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Crosstalk between lipid metabolism and mitochondrial bioenergetics in tuberous sclerosis complexKavanagh, Taylor Rose 12 June 2019 (has links)
BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem hamartomatous disease caused by inactivating mutations in the TSC1/TSC2 genes leading to hyperactivation of mammalian target of rapamycin complex 1 (mTORC1) in TSC tumors. Novel therapeutic regimens and imaging biomarkers remain critical unmet needs in TSC.
Mitochondrial fatty acid oxidation (FAO) is a major cellular source of acetyl-CoA. Acetyl-CoA is a central metabolite in lipid anabolism and catabolism. The purpose of this study was to identify novel metabolic therapeutic targets, particularly involving lipid metabolism, to achieve durable responses in TSC.
METHODS AND RESULTS: Fluoroacetate (FACE), an acetate derivative, is a surrogate biomarker of mitochondrial activity. It accumulates in the mitochondria without being oxidized to CO2, and it is converted to fluorocitrate, irreversibly inhibiting the TCA (tricarboxylic acid) cycle enzyme aconitase. Micro-positron emission tomography (PET) imaging of subcutaneous xenografts of TSC2-deficient Eker rat uterine leiomyoma-derived ELT3 cells showed rapid uptake of [18F]FACE that was maintained after 72-hour treatment with mTORC1 inhibitor rapamycin. This result suggests that mitochondrial oxidative metabolism is sustained in the presence of rapamycin.
Consistent with this finding, treatment of TSC2-deficient cells with rapamycin led to a significant increase in FAO and a decrease in glucose oxidation in vitro as measured by a 14C-CO2 collection metabolic assay. Expression of the A isoform of carnitine palmitoyltransferase I (CPT1A; FAO rate-limiting enzyme) was selectively increased in TSC2-deficient cells. Pharmacological inhibition of CPT1A by ST1326 led to a decrease in FAO, as measured by a 14C-CO2 collection metabolic assay, and a decrease in mitochondrial ATP production, measured by the Seahorse analyzer.
CONCLUSIONS: This study proposes a role for FAO in TSC tumor bioenergetics and for CPT1A as a potential therapeutic target in TSC.
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The study of defect and trapping levels in CVD polycrystalline diamond with applications to ultraviolet dosimetryTrajkov, Elizabeth Unknown Date (has links) (PDF)
The unique properties of diamond make it an excellent material for electronic and optical applications. It is particularly attractive for ultraviolet radiation dosimetry due to its intrinsic properties, which include biological tissue equivalence and visible blindness. Importantly, the advent of synthetic diamond, especially Chemical Vapour Deposition (CVD) diamond, has made it more economically viable for such applications. A thorough understanding of the electronic properties of diamond is needed before these applications can be fully explored. Consequently, this thesis investigates charge carrier trapping states in CVD polycrystalline diamond for the optimization of ultraviolet radiation dosimetry. / The technique of Thermally Stimulated Conductivity (TSC) is used to probe electrically active defects and is also applied for dosimetric read-out. A range of as-grown CVD polycrystalline diamond films are studied to determine attributes that favour dosimetric-related TSC. In doing so, we establish that dosimetric TSC in these films originate from defects at the grain boundaries with a correlation to high crystalline quality. / With this finding in hand, we then investigate the possibility of optimising diamond for dosimetry by controllably introducing extrinsic dosimetric defects using ion implantation. However, it is shown that these defects are not suitable for dosimetry and have a detrimental effect on the indigenous TSC signal. This study verifies the importance of crystalline quality on the indigenous dosimetric properties of CVD polycrystalline diamond. / The possibility of doping CVD diamond during growth is also investigated as a means for intentionally introducing extrinsic dosimetric defects. Sulphur is selected as the dopant based on the theoretical energy levels formed by this defect, and because the prospect of S doping in diamond remains an actively debated issue in the literature. We report for the first time defect levels extracted from TSC analysis of S-doped CVD diamond and find consistency with theoretical predications. In addition, the dominant TSC trap level in S-doped diamond shows promise for radiation dosimetry with certain properties exceeding many current radiation dosimeters. / The experimental results in this thesis lead to a deeper understanding of defect and trapping mechanisms in CVD polycrystalline diamond and establish attributes that favour TSC and related dosimetric properties in such films. This knowledge is fundamental to the realisation of diamond for ultraviolet dosimetry.
