Multiphase contacting in PGM hydrometallurgy

This thesis describes hydrodynamic studies of the leach and solvent extraction stages of a Platinum Group Metal (PGM) hydrometallurgical flowsheet. The studies were motivated by the need to increase PGM throughput in Johnson Matthey’s PGM refining business. In the leach stage, key components in the feed are selectively dissolved using acids in a stirred tank before they are recovered by liquid-liquid (L-L) solvent extraction and finally purified. The work described in this thesis tackles four main areas: hydrodynamic studies of L-L PGM solvent extraction in both mixer and settler stages, whilst for the leach stage, studies of particle behaviour in gas evolving solid-liquid (S-L) reactions and gas-liquid-solid (GLS) characterisation by a novel Electrical Resistance Tomography (ERT) technique are performed. In the mixer-settler, the effects of impeller diameter, D, to vessel diameter, T, ratio (D/T), the phase flow ratio, cφ/dφ; (where cφis the continuous phase flow fraction and dφ is the dispersed phase flow fraction) and the specific power input,Tε, upon the droplet size distribution in a L-L system and their phase separation were investigated. Changing a smaller D/T impeller for a larger D/T impeller at constant P/V and cφ/dφincreased droplet size because the maximum shear rate decreased as a result of increasing ratio of impeller pumping capacity (Q) with tip speed (Utip). Changing a larger cφ/dφfor smaller cφ/dφat a fixed P/V and D/T impeller increased droplet size because turbulent dampening increased since the average density, ρ ∝ dφ. Meanwhile, Kolmogoroff-Hinze’s theory was shown to apply for the measured relationship between Tε and droplet size. A settler design criterion, which relates the dispersed phase concentration (Ca) in the dispersion band to the dispersed phase throughput (Qd/A) agreed with the model by Ryon et al. (1959). Ca was significantly dependent on P/V and Qd/A, whilst the effects of Qc/Qd (where Qc is the continuous phase flowrate and Qd is the dispersed phase flowrate) and D/T were minimal. Droplet size analysis of the sedimenting region of the dispersion band and dense packed layer revealed a transitional distribution of droplet sizes due to the counteracting effects of droplet sedimentation, hindered settling and droplet-droplet coalescence. Particle behaviour in gas evolving S-L systems were quantified using the Zwietering ‘just-suspended’ impeller speed (Njs) condition in a sponge nickel® and sodium hypochlorite system. The presence of gas caused Njs to increase, however a coherent relationship between Njs in an ungassed and gassed system 3 could not be easily ascertained. Further work with Positron Emission Particle Tracking (PEPT) was advised to quantify the relationship. A well-known electrical concept called skin effect, which describes how the effective resistance of an electrical conductor varies as the frequency of an alternating current (AC) increases and decreases, was used to investigate GLS behaviour via a novel ERT spectroscopic technique. The process relies on the change in effective resistance of conducting objects with changing AC frequency to selectively detect different phases. The concept was initially validated with static phantoms of a stainless steel and plume of gas before being applied to dispersible stainless steel particles and gas. ERT spectroscopy showed that two AC frequencies (0.3 kHz and 9.6 kHz) could successfully isolate and simultaneously detect the gas and solid phases at a fixed current. By subtracting solids and gas conductivity, the change in solids and gas holdup were obtained

