NEW TECHNIQUES FOR TRACE ELEMENT AND RADIOGENIC ISOTOPE MEASUREMENT OF DIAMONDS: THEIR APPLICATION TO DIAMOND PETROGENESIS AND SOURCE TRACING

To investigate impurities in diamond we have developed an offline laser ablation method to acquire radiogenic isotope compositions and quantitative trace element determinations on diamond. This information has the potential to be used as both a petrogenetic tracer and as a tool in determining the geographic region of origin of particular diamonds. Trace element abundances are determined by sector-field ICPMS and isotope ratios are analysed via TIMS (Sr) and multi-collector ICPMS (Nd-Pb). To report quantitative trace element data the analyte mass we require from a given ablated sample volume is <1 pg for most elements, except for Sr, Zr, Ba which require between 2 – 30 pg, and for Pb ~40 pg. Diamonds show broad LILE and LREE enrichment and HFSE and HREE depletion. Trace element systematics in fibrous diamonds are mimicked in monocrystalline diamonds. Monocrystalline diamonds display 87Sr/86Sr(i) = 0.7014±0.0010 to 0.70864±0.00004 and fibrous diamonds display 87Sr/86Sr(i) = 0.70386±0.00005 to 0.712406±0.00007. The isotope data show no defined isochron systematics that could be used for dating purposes. The parental fluids of fibrous and monocrystalline diamonds are thought to be derived through a similar multi-component mechanism. Diamond formation will result from the interaction between 1) a primitive, volatile and carbonate-rich, silicate liquid with an unradiogenic Sr signature ascending from the asthenosphere and 2) other components with more radiogenic Sr, akin to more ancient, enriched and vein-dominated lower lithosphere e.g. glimmerite/ PIC assemblages and the sources of Group II kimberlites. We have demonstrated, using >100 diamonds from the Ekati, Diavik, Snap Lake and Congo kimberlites, that statistical processing of data using analysis of variance and logistic regression can allow source discrimination of ‘unknown’ samples. For logistic regression the most successful models focus on differences in Nb, Eu, Rb and Th data. This method shows good potential for use in a diamond fingerprinting programme

THE ROLES OF PI3K AND MAPK PATHWAY MUTATIONS IN GLIOMAGENESIS AND RESPONSE TO TARGETED INHIBITION

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, and even with treatment, its median survival is only 12-15 months. Molecular analyses by The Cancer Genome Atlas and others have identified the genetics underlying GBM pathogenesis, but this knowledge has yet to influence therapy. The receptor tyrosine kinase (RTK) pathway is frequently mutated in GBM, including its phosphoinositide-3-kinase (PI3K) and mitogen activated protein kinase (MAPK) effector arms. Because of their mutational frequency and established role in GBM pathogenesis, these pathways are important therapeutic targets. However, results from clinical investigations of inhibitors targeting RTK/PI3K/MAPK signaling in GBM have been disappointing. The primary aim of this dissertation was to determine how PI3K and MAPK pathway mutations influence response to targeted inhibition. We previously developed a series of non-germline genetically engineered mouse (nGEM) models in which PI3K and/or MAPK signaling were activated in immortalized astrocytes (T) by deletion of Pten (P) and expression of a constitutively active Kras mutant (R), respectively. We used these models to define how PI3K/MAPK mutations and drug potency influence signaling dynamics, efficacy, and synergism of PI3K and MEK inhibitors. We found that PI3K/MAPK signaling are alternate bypass pathways that promote resistance to inhibition of either pathway alone. Pten/Kras mutation status and drug potency interacted to influence single agent efficacy and PI3K/MEK inhibitor synergism. Subcutaneous TRP allografts were most sensitive to dual PI3K/MEK inhibitor treatment, but target inhibition and efficacy were limited in orthotopic allografts. PIK3CA missense mutations frequently occur in GBM, but their role in disease pathogenesis had not been experimentally validated. We therefore transduced immortalized, normal human astrocytes with lentiviral vectors encoding wild-type or mutant PIK3CA. We showed that mutations in the helical or kinase domains of PIK3CA activate PI3K signaling and cooperate with mutant RAS to potentiate gliomagenesis in orthotopic xenografts. PIK3CA mutations did not affect PI3K inhibitor efficacy, but they influenced synergism with MEK inhibition. Taken together, the work described here explored how PI3K and MAPK mutations altered response to targeted inhibition, and will inform future research into predictive biomarkers and rationale combination therapies.Doctor of Philosoph

Matthew Gandy. The Fabric of Space: Water, Modernity, and the Urban Imagination.