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Glycoprotein-NMB and the microphthalmia-associated transcription factor regulatory circuitry in tuberous sclerosis complex associated tumorsProbst, Clemens Kemena 08 June 2020 (has links)
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic syndrome characterized by the growth of benign tumors in multiple organ systems including brain, lung, kidney, skin, and heart. Kidney angiomyolipoma (AML) are benign, slow growing renal tumors that are seen in about 80% of TSC patients, but also occur sporadically. Although heterogeneous in nature, AMLs have a relatively low somatic mutation rate compared to most other cancers, with biallelic loss of either TSC1 or TSC2 gene considered as the primary and sufficient driver for tumor development. We hypothesized that epigenetic alterations of the AML chromatin landscape change the transcriptional dynamics of the underlying genetic system that supports and gives rise to the tumor-cell phenotype. Our data have identified microphthalmia-associated transcription factor (MITF) to be an orchestrating gene in AML development, as 6 out of the top 10 differentially expressed genes in AML are putative MITF-target genes. Integrative analysis of RNA Seq (n=28), H3K27ac ChIP Seq (n=25) and MITF ChIP Seq data (n=3), obtained from fresh-frozen kidney AML specimens, has enabled us to characterize components of a tumor-specific regulatory network under the transcriptional control of MITF. This novel approach has the potential to identify a variety of therapeutic targets, as well as provide unprecedented insight into the mechanisms behind angiomyolipoma development. / 2021-06-07T00:00:00Z
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The Balanced Scorecard Applied to the Diversification Business ¡ÐA Case Study of Taiwan Sugar CorporationLin, Li-feng 22 June 2004 (has links)
When an enterprise has developed to a certain scale and anticipated an impressive expansion, business transformation and diversification are unavoidable decisions. How to measure targets or strategies of business transformation and diversification by quantifiable performance measurements or non-quantifiable performance evaluation systems and make adequate modifications would be crucial issues.
This study applied Balanced Scorecard ¡qKaplan and Norton, 1996¡r to the Taiwan Sugar Corporation ¡qTSC¡r as a case study. Balanced Scorecard is a tool provides a strategy framework for implementation and control, and transforms company¡¦s visions and strategies into measurable indexes with four dimensions. In order to synchronize the Balanced Scorecard sheet and strategy map of TSC, the study used statistics method to analyze questionnaires and technique of in-depth interviews. Started with analyzing the results of TSC diversification, the study expanded cause-effect relationships of eight major strategic themes, and combined 13 strategic objectives and 45 strategic key performance indicators.
The study has two major findings:
1.The current management system and performance measurement of state-owned business are influenced significantly by the government agency. Furthermore, the state-owned business also emphasis too much on financial and internal business process performance indicators, thus customer needs and needs for learning are sacrificed. As the result, the transform mission and strategic target, which focus on value of customers, can¡¦t be connected.
2.Through planning and designing Balanced Scorecard for TSC and transforming organizational strategic objectives into actionable objectives and key performance indicator, we found that Balanced Scorecard is an integrated strategic management tool. Using this tool, the state-owned business can effectively move from ¡§budget performance measurement system¡¨ to ¡§performance management strategy system¡¨.
The establishment of Balanced Scorecard has brought TSC the following substantial benefits:
1.Improving the unclear decision making mechanism
2.Establishing strategy focus organization
3.Reducing the gap of current achievement evaluation systems
4.Transforming to customer-focused management mechanism
Key words: Business transformation, Diversification, Balanced Scorecard, TSC
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The Role of TSC in Oligodendrocyte Differentiation and MyelinationHan, Juliette 21 June 2013 (has links)
Tuberous Sclerosis Complex (TSC) is an autosomal dominant syndrome characterized by epilepsy, intellectual disability, and autism. Recent studies have suggested that white matter abnormalities, including hypomyelination, contribute to the cognitive deficits in TSC patients, but the mechanism has remained elusive. I used the neuron-specific Tsc1 knockout mice that display a marked decrease in myelin and show that oligodendrocytes are arrested at immature stages of development in vivo resulting in a reduction in the number of myelinating cells. I established an oligodendrocyte culture system and examined the effect of neuron-conditioned media and found that the Tsc1 mutant phenotype was replicable in vitro using medium collected from Tsc1 knockdown (TSC-KD) neurons, confirming that a secreted signal is responsible for inhibiting differentiation of the oligodendrocytes. I took an unbiased genome-wide approach and identified Connective Tissue Growth Factor (CTGF) as a putative candidate for the secreted signal. I confirmed that CTGF was upregulated in Tsc1 mutant neurons and characterized its spatial and developmental expression pattern in our mouse model. In vitro, CTGF was sufficient to inhibit differentiation of oligodendrocytes. The addition of CTGF neutralizing antibody to the TSC-KD neuronal media was able to reverse the suppression of oligodendrocyte maturation, strongly suggesting that CTGF is a major component of the oligodendrocyte inhibitory signal derived from Tsc mutant neurons. Since TSC mutation affects all cells, I investigated the role of TSC in oligodendrocytes. In response to TSC knockdown, oligodendrocytes demonstrate an upregulation of cellular stress marker. I also found a decrease in myelin protein genes, a finding that offers interesting implications for the role of TSC in hypomyelination. Furthermore, I expanded my research into Zellweger disease, a syndrome that involves TSC in its neuropathological manifestations including white matter deficits, and found that localization of TSC to the peroxisome is a critical factor in neuron development. Together, this body of work developed new approaches in Tuberous Sclerosis research in the brain to investigate a previously under-appreciated aspect of TSC pathology - myelination. I have demonstrated that the TSC pathway has important roles in neuron-oligodendrocyte communication and emphasize the critical importance of neuron-derived signals in the establishment of myelination.