EGFR and related therapeutic targets in malignant pleural mesothelioma

IntroductionMalignant pleural mesothelioma (MPM) is a rare but aggressive disease and the current first line treatment is associated with a survival rate of 40%. There is currently no second line therapy. This study aimed to explore the expression of proteins in the arachidonic acid pathway, VEGFR-2 pathway, EGFR/HER2 pathway, c-MET pathway and the PI3K/AKT/MTOR pathway in MPM archival tissue samples and cell lines. We also investigated the cytotoxic effect of inhibitors for each individual pathway as single agents and in some instances as combinations.Materials and MethodsImmunohistochemical analysis was performed in 93 archival MPM tissue samples to determine the expression of the HER2, 5-LOX, 12-LOX, VEGFR-2 and c-MET proteins. Mesothelioma cell lines NCI-H2452, NCI-H2052, MSTO-211H and a non-small cell lung cancer cell line A549 were used for western blot analysis, MTS assay and in vitro scratch assay. Western blot analysis was used to evaluate 5-LOX, 12-LOX, VEGFR-2, EGFR, p-ERK, ERK, c-MET, PTEN and p70S6K protein expression in the cell lines. The antiproliferative effect of Baicalein (12-LOX), Zileuton (5-LOX), MK886 (FLAP inhibitor), Celecoxib (COX-2), Cediranib (VEGFR-2), MGCD265 (c-MET/VEGFR inhibitor), Afatinib (EGFR/HER2), Gefitinib (EGFR), Selumetinib (MEK), Tivantinib (c-MET), Crizotinib (c-MET/ALK), SU11274 (c-MET), Onartuzumab (MET monoclonal antibody), NVPBEZ235 (PI3K/AKT/MTOR), VS5584 (PI3K/AKT/MTOR), Ku0063794 (MTOR1/MTOR2), XL388 (MTOR1/MTOR2) was assessed as single agents and in combinations and analysed using the MTS proliferation assay.ResultsPositive 5-LOX and 12-LOX protein expression was seen in 73% (56/77) and 83% (69/83) of archival MPM tissue samples respectively. NCI-H2452, NCI-H2052, MSTO-211H and A549 cells also expressed 5-LOX and 12-LOX proteins. Baicalein was effective in all cell lines. Combination of celecoxib (3 μM) and baicalein (10 μM) was synergistic in the MSTO-211H cell line. Positive VEGFR-2 protein expression was seen in 93.8% (75/80) of archival tissue samples. Cediranib demonstrated cytotoxic effect at doses higher than the clinical relevant dose. MGCD265 also reduced cell proliferation in all cell lines. Positive HER2 expression was seen in 86.2% (69/80) of archival tissue samples. All cell lines expressed EGFR, p-ERK and ERK protein. Gefitinib and Afatinib demonstrated cytotoxic effects at doses significantly higher than their therapeutically relevant doses. Positive c-MET expression was seen in 82% (58/71) of archival tissue samples. NCI-H2452, NCI-H2052, MSTO-211H and A549 cells also expressed c-MET protein. Crizotinib inhibited cell growth by 50% in MSTO-211H cells within its clinically relevant dose. SU11274 also reduced cell growth by 50%. Tivantinib reduced cell growth by 50% in all cell lines at doses significantly lower than its clinically achievable dose of 4 μM. A549 and MSTO-211H cells positively expressed the p70S6K protein and loss of PTEN was also observed in the MSTO-211H cells. PI3K/AKT/MTOR inhibitors, NVPBEZ235 and VS-5584 significantly reduced cell growth by 50% at low nanomolar IC50 values. VS-5584 was combined in turn with Tivantinib and Afatinib. The combination of VS-5584 with Tivantinib demonstrated enhanced growth inhibition in all cell lines compared to either inhibitors alone. Combination of Tivantinib and Afatinib also enhanced the inhibition of cell growth in all cell lines compared to either inhibitors alone. The addition of cisplatin to the tyrosine kinase combinations produced a synergistic effect.ConclusionsOur findings suggest that multiple signalling pathways are active in a significant proportion of MPM samples. Co-targeting the c-MET and PI3K/MTOR pathway might be a potential therapeutic strategy for mesothelioma patients. Further work is required to explore the combination of an EGFR inhibitor and a PI3K/MTOR inhibitor when the EGFR inhibitor is fixed at a therapeutically relevant dose. In addition, understanding the molecular mechanism of Tivantinib, Afatinib and VS-5584, through the use of comparative proteomic platforms, could potentially identify predictive biomarkers of response to these anti-cancer agents in mesothelioma patients

Investigation of the microstructural evolution in Ti-6A1-4V alloy during cyclic hydrogenation and dehydrogenation heat treatment

Includes abstract.Includes bibliographical references (leaves 87-90).The temporary alloying process involves a two stage heat treatment during which hydrogen is firstly introduced into the titanium sample (hydrogenation), and secondly removed from the sample under vacuum annealing (dehydrogenation), thereby completing the cycle. During the hydrogenation stage, the high diffusivity of hydrogen in titanium alloys at elevated temperatures is used to introduce hydrogen into the sample. Hydrogen being a stabilizing element of titanium alloys, lowers the β → (α+ β) transition temperature and slows the kinetics of the β → α phase transformation. This leads to the generation of new microstructures. Fine α-grain structures and martensitic plates were observed upon completion of the hydrogenation treatment

