864 research outputs found

    Church Island : a Description

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    Indentation Plastometry for Study of Anisotropy and Inhomogeneity in Maraging Steel Produced by Laser Powder Bed Fusion

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    This work concerns the use of profilometry-based indentation plastometry (PIP) to obtain mechanical property information for maraging steel samples produced via an additive manufacturing route (laser powder bed fusion). Bars are produced in both “horizontal” (all material close to the build plate) and “vertical” (progressively increasing distance from the build plate) configurations. Samples are mechanically tested in both as-built and age-hardened conditions. Stress–strain curves from uniaxial testing (tensile and compressive) are compared with those from PIP testing. Tensile test data suggest significant anisotropy, with the horizontal direction harder than the vertical direction. However, systematic compressive tests, allowing curves to be obtained for both build and transverse directions in various locations, indicate that there is no anisotropy anywhere in these materials. This is consistent with electron backscattered diffraction results, indicating that there is no significant texture in these materials. It is also consistent with the outcomes of PIP testing, which can detect anisotropy with high sensitivity. Furthermore, both PIP testing and compression testing results indicate that the changing growth conditions at different distances from the build plate can lead to strength variations. It seems likely that what has previously been interpreted as anisotropy in the tensile response is in fact due to inhomogeneity of this type

    Haemolysis and haem oxygenase-1 induction during persistent "asymptomatic" malaria infection in Burkinabé children

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    BACKGROUND: The haemolysis associated with clinical episodes of malaria results in the liberation of haem, which activates the enzyme haem oxygenase-1 (HO-1). HO-1 has been shown to reduce neutrophil function and increase susceptibility to invasive bacterial disease. However, the majority of community-associated malaria infections are subclinical, often termed "asymptomatic" and the consequences of low-grade haemolysis during subclinical malaria infection are unknown. STUDY DESIGN AND RESULTS: As part of an ongoing study of subclinical malaria in Burkina Faso, 23 children with subclinical Plasmodium falciparum infections (determined by qPCR) were compared with 21 village-matched uninfected control children. Infected children showed evidence of persistent haemolysis over 35 days, with raised plasma haem and HO-1 concentrations. Concentrations of IL-10, which can also directly activate HO-1, were also higher in infected children compared to uninfected children. Regression analysis revealed that HO-1 was associated with haemolysis, but not with parasite density, anaemia or IL-10 concentration. CONCLUSIONS: This study reveals that subclinical P. falciparum malaria infection is associated with sustained haemolysis and the induction of HO-1. Given the association between HO-1, neutrophil dysfunction and increased risk of Salmonella bacteraemia, prolonged HO-1 induction may explain epidemiological associations and geographic overlap between malaria and invasive bacterial disease. Further studies are needed to understand the consequences of persistent subclinical malaria infection, low-grade haemolysis and raised HO-1 on immune cell function and risk of comorbidities

    Tracking an exotic raw material: Aboriginal movement through the Blue Mountains, Sydney, NSW during the Terminal Pleistocene

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    A compliance-based excavation on Parramatta River (western Sydney) found evidence of a brief visitation by Aboriginal people during the terminal Pleistocene (c.14 ka), from which an exotic raw material–medium-grained porphyroblastic andalusite-cordierite hornfels–was recovered. This raw material is rare in the region, only found in the Megalong Valley situated some 75 km west of the site in Parramatta, and separated from the site by the Blue Mountains–a 40 km wide, 1 km high dissected sandstone upland. Historical observations and geological evidence suggest that the Coxs River, which runs through the upland, formed the probable connection between the two locales. The formation of the site at c.14 ka, along with our broader understanding of the region, suggests that the upland was only explored after the Last Glacial Maximum (LGM) and that the Great Dividing Range may have formed a significant barrier to early peopling of Sahul. Further, a delay between the end of the LGM and the exploration of the region implies populations were severely affected by the event and required considerable time to recover. The coincident timing of rapid sea-level rise from Meltwater Phase Pulse 1A and an increased supply of moisture associated with the Antarctic Climate Reversal at the time of many site initiations may have been factors in the upland and south west slopes visitation. Finally, the movement of the unusual hornfels artefact provides a coarse indication of the ranging territory for hunter-gatherers living in a temperate region (c. 8,000 km2) at this time. This is probably a lower estimate but begins to provide a quantitative value with which to begin to ratify the increasing divergence between archaeological and genomic studies in their definitions of mobility, sedentism and regional nomadism

