Abstract. The National Aeronautic and Space Administration (NASA) plans to launch the moderate resolution imaging spectroradiometer (MEDIS) on the polarorbiting Earth Observation System (EeS) providing morning and evening global observations in 1999 and afternoon and night observations in 2000. These four MEDIS daily fire observations will advance global fire monitoring with special 1 km resolution fire channels at 4 and 11 /xm, with high saturation of about 450 and 400 K, respectively. MEDIS data will also be used to monitor burn scars, vegetation type and condition, smoke aerosols, water vapor, and clouds for overall monitoring of the fire process and its effects on ecosystems, the atmosphere, and the climate. The MEDIS fire science team is preparing algorithms that use the thermal signature to separate the fire signal from the background signal. A database of active fire products will be generated and archived at a 1 km resolution and summarized on a grid of 10 km and 0.5 ø, daily, 8 days, and monthly. It includes the fire occurrence and location, the rate of emission of thermal energy from the fire, and a rough estimate of the smoldering/flaming ratio. This information will be used in monitoring the spatial and temporal distribution of fires in different ecosystems, detecting changes in fire distribution and identifying new fire frontiers, wildfires, and changes in the frequency of the fires or their relative strength. We plan to combine the MEDIS fire measurements with a detailed diurnal cycle of the fires from geostationary satellites. Sensitivity studies and analyses of aircraft and satellite data from the Yellowstone wildfire of 1988 and prescribed fires in the Smoke, Clouds, and Radiation (SCAR) aircraft field experiments are used to evaluate and validate the fire algorithms and to establish the relationship between the fire thermal properties, the rate of biomass consumption, and the emissions of aerosol and trace gases from fires.
Recent genetic knock-in and pharmacological approaches have suggested that, of class IA PI3Ks (phosphatidylinositol 3-kinases), it is the p110alpha isoform (PIK3CA) that plays the predominant role in insulin signalling. We have used isoform-selective inhibitors of class IA PI3K to dissect further the roles of individual p110 isoforms in insulin signalling. These include a p110alpha-specific inhibitor (PIK-75), a p110alpha-selective inhibitor (PI-103), a p110beta-specific inhibitor (TGX-221) and a p110delta-specific inhibitor (IC87114). Although we find that p110alpha is necessary for insulin-stimulated phosphorylation of PKB (protein kinase B) in several cell lines, we find that this is not the case in HepG2 hepatoma cells. Inhibition of p110beta or p110delta alone was also not sufficient to block insulin signalling to PKB in these cells, but, when added in combination with p110alpha inhibitors, they are able to significantly attenuate insulin signalling. Surprisingly, in J774.2 macrophage cells, insulin signalling to PKB was inhibited to a similar extent by inhibitors of p110alpha, p110beta or p110delta. These results provide evidence that p110beta and p110delta can play a role in insulin signalling and also provide the first evidence that there can be functional redundancy between p110 isoforms. Further, our results indicate that the degree of functional redundancy is linked to the relative levels of expression of each isoform in the target cells.
Genetic alterations in PI3K (phosphoinositide 3-kinase) signalling are common in cancer and include deletions in PTEN (phosphatase and tensin homologue deleted on chromosome 10), amplifications of PIK3CA and mutations in two distinct regions of the PIK3CA gene. This suggests drugs targeting PI3K, and p110α in particular, might be useful in treating cancers. Broad-spectrum inhibition of PI3K is effective in preventing growth factor signalling and tumour growth, but suitable inhibitors of p110α have not been available to study the effects of inhibiting this isoform alone. In the present study we characterize a novel small molecule, A66, showing the S-enantiomer to be a highly specific and selective p110α inhibitor. Using molecular modelling and biochemical studies, we explain the basis of this selectivity. Using a panel of isoform-selective inhibitors, we show that insulin signalling to Akt/PKB (protein kinase B) is attenuated by the additive effects of inhibiting p110α/p110β/p110δ in all cell lines tested. However, inhibition of p110α alone was sufficient to block insulin signalling to Akt/PKB in certain cell lines. The responsive cell lines all harboured H1047R mutations in PIK3CA and have high levels of p110α and class-Ia PI3K activity. This may explain the increased sensitivity of these cells to p110α inhibitors. We assessed the activation of Akt/PKB and tumour growth in xenograft models and found that tumours derived from two of the responsive cell lines were also responsive to A66 in vivo. These results show that inhibition of p110α alone has the potential to block growth factor signalling and reduce growth in a subset of tumours.
Abstract. A new method is described for calculating the amount of biomass burned, its type and location, and the time of burning. Active fires in 1989 were detected using daily advanced very high resolution radiometer (AVHRR) satellite imagery. The fire count was calibrated to area burned using a stratified sample of multitemporal multispectral scanner (MSS) imagery. The calibration factor is strongly dependent on mean individual fire area, which is in turn strongly related to cumulative normalized difference vegetation index (NDVI). The best available vegetation maps for southern hemisphere Africa were combined and reclassified into functional vegetation types with a similar fire ecology. The fuel load was calculated in each 0.5° × 0.5° grid square using a production model specific for each vegetation type, driven by monthly rainfall data. Multiyear fuel accumulation, herbivory, and decay were accounted for. Combustion completeness was modeled as a function of fuel mass and fuel type, established from field‐collected data. The method was compared to the conventional procedure for calculating biomass burned, based on classification. The estimated amount of biomass burned in vegetation fires in southern hemisphere Africa annually is 90–264 Tg dry matter (DM) by the new modeling method and 247–2719 Tg DM by the conventional classification method. The modeling method is conservative since it does not include burning due to forest clearing or the burning of agricultural waste or domestic biomass fuels, but it is believed to be more realistic than the classification method and provides space‐and‐time‐resolved output. The bulk of the burning occurs between June and September, with a peak in August. Half of the burning takes place in the broad‐leaved, low‐nutrient‐status savannas which dominate the zone between 5° and 18°S.
