Reduction of an enzyme required for the lysosomal degradation of glycosaminoglycan (gag) chains will result in a mucopolysaccharidosis (MPS) disorder. Substrate deprivation therapy (SDT), a new therapy option for MPS, aims to reduce the synthesis of gag chains, the natural substrate for the deficient enzyme. Reduced substrate levels would balance the reduced level of enzyme in patient cells resulting in normalised gag turnover. Rhodamine B, a non-specific inhibitor, reduced gag synthesis in a range of normal and MPS cells and also decreased lysosomal storage of gag in MPS VI (72%) and MPS IIIA (60%) cells. This positive response in vitro was extended to an in vivo therapy trial in the MPS IIIA mouse. Bodyweight gain of male MPS IIIA mice treated with 1 mg/kg rhodamine B was reduced compared to untreated MPS IIIA mice and was indistinguishable to that of normal mice. Liver size, total gag content and lysosomal gag was reduced in treated MPS IIIA animals as was urinary gag excretion. The alteration in MPS IIIA clinical pathology by rhodamine B combined with the observation that treatment had no effect on the health of normal animals demonstrates the potential for this type of therapy for MPS disorders. The water cross maze was found to be the only learning and memory test capable of detecting differences in learning behaviour in MPS IIIA and normal untreated mice. MPS IIIA mice treated with SDT rhodamine B showed an improved outcome with better learning capabilities than MPS IIIA untreated mice observed using this test. This means that rhodamine B is likely to cross the blood-brain barrier. These results are the first evidence of a positive response by the CNS to a systemic therapy for MPS IIIA. Rhodamine B administration over 4 generations did not produce any deleterious side effects in MPS IIIA. In utero therapy over four generations did not cause a reduction in litter size or bodyweight profile demonstrating that reduction of gag over a combined timeframe of two years was safe. A higher dose of 5 mg/kg rhodamine B did not produce any additional benefits on MPS IIIA pathology and no signs of hepatoxicity were noted. Rhodamine B proved to be a general inhibitor of gag synthesis and had a positive outcome on a number of clinical parameters in MPS IIIA mice. SDT in MPS IIIA mice improved learning capabilities as detected by the water cross maze which has not been previously reported. This provides evidence that small molecules such as rhodamine B, that are able to cross the blood-brain barrier, can have some effect on neurological pathology. This proof of principle study showed that SDT can be used to have a positive outcome on MPS pathology. Additional inhibitors of gag synthesis can also be investigated before this type of therapy can be translated into clinical use in MPS patients. Although it may be feasible to use rhodamine B as a SDT agent in vivo, other inhibitors may be more practical. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1287050 / Thesis (PhD) -- School of Paediatrics and Reproductive Health, 2007.

Les processus moléculaires mis en jeu lors de maladies de surcharge lysosomale (MSL) et qui conduisent à des dysfonctions neuronales sont peu connus. Afin de mieux comprendre comment s’opèrent ces dysfonctions neuronales associées à la mucopolysaccharidose de type VII (MPS VII), une MSL causée par la déficience en l’activité enzymatique de la ß-glucuronidase, nous avons généré des neurones humains MPS VII à partir cellules souches pluripotentes induites (iPSC). Grâce à la reprogrammation des fibroblastes de patients MPS VII, nous avons généré et caractérisé des neuroprécurseurs dérivés d’iPSC (NSC) et des neurones. Les iPSC MPS VII ont été positives pour les tests de pluripotence (activité de la phosphatase alcaline, expression des marqueurs de pluripotence SSEA3, TRA-2-49 et Nanog par immunofluorescence et expression des gènes de pluripotence SOX2, Oct4 et Lin28 par qRT-PCR, formation des corps embryonnaires et génération de cellules dérivées des trois feuillets embryonnaires in vivo par la formation de tératomes) et présentaient un caryotype normal. Les NSC dérivés d’iPSC exprimaient les marqueurs Nestin et SOX2, et ont été utilisés pour générer des neurones. Les neurones MPS VII exprimaient des marqueurs neuronaux comme MAP2, formaient des synapses et présentaient une activité calcium-dépendante.Afin d’identifier les dysfonctions moléculaires présentes dans la MPS VII, nous avons comparé les NSC et les neurones, avec ou sans milieu conditionné contenant l’enzyme recombinante humaine de la ß-glucuronidase (rhGUS), enzyme actuellement utilisée en phase 1/2, de chez Ultragenyx. Cette enzyme est internalisée par les cellules, rejoint leurs lysosomes et corrige les dysfonctions lysosomales de la MPS VII, restaurant ainsi un phénotype cellulaire physiologique (phénomène aussi appelé ‘enzyme replacement therapy’ (ERT)). Ces diverses conditions nous permettent d’éviter la variabilité clonale des iPSC, et de mieux identifier les déficiences neuronales, corrigées par l’ERT, qui sont associées à la MPS VII. / The molecular pathways linking lysosomal storage diseases (LSD) to neuronal dysfunction are poorly understood. To better understand neuronal dysfunction associated with mucopolysaccharidosis type VII (MPS VII), a LSD due to deficiency in ß-glucuronidase activity, we generated human MPS VII neurons from induced pluripotent stem cells (iPSC). Starting from MPS VII patient fibroblasts, iPSC-derived neural stem cells (NSC) and neurons were generated and characterized. MPS VII iPSC were positive for pluripotency tests (alkaline phosphatase activity, expression of pluripotency markers SSEA3, TRA-2-49 and Nanog by immunostaining and pluripotency gene SOX2, Oct4 and Lin28 expression by qRT-PCR, embryonic bodies formation and generation of cells derivated from the three germ layers in vivo by teratoma formation) and had a normal karyotype. IPSC-derived NSC expressed the markers Nestin and SOX2, and were used to generate neurons. MPS VII neurons expressed mature neuronal markers as MAP2, formed synapses and displayed a calcium-dependent activity. To identify molecular defects in MPS VII, we compared NSC and neurons, with or without conditioned medium containing a recombinant human ß-glucuronidase (rhGUS), enzyme currently used in phase 1/2, from Ultragenyx. This enzyme is taken up by cells, reaches their lysosoms and corrects MPS VII lysosoms dysfunctions, restoring cells to healthy phenotype (phenomena also called enzyme replacement therapy (ERT)). Our assays allow us to circumvent clonal variability associated with iPSC, and to better identify neuronal defects, corrected by ERT, which are associated with MPS VII disease.