    Identification of Pharmacodynamic Transcript Biomarkers in Response to FGFR Inhibition by AZD4547

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    The challenge of developing effective pharmacodynamic biomarkers for preclinical and clinical testing of FGFR signaling inhibition is significant. Assays that rely on the measurement of phospho-protein epitopes can be limited by the availability of effective antibody detection reagents. Transcript profiling enables accurate quantification of many biomarkers and provides a broader representation of pathway modulation. To identify dynamic transcript biomarkers of FGFR signaling inhibition by AZD4547, a potent inhibitor of FGF receptors 1, 2, and 3, a gene expression profiling study was performed in FGFR2-amplified, drug-sensitive tumor cell lines. Consistent with known signaling pathways activated by FGFR, we identified transcript biomarkers downstream of the RAS-MAPK and PI3K/AKT pathways. Using different tumor cell lines in vitro and xenografts in vivo, we confirmed that some of these transcript biomarkers (DUSP6, ETV5, YPEL2) were modulated downstream of oncogenic FGFR1, 2, 3, whereas others showed selective modulation only by FGFR2 signaling (EGR1). These transcripts showed consistent time-dependent modulation, corresponding to the plasma exposure of AZD4547 and inhibition of phosphorylation of the downstream signaling molecules FRS2 or ERK. Combination of FGFR and AKT inhibition in an FGFR2-mutated endometrial cancer xenograft model enhanced modulation of transcript biomarkers from the PI3K/AKT pathway and tumor growth inhibition. These biomarkers were detected on the clinically validated nanoString platform. Taken together, these data identified novel dynamic transcript biomarkers of FGFR inhibition that were validated in a number of in vivo models, and which are more robustly modulated by FGFR inhibition than some conventional downstream signaling protein biomarkers

    Retaining individualities : the photodynamics of self-ordering porphyrin assemblies

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    YesThe retention of photochemical properties of individual chromophores is a key feature of biological light harvesting complexes. This is achieved despite extensive aggregation of the chromophores, which in synthetic chromophore assemblies often yields a change in spectral characteristics. As an alternative approach towards mimicking biological light harvesting complexes, we report the synthesis of porphyrin assemblies which retained the photochemical properties of the individual chromophore units despite their substantial aggregation. These new materials highlight a new bottom-up approach towards the design and understanding of more complex biomimetic and naturally occurring biological systems.Seventh Framework Programme (European Commission) (FP7), Engineering and Physical Sciences Research Council (EPSRC), Royal Society (Great Britain

    The Use of a Pressure-Indicating Sensor Film to Provide Feedback upon Hydrogel-Forming Microneedle Array Self-Application In Vivo

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    PURPOSE:To evaluate the combination of a pressure-indicating sensor film with hydrogel-forming microneedle arrays, as a method of feedback to confirm MN insertion in vivo.METHODS:Pilot in vitro insertion studies were conducted using a Texture Analyser to insert MN arrays, coupled with a pressure-indicating sensor film, at varying forces into excised neonatal porcine skin. In vivo studies involved twenty human volunteers, who self-applied two hydrogel-forming MN arrays, one with a pressure-indicating sensor film incorporated and one without. Optical coherence tomography was employed to measure the resulting penetration depth and colorimetric analysis to investigate the associated colour change of the pressure-indicating sensor film.RESULTS:Microneedle insertion was achieved in vitro at three different forces, demonstrating the colour change of the pressure-indicating sensor film upon application of increasing pressure. When self-applied in vivo, there was no significant difference in the microneedle penetration depth resulting from each type of array, with a mean depth of 237 μm recorded. When the pressure-indicating sensor film was present, a colour change occurred upon each application, providing evidence of insertion.CONCLUSIONS:For the first time, this study shows how the incorporation of a simple, low-cost pressure-indicating sensor film can indicate microneedle insertion in vitro and in vivo, providing visual feedback to assure the user of correct application. Such a strategy may enhance usability of a microneedle device and, hence, assist in the future translation of the technology to widespread clinical use
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