Xenophobia and its implications for social order in Africa

Xenophobia, a form of discrimination practiced in countries, particularly in South Africa, is one of the major challenges confronting the modern day society. This paper examines xenophobia as a menace showing at the same time that this discriminatory practice  bifurcates societies by creating a dichotomy amidst the various occupants of the  society, thereby giving room for “otherness” rather than “orderliness”. The paper also highlights the philosophical implications of this societal bifurcation, particularly to the human community. Seeking a plausible way of addressing this challenge, the paper concludes by emphasizing the relevance of the value of tolerance in curbing xenophobia.Keywords: Xenophobia, Social discrimination, Tolerance, order and other, Africa

The investigation of lipoxygenases as therapeutic targets in malignant pleural mesothelioma

Advanced malignant pleural mesothelioma (MPM) has an extremely poor prognosis with limited chemotherapy options, therefore the identification of new therapeutic targets would aid in disease management. Arachidonic acid is metabolised by cyclooxygenase and lipoxygenase enzymes. The lipoxygenase isoenzymes 5-LOX and 12-LOX have been implicated in carcinogenesis. We aimed to examine 5-LOX and 12-LOX protein expression in a large retrospective series of mesothelioma samples. Further to this, the in vitro cytotoxic effects of lipoxygenase pathway inhibitors were investigated in mesothelioma cells. Archival samples from 83 patients with MPM were examined by immunohistochemistry for expression of the 5-LOX and 12-LOX proteins. The MTS assay was used to assess cell viability following 72h treatment with the lipoxygenase pathway inhibitors baicalein, licofelone, MK-886 and zileuton in the MPM cell lines NCI-H2052, NCI-H2452 and MSTO-211H. Positive 12-LOX protein expression was recorded in 69/83 (83%) and positive 5-LOX expression was observed in 56/77 (73%) of MPM tissue samples. Co-expression of 5-LOX with 12-LOX was seen in 46/78 (58%) of MPM samples. Positive expression of 5-LOX, 12-LOX and COX-2 proteins was identified in the NCI-H2052, NCI-H2452 and MSTO-211H MPM cell lines. Baicalein (12-LOX and 15-LOX inhibitor) was effective in 3/3 MPM cell lines at low concentrations with an IC50 range of 9.6μM to 20.7μM. We have demonstrated that the 5-LOX and 12-LOX proteins are expressed in a significant proportion of MPM samples (73% and 83% respectively) and may represent novel therapeutic targets in this disease. We have demonstrated that the inhibition of the LOX pathway using baicalein may be effective as a novel treatment for MPM, however further human pharmacokinetic studies are required in order to establish whether the concentration used in vitro is clinically achievable

Capitalism and Earth System Governance: An Ecological Marxist Approach

Growing recognition of the Anthropocene era has led to a chorus of calls for Earth System Governance (ESG). Advocates argue that humanity's newfound sociotechnical powers require institutional transformations at all scales of governance to wield these powers with wisdom and foresight. Critics, on the other hand, fear that these initiatives embody a technocratic impulse that aims to subject the planet to expert management without addressing the political-economic roots of the earth system crisis. This article proposes a more affirmative engagement with existing approaches to ESG while also building on these critiques. While advocates of ESG typically ignore the capitalistic roots of the earth system crisis and propose tepid reforms that risk authoritarian expressions, their critics also have yet to systematically consider the potential for more democratic and postcapitalist forms of ESG. In response, I propose an ecological Marxist approach based on a structural analysis of capitalism as the primary driver of the earth system crisis and an "ecosocialist" vision of ESG that subordinates the market to democratic planning at multiple scales. I argue that an ecological Marxist perspective is needed to foreground the structural political-economic constraints on earth system stability, though existing approaches to ESG can in turn inform ecosocialist strategies for global institutional design and democratization

COPPADIS-2015 (COhort of Patients with PArkinson's DIsease in Spain, 2015), a global--clinical evaluations, serum biomarkers, genetic studies and neuroimaging--prospective, multicenter, non-interventional, long-term study on Parkinson's disease progressio

