An investigation of crustal contamination through petrology and geochemisty

The contamination of mantle-derived magmas by the continental crust is an important process during petrogenesis of volcanic rocks at active continental margins e.g. The Andes. Investigating the evolution of continental arc magmas is, however, hampered by our limited knowledge of, and poor constraints on, the nature of the underlying crustal basement and the mechanisms of crustal anatexis. This thesis reports results from: 1) a whole rock geochemical and in-situ geochronological investigation of a suite of crustal xenoliths from the Bolvian Altiplano, Central Andes; 2) a whole rock geochemical study of the xenoiths’ host lavas and; 3) detailed in-situ geochemical studies of crustal partial melts (quenched to glasses) trapped within their crustal progenitors from Bolivia, NE China and SE Spain. Sampled crustal xenoliths from the Bolivan Altiplano provide a rare insight into the nature of the Central Andean continental basement and reveal lithological and geochemical heterogeneity exists at depth with 87 Sr/86 Sr values extending to 0.7368 which is more radiogenic than any Srisotopic signature exhibited by the recent (< 60 Ma) volcanic record. In-situ U-Pb dating of zircon separates reveal predominant age peaks at 1.7-1.9 Ga, 1.0-1.2 Ga and 495-380 Ma which correspond to periods of supercontinent formation and break-up e.g. construction of Rodinia. Lavas erupted from monogenetic centres on the eastern Bolivian Altiplano show petrographic and geochemical evidence for crustal contamination. The geochemical heterogeneity exhibited by the lavas is, however, difficult to reconcile through simple two component crust-magma interaction models (bulk mixing, AFC and EC-AFC). Instead, contamination is inferred to have involved numerous crustal components. The geochemical signatures observed in lavas from monogenetic centres towards the active Andean arc (between ~18-21o S) are distinct (e.g. lower 87 Sr/86 Sr, higher Sr/Y, higher Ba/Nb at higher Zr/Nb) and may indicate a lower degree of crust-magma interaction, an increase in the contribution from slab-derived fluids and thinner crust arc-wards, the latter which has previously been inferred from geophysical studies. In-situ analysis of anatectic melts reveals that Sr-isotopic disequilibrium between a crustal melt and its source can exist on the sub-millimetre scale. This is understood to reflect the melting of aged minerals with different Rb/Sr (and therefore 87 Sr/86 Sr) more quickly than the isotopic composition can diffusively equilibrate between melt and minerals. Results suggest therefore that crustal anatexis can produce melts which are geochemically heterogeneous both spatially and temporally. This highlights the need for detailed microscopic investigations coupled with petrogenetic modelling in order to develop a more robust characterisation and well-constrained quantification of crustal contamination in open magmatic systems

Single Cell Molecular Heterogeneity In Musculoskeletal Differentiation

Mesenchymal stem cells (MSCs) display substantial cell-to-cell variation that manifests across many aspects of cell phenotype and complicates the use of MSCs in regenerative applications. However, most conventional assays measure MSC properties in bulk and, as a consequence, mask this cell-to-cell variation. To better understand MSC heterogeneity and its underlying mechanisms, we quantitatively assessed MSC phenotype within the context of chondrogenesis, amongst clonal populations and single cells. Clonal MSCs differed in their contractility, ability to transmit extracellular strain the nucleus, capacity to form cartilage-like matrix, and transcriptomic signature. RNA FISH measurements of single cell gene expression found that both primary chondrocytes and chondrogenically-induced MSCs showed substantial mRNA expression heterogeneity. Surprisingly, variation in differentiation marker transcript levels only weakly associated with cartilage-like matrix production at the single cell level. This finding suggested that, although canonical markers have very clear functional roles in differentiation and matrix formation, their instantaneous mRNA abundance is only tenuously linked to the chondrogenic phenotype and matrix accumulation at the single cell level. One possible explanation for the apparent disconnect between gene and protein expression is that mRNA and protein exhibit different temporal dynamics. Using stochastic models of single cell behavior, we explored the impact of transcriptional stochasticity and temporal matrix dynamics on the perceived relationship between single cell mRNA and protein abundance. Simulations suggested that considering recent temporal fractions of protein (vs. total protein) increased the correlation between mRNA and protein abundance, and illustrated that mRNA stability was a crucial determinant of the timescale over which any such correlation persisted. Experimentally, non-canonical amino acid tagging was used to visualize and quantify temporal fractions of nascent extracellular matrix with high fidelity. The organization and temporal dynamics of the proteinaceous matrix depended on the biophysical features of the microenvironment, including the biomaterial scaffold and the niche constructed by cells themselves. Both chondrocytes and MSCs demonstrated marked cell-to-cell heterogeneity in nascent matrix production, consistent with model predictions. Ongoing work aims to combine these experimental measurements of nascent protein expression with instantaneous measures of mRNA abundance to better understand the mRNA-protein relationship, and to harness this understanding to improve regenerative therapies