No description available.

This thesis work presents a study on the impact of mutual coupling among antenna arrays on the performance of the multipath simulator (MPS) system. In MIMO systems, it is a wellknown fact that the mutual coupling significantly affects their system performance. The impact of mutual coupling on MIMO system performance is an important consideration for compact antenna arrays. Hence, it is very important to investigate the impact of mutual coupling on the accuracy of measurements in a MPS system. In this project, the impact of coupling within the MPS array antennas is addressed by performing simulations based on the proposed MPS scattering model which fulfills the far-field (Fraunhoferdistance) boundary conditions. The coupling phenomenon within the MPS array antennas is studied by designing a uniform circular array (UCA) of radius,R consisting of NMPS antennas with single device under test (DUT) antenna at the center. The elements of the array are matched half-wave dipole antennas and the phase of the array elements is kept constant throughout. In this work it is assumed that all the elements in the array are identical and located in the far-field region. This study is carried out by performing MPS simulations in HFSS at the LTE-A band of 2.6GHz. The approach used to model the entire system is by comparing the S-parameters (S21: Forward transmission coefficient parameter) between various array configuration. The simulation results suggest that the impact of mutual coupling increases with the number of MPS antennas and decreases with the radius of the MPS ring. Theradiated power is also measured with and without mutual coupling. Finally, it is concluded that the impact of coupling within the MPS antennas is best countered by designing a large MPS system (preferably R = 10λ or greater), despite the higher incurred costs.

No description available.

The Real-time Specification of Java (RTSJ) is an intention to introduce Java as a language for developing real-time system. However, the complexity of their development and a non-trivial programming model of RTSJ with its manual memory management often lead to programming errors. To mitigate the development of RTSJ systems it would be beneficial to provide an internal domain-specific language (DSL) extending the Java language which would allow to develop the systems in more intuitive and safer way. However, it is needed to find compromise between solution's power and level of usability, because this two attributes go often against each other. One possible way of DSLs creation concerns the Meta-Programming System (MPS). It allows to develop new domain-specific languages and corresponding projectional editors enabling different views on code. This thesis proposes a design and implementation of the DSL on the top of the MPS platform and corresponding code generator enabling development of RTSJ systems. Furthermore, the thesis provides a simple case-study to evaluate a proposed DSL. Additionally, the thesis assesses the suitability of MPS as a DSL-development platform.

Since the failure of the Scan Line Corrector (SLC) instrument on Landsat 7, observable gaps occur in the acquired Landsat 7 imagery, impacting the spatial continuity of observed imagery. Due to the highly geometric and radiometric accuracy provided by Landsat 7, a number of approaches have been proposed to fill the gaps. However, all proposed approaches have evident constraints for universal application. The main issues in gap-filling are an inability to describe the continuity features such as meandering streams or roads, or maintaining the shape of small objects when filling gaps in heterogeneous areas. The aim of the study is to validate the feasibility of using the Direct Sampling multiple-point geostatistical method, which has been shown to reconstruct complicated geological structures satisfactorily, to fill Landsat 7 gaps. The Direct Sampling method uses a conditional stochastic resampling of known locations within a target image to fill gaps and can generate multiple reconstructions for one simulation case. The Direct Sampling method was examined across a range of land cover types including deserts, sparse rural areas, dense farmlands, urban areas, braided rivers and coastal areas to demonstrate its capacity to recover gaps accurately for various land cover types. The prediction accuracy of the Direct Sampling method was also compared with other gap-filling approaches, which have been previously demonstrated to offer satisfactory results, under both homogeneous area and heterogeneous area situations. Studies have shown that the Direct Sampling method provides sufficiently accurate prediction results for a variety of land cover types from homogeneous areas to heterogeneous land cover types. Likewise, it exhibits superior performances when used to fill gaps in heterogeneous land cover types without input image or with an input image that is temporally far from the target image in comparison with other gap-filling approaches.

