京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20973号 / 医博第4319号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 溝脇 尚志, 教授 村井 俊哉, 教授 鈴木 実 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

L'imagerie par résonance magnétique (IRM) permet maintenant d'observer différents types de tissus avec des résolutions de plus en plus fines. L'arbre vasculaire artériel et veineux est explorable et les flux peuvent y être caractérisés de façon non invasive. Le versant artériel de l'arbre vasculaire peut être obtenu par une imagerie dite par « temps de vol » et le versant veineux par une imagerie en contraste de phase. Le développement de reconstructions de cartographies de susceptibilité magnétique (QSM) permet d'améliorer le niveau de détails atteignable sur les veines en fournissant en plus la possibilité de quantifier des paramètres physiologiques comme la saturation veineuse en oxygène. La mise en place d'algorithmes et outils dédiés permet la reconstruction in-silico d'une architecture cohérente sujet-spécifique. Par ailleurs grâce à l'emploi de séquences de la dynamique telles que le contraste de phase dynamique et l'imagerie par marquage des protons artériels du sang, les débits artériels, veineux, et perfusionnels sont mesurables. L'intégralité de ces acquisitions est non invasive, donc applicable à l'intégralité des sujets passant des IRM. Sur la base de ces données anatomiques et dynamiques, un modèle complet et sujet-spécifique de l'hydrodynamique intracrânienne est proposé. Le flux sanguin et cérébro-spinal est décrit dans ce modèle par les équations bilans fondamentales de l'hydrodynamique : conservation de la masse, conservation de la quantité de mouvement. Pour tenir compte de l'adaptation du diamètre des vaisseaux aux pressions on introduit pour chaque compartiment un paramètre d'élasticité de la paroi et une équation correspondante. Grâce aux données d'imagerie IRM, les compartiments sanguins des artères aux veines, le parenchyme cérébral et le système ventriculaire sont inclus. Le modèle permet de simuler la répartition des flux et des pressions dans les différents compartiments de la vascularisation du patient ainsi que d'évaluer les effets d'occlusions localisées sur l'ensemble de l'architecture. / The magnetic resonance imaging (MRI) allows the observation of various kind of tissues with always increasing resolution. The arterial and venous vascular trees can be explored, and the flows can be characterized in a noninvasive way. As an example, the arterial part of the tree can be obtained using so-called “Time Of Flight” MRI, and the venous part with phase contrast techniques. The development of quantitative susceptibility maps (QSM) improves the level of details achievable regarding veins; furthermore, it provides a new way to estimate physiological parameters such as venous saturation in oxygen. Eventually the implementation of dedicated algorithms and tools allows the in-silico reconstruction of a subject-specific coherent architecture. Moreover, due to the use of dynamic imaging sequences such as the dynamic phase contrast imaging and the arterial spin labeling, the arterial, venous and cerebral blood flow are measurable. All of these sequences are noninvasive and so usable on every subjects. Based on these anatomical and dynamics data, a full subject-specific model of the brain hydrodynamics is proposed here. The blood and cerebrospinal flow are described using basic balance equations of the hydrodynamics: continuity and momentum. To take into account of the adaptation of vessel diameter to the pressure, a wall elasticity parameter is added for each compartment together with the corresponding equation. Thanks to the MRI data, all the blood compartments, from arteries to vein, the cerebral parenchyma and the ventricular system are included. The model is able to simulate the flow and pressure repartition in all compartments of the subjects as well as show the impact of a located occlusion on the whole architecture.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24489号 / 医博第4931号 / 新制||医||1063(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋 良輔, 教授 永井 洋士, 教授 森田 智視 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

