Highest ocean heat in four centuries places Great Barrier Reef in danger.

Mass coral bleaching on the Great Barrier Reef (GBR) in Australia between 2016 and 2024 was driven by high sea surface temperatures (SST)1. The likelihood of temperature-induced bleaching is a key determinant for the future threat status of the GBR2, but the long-term context of recent temperatures in the region is unclear. Here we show that the January-March Coral Sea heat extremes in 2024, 2017 and 2020 (in order of descending mean SST anomalies) were the warmest in 400 years, exceeding the 95th-percentile uncertainty limit of our reconstructed pre-1900 maximum. The 2016, 2004 and 2022 events were the next warmest, exceeding the 90th-percentile limit. Climate model analysis confirms that human influence on the climate system is responsible for the rapid warming in recent decades. This attribution, together with the recent ocean temperature extremes, post-1900 warming trend and observed mass coral bleaching, shows that the existential threat to the GBR ecosystem from anthropogenic climate change is now realized. Without urgent intervention, the iconic GBR is at risk of experiencing temperatures conducive to near-annual coral bleaching3, with negative consequences for biodiversity and ecosystems services. A continuation on the current trajectory would further threaten the ecological function4 and outstanding universal value5 of one of Earth's greatest natural wonders.

Technological drought: a new category of water scarcity.

In this paper, we argue that current definitions of drought, especially in the context of small-scale agricultural production, are incomplete. We introduce the concept of 'technological drought' to account for crop failures, reduced yields or water scarcity, which are the consequence of an inability to supplement water when there is a lack of irrigation technology and/or existing poor water management. We illustrate the diversity of causes of technological drought, which can include shortages of fuel or electricity to operate pumps, problematically high costs to access irrigation infrastructure, or constrained access to pumps that have to be shared among multiple farmers. We argue that vulnerability to technological drought can be strongly conditioned by socio-economic conditions and that its impact can be magnified when population growth and the demand for food mean that any decline in yield can have serious consequences for food security. We show that technological drought is a complex phenomenon, and can be differentiated from the more widely-recognised classes of drought (meteorological, agricultural, hydrological, and socio-economic) in multiple ways. In particular, technological drought exhibits an important dependence on the socio-economic context of agricultural production. It is perhaps most evident in developing economies, especially where agricultural output depends strongly on the capacity of individual farmers to manage crop water supply on small holdings. Technological drought can follow from even brief interruptions to monsoon rainfall during critical stages of crop growth, such that technological droughts can be distinguished from other forms of drought by their brevity.

Decadal climate variability in the tropical Pacific: Characteristics, causes, predictability, and prospects.

Climate variability in the tropical Pacific affects global climate on a wide range of time scales. On interannual time scales, the tropical Pacific is home to the El Niño­Southern Oscillation (ENSO). Decadal variations and changes in the tropical Pacific, referred to here collectively as tropical Pacific decadal variability (TPDV), also profoundly affect the climate system. Here, we use TPDV to refer to any form of decadal climate variability or change that occurs in the atmosphere, the ocean, and over land within the tropical Pacific. "Decadal," which we use in a broad sense to encompass multiyear through multidecadal time scales, includes variability about the mean state on decadal time scales, externally forced mean-state changes that unfold on decadal time scales, and decadal variations in the behavior of higher-frequency modes like ENSO.

Consistent multi-decadal variability in global temperature reconstructions and simulations over the Common Era.

Multi-decadal surface temperature changes may be forced by natural as well as anthropogenic factors, or arise unforced from the climate system. Distinguishing these factors is essential for estimating sensitivity to multiple climatic forcings and the amplitude of the unforced variability. Here we present 2,000-year-long global mean temperature reconstructions using seven different statistical methods that draw from a global collection of temperature-sensitive paleoclimate records. Our reconstructions display synchronous multi-decadal temperature fluctuations, which are coherent with one another and with fully forced CMIP5 millennial model simulations across the Common Era. The most significant attribution of pre-industrial (1300-1800 CE) variability at multi-decadal timescales is to volcanic aerosol forcing. Reconstructions and simulations qualitatively agree on the amplitude of the unforced global mean multi-decadal temperature variability, thereby increasing confidence in future projections of climate change on these timescales. The largest warming trends at timescales of 20 years and longer occur during the second half of the 20th century, highlighting the unusual character of the warming in recent decades.