Background: Parkinson?s disease (PD) is a progressive neurodegenerative disorder causing motor and non-motor symptoms that can affect independence, social adjustment and the quality of life (QoL) of both patients and caregivers. Studies designed to find diagnostic and/or progression biomarkers of PD are needed. We describe here the study protocol of COPPADIS-2015 (COhort of Patients with PArkinson?s DIsease in Spain, 2015), an integral PD project based on four aspects/concepts: 1) PD as a global disease (motor and non-motor symptoms); 2) QoL and caregiver issues; 3) Biomarkers; 4) Disease progression.Methods/design: Observational, descriptive, non-interventional, 5-year follow-up, national (Spain), multicenter (45 centers from 15 autonomous communities), evaluation study. Specific goals: (1) detailed study (clinical evaluations, serum biomarkers, genetic studies and neuroimaging) of a population of PD patients from different areas of Spain, (2) comparison with a control group and (3) follow-up for 5 years. COPPADIS-2015 has been specifically designed to assess 17 proposed objectives. Study population: approximately 800 non-dementia PD patients, 600 principal caregivers and 400 control subjects. Study evaluations: (1) baseline includes motor assessment (e.g., Unified Parkinson?s Disease Rating Scale part III), non-motor symptoms (e.g., Non-Motor Symptoms Scale), cognition (e.g., Parkinson?s Disease Cognitive Rating Scale), mood and neuropsychiatric symptoms (e.g., Neuropsychiatric Inventory), disability, QoL (e.g., 39-item Parkinson?s disease Quality of Life Questionnaire Summary-Index) and caregiver status (e.g., Zarit Caregiver Burden Inventory); (2) follow-up includes annual (patients) or biannual (caregivers and controls) evaluations. Serum biomarkers (S-100b protein, TNF-?, IL-1, IL-2, IL-6, vitamin B12, methylmalonic acid, homocysteine, uric acid, C-reactive protein, ferritin, iron) and brain MRI (volumetry, tractography and MTAi [Medial Temporal Atrophy Index]), at baseline and at the end of follow-up, and genetic studies (DNA and RNA) at baseline will be performed in a subgroup of subjects (300 PD patients and 100 control subjects). Study periods: (1) recruitment period, from November, 2015 to February, 2017 (basal assessment); (2) follow-up period, 5 years; (3) closing date of clinical follow-up, May, 2022. Funding: Public/Private. Discussion: COPPADIS-2015 is a challenging initiative. This project will provide important information on the natural history of PD and the value of various biomarkers

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Reimagining global criminal justice accountability: is the time ripe for a tripartite complementarity of courts?

This thesis examines whether there are compelling reasons for creating a regime of regional criminal courts (RCC) that can serve as complementary means of global criminal justice accountability alongside municipal criminal courts and global courts like the International Criminal Court (ICC). The research is an attempt to respond to growing controversies and frequent contentions regarding certain lapses and apparent frailties in the existing international criminal law (ICL) enforcement system. Much of the debate relates to perceived legitimacy and proximity deficits of several international criminal courts whose activities have sometimes been described as ‘distanced justice’ largely as a criticism of the fact that the courts seldom hold trials near the areas where they operate. But why is yet another study warranted in this area? This PhD research is possibly the first elaborate normative investigation of the principal contentions regarding the use of RCCs as an ICL enforcement model. Above all, it is the first study that contemplates and expatiates the feasibility of a tripartite complementarity of national courts, RCCs, and the International Criminal Court. It considers not only an acceptable international policy for regionalising ICL, but also proposes and develops appropriate principles that could support efficient collaborative interactions within the envisioned three-tiered complementarity of courts. Through the rigorous examination of its objects, the thesis makes new contribution to the literature. The study also contributes to knowledge by extending related research in the area. It draws from and expands Robert Woetzel’s early outline of the indicia of an international criminal court. Previously, there had been scanty detailed analyses of the identity and characteristics of an international criminal tribunal. Exploring this subject enables the thesis to closely grapple with a number of the vexing issues surrounding the global justice system in addition to uncovering certain basic properties that confer legitimacy, credibility, and quiddity to international criminal courts