Changes to population-based emergence of climate change from CMIP5 to CMIP6

Abstract The Coupled Model Intercomparison Project Phase 6 (CMIP6) model ensemble projects climate change emerging soonest and most strongly at low latitudes, regardless of the emissions pathway taken. In terms of signal-to-noise (S/N) ratios of average annual temperatures, these models project earlier and stronger emergence under the Shared Socio-economic Pathways than the previous generation did under corresponding Representative Concentration Pathways. Spatial patterns of emergence also change between generations of models; under a high emissions scenario, mid-century S/N is lower than previous studies indicated in Central Africa, South Asia, and parts of South America, West Africa, East Asia, and Western Europe, but higher in most other populated areas. We show that these global and regional changes are caused by a combination of higher effective climate sensitivity in the CMIP6 ensemble, as well as changes to emissions pathways, component-wise effective radiative forcing, and region-scale climate responses between model generations. We also present the first population-weighted calculation of climate change emergence for the CMIP6 ensemble, quantifying the number of people exposed to increasing degrees of abnormal temperatures now and into the future. Our results confirm the expected inequity of climate change-related impacts in the decades between now and the 2050 target for net-zero emissions held by many countries. These findings underscore the importance of concurrent investments in both mitigation and adaptation.</jats:p

Changes to population-based emergence of climate change from CMIP5 to CMIP6

The Coupled Model Intercomparison Project Phase 6 (CMIP6) model ensemble projects climate change emerging soonest and most strongly at low latitudes, regardless of the emissions pathway taken. In terms of signal-to-noise (S/N) ratios of average annual temperatures, these models project earlier and stronger emergence under the Shared Socio-economic Pathways (SSPs) than the previous generation did under corresponding Representative Concentration Pathways (RCPs). Spatial patterns of emergence also change between generations of models; under a high emissions scenario, mid-century S/N is lower than previous studies indicated in Central Africa, South Asia, and parts of South America, West Africa, East Asia, and Western Europe, but higher in most other populated areas. We show that these global and regional changes are caused by a combination of higher effective climate sensitivity (ECS) in the CMIP6 ensemble, as well as changes to emissions pathways, component-wise effective radiative forcing (ERF), and region-scale climate responses between model generations. We also present the first population-weighted calculation of climate change emergence for the CMIP6 ensemble, quantifying the number of people exposed to increasing degrees of abnormal temperatures now and into the future. Our results confirm the expected inequity of climate change-related impacts in the decades between now and the 2050 target for net-zero emissions held by many countries. These findings underscore the importance of concurrent investments in both mitigation and adaptation

Rapid Discovery and Structure-Activity Relationships of Pyrazolopyrimidines that Potently Suppress Breast Cancer Cell Growth via SRC Kinase Inhibition with Exceptional Selectivity over ABL Kinase

Novel pyrazolopyrimidines displaying high potency and selectivity toward SRC family kinases have been developed by combining ligand-based design and phenotypic screening in an iterative manner. Compounds were derived from the promiscuous kinase inhibitor PP1 to search for analogs that could potentially target a broad spectrum of kinases involved in cancer. Phenotypic screening against MCF7 mammary adenocarcinoma cells generated target-agnostic structure–activity relationships that biased subsequent designs toward breast cancer treatment rather than to a particular target. This strategy led to the discovery of two potent antiproliferative leads with phenotypically distinct anticancer mode of actions. Kinase profiling and further optimization resulted in eCF506, the first small molecule with subnanomolar IC₅₀ for SRC that requires 3 orders of magnitude greater concentration to inhibit ABL. eCF506 exhibits excellent water solubility, an optimal DMPK profile and oral bioavailability, halts SRC-associated neuromast migration in zebrafish embryos without inducing life-threatening heart defects, and inhibits SRC phosphorylation in tumor xenografts in mice

Necdin, a Negative Growth Regulator, Is a Novel STAT3 Target Gene Down-Regulated in Human Cancer

Cytokine and growth factor signaling pathways involving STAT3 are frequently constitutively activated in many human primary tumors, and are known for the transcriptional role they play in controlling cell growth and cell cycle progression. However, the extent of STAT3's reach on transcriptional control of the genome as a whole remains an important question. We predicted that this persistent STAT3 signaling affects a wide variety of cellular functions, many of which still remain to be characterized. We took a broad approach to identify novel STAT3 regulated genes by examining changes in the genome-wide gene expression profile by microarray, using cells expressing constitutively-activated STAT3. Using computational analysis, we were able to define the gene expression profiles of cells containing activated STAT3 and identify candidate target genes with a wide range of biological functions. Among these genes we identified Necdin, a negative growth regulator, as a novel STAT3 target gene, whose expression is down-regulated at the mRNA and protein levels when STAT3 is constitutively active. This repression is STAT3 dependent, since inhibition of STAT3 using siRNA restores Necdin expression. A STAT3 DNA-binding site was identified in the Necdin promoter and both EMSA and chromatin immunoprecipitation confirm binding of STAT3 to this region. Necdin expression has previously been shown to be down-regulated in a melanoma and a drug-resistant ovarian cancer cell line. Further analysis of Necdin expression demonstrated repression in a STAT3-dependent manner in human melanoma, prostate and breast cancer cell lines. These results suggest that STAT3 coordinates expression of genes involved in multiple metabolic and biosynthetic pathways, integrating signals that lead to global transcriptional changes and oncogenesis. STAT3 may exert its oncogenic effect by up-regulating transcription of genes involved in promoting growth and proliferation, but also by down-regulating expression of negative regulators of the same cellular processes, such as Necdin

ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) synthesis of Siglec ligands mediates anti-tumour immunity in prostate cancer

Immune checkpoint blockade has yet to produce robust anti-cancer responses for prostate cancer. Sialyltransferases have been shown across several solid tumours, including breast, melanoma, colorectal and prostate to promote immune suppression by synthesising sialoglycans, which act as ligands for Siglec receptors. We report that ST3 beta-galactoside alpha-2,3-sialyltransferase 1 (ST3Gal1) levels negatively correlate with androgen signalling in prostate tumours. We demonstrate that ST3Gal1 plays an important role in modulating tumour immune evasion through the synthesises of sialoglycans with the capacity to engage the Siglec-7 and Siglec-9 immunoreceptors preventing immune clearance of cancer cells. Here, we provide evidence of the expression of Siglec-7/9 ligands and their respective immunoreceptors in prostate tumours. These interactions can be modulated by enzalutamide and may maintain immune suppression in enzalutamide treated tumours. We conclude that the activity of ST3Gal1 is critical to prostate cancer anti-tumour immunity and provide rationale for the use of glyco-immune checkpoint targeting therapies in advanced prostate cancer