Cancer cell dependence on unsaturated fatty acids implicates stearoyl-CoA desaturase as a target for cancer therapy.

Emerging literature suggests that metabolic pathways play an important role in the maintenance and progression of human cancers. In particular, recent studies have implicated lipid biosynthesis and desaturation as a requirement for tumor cell survival. In the studies reported here, we aimed to understand whether tumor cells require the activity of either human isoform of stearoyl-CoA-desaturase (SCD1 or SCD5) for survival. Inhibition of SCD1 by siRNA or a small molecule antagonist results in strong induction of apoptosis and growth inhibition, when tumor cells are cultured in reduced (2%) serum conditions, but has little impact on cells cultured in 10% serum. Depletion of SCD5 had minimal effects on cell growth or apoptosis. Consistent with the observed dependence on SCD1, but not SCD5, levels of SCD1 protein increased in response to decreasing serum levels. Both induction of SCD1 protein and sensitivity to growth inhibition by SCD1 inhibition could be reversed by supplementing growth media with unsaturated fatty acids, the product of the enzymatic reaction catalyzed by SCD1. Transcription profiling of cells treated with an SCD inhibitor revealed strong induction of markers of endoplasmic reticulum stress. Underscoring its importance in cancer, SCD1 protein was found to be highly expressed in a large percentage of human cancer specimens. SCD inhibition resulted in tumor growth delay in a human gastric cancer xenograft model. Altogether, these results suggest that desaturated fatty acids are required for tumor cell survival and that SCD may represent a viable target for the development of novel agents for cancer therapy.

Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors.

Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.

The antiangiogenic activity in xenograft models of brivanib, a dual inhibitor of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinases.

Tumor angiogenesis is a complex and tightly regulated network mediated by various proangiogenic factors. The fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) family of growth factors, and associated tyrosine kinase receptors have a major influence in tumor growth and dissemination and may work synergistically to promote angiogenesis. Brivanib alaninate is the orally active prodrug of brivanib, a selective dual inhibitor of FGF and VEGF signaling. Here, we show that brivanib demonstrates antitumor activity in a broad range of xenograft models over multiple dose levels and that brivanib alaninate shows dose-dependent efficacy equivalent to brivanib in L2987 human tumor xenografts. Brivanib alaninate (107 mg/kg) reduced tumor cell proliferation as determined by a 76% reduction in Ki-67 staining and reduced tumor vascular density as determined by a 76% reduction in anti-CD34 endothelial cell staining. Furthermore, Matrigel plug assays in athymic mice showed that brivanib alaninate inhibited angiogenesis driven by VEGF or basic FGF alone, or combined. Dynamic contrast-enhanced magnetic resonance imaging, used to assess the effects of brivanib alaninate on tumor microcirculation, showed a marked decrease in gadopentetate dimeglumine contrast agent uptake at 107 mg/kg dose, with a reduction in area under the plasma concentration-time curve from time 0 to 60 minutes at 24 and 48 hours of 54% and 64%, respectively. These results show that brivanib alaninate is an effective antitumor agent in preclinical models across a range of doses, and that efficacy is accompanied by changes in cellular and vascular activities.

Synthesis, SAR, and Evaluation of 4-[2,4-Difluoro-5-(cyclopropylcarbamoyl)phenylamino]pyrrolo[2,1-f][1,2,4]triazine-based VEGFR-2 kinase inhibitors.

Introduction of the 2,4-difluoro-5-(cyclopropylcarbamoyl)phenylamino group at the C-4 position of the pyrrolo[2,1-f][1,2,4] triazine scaffold led to the discovery of a novel sub-series of inhibitors of VEGFR-2 kinase activity. Subsequent SAR studies on the 1,3,5-oxadiazole ring appended to the C-6 position of this new sub-family of pyrrolotriazines resulted in the identification of low nanomolar inhibitors of VEGFR-2. Antitumor efficacy was observed with compound 37 against L2987 human lung carcinoma xenografts in athymic mice.