<p>The prediction and characterisation of chemical and biochemical processes are fundamental tasks in computational chemistry. Small chemical systems can be characterised by the stationary points on potential energy surface and reaction paths linking them. For large biological systems, statistical sampling is required to characterising their average properties.</p> <p>This thesis presents my Ph.D. work on developing new methods to predict and characterise chemical and biological processes. Two path-finding methods for finding the minimum energy reaction path and alternative reaction paths for small gas-phase reactions have been elucidated with examples, and molecular dynamic simulations have been used to characterise the binding affinity of protein-ligand complex and the free energy of protonation processes in a protein.</p> <p>Specifically, the fast marching method (FMM) has been used to find the minimum energy path (MEP) on the potential energy surface (PES) for small gas-phase reactions. In this thesis, FMM is shown to be one of the most general and reliable surface-walking algorithms for finding the MEP. However, it is an expensive method. Some improvements have been illustrated in chapter 2 and chapter 3.</p> <p>I also proposed a new method (called QSM-NT) for finding all stationary points, accordingly all alternative reaction paths on the PES. Unlike other path-finding methods, QSM-NT overcomes the need of an initial guess of the path, and it can find all stationary points on the PES. QSM-NT has been proven to be efficient and reliable through applications on analytical PES and real chemical reaction. The difficulties and pitfalls associated with QSM-NT have been elucidated with examples.</p> <p>Molecular dynamic (MD) simulation and associated postprocessing procedures have been used to study the binding properties of caffeine-A_2A complex. The binding affinities of different binding modes have been calculated using MM/PBSA method. The binding pocket has been characterised with MM/GBSA energy decomposition. Our computational work provides significant insight to the targeted drug design of the adenosine A_2A receptor.</p> <p>The pH-dependent properties of a protein play important roles in the fundamental biological processes. The protonation states, namely, the pK_a values of ionisable residues, especially active-site residues are the prerequisites to understanding of the mechanisms of many biological processes. In this thesis, acetoacetate decarboxylase (AADase) is used as a test case for studying different types of pK_a prediction methods. Our computational results have shown that the site-site interactions from other ionisable residues are crucial to the pK_a prediction of the target residue.</p> <p>This thesis covers the range from small gas phase reaction prediction to large complex biological systems characterisation using quantum mechanical and molecular mechanical methods.</p> / Doctor of Philosophy (PhD)

Brain aging is a heterogeneous phenomenon, and this thesis illustrates how the course of aging can vary within individuals over time and between individuals as a function of age, sex, and genetic variability. We used two contrasts from magnetic resonance imaging (MRI), namely spin-lattice T1-weighted imaging, and quantitative susceptibility mapping (QSM) from gradient-echo images, to picture the aging brain, by means of morphometric measures and brain-iron concentrations. Within each study, the same rigorous imaging acquisitioning protocols were used over large samples sizes of 167-183 individuals, which contribute to the uniqueness of the studies. Most of the current knowledge about the aging brain rests on the foundation of cross-sectional age-related differences, and studies I and III contribute to current knowledge with longitudinal designs to investigate individual rates of change. The importance of genetic variation in relation to regional brain changes was addressed with a specific emphasis on functional polymorphisms involved in pro-inflammatory responses. These studies further shed light on the importance of bi-directional relations between structural integrity and maintained cognitive abilities over time. Study II is the largest study to date to have quantitative susceptibility estimates examined in healthy adults, and the first in-vivo report to show a lowering in overall subcortical brain iron estimates in women from midlife to old age. Studies I and III are unique by examining longitudinal differences in anatomical brain regions using high resolution images from a 4 Tesla scanner. Peripheral vascular risk factors were not strong determinants of either brain- or cognitive changes in the studied samples. The results are discussed in the context of cognitive reserve, the brain maintenance hypothesis, and potential influences of hormones, inflammation and oxidative stress.

No description available.

The thesis investigates above-ground biomass (AGB) with terrestrial laser scanning (TLS) for estimating AGB in a study area in Valls Hage, Gävle. The study used TLS for field measurements to collect highly detailed point clouds of two tree species for AGB estimation and comparison against validation data. TLS-derived data were validated using a non-destructive method involving direct field measurements using tape measures and a Trimble SX12 for extracting diameter at breast height (DBH), tree height, and crown diameter. Wood density was obtained from the literature. Data processing for segmentation, filtering, and generation of the quantitative structure model (QSM) was performed by using SimpleForest tool in Computree software. A statistical analysis was performed using linear regression, and AGB was estimated using QSM-derived volume multiplied by wood density. The finding in the results for the comparison of AGB estimation between TLS QSM and field validation from DBH-based tree-specific allometric equation had an RMSE of 154 kg, with a near-perfect agreement of 0.997 %, and RMSE of 189 kg, with the agreement of 0.990% for TLS QSM and TLS validation DBH-based tree specific equation. The comparison between TLS-derived DBH and field validation was accurate, leaving with insignificant differences, while the tree height had noticeable differences, and crown diameter had relatively low differences. The challenges during data processing were highlighted and the importance of TLS data for accurate AGB estimation, with the potential for refinement and integrating internal tree structure information to improve allometric models for future studies.

