in NAGLU and p.N370S mutation in GBA1. MPS IIIB and GD human skin fibroblasts were reprogrammed to iPSCs using non-integrating Sendai viral vectors with a reprogramming efficiency of 0.2% and 0.3%, respectively. Resulting iPS cell lines were confirmed as being pluripotent through a barrage of analyses for markers of pluripotency and differentiation. Intriguingly, early passage MPS IIIB iPSCs were found to exhibit increased cell death and spontaneous differentiation to embryoid body-like structures, which was hypothesized to be caused by fibroblast growth factor 2 (FGF2) sequestration or degradation due to inherent heparan sulfate dysregulation. Supplemental FGF2 (100 ng/mL) was found to significantly increase confluency of MPS IIIB iPSCs after 48 hours (n = 5, p ≤ 0.05) and persisting to 96 hrs (n = 5, p ≤ 0.05), thus providing evidence for an important role of FGF2-heparan sulfate interactions in the maintenance of stem cell pluripotency. These findings highlight the importance of considering inherent disease pathology when developing disease models. Three genome editing strategies, CRISPR-Cas9, base and prime editing, are addressed throughout this dissertation. Genome editing outcomes in NAGLU and GBA1, as well as a control gene, HPRT1, are reported in HEK293 cells, human skin fibroblasts, and induced pluripotent stem cells (iPSCs). Although CRISPR-HDR failed to yield mutation correction, base editing of the common p.N370S (c.1226 A>G) in GD skin fibroblasts using with 42% efficiency is reported. Base editing of HPRT1 in HEK293 cells with an overall editing efficiency of 6 ± 0.5% (n = 3), but interestingly, when base editing at the centered nucleotide was analyzed, the editing efficiency increases to 27 ± 4.3% (n = 3). These findings align with other reports of a centered nucleotide preference for base editors and will help direct genome editing strategies in the future. This dissertation describes the first genome editing in NAGLU, and the first base editing in GBA1, and underscores the importance of optimizing genome editing strategies when targeting disease-causing mutations in patient-derived cells. The findings reported here will direct future genome editing strategies for developing cell and gene-based therapies for MPS IIIB and GD. / Graduate / 2021-12-15

No description available.

No description available.

O concreto é um dos materiais de construção civil mais versáteis, podendo se adaptar a formas diversas quando em seu estado fresco e resistindo a grandes cargas de compressão em seu estado rígido. No entanto, em estruturas mais densamente armadas ou com geometrias mais complexas, pode-se apresentar dificuldades para a moldagem, causando falhas no preenchimento da forma, o que reduz a capacidade resistente da peça e sua vida útil. Neste trabalho foi utilizado o método de partículas lagrangeanas Moving Particle Semi-Implicit (MPS) como base para um simulador para o estudo do comportamento do escoamento de pastas e argamassas cujo comportamento pode se aproximado por modelos reológicos como Bingham e Herschel-Bulkley. Foram propostos módulos para a simulação da viscosidade não-newtoniana, variação térmica no processo de cura e modelagem de turbulência. Para modelar a variação de viscosidade de um fluido não-newtoniano foi utilizado o modelo de Herschel-Bulkley. O modelo de Herschel-Bulkley possui uma singularidade para taxas de deformação muito pequenas, que resulta em valores de viscosidade infinitas, dificuldade contornada pela solução proposta por Papanastasiou (1987). Na modelagem térmica foram analisados dois modelos de dissipação, sendo um original do método e outro calculado por meio do divergente do gradiente utilizando os modelos de partículas e que teria melhores resultados para o cálculo da dissipação térmica. Também foi modelada a convecção térmica, utilizando para isso a hipótese de Boussinesq. A reação de hidratação do concreto foi modelada utilizando uma equação do tipo Hill para representar a elevação de temperatura obtida por meio um ensaio adiabático. Para complementar as simulações, foi utilizado o modelo de turbulência Detached Eddy Simulation (DES), baseado no método Large Eddy Simulation (LES), que utiliza um modelo de parede para simular a interação do fluido. Para a implementação deste modelo de turbulência foi proposto um algoritmo para o cálculo da distância da partícula de fluido à parede. Este algoritmo utiliza estruturas de dados já existentes no método de partículas de modo que sua execução requer muito menos recursos que a busca binária. Apesar do trabalho ter se guiado pela simulação do concreto fresco, que é um material particularmente complexo, outros escoamentos encontrados na engenharia civil também podem ser beneficiados pelo método, como os estudos do escoamento em sistemas prediais de água e esgoto, do escoamento e prevenção de erosão em rios e córregos, do escorregamento de encostas, dos reatores para depuração de esgotos, entre outros. / The concrete is one of the more versatile civil construction materials, it can adapt to various forms when in its fresh state while resisting to high compression loads in its rigid state. However, in some cases like densely reinforced concrete structures and complex geometry concrete structures can present issues to the casting, and failure in proper form filling can occur. These failures can reduce the resistance and the lifetime of the structure. This work used a simulator based on the lagrangean particle method called Moving Particle Semi-Implicit (MPS) to study the concrete behavior in its distinctive characteristics. Also, this work proposed modules to simulate the non-Newtonian viscosity, the thermal process of concrete cure and to model the turbulent flow. To model the variation of viscosity of a non-Newtonian fluid, the Herschel-Bulkley model, which relates the shear stress with the strain rate, was applied. The Herschel-Bulkley model has a singularity at low strain rates, which results in infinite viscosities. To overcome this issue, Papanastasiou (1987) proposed a modification in the model in order to eliminate the singularity. For the thermal modeling, two models for thermal dissipation were compared, the original method and other calculated from the divergence of gradient using the differential operators for the particle model and that could present improved results for the thermal dissipation calculation. Also, the thermal convection was modeled using the Boussinesq hypothesis. The hydration reaction of the concrete was modeled using a Hill type equation to reproduce the temperature elevation. In addition, a Detached Eddy Simulation (DES) based turbulence model with a simple wall model in the interaction of wall and fluid was applied in the simulations. To improve the turbulence model, an algorithm to calculate the distance between fluid and the nearest wall particle was proposed. The algorithm uses already calculated information from particles so that the execution requires much less resources than a binary search. Although the work has been focused on to the modeling of fresh concrete simulation, which is a particularly complex material, other flows found in civil engineering can also be benefited by the method, such as studies of drainage in water and sewage systems, drainage and prevention of erosion into rivers and streams, prevention and damage mitigation of landslides, reactors for sewage treatment among many others.