Australian dust storm associated with extensive Aspergillus sydowii fungal "Bloom" in coastal waters

A massive central Australian dust storm in September 2009 was associated with abundant fungal spores (150,000/m(3)) and hyphae in coastal waters between Brisbane (27 degrees S) and Sydney (34 degrees S). These spores were successfully germinated from formalinpreserved samples, and using molecular sequencing of three different genes (the large subunit rRNA gene [LSU], internal transcribed spacer [ITS], and beta-tubulin gene), they were conclusively identified as Aspergillus sydowii, an organism circumstantially associated with gorgonian coral fan disease in the Caribbean. Surprisingly, no human health or marine ecosystem impacts were associated with this Australian dust storm event. Australian fungal cultures were nontoxic to fish gills and caused a minor reduction in the motility of Alexandrium or Chattonella algal cultures but had their greatest impacts on Symbiodinium dinoflagellate coral symbiont motility, with hyphae being more detrimental than spores. While we have not yet seen any soft coral disease outbreaks on the Australian Great Barrier Reef similar to those observed in the Caribbean and while this particular fungal population was non-or weakly pathogenic, our observations raise the possibility of future marine ecosystem pathogen impacts from similar dust storms harboring more pathogenic strains

'The live dynamic whole of feeling and behavior': capital punishment and the politics of emotion, 1945–1957

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Improving the general health of people with learning difficulties in the UK: experiences of the implementation of Annual Health Checks

This paper offers a brief overview of the background to implementing a policy of offering Annual Health Checks (AHCs) to all people with a learning disability/difficulty in the UK. It outlines what has been developed through national policy and then offers an insight into the experiences of four people with learning difficulties in relation to understanding and accessing AHCs. All four people are members of The Lawnmowers Independent Theatre Company (ITC) a company that aims to lay solid foundations for people with learning disabilities to participate fully in their own society, shaping their own environment and controlling their own futures

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance

In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury

Traumatic brain injury (TBI) can trigger progressive neurodegeneration, with tau pathology seen years after a single moderate-severe TBI. Identifying this type of posttraumatic pathology in vivo might help to understand the role of tau pathology in TBI pathophysiology. We used flortaucipir positron emission tomography (PET) to investigate whether tau pathology is present many years after a single TBI in humans. We examined PET data in relation to markers of neurodegeneration in the cerebrospinal fluid (CSF), structural magnetic resonance imaging measures, and cognitive performance. Cerebral flortaucipir binding was variable, with many participants with TBI showing increases in cortical and white matter regions. At the group level, flortaucipir binding was increased in the right occipital cortex in TBI when compared to healthy controls. Flortaucipir binding was associated with increased total tau, phosphorylated tau, and ubiquitin carboxyl-terminal hydrolase L1 CSF concentrations, as well as with reduced fractional anisotropy and white matter tissue density in TBI. Apolipoprotein E (APOE) ε4 genotype affected the relationship between flortaucipir binding and time since injury, CSF β amyloid 1–42 (Aβ42) concentration, white matter tissue density, and longitudinal Mini-Mental State Examination scores in TBI. The results demonstrate that tau PET is a promising approach to investigating progressive neurodegeneration associated with tauopathy after TBI

The NICE-GUT trial protocol:A randomised, placebo controlled trial of oral nitazoxanide for the empiric treatment of acute gastroenteritis among Australian Aboriginal children

Diarrhoeal disease is the second leading cause of death in children under 5 years globally, killing 525 000 annually. Australian Aboriginal and Torres Strait Islander (hereafter Aboriginal) children suffer a high burden of disease. Randomised trials in other populations suggest nitazoxanide accelerates recovery for children with Giardia, amoebiasis, Cryptosporidium, Rotavirus and Norovirus gastroenteritis, as well as in cases where no enteropathogens are found. This double blind, 1:1 randomised, placebo controlled trial is investigating the impact of oral nitazoxanide on acute gastroenteritis in hospitalised Australian Aboriginal children aged 3 months to <5 years. Dosing is based on age-based dosing. The primary endpoint is the time to resolution of 'significant illness' defined as the time from randomisation to the time of clinical assessment as medically ready for discharge, or to the time of actual discharge from hospital, whichever occurs first. Secondary endpoints include duration of hospitalisation, symptom severity during the period of significant illness and following treatment, duration of rehydration and drug safety. Patients will be followed for medically significant events for 60 days. Analysis is based on Bayesian inference. Subgroup analysis will occur by pathogen type (bacteria, virus or parasite), rotavirus vaccination status, age and illness severity. Ethics approval has been granted by the Central Australian Human Research Ethics Committee (HREC-14-221) and the Human Research Ethics Committee of the Northern Territory Department of Health and Menzies School of Health Research (HREC2014-2172). Study investigators will ensure that the trial is conducted in accordance with the principles of the Declaration of Helsinki. Individual participant consent will be obtained. Results will be disseminated via peer-reviewed publication. ACTRN12614000381684