Although multiple natural products are potent ligands for the diacylglycerol binding C1 domain of protein kinase C (PKC), RasGRP, and related targets, the high conservation of C1 domains has impeded the development of selective ligands. We characterized here a diacylglycerol-lactone, 130C037, emerging from a combinatorial chemical synthetic strategy, which showed substantial selectivity. 130C037 gave shallow binding curves for PKC isoforms ␣, ␤, ␥, ␦, and ⑀, with apparent K i values ranging from 340 nM for PKC␣ to 29 nM for PKC⑀. When binding to isolated C1 domains of PKC␣ and -␦, 130C037 showed good affinity (K i ‫؍‬ 1.78 nM) only for ␦C1b, whereas phorbol 12,13-dibutyrate showed affinities within 10-fold for all. In LNCaP cells, 130C037 likewise selectively induced membrane translocation of ␦C1b. 130C037 bound intact RasGRP1 and RasGRP3 with K i values of 3.5 and 3.8 nM, respectively, reflecting 8-and 90-fold selectivity relative to PKC⑀ and PKC␣. By Western blot of Chinese hamster ovary cells, 130C037 selectively induced loss from the cytosol of RasGRP3 (ED 50 ‫؍‬ 286 nM), partial reduction of PKC⑀ (ED 50 > 10 M), and no effect on PKC␣. As determined by confocal microscopy in LNCaP cells, 130C037 caused rapid translocation of RasGRP3, limited slow translocation of PKC⑀, and no translocation of PKC␣. Finally, 130C037 induced Erk phosphorylation in HEK-293 cells ectopically expressing RasGRP3 but not in control cells, whereas phorbol ester induced phosphorylation in both. The properties of 130C037 provide strong proof of principle for the feasibility of developing ligands with selectivity among C1 domain-containing therapeutic targets. Diacylglycerol (DAG)1 is a lipid second messenger, produced through hydrolysis of phosphatidylinositol 4,5-bisphosphate following the activation of receptor-coupled phospholipase C or indirectly from phosphatidylcholine via phospholipase D (1). Most but not all effects of DAG reflect its interaction with proteins containing C1 domains, resulting in their activation and/or driving their membrane translocation. Reflecting the importance and diversity of its downstream effectors, DAG is involved in signal transduction of numerous physiological and pathological processes, including proliferation, differentiation, apoptosis, angiogenesis, and drug resistance (2). These functions have focused attention on C1 domain-containing proteins as molecular targets for cancer chemotherapy (3).The interaction between DAG and its receptors is typically mediated by a DAG-responsive motif called a "C1 domain" (4). The highly conserved C1 domain (ϳ50 amino acids) is a cysteine-rich zinc finger structure (5) that was first identified in protein kinase C (PKC) as the interaction site for DAG and the phorbol esters (6). The PKC family of serine/threonine protein kinases comprises the best studied mediators of DAG signaling. 8 of its 11 family members have DAG-responsive C1 domains: (i) the conventional PKCs (␣, ␤I, ␤II, and ␥) and (ii) the novel PKCs (␦, ⑀, , and ). Both the classic and novel PKCs conta...

We describe the development of a next-generation mentoring survey drawing from prior surveys, capital theory, and critical race theory, with the goal of improving mentoring for students from underrepresented groups in science, technology, engineering, and mathematics. This survey focused on deaf mentees. The results show that the mentor’s cultural competence affected mentoring experiences.

Scientists are shaped by their unique life experiences and bring these perspectives to their research. Diversity in life and cultural experiences among scientists, therefore, broadens research directions and, ultimately, scientific discoveries. Deaf individuals, for example, have successfully contributed their unique perspectives to scientific inquiry. However, deaf individuals still face challenges in university science education. Most deaf students in science, technology, engineering, and mathematics (STEM) disciplines interact with faculty who have little to no experience working with deaf individuals and who often have preconceptions or simply a lack of knowledge about deaf individuals. In addition to a lack of communication access, deaf students may also feel unwelcome in STEM, as do other underrepresented groups. In this essay, we review evidence from the literature and, where data are lacking, contribute the expert opinions of the authors, most of whom are deaf scientists themselves, to identify strategies to best support deaf students in university STEM education. We describe the journey of a hypothetical deaf student and methods for faculty to create a welcoming environment. We describe and provide recommendations for classroom seating and layout, accommodations, teaching strategies, and research mentoring. We also discuss the importance of including deaf scientists in research about deaf individuals.

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