The Discovery of MORF-627, a Highly Selective Conformationally-Biased Zwitterionic Integrin αvβ6 Inhibitor for Fibrosis.

Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvβ6. Crystal structures of these compounds bound to αvβ6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations.

Exploring practices, challenges, and priorities for human health and ecological risk assessments in Indigenous communities in Canada.

Indigenous peoples in Canada are disproportionately exposed to environmental contaminants and may face elevated health risks related to their unique cultural, spiritual, and economic relationships with the land, including the use of traditional food systems. However, to date, institutionalized approaches to assess risks to human and ecological health from contaminants have not been well developed or implemented with Indigenous community contexts in mind. There is regulatory interest in developing new approach methods for risk assessment, and thus an opportunity to increase their relevance to Indigenous communities in which they will be ultimately applied.

Contaminated sites and Indigenous peoples in Canada and the United States: A scoping review.

Indigenous communities are disproportionately exposed to contaminated sites, and this poses unique challenges as many Indigenous peoples consider land as an integral part of their culture and economy. This scoping review aimed to identify and map information on contaminated sites and Indigenous peoples in Canada and the United States, namely (1) the relationship between contaminated sites and Indigenous peoples and their land and food systems; (2) strategies, challenges, and successes for contaminated sites assessment and management on Indigenous land; and (3) Indigenous leadership and inclusion in contaminated site assessment and management. We followed a PRISMA-ScR (Transparent Reporting of Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews) checklist to collect data that could be categorized into these three objectives.

Parental Preconception Exposures to Outdoor Neighbourhood Environments and Adverse Birth Outcomes: A Protocol for a Scoping Review and Evidence Map.

Parental preconception exposures to built and natural outdoor environments could influence pregnancy and birth outcomes either directly, or via a range of health-related behaviours and conditions. However, there is no existing review summarising the evidence linking natural and built characteristics, such as air and noise pollution, walkability, greenness with pregnancy and birth outcomes. Therefore, the planned scoping review aims to collate and map the published literature on parental preconception exposures to built and natural outdoor environments and adverse pregnancy and birth outcomes.

The use of fluorescently-tagged apoptolidins in cellular uptake and response studies.

The apoptolidins are glycomacrolide microbial metabolites reported to be selectively cytotoxic against tumor cells. Using fluorescently tagged active derivatives we demonstrate selective uptake of these four tagged glycomacrolides in cancer cells over healthy human blood cells. We also demonstrate the utility of these five fluorescently tagged glycomacrolides in fluorescent flow cytometry to monitor cellular uptake of the six glycomacrolides and cellular response.

Decoupling Activation of Heme Biosynthesis from Anaerobic Toxicity in a Molecule Active in Staphylococcus aureus.

Small molecules active in the pathogenic bacterium Staphylococcus aureus are valuable tools for the study of its basic biology and pathogenesis, and many molecules may provide leads for novel therapeutics. We have previously reported a small molecule, 1, which activates endogenous heme biosynthesis in S. aureus, leading to an accumulation of intracellular heme.

A general, enantioselective synthesis of -alkyl terminal aziridines and C2-functionalized azetidines via organocatalysis.

A short, high-yielding protocol involving the enantioselective α-chlorination of aldehydes has been developed for the enantioselective synthesis of C2-functionalized aziridines and -alkyl terminal azetidines from a common intermediate. This methodology allows for the rapid preparation of functionalized aziridines in 50-73% overall yields and 88-94% ee, and azetidines in 22-32% overall yields and 84-92% ee. Moreover, we developed a scalable and cost-effective route to the key organocatalyst (54% overall yield, >95% dr).

Fluorescent probes of the apoptolidins and their utility in cellular localization studies.

Apoptolidin A has been described among the top 0.1% most-cell-selective cytotoxic agents to be evaluated in the NCI 60 cell line panel. The molecular structure of apoptolidin A consists of a 20-membered macrolide with mono- and disaccharide moieties.