No abstract

The 2019/20 Black Summer bushfire disaster in southeast Australia was unprecedented: the extensive area of forest burnt, the radiative power of the fires, and the extraordinary number of fires that developed into extreme pyroconvective events were all unmatched in the historical record. Australia’s hottest and driest year on record, 2019, was characterised by exceptionally dry fuel loads that primed the landscape to burn when exposed to dangerous fire weather and ignition. The combination of climate variability and long-term climate trends generated the climate extremes experienced in 2019, and the compounding effects of two or more modes of climate variability in their fire-promoting phases (as occurred in 2019) has historically increased the chances of large forest fires occurring in southeast Australia. Palaeoclimate evidence also demonstrates that fire-promoting phases of tropical Pacific and Indian ocean variability are now unusually frequent compared with natural variability in pre-industrial times. Indicators of forest fire danger in southeast Australia have already emerged outside of the range of historical experience, suggesting that projections made more than a decade ago that increases in climate-driven fire risk would be detectable by 2020, have indeed eventuated. The multiple climate change contributors to fire risk in southeast Australia, as well as the observed non-linear escalation of fire extent and intensity, raise the likelihood that fire events may continue to rapidly intensify in the future. Improving local and national adaptation measures while also pursuing ambitious global climate change mitigation efforts would provide the best strategy for limiting further increases in fire risk in southeast Australia.

Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.