Colony-stimulating-factor-1 (CSF-1) signaling through cFMS receptor kinase is increased in several diseases. To help investigate the role of cFMS kinase in disease, we identified GW2580, an orally bioavailable inhibitor of cFMS kinase. GW2580 completely inhibited human cFMS kinase in vitro at 0.06 M and was inactive against 26 other kinases. GW2580 at 1 M completely inhibited CSF-1-induced growth of mouse M-NFS-60 myeloid cells and human monocytes and completely inhibited bone degradation in cultures of human osteoclasts, rat calvaria, and rat fetal long bone. In contrast, GW2580 did not affect the growth of mouse NS0 lymphoblastoid cells, human endothelial cells, human fibroblasts, or five human tumor cell lines. GW2580 also did not affect lipopolysaccharide (LPS)-induced TNF, IL-6, and prostaglandin E2 production in freshly isolated human monocytes and mouse macrophages. After oral administration, GW2580 blocked the ability of exogenous CSF-1 to increase LPS-induced IL-6 production in mice, inhibited the growth of CSF-1-dependent M-NFS-60 tumor cells in the peritoneal cavity, and diminished the accumulation of macrophages in the peritoneal cavity after thioglycolate injection. Unexpectedly, GW2580 inhibited LPS-induced TNF production in mice, in contrast to effects on monocytes and macrophages in vitro. In conclusion, GW2580's selective inhibition of monocyte growth and bone degradation is consistent with cFMS kinase inhibition. The ability of GW2580 to chronically inhibit CSF-1 signaling through cFMS kinase in normal and tumor cells in vivo makes GW2580 a useful tool in assessing the role of cFMS kinase in normal and disease processes.CSF-1 ͉ macrophage colony-stimulating factor

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Zircon (U-Th)/He thermochronometry is an established radiometric dating technique used to place temporal constraints on a range of thermally sensitive geological events, such as crustal exhumation, volcanism, meteorite impact, and ore genesis. Isotopic, crystallographic, and/or mineralogical heterogeneities within analyzed grains can result in dispersed or anomalous (U-Th)/He ages. Understanding the effect of these grain-scale phenomena on the distribution of He in analyzed minerals should lead to improvements in data interpretation. We combine laser ablation microsampling and noble gas and trace element mass spectrometry to provide the first twodimensional, grain-scale zircon He "maps" and quantify intragrain He distribution. These maps illustrate the complexity of intracrystalline He distribution in natural zircon and, combined with a correlated quantification of parent nuclide (U and Th) distribution, provide an opportunity to assess a number of crystal chemistry processes that can generate anomalous zircon (U-Th)/He ages. The technique provides new insights into fluid inclusions as potential traps of radiogenic He and confirms the effect of heterogeneity in parent-daughter isotope abundances and metamictization on (U-Th)/He systematics. Finally, we present a new inversion method where the He, U, and Th mapping data can be used to constrain the high-and low-temperature history of a single zircon crystal.