Model-Driven Engineering has been developing since the first release of the Unified Modeling Language, passing several milestones and advancing ever since. Model-Driven Engineering is being used in various fields like medical, cyber-physical systems, web applications, etc. It is an engineering paradigm that allows developers to model systems at the level of abstraction of their choice. There are many available tools in the market offering different modelling capabilities to their users. Making use of more than one tool would give the users a wider range of options and higher flexibility in modelling their applications. The current market of open-source modelling tools has two main actors, being JetBrains MPS, mostly focused on textual modelling languages, and Eclipse Modelling Framework, mostly focused on graphical modelling languages. The goal of this thesis is to design and implement a bridge between these two modelling environments. More specifically, we engineer the modelling language Ecore, at the heart of the Eclipse Modeling Framework, in JetBrains MPS in order to enable the exchange of metamodels based on Ecore from MPS to Eclipse Modeling Framework.

Despite the prevalent utilization of capillary electrophoresis (CE) in the analysis of short tandem repeats (STRs) to generate deoxyribonucleic acid (DNA) profiles for forensic comparisons, the method is not without its inherent drawbacks. Massively parallel sequencing (MPS) is still a relatively novel technology in the forensics field, but contains the capacity to address current challenges faced by the traditional CE approach - such as degraded samples, low template DNA, and artifacts - while also providing additional information such as isoalleles, same-length alleles with sequence variation, and ancestry, mixture, and phenotyping-informative single nucleotide polymorphisms (SNPs). One of the principal ongoing challenges faced by both technologies is the presence of artifacts such as stutter, a byproduct of slipped strand mispairing during amplification of STRs, which can further complicate interpretation of DNA profiles. Understanding and predicting the behavior of stutter is important in establishing appropriate thresholds to distinguish these artifacts from true alleles. With complex MPS data, new approaches in characterizing stutter have been established such as the BLMM and simplified sequence. In this study, twenty-one oral samples from individuals belonging to the same family were constructed into libraries containing 58 STR regions and 98 identity SNPs using Verogen’s Forenseq™ DNA Signature Prep Kit and sequenced on the MiSeq FGx™ Forensics Genomics System. Isoallele and stutter sequences were extracted from the data and simplified using the longest uninterrupted stretch (LUS), block length of missing motif (BLMM) and simplified sequence approaches. It was found that the stutter ratio for the 11 isoallele pairs at the D13S317 locus did not follow the linear correlation with increasing LUS. Instead, the isoallele with the higher LUS demonstrated equal or lower stutter ratios. Additionally, three different stutter patterns were identified for the same locus. Based on the provided pedigree, ten different relations were defined and the amount of allele sharing between the individuals in the pedigree was analyzed with and in the absence of isoallelic information to determine its impact on predicting relatedness. It was found that there was an average of 1.3% difference across the ten defined categories when isoalleles were taken into consideration. However, the difference in the percentage of shared alleles was not found to be significant for each of the relations category between the results before and after the consideration of isoallelelic data.

[pt] Neste trabalho, foi realizado um estudo comparativo de eficiência e acurácia dos métodos de partículas Moving Particle Semi-implicit Method (MPS) e Smoothed Particle Hydrodynamics (SPH). A acurácia dos métodos de partículas foi determinada tomando-se como referência os métodos dos Volumes Finitos e Volume of Fluid (VOF). A comparação de acurácia entre os métodos MPS e SPH foi realizada através da simulação dos problemas de quebra de barragem e de descarga de água. Além disso, o problema de escoamento laminar em uma cavidade quadrada e o problema do tubo de choque foram simulados com sucesso pelo método SPH. A análise de eficiência foi realizada pela determinação do tempo total de processamento em função do número de partículas. Adicionalmente, uma análise da influencia do número de partículas na solução foi realizada. Os resultados obtidos mostram que ambos os métodos podem ser considerados como boas ferramentas para a simulação de fluidos. / [en] This work comprises a comparative study of the particle methods Moving Particle Semi-implicit (MPS) and Smoothed Particle Hydrodynamics (SPH) in terms of their efficiency and accuracy. The methods of Finite Volume and Volume of Fluid (VOF) were used as reference for determining the accuracy of the particle methods. The methods MPS and SPH were compared with each other by means of simulations of the problems of dam collapse and water discharge. On top of that, the problems of shear driven cavity and shock tube were successfully simulated using SPH. In order to analyze the methods` efficiency, the total processing time as a function of the number of particles was calculated. Finally, an analysis of the influence of the number of particles in solution was performed. The results obtained in this work show that both the MPS and SPH methods can be considered as good tools for fluid simulation.