Investigation of the secondary dispersion of nickel in Rhodesia and Zambia

Imperial Users onl

Science and action in the work of Talcott Parsons 1928-50

A science of action has traditionally been associated with a range of methodological problems. Parsons' exposure to German idealism gave him an awareness of such problems. The question examined by this study is how Parsons addresses and attempts to resolve three methodological problems in a science of action; the nature of subjectivity, the relationship of normative entities and action and the place of values in knowledge. Central to the argument pursued here is that Parsons formulates and answers these problems within the interrelated framework of his analytical conception of science and his voluntaristic metaphysic. Chapters II and III are concerned with The Structure of Social Action, In the first, Parsons' general methodology of science is outlined leading up to his understanding and reasons for 'structural analysis': the importance of systematically articulated schemes of general elements of action. In chapter III Parsons' voluntarism is analyzed before examining the three problems noted above and showing their relationship to the analytic/voluntaristic framework. Chapters IV and V follow through these themes into Parsons’ work between 1938 and 1950 when he explicitly adopts a structural functional approach. Chapter IV returns to general methodology and Parsons’ rationale for structural functionalism but notes a number of anomolies in this which lead to chapter V in which structural functionalism is considered in the light of methodological problems of a science of action. Here the close relationship between voluntarism and structural functionalism is stressed. In conclusion alternative interpretations of voluntarism are critically assessed and a closing comment on Parsons’ contribution to sociological theory is offered

Evaluating the impact of task demands and block resolution on the effectiveness of pixel-based visualization

Pixel-based visualization is a popular method of conveying large amounts of numerical data graphically. Application scenarios include business and finance, bioinformatics and remote sensing. In this work, we examined how the usability of such visual representations varied across different tasks and block resolutions. The main stimuli consisted of temporal pixel-based visualization with a white-red color map, simulating monthly temperature variation over a six-year period. In the first study, we included 5 separate tasks to exert different perceptual loads. We found that performance varied considerably as a function of task, ranging from 75% correct in low-load tasks to below 40% in high-load tasks. There was a small but consistent effect of resolution, with the uniform patch improving performance by around 6% relative to higher block resolution. In the second user study, we focused on a high-load task for evaluating month-to-month changes across different regions of the temperature range. We tested both CIE L*u*v* and RGB color spaces. We found that the nature of the change-evaluation errors related directly to the distance between the compared regions in the mapped color space. We were able to reduce such errors by using multiple color bands for the same data range. In a final study, we examined more fully the influence of block resolution on performance, and found block resolution had a limited impact on the effectiveness of pixel-based visualization.peer-reviewe

Nonnative SOD1 trimer is toxic to motor neurons in a model of amyotrophic lateral sclerosis

Protein aggregation is a hallmark of neurodegenerative disease and is hypothesized to cause neuron death. Despite extensive study of disease-associated aggregating proteins, mechanisms of neuron death remain a mystery, and no cures or effective treatments yet exist. Here, we demonstrate the toxicity of a small aggregate of the Cu,Zn superoxide dismutase (SOD1) protein, associated with amyotrophic lateral sclerosis (ALS). We present an experimentally verified structural model of this toxic species and show that SOD1 mutants designed to promote formation of this aggregate increase cell death, providing a direct link between aggregate presence and neuron death. Knowledge of toxic species and the ability to manipulate their formation provides a valuable direction for pursuit of therapeutic strategies in ALS

TimiRGeN: R/Bioconductor package for time series microRNA-mRNA integration and analysis

Motivation: The analysis of longitudinal datasets and construction of gene regulatory networks (GRNs) provide a valuable means to disentangle the complexity of microRNA (miRNA)-mRNA interactions. However, there are no computational tools that can integrate, conduct functional analysis and generate detailed networks from longitudinal miRNA-mRNA datasets. Results: We present TimiRGeN, an R package that uses time point-based differential expression results to identify miRNA-mRNA interactions influencing signaling pathways of interest. miRNA-mRNA interactions can be visualized in R or exported to PathVisio or Cytoscape. The output can be used for hypothesis generation and directing in vitro or further in silico work such as GRN construction

Biallelic deleterious germline SH2B3 variants cause a novel syndrome of myeloproliferation and multi-organ autoimmunity

SH2B3 is a negative regulator of multiple cytokine receptor signalling pathways in haematopoietic tissue. To date, a single kindred has been described with germline biallelic loss-of-function SH2B3 variants characterized by early onset developmental delay, hepatosplenomegaly and autoimmune thyroiditis/hepatitis. Herein, we described two further unrelated kindreds with germline biallelic loss-of-function SH2B3 variants that show striking phenotypic similarity to each other as well as to the previous kindred of myeloproliferation and multi-organ autoimmunity. One proband also suffered severe thrombotic complications. CRISPR-Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifest significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype. Treatment of the sh2b3 crispant fish with ruxolitinib intercepted this myeloproliferative phenotype. Skin-derived fibroblasts from one patient demonstrated increased phosphorylation of JAK2 and STAT5 after stimulation with IL-3, GH, GM-CSF and EPO compared to healthy controls. In conclusion, these additional probands and functional data in combination with the previous kindred provide sufficient evidence for biallelic homozygous deleterious variants in SH2B3 to be considered a valid gene-disease association for a clinical syndrome of bone marrow myeloproliferation and multi-organ autoimmune manifestations

