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The bromodomain and extra terminal (BET) family of proteins are an integral part of human epigenome regulation, the dysregulation of which is implicated in multiple oncology and inflammatory diseases. Disrupting the BET family bromodomain acetyl-lysine (KAc) histone protein-protein interaction with small-molecule KAc mimetics has proven to be a disease-relevant mechanism of action, and multiple molecules are currently undergoing oncology clinical trials. This work describes an efficiency analysis of published GSK pan-BET bromodomain inhibitors, which drove a strategic choice to focus on the identification of a ligand-efficient KAc mimetic with the hypothesis that lipophilic efficiency could be drastically improved during optimization. This focus drove the discovery of the highly ligand-efficient and structurally distinct benzoazepinone KAc mimetic. Following crystallography to identify suitable growth vectors, the benzoazepinone core was optimized through an explore-exploit structure-activity relationship (SAR) approach while carefully monitoring lipophilic efficiency to deliver I-BET432 (

Many studies have examined the vulnerability of calcifying organisms, such as the eastern oyster (Crassostrea virginica), to externally forced ocean acidification, but the opposite interaction whereby oysters alter their local carbonate conditions has received far less attention. We present an exploratory model for isolating the impact that net calcification and respiration of aquacultured eastern oysters can have on calcite and aragonite saturation states, in the context of varying temperature, ocean-estuary mixing, and air-sea gas exchange. We apply the model to the Damariscotta River Estuary in Maine which has experienced rapid expansion of oyster aquaculture in the last decade. Our model uses oyster shell growth over the summer season and a previously derived relationship between net calcification and respiration to quantify impacts of net oyster calcification and gross metabolism on carbonate saturation states in open tidal waters. Under 2018 industry size and climate conditions, we estimate that oysters can lower carbonate saturation states by up to 5% (i.e., 0.17 and 0.11 units on calcite and aragonite saturation states, respectively) per day in late summer, with an average of 3% over the growing season. Perturbations from temperature and air-sea exchange are similar in magnitude. Under 2050 climate conditions and 2018 industry size, calcite saturation state will decrease by up to an additional 0.54 units. If the industry expands 3-fold by 2050, the calcite and aragonite saturation states may decrease by 0.73 and 0.47 units, respectively, on average for the latter half of the growing season when compared to 2018 climate conditions and industry size. Collectively, our results indicate that dense aggregations of oysters can have a significant role on estuarine carbonate chemistry.

We present oyster larval microbiota from two feeding studies, in which wild type and low-salinity tolerant lines were either fed or starved. In one study, all larvae unexpectedly died, which was concurrent with an event in which all larvae in an adjoining oyster hatchery also died. In the other study, no crash occurred in either the study or hatchery. In both cases, larvae were collected and stored frozen, and microbial and host DNA was isolated by phenol-chloroform extraction. Both host 18 s rRNA genes and microbial 16 and 18 s rRNA genes were sequenced using universal primers. We present raw sequences, the pipeline that was used to quantify amplicon sequence variants, and our analysis pipeline that we used to describe how the overall microbial community varied between projects (crashed and non-crashed), feeding status (fed vs not), and strain (wild vs not). These data will be valuable to anyone interested in the microbiota of larval oysters, especially anyone interested in exploring hatchery crashes, effects of starvation, or strain level differences. They also contain a reproducible pipeline of amplicon analysis of host associated microbiota which may serve as a template for other studies. These data are a co-submission to a manuscript submitted to Aquaculture by Matthew grey et al. (2021) entitled Hatchery crashes among shellfish research hatcheries along the Atlantic coast of the United States: a case study at Horn Point Laboratory oyster hatchery. (Manuscript#: AQUACULTURE-D-21–01351R1)