Reactivity of some aluminosilicate minerals in the water-sodium hydroxidelime system

Imperial Users onl

Genetic and epigenetic studies of acute myeloid leukemia and therapeutic possibilities

Acute myeloid leukaemia (AML) is malignant tumour that forms in the bone marrow and arises from immature myeloid progenitors. Consequently, this leads to excessive accumulation of dysfunctional blast cells and lack of normal blood cells. The molecular and genetic heterogeneity of the disease is substantial which makes the disease challenging to classify and treat. Although the AML classification is updated continuously and more data and research on AML pathophysiology emerges, first line treatment for the vast majority of AML patients remains a combination of cytarabine and an anthracycline. While most patients attain a complete remission, the majority of AML patients relapse and develop drug resistance. Recently, new drugs have been approved for the treatment of specific AML subtypes. However, there is need for better understanding of disease pathogenesis including better genetic and epigenetic risk factors in order to develop more effective treatment regimens to improve the outcome of the disease. In Study I, we studied off-target effects of APR-246, a drug that originally was developed to restore the activity of mutated TP53 protein. Oxidative stress related genes heme oxygenase-1 (HMOX1, also termed HO-1), SLC7A11 and RIT1 were significantly upregulated. Also, Nrf2 that induces the expression of HO-1 was upregulated and depletion of Nrf2 mRNA resulted in increased cytotoxicity of APR-246. Moreover, blocking Nrf2 from translocating into the nucleus by using PI3K and mTOR inhibitors led to enhanced cell killing. This suggests that a combination of APR-246 with PI3K and mTOR inhibitors improves sensitivity to APR-246 by interfering with the cellular response to ROS activation to achieve better anti-leukemic effects of APR-246. In Study II, we aimed to define the potential of using stroma cells in diagnostic AML samples as a source of germline DNA. To obtain germline DNA, together with DNA from leukemic cells, it is essential to reliably define somatic mutations in AML cells. Consequently, we cultivated and expanded bone marrow stroma cells from vitally frozen mononuclear cells from AML patients with monosomy 7 as well as defined somatic mutations. In vitro expanded bone marrow stroma cells were stable after 6 weeks of culture and were able to differentiate into adipocytes or osteocytes. We could also show that cultivated stroma cells do not harbour the somatic mutations found in the malignant cells. Thus, we could conclude that bone marrow stroma cells from diagnostic bone marrow samples could be used as a source of germline DNA in AML patients. In Study III, we studied the binding occupancy of the chromatin organizer CTCF in AML patient cells and compared it to binding in normal CD34+ cells. We found that AML cells display an aberrant increase of CTCF binding. Motif analysis revealed that gained CTCF sites are enriched for transcription factors such as PU.1, RUNX1 and CEBPA, which is found to be important for normal myeloid development. TET2 mutated AML patients exhibit a greater gain of CTCF occupancy that is mainly annotated to promoters. Generally, gained CTCF sites were found to be hypomethylated and associated with genes that were upregulated in AML. Knockdown of CTCF in K562 cells resulted in loss of CTCF and decreased gene expression of targeted genes as well as loss of RUNX1 binding at common CTCF and RUNX1 binding sites. Knockdown of CTCF also resulted in increased differentiation of K562 cells. In vitro exposure of AML patient cells with azacytidine resulted in major changes in CTCF occupancy where most gained sites restored the binding pattern found in normal CD34+ cells. In conclusion, our results suggest that an aberrant CTCF occupancy in AML can have a role in driving leukemogenic gene expression patterns in AML