O concreto é um dos materiais de construção civil mais versáteis, podendo se adaptar a formas diversas quando em seu estado fresco e resistindo a grandes cargas de compressão em seu estado rígido. No entanto, em estruturas mais densamente armadas ou com geometrias mais complexas, pode-se apresentar dificuldades para a moldagem, causando falhas no preenchimento da forma, o que reduz a capacidade resistente da peça e sua vida útil. Neste trabalho foi utilizado o método de partículas lagrangeanas Moving Particle Semi-Implicit (MPS) como base para um simulador para o estudo do comportamento do escoamento de pastas e argamassas cujo comportamento pode se aproximado por modelos reológicos como Bingham e Herschel-Bulkley. Foram propostos módulos para a simulação da viscosidade não-newtoniana, variação térmica no processo de cura e modelagem de turbulência. Para modelar a variação de viscosidade de um fluido não-newtoniano foi utilizado o modelo de Herschel-Bulkley. O modelo de Herschel-Bulkley possui uma singularidade para taxas de deformação muito pequenas, que resulta em valores de viscosidade infinitas, dificuldade contornada pela solução proposta por Papanastasiou (1987). Na modelagem térmica foram analisados dois modelos de dissipação, sendo um original do método e outro calculado por meio do divergente do gradiente utilizando os modelos de partículas e que teria melhores resultados para o cálculo da dissipação térmica. Também foi modelada a convecção térmica, utilizando para isso a hipótese de Boussinesq. A reação de hidratação do concreto foi modelada utilizando uma equação do tipo Hill para representar a elevação de temperatura obtida por meio um ensaio adiabático. Para complementar as simulações, foi utilizado o modelo de turbulência Detached Eddy Simulation (DES), baseado no método Large Eddy Simulation (LES), que utiliza um modelo de parede para simular a interação do fluido. Para a implementação deste modelo de turbulência foi proposto um algoritmo para o cálculo da distância da partícula de fluido à parede. Este algoritmo utiliza estruturas de dados já existentes no método de partículas de modo que sua execução requer muito menos recursos que a busca binária. Apesar do trabalho ter se guiado pela simulação do concreto fresco, que é um material particularmente complexo, outros escoamentos encontrados na engenharia civil também podem ser beneficiados pelo método, como os estudos do escoamento em sistemas prediais de água e esgoto, do escoamento e prevenção de erosão em rios e córregos, do escorregamento de encostas, dos reatores para depuração de esgotos, entre outros. / The concrete is one of the more versatile civil construction materials, it can adapt to various forms when in its fresh state while resisting to high compression loads in its rigid state. However, in some cases like densely reinforced concrete structures and complex geometry concrete structures can present issues to the casting, and failure in proper form filling can occur. These failures can reduce the resistance and the lifetime of the structure. This work used a simulator based on the lagrangean particle method called Moving Particle Semi-Implicit (MPS) to study the concrete behavior in its distinctive characteristics. Also, this work proposed modules to simulate the non-Newtonian viscosity, the thermal process of concrete cure and to model the turbulent flow. To model the variation of viscosity of a non-Newtonian fluid, the Herschel-Bulkley model, which relates the shear stress with the strain rate, was applied. The Herschel-Bulkley model has a singularity at low strain rates, which results in infinite viscosities. To overcome this issue, Papanastasiou (1987) proposed a modification in the model in order to eliminate the singularity. For the thermal modeling, two models for thermal dissipation were compared, the original method and other calculated from the divergence of gradient using the differential operators for the particle model and that could present improved results for the thermal dissipation calculation. Also, the thermal convection was modeled using the Boussinesq hypothesis. The hydration reaction of the concrete was modeled using a Hill type equation to reproduce the temperature elevation. In addition, a Detached Eddy Simulation (DES) based turbulence model with a simple wall model in the interaction of wall and fluid was applied in the simulations. To improve the turbulence model, an algorithm to calculate the distance between fluid and the nearest wall particle was proposed. The algorithm uses already calculated information from particles so that the execution requires much less resources than a binary search. Although the work has been focused on to the modeling of fresh concrete simulation, which is a particularly complex material, other flows found in civil engineering can also be benefited by the method, such as studies of drainage in water and sewage systems, drainage and prevention of erosion into rivers and streams, prevention and damage mitigation of landslides, reactors for sewage treatment among many others.