<p dir="ltr">Manganese (Mn) is an essential trace element for humans that functions primarily as a coenzyme in several biological processes such as nerve and brain development, energy metabolism, bone growth and development, as well as cognitive functioning. However, overexposure to environmental Mn via occupational settings or contaminated drinking water can lead to toxic effects on the central nervous systems and cause a Parkinsonian disorder that features symptoms such as fine motor control deficits, dystonia rigidity, speech and mood disturbances, and cognitive deficits summarized under the term “manganism”. Over time, Mn exposure has shifted from acute, high-level instances leading to manganism, to low-level chronic exposure. Considering that Mn exposure is significantly lower than in the past, it is unlikely to expect manganism from chronic Mn exposure under current working conditions. Therefore, there is a need to develop sensitive methods to aid in updating the clinical diagnostic standards for manganism and Mn neurotoxicity as chronic exposure to Mn leads to more subtle symptoms.</p><p><br></p><p dir="ltr">Historically, magnetic resonance imaging (MRI) has been used as a non-invasive tool for detecting excess brain Mn accumulation. Specifically, T1-weighted images show bilateral hyperintensities of the globus pallidus (GP) due to the paramagnetic properties of Mn which increases the MR relaxation rate R1. Although the GP is considered the hallmark of excess brain Mn, this brain area is not necessarily associated with symptoms, exposure, or neuropsychological outcomes. Thus, the focus should not be on the GP only but on the entire brain. With recent advances in quantitative MRI (qMRI), whole brain mapping techniques allow for the direct measurement of relaxation rate changes due to Mn accumulation. The work in this dissertation uses such quantitative techniques and network science to establish novel computational in vivo imaging methods to a) visualize and quantify excess Mn deposition at the group and individual level, and b) characterize the toxicokinetics of excess brain Mn accumulation and the role of different brain regions in the development of neurotoxicity effects.</p><p><br></p><p dir="ltr">First, we developed a novel method for depicting excess Mn accumulation at the group level using high-resolution R1 relaxation maps to identify regional differences using voxel-based quantification (VBQ) and statistical parametric mapping. Second, we departed from a group analysis and developed subject-specific maps of excess brain Mn to gain a better understanding of the relationship between the spatial distribution of Mn and exposure settings. Third, we developed a novel method that combines network science with MRI relaxometry to characterize the storage and propagation of Mn and Fe in the human brain and the role of different brain regions in the development of neurotoxic effects. Lastly, we explore the application of ultra-short echo (UTE) imaging to map Fe content in the brain and compare it against R2* and quantitative susceptibility mapping (QSM).</p><p><br></p><p dir="ltr">Overall, this dissertation is a successful step towards establishing sensitive neuroimaging screening methods to study the effects of occupational Mn exposure. The individual Mn maps offer great potential for evaluating personal risk assessment for Mn neurotoxicity and allow monitoring of temporal changes in an individual, offering valuable information about the toxicokinetics of Mn. The integration of network science provides a holistic analysis to identify subtle changes in the brain’s mediation mechanisms of excess metal depositions and their associations with health outcomes.</p>

This thesis describes extensions to state machines in the Umple model-oriented programming language to offer queued state machines (QSM), pooled state machines (PSM) and handing of the arrival of unexpected events. These features allow for modeling the behavior of a system or protocol in a more accurate way in Umple because they enable detecting and fixing common design errors such as unspecified receptions. In addition, they simplify the communication between communicating state machines by allowing for asynchronous calls of events and passing of messages between state machines. Also, a pooled state machine (PSM) has been developed to provide a different policy of handling events that avoid unspecified receptions. This mechanism has similar semantics as a queued state machine, but it differs in the way of detecting unspecified receptions because it helps handling these errors. Another mechanism has been designed to use the keyword ‘unspecified’ in whatever state of a state machine the user wants to detect these errors. In this thesis, the test-driven development (TDD) process has been followed to first modify the Umple syntax to add ‘queued,’ ‘pooled,’ and ‘unspecified’ keywords to Umple state machine’s grammar; and second, to make a change to the Umple semantics in order to implement these extensions in Umple. Then, additional modifications have been made to allow for Java code generation from those types of state machines. Finally, more test cases have been written to ensure that these models are syntactically and semantically correct. In order to show the usefulness and usability of these new features, an example is shown as a case study that is modeled using the queued state machine (QSM) besides other small tests cases.

No description available.