Large-scale local-orbital DFT calculations of Si - Ge core - shell nanowires

Nanowires, represent the smallest device dimensionality for efficient transport of electrons and other more exotic quasiparticles. Among a plethora of applications identified, research directed towards field-effect transistors (FETs), the building blocks of next-generation computer processors, is of utmost importance considering current 7 nm FET technologies are expected to be the limit of “top-down” manufacturing techniques. Characterisation of the mechanical and electronic properties of nanowires, by conventional electronic structure techniques, have coincidentally reached a limit due to the maximum simulation sizes they are capable of. CONQUEST is a code capable of simulation of millions of atoms using O(N) methods and thousands of atoms using Hamiltonian diagonalisation with a pseudo-atomic orbital basis. Physical quantities calculated using CONQUEST do not exhibit systematic convergence using PAO basis sets, unlike plane-wave codes, so we quantify PAO basis sizes needed to achieve comparable accuracy to plane-wave calculations for a variety of bulk and molecular systems with varying chemical environments. Implementation of the stress tensor, presented in this thesis, resulted in the discovery of slow stress convergence with respect to density matrix localisation. We quantify the O(N) simulation parameters necessary to achieve stress calculations to a required accuracy. We present the first study of experimentally relevant, surface reconstructed, Si (core) - Ge (shell) nanowires. Vegard’s law, used to quantify experimental results and as an approximation in theoretical calculations, has been found to poorly describe our nanowires and we assess the relative error due to its usage. Young’s modulus is shown to decrease with increasing shell deposition and dependent on relative nanowire composition. Poisson ratios, also correlated to composition, exhibit anisotropy. Shell deposition induced strain has been mapped by our method and shows strong anisotropy in different bonding directions. Our nanowires exhibit a direct-to-indirect band gap transition with intrinsic uniaxial strains > 0.5% and effective hole masses 50% smaller than similar unreconstructed nanowires. Finally, valence band offsets which are responsible for the formation of hole gases, were found to be double that of unreconstructed models

Policy design tool for managing indoor residential water demand in water-scarce regions

In view of population growth; climate change; and economic evolution, water resources in numerous parts of the world have reached their natural capacities. Consequently, the ability of many countries to grow; meet the basic needs of inhabitants; and protect the environment will be endangered like never before unless water resources are smartly handled and managed. ^ In the past few decades, many developed and developing countries have suffered from water scarcity, and more are certain to follow. The water security dilemma is much more challenging in developing countries. Water utilities have had to follow regulatory plans to manage demand on water resources. Not surprisingly, demand on residential water is deemed to be the most critical sector over other competing sectors.^ Despite the vast amount of research on residential water demand management, little is known about the willingness of consumers to participate in demand management plans. This has been attributed to the complex nature of modelling consumers’ participatory actions, leaving policy makers with unexpected outcomes from their demand management plans. In order to overcome this challenge and enable policy makers to understand the complex interactions between water consumers, a comprehensive tool is needed to account for the heterogeneity of water consumers without compromising the complex nature of water systems. The development and application of the comprehensive tool is demonstrated using Amman, the capital city of the Kingdom of Jordan as a case study.^ This research addresses water supply and demand from a complex adaptive systems’ perspective. The primary objectives of this investigation are to: (1) develop a model for consumer’s awareness of water conservation that is capable of addressing the role of individual attributes in participating in demand management policies; (2) develop a complex adaptive systems framework for residential water supply and demand to capture the interactions between consumers and policy makers; and (3) develop a model to capture the possible impacts of the non-piped water source on efforts to manage water consumption. ^ First, an econometric model is constructed that explains the extent to which consumers’ attributes affect their participation in demand management activities. Participation in water conservation plans can be achieved through installation of efficient plumbing fixtures and the adoption of conservative water-use habits. Thus, correlation between efficient fixtures and habits should be considered.^ Second, a complex adaptive systems framework is developed to facilitate the application of different demand management policies on residential water consumers. The framework is capable of capturing the complex interactions between consumers themselves and the policy maker (the entity in charge of applying demand management policies while supplying piped water), while explicitly considering their heterogeneity. This bottom-up approach can forecast the diffusion of efficient fixtures and conservative habits.^ Third, a system dynamics model is built to investigate the feedbacks between different sources of supply and demand management efforts. This model will examine the possible interactions between water availability and consumers’ participation in demand management by predicting the compensatory actions taken by consumers to reduce their water shortage.^ The primary research developments presented in this work hold strong potential to advance current tools of residential water demand management through: (1) improving the understanding of what lies behind consumers’ participation in demand management policies; (2) explicit accounting for the correlation between the adoption of water-saving fixtures and conservative water use habits; (3) addressing the heterogeneity of water consumers and thus capturing the complexity of demand management; and (4) reducing uncertainty in estimating the effectiveness of different demand management policies by capturing the influence of mixed sources of supply on water demand

Intention to use e-government services among the academic staff in Saudi universities

