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Biology subjects

Smyth, T.

Publications and source records attributed to Smyth, T..

2 recordsLinked to original sources

Influence of short and long term processes on SAR11 communities in open ocean and coastal systems

SAR11 bacteria dominate the surface ocean and are major players in converting fixed carbon back to atmospheric carbon dioxide. The SAR11 clade is comprised of niche-specialized ecotypes that display distinctive spatiotemporal transitions. We analysed SAR11 ecotype seasonality in two long-term 16S rRNA amplicon time series representing different North Atlantic regimes: the Sargasso Sea (subtropical ocean-gyre; BATS) and the temperate coastal Western English Channel (WEC). Using phylogenetically resolved amplicon sequence variants (ASVs), we evaluated seasonal environmental constraints on SAR11 ecotype periodicity. Despite large differences in temperature and nutrient availability between the two sites, at both SAR11 succession was defined by summer and winter clusters of ASVs. Summer cluster was dominated by ecotype Ia.3 in both sites. Winter clusters were dominated by ecotypes Ib and IIa.A at BATS and Ia.1 and IIa.B at WEC. A two-year weekly analysis within the WEC time series showed that the response of SAR11 communities to short-term environmental fluctuations was variable. In 2016, community shifts were abrupt and synchronised to environmental shifts. However, in 2015, changes were gradual and decoupled from environmental fluctuations, likely due to increased mixing from strong winds. We demonstrate that interannual weather variability disturb the pace of SAR11 seasonal progression.

microbiology↗

Clinical positioning of the IAP antagonist tolinapant (ASTX660) in colorectal cancer

Cancer cells frequently express elevated levels of Inhibitor of Apoptosis Proteins (IAPs): cIAPI, cIAP2 and XIAP. Elevated expression of cIAP1 and cIAP2 (but not XIAP) significantly correlated with poor prognosis in microsatellite stable (MSS) stage-III colorectal cancer (CRC) patients treated with adjuvant chemotherapy, suggesting their involvement in promoting resistance. Preclinical analysis of the IAP inhibitor tolinapant in CRC cell lines demonstrated robust on-target effects and caspase-8-dependent apoptosis that was inhibited by the caspase-8 paralogs FLIP and, unexpectedly, caspase-10. Importantly, tolinipant-induced apoptosis was augmented by standard-of-care chemotherapy (FOLFOX) in CRC disease models, due (at least in part) to FOLFOX-induced downregulation of Class-I histone deacetylases, leading to acetylation of the FLIP-binding partner Ku70 and downregulation of FLIP. Moreover, this effect could be phenocopied using a Class-I HDAC inhibitor. Further analyses revealed that caspase-8-knockout RIPK3-positive CRC models were sensitive to tolinostat-induced necroptosis, an effect that could be exploited with the FDA-approved caspase inhibitor emricasan. Our study provides evidence for immediate clinical exploration of tolinapant in combination with FOLFOX chemotherapy in poor prognosis MSS CRC with elevated cIAP1/2 expression.

cancer biology↗