The microanatomy of calcium stores in human neutrophils, Relationship of structure to function

As changes in cytosoiic free ca2+ play key roles in coupling responses in neutrophils, it is important to locate and identify ca2+ storage sites within these cells. Here, recent data is presented which highlights the functional link between rnicroanatomical structure and cell signailing function. Fluorescent opticai probes for cytosolic free ca2+ have been used, together with organelle specific markers. We present evidence from conventional fluorescence microscopy, together with ratiometric and confocal laser scanning fluorescence microscopy, which pin-points two celiular locations for ca2+ within the neutrophil; one within the nuclear lobes, and the other towards the ceii periphery. Knowledge of these two locations provides a clear insight into how signailing in this cell type is regulated and provides a framework for explaining how specific stimuli act to produce specific responses

Exclusion of exogenous phosphatidylinositol‐3,4,5‐trisphosphate from neutrophil‐polarizing pseudopodia: stabilization of the uropod and cell polarity

Although there is accumulating evidence that the generation and localization of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) have important functions in neutrophil polarization and chemotaxis, the mechanism of this linkage has yet to be established. Here, using exogenous fluorescent PtdIns(3,4,5)P(3) introduced into the inner leaflet of the neutrophil plasma membrane by a cationic carrier, we show that: first, PtdIns(3,4,5)P(3) uniformly delivered to the neutrophil plasma membrane is excluded from newly forming pseudopodia; second, PtdIns(3,4,5)P(3) translocates to and is immobilized at the pole opposite a stable polarizing pseudopod; third, asymmetric delivery of PtdIns(3,4,5)P(3) to the neutrophil triggers the generation of polarizing pseudopodia at the opposite pole; and finally, PtdIns(3,4,5)P(3) triggers repetitive Ca(2+) signals, the onset of which precedes morphological polarization. These data suggest that translocation and immobilization of PtdIns(3,4,5)P(3) or a 3,x-phosphorylated metabolite in the uropod functions as an important polarization cue that defines neutrophil polarity and stabilizes the generation of pseudopodia at the opposite pole

THE SYSTEMATIC RISK OF DEBT: AUSTRALIAN EVIDENCE *

This paper examines systematic risk (betas) of Australian government debt securities for the period 1979-2004 and makes three contributions to academic research and practical debate. First, the empirical work provides direct evidence on the systematic risk of government debt, and provides a benchmark for estimating the systematic risk of corporate debt which is relevant for cost of capital estimation and for optimal portfolio selection by asset managers such as superannuation funds. Second, analysis of reasons for non-zero (and time varying) betas for fixed income securities aids understanding of the primary sources of systematic risk. Third, the results cast light on the appropriate choice of maturity of risk free interest rate for use in the Capital Asset Pricing Model and have implications for the current applicability of historical estimates of the market risk premium. Debt betas are found to be, on average, significantly positive and (as expected) closely related, cross sectionally, to duration. They are, however, subject to significant time series variation, and over the past few years the pre-existing positive correlation between bond and stock returns appears to have vanished. Copyright Blackwell Publishing Ltd/ University of Adelaide and Flinders University 2005..