E-government diffusion and usage is a global topic that concerns many countries worldwide. E-government is a way for providing services of government over online channels of communication to its citizens. Saudi Arabia has implemented a program of e-government in 2005 to encourage performance of public sectors through acquiring the benefits of Information Communication Technology (ICT) advances. This study focuses on the factors that influence intention to use e-government among the academic staff in Saudi Arabia. In addition, this study is to identify the mediating role of e-government awareness on the relationships between social influence, trust of internet and trust in intermediaries and intention to use e-government and the mediating role of perceived risk on the relationships between trust of internet and trust in intermediaries and intention to use e-government. Based on the Theory of Planned Behaviour (TPB), this study integrated these factors to examine their influences on intention to use e-government. This study utilized a quantitative approach using a survey to reflect consumers’ perspectives towards e-government usage. To examine the hypothesized model, the data were collected from the academic staff working in Saudi public universities. This study employed Partial Least Squares techniques to confirm the validity and reliability of the measurement model and to examine the structural relationships. The findings of the study confirmed the influences of social influence, e-government awareness, trust in intermediary and perceived risk on intention to use e-government. Further, awareness of e-government is influenced by social influence, trust in Internet and trust in intermediary and mediates the relationship between these factors and intention to use e-government. Trust in Internet factor emerged as significant predictor of consumers’ risk perceptions and mediates the relationship between this factor and intention to use e-government. This study has important implications for e-government practitioners, researchers and policy decision makers interested in the implementation of e-governmen

Hybrid photovoltaic-thermoelectric generator powered synchronous reluctance motor for pumping applications

The interest in photovoltaic (PV) pumping systems has increased, particularly in rural areas where there is no grid supply available. However, both the performance and the cost of the whole system are still an obstacle for a wide spread of this technology. In this article, a hybrid photovoltaic (PV)-thermoelectric generator (TEG) is investigated for pumping applications. The electric drivetrain comprises a synchronous reluctance motor and an inverter. A control strategy for the drivetrain is employed to execute two main tasks: 1) driving the motor properly to achieve a maximum torque per Ampere condition and 2) maximizing the output power of the PV system at different weather conditions. This means that the conventional DC-DC converter is not used in the proposed system. Moreover, batteries, which are characterized by short life expectancy and high replacement cost, are also not used. It is found that the motor output power and the pump flow rate are increased by about 9.5% and 12% respectively when the hybrid PV-TEG array is used compared to only using PV array. Accordingly, the performance, cost and complexity of the system are improved. Measurements on an experimental laboratory setup are constructed to validate the theoretical results of this work

Solar array fed synchronous reluctance motor driven water pump : an improved performance under partial shading conditions

An improved performance of a photovoltaic (PV) pumping system employing a synchronous reluctance motor (SynRM) under partial shading conditions is proposed. The system does not include the dc-dc converter that is predominantly being utilized for maximizing the output power of the PV array. In addition, storage batteries are also not contained. A conventional inverter connected directly to the PV array is used to drive the SynRM. Further, a control strategy is proposed to drive the inverter so that the maximum output power of the PV array is achieved while the SynRM is working at the maximum torque per Ampere condition. Consequently, this results in an improved system efficiency and cost. Moreover, two maximum power point tracking (MPPT) techniques are compared under uniform and partial shadow irradiation conditions. The first MPPT algorithm is based on the conventional perturbation and observation (P&O) method and the second one uses a differential evolution (DE) optimization technique. It is found that the DE optimization method leads to a higher PV output power than using the P&O method under the partial shadow condition. Hence, the pump flow rate is much higher. However, under a uniform irradiation level, the PV system provides the available maximum power using both MPPT techniques. The experimental measurements are obtained to validate the theoretical work

A case of new-onset vitiligo in a patient on tofacitinib and brief review of paradoxical presentations with other novel targeted therapies

With recent advancements in the understanding of vitiligo pathogenesis, Janus kinase (JAK) inhibitors have emerged as a promising new treatment modality, but their effects remain incompletely elucidated. Tofacitinib, an oral JAK 1/3 inhibitor approved for the treatment of rheumatoid arthritis, has previously been shown to induce significant re-pigmentation in vitiligo. However, as with other novel targeted therapies, cutaneous adverse effects have been observed. We report a 36-year-old woman with a history of rheumatoid arthritis, refractory to multiple pharmacotherapies, who was initiated on tofacitinib and subsequently developed progressive depigmented patches consistent with new-onset vitiligo. Although definitive causation cannot be established in this case without additional studies, it is important to note that many targeted therapies have the potential to induce paradoxical effects, that is, the occurrence or exacerbation of pathologic conditions that have been shown to respond to these medications. Paradoxical findings with other targeted therapies include the occurrence of melanoma during treatment with BRAF inhibitors, keratoacanthomas with PD-1 inhibitors, vitiligo and psoriasis with TNF-alpha inhibitors, and hidradenitis suppurativa with various biologic agents. Although JAK inhibitors hold therapeutic promise in the treatment of inflammatory skin disorders, further research is warranted to more fully comprehend their effects