28 research outputs found
The influence of microstructure and residual stress on pre-yield cracking in TiAl-based alloys
The influence of microstructure and residual stress on pre-yield cracking in TiAl-based alloys
Farnesyltransferase and geranylgeranyltransferase I inhibitors in cancer therapy: important mechanistic and bench to bedside issues
Evidence for a spike in mantle carbon outgassing during the Ediacaran period
© 2017 The Author(s). Long-term cycles in Earth\u27s climate are thought to be primarily controlled by changes in atmospheric CO2 concentrations. Changes in carbon emissions from volcanic activity can create an imbalance in the carbon cycle. Large-scale changes in volcanic activity have been inferred from proxies such as the age abundance of detrital zircons, but the magnitude of carbon emissions depends on the style of volcanism as well as the amount. Here we analyse U-Pb age and trace element data of detrital zircons from Antarctica and compare the results with the global rock record. We identify a spike in CO2-rich carbonatite and alkaline magmatism during the Ediacaran period. Before the Ediacaran, secular cooling of the mantle and the advent of cooler subduction regimes promoted the sequestration of carbon derived from decarbonation of subducting oceanic slabs in the mantle. We infer that subsequent magmatism led to the extensive release of carbon that may at least in part be recorded in the Shuram-Wonoka carbon isotope excursion. We therefore suggest that this pulse of alkaline volcanism reflects a profound reorganization of the Neoproterozoic deep and surface carbon cycles and promoted planetary warming before the Cambrian radiation
Plasma membrane nanoswitches generate high-fidelity Ras signal transduction
Ras proteins occupy dynamic plasma membrane nanodomains called nanoclusters. The significance of this spatial organization is unknown. Here we show, using in silico and in vivo analyses of mitogen-activated protein (MAP) kinase signalling, that Ras nanoclusters operate as sensitive switches, converting graded ligand inputs into fixed outputs of activated extracellular signal-regulated kinase (ERK). By generating Ras nanoclusters in direct proportion to ligand input, cells build an analogue–digital–analogue circuit relay that transmits a signal across the plasma membrane with high fidelity. Signal transmission is completely dependent on Ras spatial organization and fails if nanoclustering is abrogated. A requirement for high-fidelity signalling may explain the non-random distribution of other plasma membrane signalling complexes
Standardization of the antibody-dependent respiratory burst assay with human neutrophils and Plasmodium falciparum malaria
The assessment of naturally-acquired and vaccine-induced immunity to blood-stage Plasmodium falciparum malaria is of long-standing interest. However, the field has suffered from a paucity of in vitro assays that reproducibly measure the anti-parasitic activity induced by antibodies in conjunction with immune cells. Here we optimize the antibody-dependent respiratory burst (ADRB) assay, which assesses the ability of antibodies to activate the release of reactive oxygen species from human neutrophils in response to P. falciparum blood-stage parasites. We focus particularly on assay parameters affecting serum preparation and concentration, and importantly assess reproducibility. Our standardized protocol involves testing each serum sample in singlicate with three independent neutrophil donors, and indexing responses against a standard positive control of pooled hyper-immune Kenyan sera. The protocol can be used to quickly screen large cohorts of samples from individuals enrolled in immuno-epidemiological studies or clinical vaccine trials, and requires only 6 μL of serum per sample. Using a cohort of 86 samples, we show that malaria-exposed individuals induce higher ADRB activity than malaria-naïve individuals. The development of the ADRB assay complements the use of cell-independent assays in blood-stage malaria, such as the assay of growth inhibitory activity, and provides an important standardized cell-based assay in the field