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Regulation of YAP by mTOR and autophagy reveals a therapeutic target of Tuberous Sclerosis Complex / Régulation de YAP par mTOR et l'autophagie se révèle une cible thérapeutique de la sclérose tubéreuse complexeLiang, Ning 29 September 2014 (has links)
La sclérose tubéreuse complexe (TSC) est une maladie génétique caractérisée par une croissance des hamartomes dans différents organes y compris le cerveau, les reins, les poumons, la peau et le cœur. Ces lésions sont des sources de morbidité et de mortalité chez les patients TSC, car ils peuvent provoquerl’ épilepsie, l’autisme, le retard de développement et l’insuffisance rénale et pulmonaire. Les causes connues de TSC sont la perte de la fonction et les mutations des gènes TSC1 et TSC2. La majorité des lésions TSC contient plusieurs types cellulaires de la lignée mésenchymateuse, comme dans le cas des angiomyolipomes, l’lymphangioleiomyomatose et les angiofibromes. Un type unique de cellules épithélioïdes périvasculaires nommé (PEC) est constamment présent dans les lésions de TSC mésenchymateuses, comme angiomyolipomes et lymphangioleiomyomatose, basant sur les caractérisations morphologiques et l'expression des marqueurs communs mélanocytaires et myogéniques. Par conséquent, ces lésions sont officiellement classées, ainsi que d'autres tumeurs, comme PEComes. Leur origine cellulaire et les mécanismes moléculaires impliqués dans la pathologie restent à élucider. Ici, nous avons généré un modèle souris mosaïque TSC1 knockout qui développe des lésions rénales mésenchymateuses récapitulant périvasculaire épithélioïde cellules tumorales humaines (Pecoma) observés chez les patients TSC. Nous avons identifié YAP, le co-activateur transcriptionnel de la voie Hippo, a été régulée d'une manière mTOR-dépendante dans les lésions rénales de notre TSC1 knockout souris et les échantillons de l’angiomyolipome humaines. L'inhibition de YAP avec des outils génétiques ou pharmacologiques atténue considérablement la prolifération et la survie des cellules nulles TSC1 in vivo et in vitro. En outre, l’accumulation de YAP dans les cellules déficientes TSC1 / TSC2 pourra être dû à la dégradation de la protéine altéré par le système de l’autophagosome / lysosome. Ainsi, la régulation de YAP par mTOR et l'autophagie est un nouveau mécanisme de contrôle de la croissance, l'activité de YAP correspondant à la disponibilité des éléments nutritifs dans les conditions de croissance permissives. Il pourra servir comme une cible thérapeutique potentielle pour TSC et d'autres maladies avec une activité de mTOR dérégulée. / The Tuberous Sclerosis Complex (TSC) is a genetic disease characterized by growth of hamartomas in different organs including brain, kidney, lung, skin, and heart. These lesions are sources of morbidity and mortality in patients with TSC, as they may cause intractable epilepsy, autism, developmental delay, renal and pulmonary failure. Known causes of TSC are loss of function mutations in TSC1 and TSC2 genes. The majority of TSC lesions contain multiple cell types of the mesenchymal lineage, as in the case of angiomyolipomas, lymphangioleiomyomatosis and angiofibromas. A unique cell type named perivascular epithelioid cell (PEC) is constantly present in mesenchymal TSC lesions, such as angiomyolipomas and lymphangioleiomyomatosis, basing on morphological features and the common expression of melanocytic and myogenic markers. Therefore, these lesions are officially classified, along with other tumors, as PEComas. Their cell of origin and the molecular mechanisms underlying their pathogenesis remain poorly defined. Here we generated a novel mosaic Tsc1 knockout mouse model which develop renal mesenchymal lesions recapitulating human Perivascular Epithelioid Cell tumor (PEComa) observed in TSC patients. We identified YAP, the transcriptional coactivator of Hippo pathway, was upregulated in both renal lesions of TSC mouse model and human angiomyolipoma samples in a mTOR-dependent manner. Inhibition of YAP with genetic or pharmacological tools greatly attenuates the proliferation and survival of Tsc1 null cells in vivo and in vitro. Futhermore, we found YAP accumulation in TSC1/TSC2 deficient cells is due to impaired degradation of the protein through the autophagosome/lysosome system. Thus the regulation of YAP by mTOR and autophagy is a novel mechanism of growth control, matching YAP activity with nutrient availability under growth permissive conditions. It may serve as a potential therapeutical target for TSC and other diseases with dysregulated mTOR activity.
