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Rapamycin and FK506 are macrocyclic natural products with an extraordinary mode of action—they form binary complexes with FKBP through a shared FKBP-binding domain before forming ternary complexes with their respective targets, mTOR and calcineurin, respectively. Inspired by this, we sought to build a rapamycin-like macromolecule library to target new cellular proteins by replacing the effector domain of rapamycin with a combinatorial library of oligopeptides. We developed a robust macrocyclization method using ring-closing metathesis and synthesized a 45,000-compound library of hybrid macrocycles that are named rapafucins using optimized FKBP-binding domains. Screening of the rapafucin library in human cells led to the discovery of rapadocin, an inhibitor of nucleoside uptake. Rapadocin is a potent, isoform-specific and FKBP-dependent inhibitor of the equilibrative nucleoside transporter 1 and is efficacious in an animal model of kidney ischemia reperfusion injury. Together, these results demonstrate that rapafucins are a new class of chemical probes and drug leads that can expand the repertoire of protein targets well beyond mTOR and calcineurin., Graphical abstract

Adherent cultured cells are widely used biological tools for a variety of biochemical and biotechnology applications, including drug screening and gene expression analysis. One critical step in culturing adherent cells is the dissociation of cell monolayers into single-cell suspensions. Different enzymatic and non-enzymatic methods have been proposed for this purpose. Trypsinization, the most common enzymatic method for dislodging adhered cells, can be detrimental to cells, as it can damage cell membranes and ultimately cause cell death. Additionally, all available techniques require a prolonged treatment duration, typically on the order of minutes (5-10 min). Dissociation of cells becomes even more challenging in microfluidic devices, where, due to the nature of low Reynolds number flow and reduced mixing efficiency, multiple washing steps and prolonged trypsinization may be necessary to treat all cells. Here, we report a novel acoustofluidic method for the detachment of cells adhered onto a microchannel surface without exposing the cells to any enzymatic or non-enzymatic chemicals. This method enables a rapid (i.e., on the order of seconds), cost-effective, and easy-to-operate cell detachment strategy, yielding a detachment efficiency of similar to 99% and cellular viability similar to that of the conventional trypsinization method. Also, as opposed to biochemical-based techniques (e.g., enzymatic), in our approach, cells are exposed to the dissociating agent (i.e., substrate-mediated acoustic excitation and microstreaming flow) only for as long as they remain attached to the substrate. After dissociation, the effect of acoustic excitation is reduced to microstreaming flow, therefore, minimizing unwanted effects of the dissociating agent on the cell phenotype. Additionally, our results suggest that cell excitation at acoustic powers lower than that required for complete cell detachment can potentially be employed for probing the adhesion strength of cell-substrate attachment. This novel approach can, therefore, be used for a wide range of lab-on-a-chip applications.

An awakening to systemic anti-Black racism, anti-Indigenous racism, and harmful colonial structures in the context of a pandemic has made health inequities and injustices impossible to ignore, and is driving healthcare organizations to establish and strengthen approaches to inclusion, diversity, equity, and accessibility (IDEA). Health research and care organizations, which are shaping the future of healthcare, have a responsibility to make IDEA central to their missions. Many organizations are taking concrete action critically important to embedding IDEA principles, but durable change will not be achieved until IDEA becomes a core leadership competency. Drawing from the literature and consultation with individuals recognized for excellence in IDEA-informed leadership, this study will help Canadian healthcare and health research leaders—particularly those without lived experience—understand what it means to embed IDEA within traditional leadership competencies and propose opportunities to achieve durable change by rethinking governance, mentorship, and performance management through an IDEA lens.

Dr. Margaret-Ann Armour’s career as a research chemist, educator, and advocate spanned more than 40 years. Much of her work took place within a disciplinary culture ignorant of the scholarship supporting organizational change towards inclusive excellence. Her contributions are extensively covered in other articles in this special issue, and her achievements are all the more remarkable given that her colleague, Dr. Gordon Freeman, held gender-biased attitudes that he shared in a peer reviewed article in a national science journal. Three decades later, another Canadian chemist, Dr. Tomáš Hudlický, published a peer reviewed essay in an international chemistry journal that included his views on the negative impacts of diversity initiatives on organic synthesis research. Both articles were retracted, but clearly a faulty and pervasively biased peer review system enabled the distribution of prejudiced opinions that were neither informed by demonstrated expertise, nor supported by data. These two events are reflective of challenges that Dr. Armour faced in her efforts to diversify chemical sciences. We need to build on her critical work to increasing awareness about inclusive excellence in chemistry, as well as educating scientists on what constitutes an informed opinion. Here, we use Freeman and Hudlický incidents as case studies to indicate how pervasive bias can be superficially perceived as scientific scholarship. Furthermore, we use analogies of analytical processes to illustrate how talent gets systemically excluded. Finally, we provide recommendations to chemistry community members for improving outcomes in terms of synthesis of new knowledge, ideas, and solutions, toward leveraging all the available human talent and creating an environment that is both excellent and inclusive.