Quantification of stochastic or quantum systems by a joint probability density or wave function is a notoriously difficult computational problem, since the solution depends on all possible states (or realizations) of the system. Due to this combinatorial flavor, even a system containing as few as ten particles may yield as many as $10^{10}$ discretized states. None of even modern supercomputers are capable to cope with this curse of dimensionality straightforwardly, when the amount of quantum particles, for example, grows up to more or less interesting order of hundreds. A traditional approach for a long time was to avoid models formulated in terms of probabilistic functions, and simulate particular system realizations in a randomized process. Since different times in different communities, data-sparse methods came into play. Generally, they aim to define all data points indirectly, by a map from a low amount of representers, and recast all operations (e.g. linear system solution) from the initial data to the effective parameters. The most advanced techniques can be applied (at least, tried) to any given array, and do not rely explicitly on its origin. The current work contributes further progress to this area in the particular direction: tensor product methods for separation of variables. The separation of variables has a long history, and is based on the following elementary concept: a function of many variables may be expanded as a product of univariate functions. On the discrete level, a function is encoded by an array of its values, or a tensor. Therefore, instead of a huge initial array, the separation of variables allows to work with univariate factors with much less efforts. The dissertation contains a short overview of existing tensor representations: canonical PARAFAC, Hierarchical Tucker, Tensor Train (TT) formats, as well as the artificial tensorisation, resulting in the Quantized Tensor Train (QTT) approximation method. The contribution of the dissertation consists in both theoretical constructions and practical numerical algorithms for high-dimensional models, illustrated on the examples of the Fokker-Planck and the chemical master equations. Both arise from stochastic dynamical processes in multiconfigurational systems, and govern the evolution of the probability function in time. A special focus is put on time propagation schemes and their properties related to tensor product methods. We show that these applications yield large-scale systems of linear equations, and prove analytical separable representations of the involved functions and operators. We propose a new combined tensor format (QTT-Tucker), which descends from the TT format (hence TT algorithms may be generalized smoothly), but provides complexity reduction by an order of magnitude. We develop a robust iterative solution algorithm, constituting most advantageous properties of the classical iterative methods from numerical analysis and alternating density matrix renormalization group (DMRG) techniques from quantum physics. Numerical experiments confirm that the new method is preferable to DMRG algorithms. It is as fast as the simplest alternating schemes, but as reliable and accurate as the Krylov methods in linear algebra.