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Identification and Functional Characterization of Adipogenesis-related GenesWu, Yu 18 December 2008 (has links)
No description available.
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The Effect of Dissolved Air on the Cooling Performance of a Partially-Confined FC-72 SprayPuterbaugh, Rebekah Lee 09 September 2008 (has links)
No description available.
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Projektframgång : och vilka faktorer påverkar denna? / What is a successful project : and which factors are affecting it?Karlsson, Ki January 2007 (has links)
Definitionen av ett projekt är att det måste gå att mäta om ett projekt nått sitt mål eller inte. Ett projekt skall också ha en klar och tydligt fastställd slutpunkt, där projektgruppen upplöses och projektet avslutas. De metoder som valts att användas för datainsamling är intervjuer med projektledarna och kunderna. Även litteraturstudier har använts för att kartlägga redan existerande kunskap inom området samt för att bygga upp en teoretisk referensram. I denna studie beskrivs arbetsgången hos två projekt. Vid jämförande och analys av arbetsgången vid de båda projekten visade det sig att det fanns både likheter och skillnader. I resultatet redovisas de båda projektens arbetsgång, samt vad projektledarna och kunderna har för åsikter om respektive projekts genomförande och slutresultat. Slutsatsen som man kan dra av jämförandet av Projekt A och B med den teoretiska projektgången är att i många fall oberoende på storleken på ett projekt så genomförs kundorderprojekt på samma sätt. / The definition of a project is that the goal must be able to be measured after the project is finished. A project must have a clear ending point where the project group is dissolved. The methods that have been chosen for collecting material are interviews with the project managers and the customers. Litterature has also been studied for a theoretical view. In this study two projects are analyzed. At comparison between the projects, it shows that there are both similarities and differences between the way to work in a project. In the result it is described how the two projects where carried out and also what the project managers and the customers thought of the realization and end result. The conclusion that you can draw is that in many cases the realization are not depending of size of the project. The projects are carried out the same way independent of the projects size.
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Projektframgång : och vilka faktorer påverkar denna? / What is a successful project : and which factors are affecting it?Karlsson, Ki January 2007 (has links)
<p>Definitionen av ett projekt är att det måste gå att mäta om ett projekt nått sitt mål eller inte. Ett projekt skall också ha en klar och tydligt fastställd slutpunkt, där projektgruppen upplöses och projektet avslutas.</p><p>De metoder som valts att användas för datainsamling är intervjuer med projektledarna och kunderna. Även litteraturstudier har använts för att kartlägga redan existerande kunskap inom området samt för att bygga upp en teoretisk referensram.</p><p>I denna studie beskrivs arbetsgången hos två projekt. Vid jämförande och analys av arbetsgången vid de båda projekten visade det sig att det fanns både likheter och skillnader. I resultatet redovisas de båda projektens arbetsgång, samt vad projektledarna och kunderna har för åsikter om respektive projekts genomförande och slutresultat. Slutsatsen som man kan dra av jämförandet av Projekt A och B med den teoretiska projektgången är att i många fall oberoende på storleken på ett projekt så genomförs kundorderprojekt på samma sätt.</p> / <p>The definition of a project is that the goal must be able to be measured after the project is finished. A project must have a clear ending point where the project group is dissolved. The methods that have been chosen for collecting material are interviews with the project managers and the customers. Litterature has also been studied for a theoretical view.</p><p>In this study two projects are analyzed. At comparison between the projects, it shows that there are both similarities and differences between the way to work in a project. In the result it is described how the two projects where carried out and also what the project managers and the customers thought of the realization and end result. The conclusion that you can draw is that in many cases the realization are not depending of size of the project. The projects are carried out the same way independent of the projects size.</p>
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