Active fires in southern Africa were detected using daily NOAA advanced very high resolution radiometer (AVHRR) 1‐km satellite data. The active fire distribution during the period of the SAFARI intensive field campaign in September and October 1992 is described. The distribution of fires for the period of the campaign is presented along with a comparison for the same period in 1989. For the latitudinal belt between 15° and 30°S which was affected by drought in 1992, there was an average of 49% fewer fires in 1992 than in 1989. However, most of the burning in southern Africa takes place between 5° and 20°S with peak activity between the months of July and September. The interannual variability in the amount and timing of fires was noted. The relationship between fires, rainfall, and vegetation state for the two years are described for sample locations. The extent of the 1992 drought and its impact on the occurrence of fire are also discussed.
Phosphoinositide (PI) 3-kinases play an important role in regulating the adhesive function of a variety of cell types through affinity modulation of integrins. Two type I PI 3-kinase isoforms (p110 and p110␥) have been implicated in G i -dependent integrin ␣ IIb  3 regulation in platelets, however, the mechanisms by which they coordinate their signaling function remains unknown. By employing isoform-selective PI 3-kinase inhibitors and knock-out mouse models we have identified a unique mechanism of PI 3-kinase signaling co-operativity in platelets. We demonstrate that p110 is primarily responsible for G i -dependent phosphatidylinositol 3,4-bisphosphate (PI(3,4)P 2 ) production in ADP-stimulated platelets and is linked to the activation of Rap1b and AKT. In contrast, defective integrin ␣ IIb  3 activation in p110␥ ؊/؊ platelets was not associated with alterations in the levels of PI(3,4)P 2 or active Rap1b/AKT. Analysis of the effects of active site pharmacological inhibitors confirmed that p110␥ principally regulated integrin ␣ IIb  3 activation through a non-catalytic signaling mechanism. Inhibition of the kinase function of PI 3-kinases, combined with deletion of p110␥, led to a major reduction in integrin ␣ IIb  3 activation, resulting in a profound defect in platelet aggregation, hemostatic plug formation, and arterial thrombosis. These studies demonstrate a kinaseindependent signaling function for p110␥ in platelets. Moreover, they demonstrate that the combined catalytic and non-catalytic signaling function of p110 and p110␥ is critical for P2Y 12 /G i -dependent integrin ␣ IIb  3 regulation. These findings have potentially important implications for the rationale design of novel antiplatelet therapies targeting PI 3-kinase signaling pathways.The phosphoinositide (PI) 2 3-kinases are a well defined family of lipid kinases that participate in a broad range of signaling processes downstream of growth factor, antigen, hormone, and adhesion receptors (1, 2). They are classified into several distinct groups (types I-III), based on their primary structure, mode of regulation, and substrate specificity (3, 4). The most intensely studied members of the PI 3-kinase superfamily are the type I PI 3-kinases, due to their involvement in the regulation of fundamental cell processes, including proliferation, glucose metabolism, survival, and migration (1). PI 3-kinases principally transduce signals through the catalytic generation of phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P 3 ) and phosphatidylinositol 3,4-bisphosphate (PI(3,4)P 2 ); second messengers that facilitate the recruitment of pleckstrin homology domain-containing signaling proteins to the plasma membrane (5). The type I enzymes are divided into two subtypes, Ia and Ib; type Ia isoforms include p110␣, -, and -␦ and type Ib includes a single isoform p110␥. p110␣, -, and -␦ share common regulatory subunits (p85␣, p85, p55␣, p55␥, p50␣) and are classically regulated by tyrosine kinase-linked receptors, although G protein-coupled receptor-medi...
6-Cyclohexyl-N-hydroxy-3-(1,2,4-oxadiazol-5-yl)hexanamides were previously disclosed as inhibitors of procollagen C-proteinase (PCP) culminating in the identification of amide 1. Our objective was to discover a second inhibitor that would have improved affinity for PCP and to optimize properties for transepidermal delivery (TED) to intact skin. Further investigation of this template identified a number of potent PCP inhibitors (IC50 values of 2-6 nM) with improved TED flux. Sulfonamide 56 had excellent PCP enzyme activity when measured with a peptide substrate (Ki 8.7 nM) or with the endogenous substrate procollagen (IC50 3.4 nM) and demonstrates excellent selectivity over MMPs involved in wound healing (>10 000-fold). In the fibroplasia model, 56 inhibited deposition of insoluble collagen by 76 +/- 2% at 10 microM and was very effective at penetrating human skin in vitro with a TED flux of 1.5 microg/cm2/h, which compares favorably with values for agents that are known to penetrate skin well in vivo. Based on this profile, 56 (UK-421,045) was selected as a candidate for further preclinical evaluation as a topically applied, dermal anti-scarring agent.
A structure-activity relationship (SAR) study of the pan class I PI 3-kinase inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474) identified substitution at the 4 and 6 positions of the benzimidazole ring as having significant effects on the potency of substituted derivatives. The 6-amino-4-methoxy analogue displayed a greater than 1000-fold potency enhancement over the corresponding 6-aza-4-methoxy analogue against all three class Ia PI 3-kinase enzymes (p110α, p110β, and p110δ) and also displayed significant potency against two mutant forms of the p110α isoform (H1047R and E545K). This compound was also evaluated in vivo against a U87MG human glioblastoma tumor xenograft model in Rag1(-/-) mice, and at a dose of 50 mg/kg given by ip injection at a qd × 10 dosing schedule it dramatically reduced cancer growth by 81% compared to untreated controls.
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