The Polycomb Repressive Complex 2 (PRC2) epigenetically regulates gene expression by methylating lysine 27 on histone 3 (H3K27me3). While the role of PRC2 core members during hematopoiesis has been elucidated, the role of PRC2 accessory protein, Mtf2, has not been well characterized outside of mouse embryonic stem cells. To investigate the role of Mtf2 in vivo, we created a gene-targeted knockout mouse model. Using this model, we discovered that Mtf2 was a critical regulator of hematopoiesis and its loss within the hematopoietic cells leads to loss of global H3K27me3 levels at the transcriptional start sites (TSS) therefore leading to the overexpression of multiple signalling networks. These findings presented in the first part of my thesis place Mtf2 as a critical regulator of hematopoiesis and expand the role of Mtf2 beyond a canonical accessory PcG protein. While our murine studies revealed that the loss of Mtf2 did not cause leukemia in mice, our studies of MTF2 in human cells demonstrated that MTF2 deficiency within human Hematopoietic Stem and Progenitor Cells (HSPCs) causes a myelo-proliferative phenotype that is reminiscent of pre-leukemia. Furthermore, when we screened MTF2 expression within leukemic stem cell (LSC) enriched CD34+ CD38- cells isolated from primary Acute Myeloid Leukemia (AML) patient samples at diagnosis, we observed that MTF2 is miss-regulated in AML and its loss predicted refractory AML. Using MTF2 knockdown (KD) transcriptomic and ChIP-seq data, we drafted MTF2-PRC2 Gene Regulatory Network (GRN) in human HSPCs and LSC enriched cells. Finally, using the MTF2-PRC2 GRN, we uncovered a direct mechanism by which MTF2 regulates chemoresistance in AML and show that targeting this mechanism via MDM2 inhibitors sensitizes refractory AML to standard induction therapy. These findings presented in second part of my thesis demonstrate MTF2 as a novel prognostic marker for refractory AML and provide a novel therapy that helps target MTF2 deficient refractory AML.

The literature in Vacuum Induction Melting is briefly reviewed, with especial emphasis on refractory practices and refractory-metal interactions. Since it was determined that in both steel and superalloy vacuum melting in large furnaces lining failures are associated with attack on the cement joints, tests were performed to characterize this attack and determine the most suitable cements from this standpoint. The presence of low-stability oxides (SiO₂, P₂O₅,...) was shown to be the main reason for the cement's low resistance to metal attack. It is suggested that in the case of steels, diffusion of the less stable oxides may be the rate controlling step in the corrosion process. In the case of superalloys, the high interaction between oxygen and the elements present in the alloy (Ti, Al, Cr) causes an extreme depression of the oxygen activity in the melt, hence enhancing the dissolution of all refractory oxides. In order to produce cements with a very small content of the low-stability oxides, the use of fluorides as fluxes was attempted. The cements so produced performed well, as far as resistance to attack, adherence to bricks and technological properties were concerned. To verify the validity (on a large scale) of the mechanisms observed and proposed in the tests, samples from industrial Vacuum Furnaces were examined. It was concluded that the processes occurring in a large furnace can be rationalized based on the test observations. Also comments were made on the need for improved pouring facilities, if the products of the metal-refractory interaction are to be kept out of the final material produced. This is because in the present state of the refractory technology and practice, these interactions cannot be avoided. / Applied Science, Faculty of / Materials Engineering, Department of / Unknown

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Understanding high temperature interfacial phenomena with Al-alloys is essential for improving corrosion performance of refractories in melting/holding furnaces. Both physical and chemical properties are known to influence wetting and corrosion behaviour. However, uncertainties exist regarding the influence of SiO2 in refractory compositions on interfacial reactions/mechanisms, particularly when present along with non-wetting chemical additives like BaSO4, CaF2 and AlF3. An experimental study was conducted to clarify the interfacial phenomena of Al-alloy7075 with high-alumina refractories at extreme furnace temperatures of 1250??C and 815??C, using classical sessile drop approach and industrial cup tests respectively. At 1250??C, Al-alloy reacted more intensely with SiO2 compared to Al2O3. The interfacial behaviour of SiO2-Al2O3 system with Al-alloy was strongly dependent on SiO2 percentage, such that when upto 25% silica was present, wetting was reduced due to the presence of both original and newly formed corundum. Formation of mullite and originally present silica, along with decreasing corundum contents increased wetting in systems where silica varied from 25-45wt% and more than 45wt% respectively. Moreover, the nature of silica did not influence wetting when present in concentrations less than 20wt%. Different additives produced varying interfacial reactions in the Al-alloy/high-alumina refractory system. AlF3 did not improve the wetting resistance, except when present in high concentrations (>10wt%) in the refractory; this improvement attributed to corundum-rich matrix formation resulting from silica loss as gaseous fluorides. Low CaF2 amounts (<3wt%) improved the wetting resistance due to corundum presence and anorthite formation in the refractory. As CaF2 content exceeded 5wt%, proportion of glassy phases increased, hence enhancing interfacial reactions. However unlike CaF2, low BaSO4 levels (<5wt%) decreased the wetting resistance due to barium silicate formation, while high BaSO4 concentrations (≥10wt%) increased the wetting resistance due to celsian formation. Also, CaF2 dominated interfacial mechanisms when present along with BaSO4 in the refractory. The effect of additives on modifying wetting resistance was found to strongly vary with SiO2 levels of the refractory. The study demonstrated that additive effect is also influenced by treatment temperatures such that generally higher additive amounts are required at lower temperatures for improving the wetting resistance of high-alumina refractories.

Eating disorders are known for their chronic and relapse-ridden course. The cyclical nature of these disorders poses not only grave physical and mental health risks for the sufferer; it also presents serious challenges for the treating professionals and places a high demand and cost on the health care system. In spite of extensive research, no reliable predictors of long-term EDs have been identified in either adult or adolescent populations, nor have treatments emerged that are specifically targeted towards treating those with a long-term ED. It is fundamental to understand who is at risk and what factors are involved in long-term EDs, as the clinical and treatment implications gleaned from this evidence could be quite impactful. The current project will include three studies that will explore long-term EDs in a large transdiagnostic sample of adolescents with an ED. It will also attempt to overcome methodological limitations associated with past studies of this type, and apply an operational definition of this course of illness that may provide a more reliable and valid method with which to identify these cases. As such, the use of the term refractory ED, defined as a return to same-type treatment, will be applied to best identify this group. The three studies proposed in this research project will provide long overdue information on predictors, profiles and growth trajectories of those adolescents who suffer from a refractory course of an ED. This research project attempts to answer the question of: who will be affected, and how will the individual be affected by a refractory ED. With the ability to identify these cases and how the course of illness is being affected, treatment approaches can better aim to provide the appropriate treatment to those individuals most at risk of suffering from a refractory course of illness.

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