Matthew Gandy is a geographer at University College London whose work focuses on cities, how they work, and how their workings are represented in art and literature. His first book, entitled Concrete and Clay (2002), about New York, won a prize. Since its appearance, he has published dozens of articles and several edited books, and his output has earned him election to the British Academy. This latest book concerns six big cities at various points in their recent history: Paris, Berlin, Lagos, Mumbai, Los Angeles, and London

Long-Term Measurements of Ground Motions Offshore

Long-Term measurements of earthquake ground motions offshore, using the Sandia National Laboratories\u27 SEMS device which records only the strongest motions and transmits them upon command to a boat at the surface, have shown that offshore ground motions may in certain cases be substantially different from empirically predicted ground motions based on onshore data. In particular, the attenuation effects of soft and/or gassy soils, the wedging of offshore deposits as a function of direction to and distance from the source, and sharp velocity-depth profiles, are shown to be possible actors contributing to such differences. For the well constrained recording to date, the offshore ground motions are only 13 to 23 percent of those which would be calculated using empirical predictions based on onshore data. To address this situation, Sandia has installed a net of three long-lived (SEMS), two of them in the vicinity of instrumented platforms, in the Sandia Barbara Channel. The results are intended to evaluate the earthquake hazards of offshore energy developments and to provide firm data on the design parameters required for the harvesting of 0ffshore energy resources

Extreme asteroids in the Pan-STARRS 1 Survey

Using the first 18 months of the Pan-STARRS 1 survey we have identified 33 candidate high-amplitude objects for follow-up observations and carried out observations of 22 asteroids. 4 of the observed objects were found to have observed amplitude $A_{obs}\geq 1.0$ mag. We find that these high amplitude objects are most simply explained by single rubble pile objects with some density-dependent internal strength, allowing them to resist mass shedding even at their highly elongated shapes. 3 further objects although below the cut-off for 'high-amplitude' had a combination of elongation and rotation period which also may require internal cohesive strength, depending on the density of the body. We find that none of the 'high-amplitude asteroids' identified here require any unusual cohesive strengths to resist rotational fission. 3 asteroids were sufficiently observed to allow for shape and spin pole models to be determined through light curve inversion. 45864 was determined to have retrograde rotation with spin pole axes $\lambda=218\pm 10^{\circ}, \beta=-82\pm 5^{\circ}$ and asteroid 206167 was found to have best fit spin pole axes $\lambda= 57 \pm 5^{\circ}$, $\beta=-67 \pm 5^{\circ}$. An additional object not initially measured with $A_{obs}>1.0$ mag, 49257, was determined to have a shape model which does suggest a high-amplitude object. Its spin pole axes were best fit for values $\lambda=112\pm 6^{\circ}, \beta=6\pm 5^{\circ}$. In the course of this project to date no large super-fast rotators ($P_{rot} < 2.2$ h) have been identified.Comment: 31 pages; accepted by A

The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses

SummaryThe molecular mechanisms whereby the CD45 tyrosine phosphatase (PTPase) regulates T cell receptor (TCR) signaling responses remain to be elucidated. To investigate this question, we have reconstituted CD45 (encoded by Ptprc)-deficient mice, which display severe defects in thymic development, with five different expression levels of transgenic CD45RO, or with mutant PTPase null or PTPase-low CD45R0. Whereas CD45 PTPase activity was absolutely required for the reconstitution of thymic development, only 3% of wild-type CD45 activity restored T cell numbers and normal cytotoxic T cell responses. Lowering the CD45 expression increased CD4 lineage commitment. Peripheral T cells with very low activity of CD45 phosphatase displayed reduced TCR signaling, whereas intermediate activity caused hyperactivation of CD4+ and CD8+ T cells. These results are explained by a rheostat mechanism whereby CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56lck tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56lck pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity

Criteria for Side-Force Control in Air-to-Ground Target Acquisition and Tracking

A moving-base simulator experiment conducted at Ames Research Center demonstrated that a wings-level-turn control mode improved flying qualities for air-to-ground weapons delivery compared with those of a conventional aircraft. Evaluations of criteria for dynamic response for this system have shown that pilot ratings correlate well with equivalent time constant of the initial response and with system bandwidth. Ranges of this time constant, as well as digital-system transport delays and lateral-acceleration control authorities that encompassed level 1 through level 3 handling qualities, were determined

Is the use of electronic cigarettes while smoking associated with smoking cessation attempts, cessation and reduced cigarette consumption? A survey with a 1-year follow-up

To use a unique longitudinal data set to assess the association between e-cigarette use while smoking with smoking cessation attempts, cessation and substantial reduction, taking into account frequency of use and key potential confounders

Limiting Swine Stress with Evaporative Cooling in the Southeast

Three-hourly weather data for 7 locations in the Southeast and Central United States were used to evaluate the feasibility of evaporative cooling for reducing swine stress. Stress was defined as a relationship between dry and wet bulb temperatures which exceeded a stress index of 85. This analysis indicates that properly installed evaporative coolers could reduce the number of hours that stress would occur in swine facilities from 89.6 to 96.4% depending on location