Modelling the Role of the Hsp70/Hsp90 System in the Maintenance of Protein Homeostasis

Neurodegeneration is an age-related disorder which is characterised by the accumulation of aggregated protein and neuronal cell death. There are many different neurodegenerative diseases which are classified according to the specific proteins involved and the regions of the brain which are affected. Despite individual differences, there are common mechanisms at the sub-cellular level leading to loss of protein homeostasis. The two central systems in protein homeostasis are the chaperone system, which promotes correct protein folding, and the cellular proteolytic system, which degrades misfolded or damaged proteins. Since these systems and their interactions are very complex, we use mathematical modelling to aid understanding of the processes involved. The model developed in this study focuses on the role of Hsp70 (IPR00103) and Hsp90 (IPR001404) chaperones in preventing both protein aggregation and cell death. Simulations were performed under three different conditions: no stress; transient stress due to an increase in reactive oxygen species; and high stress due to sustained increases in reactive oxygen species. The model predicts that protein homeostasis can be maintained during short periods of stress. However, under long periods of stress, the chaperone system becomes overwhelmed and the probability of cell death pathways being activated increases. Simulations were also run in which cell death mediated by the JNK (P45983) and p38 (Q16539) pathways was inhibited. The model predicts that inhibiting either or both of these pathways may delay cell death but does not stop the aggregation process and that eventually cells die due to aggregated protein inhibiting proteasomal function. This problem can be overcome if the sequestration of aggregated protein into inclusion bodies is enhanced. This model predicts responses to reactive oxygen species-mediated stress that are consistent with currently available experimental data. The model can be used to assess specific interventions to reduce cell death due to impaired protein homeostasis

Modification and preservation of environmental signals in speleothems

Speleothems are primarily studied in order to generate archives of climatic change and results have led to significant advances in identifying and dating major shifts in the climate system. However, the climatological meaning of many speleothem records cannot be interpreted unequivocally; this is particularly so for more subtle shifts and shorter time periods, but the use of multiple proxies and improving understanding of formation mechanisms offers a clear way forward. An explicit description of speleothem records as time series draws attention to the nature and importance of the signal filtering processes by which the weather, the seasons and longer-term climatic and other environmental fluctuations become encoded in speleothems. We distinguish five sources of variation that influence speleothem geochemistry: atmospheric, vegetation/soil, karstic aquifer, primary speleothem crystal growth and secondary alteration and give specific examples of their influence. The direct role of climate diminishes progressively through these five factors. \ud \ud We identify and review a number of processes identified in recent and current work that bear significantly on the conventional interpretation of speleothem records, for example: \ud \ud 1) speleothem geochemistry can vary seasonally and hence a research need is to establish the proportion of growth attributable to different seasons and whether this varies over time. \ud \ud 2) whereas there has traditionally been a focus on monthly mean Ã�´18O data of atmospheric moisture, current work emphasizes the importance of understanding the synoptic processes that lead to characteristic isotope signals, since changing relative abundance of different weather types might 1Corresponding author, fax +44(0)1214145528, E-mail: [email protected] control their variation on the longer-term. \ud \ud 3) the ecosystem and soil zone overlying the cave fundamentally imprint the carbon and trace element signals and can show characteristic variations with time. \ud \ud 4) new modelling on aquifer plumbing allows quantification of the effects of aquifer mixing. \ud \ud 5) recent work has emphasized the importance and seasonal variability of CO2-degassing leading to calcite precipitation upflow of a depositional site on carbon isotope and trace element composition of speleothems. \ud \ud 6) Although much is known about the chemical partitioning between water and stalagmites, variability in relation to crystal growth mechanisms and kinetics is a research frontier. \ud \ud 7) Aragonite is susceptible to conversion to calcite with major loss of chemical information, but the controls on the rate of this process are obscure. \ud \ud Analytical factors are critical to generate high-resolution speleothem records. A variety of methods of trace element analysis are available, but standardization is a common problem with the most rapid methods. New stable isotope data on Irish stalagmite CC3 compares rapid laser-ablation techniques with the conventional analysis of micromilled powders and ion microprobe methods. A high degree of comparability between techniques for Ã�´18O is found on the mm-cm scale, but a previously described high-amplitude oxygen isotope excursion around 8.3 ka is identified as an analytical artefact related to fractionation of the laser-analysis associated with sample cracking. High-frequency variability of not less than 0.5o/oo may be an inherent feature of speleothem Ã�´18O records