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Discovery of Potent and Selective Inhibitors against Protein-Derived Electrophilic Cofactors
No full textElectrophilic cofactors are widely distributed in nature and play important roles in many physiological and disease processes, yet they have remained blind spots in traditional activity-based protein profiling (ABPP) approaches that target nucleophiles. More recently, reverse-polarity (RP)-ABPP using hydrazine probes identified an electrophilic N-terminal glyoxylyl (Glox) group for the first time in secernin-3 (SCRN3). The biological function(s) of both the protein and Glox as a cofactor has not yet been pharmacologically validated because of the lack of selective inhibitors that could disrupt and therefore identify its activity. Here, we present the first platform for analyzing the reactivity and selectivity of an expanded nucleophilic probe library toward main-chain carbonyl cofactors such as Glox and pyruvoyl (PyvI) groups. We first applied the library proteome-wide to profile and confirm engagement with various electrophilic protein targets, including secernin-2 (SCRN2), shown here also to possess a Glox group. A broadly reactive indole ethylhydrazine probe was used for a competitive in vitro RP-ABPP assay to screen for selective inhibitors against such cofactors from a set of commercially available nucleophilic fragments. Using Glox-containing SCRN proteins as a case study, naphthyl hydrazine was identified as a potent and selective SCRN3 inhibitor, showing complete inhibition in cell lysates with no significant cross-reactivity detected for other enzymes. Moving forward, this platform provides the fundamental basis for the development of selective Glox inhibitors and represents a starting point to advance small molecules that modulate electrophile-dependent function
Male zebrafish (Danio rerio) do not preferentially associate with familiar over unfamiliar conspecifics
No full textMembers of several shoaling species have been shown to prefer to associate with familiar individuals, enhancing the benefits of aggregation. The authors used a series of social preference tasks in the laboratory to evaluate whether prior familiarity with potential partners influences preference of shoaling partner in male zebrafish (Danio rerio), a social species found in shallow, slow-moving waters. The authors found that though male zebrafish exhibited a strong preference for shoaling with a male conspecific as opposed to remaining alone, they exhibited no preference for familiar over unfamiliar conspecifics. This suggests that the benefits of familiarity for shoaling behaviour may not be as important for male zebrafish as has been shown in other social fish species
Nucleobases in Meteorites to Nucleobases in RNA and DNA?
No full textNucleic acids likely played a foundational role in the origin of life. However, the prebiotic chemistry of nucleoside and nucleotide synthesis has proved challenging on a number of fronts. The recent discovery of both pyrimidine and purine nucleobases in carbonaceous chondrite meteorites has garnered much attention from both the popular press and the scientific community. Here, we discuss these findings in the context of nucleoside/nucleotide prebiotic chemistry. We consider that the main challenge of prebiotic nucleoside synthesis, that of nucleosidic bond formation, is not addressed by the identification nucleobases in meteorites. We further discuss issues of selection that arise from the observation that such meteorites contain both canonical and non-canonical nucleobases. In sum, we argue that, despite the major analytical achievement of identifying and characterizing nucleobases in meteorites, this observation does little to advance our understanding of the prebiotic chemistry that could have led to the first genetic molecules that gave rise to us
Visible Light-Mediated, Highly Diastereoselective Epimerization of Lactams from the Most Accessible to the More Stable Stereoisomer
No full textMost known methods to access delta-lactams with stereogenic centers at the alpha- and beta-positions are highly selective for the contra-thermodynamic syn diastereomer, typically via hydrogenation of the corresponding pyridinones or quinolinones. We describe here the development of a photoredox-mediated hydrogen atom transfer approach for the epimerization of delta-lactams to access the more stable anti diastereomers from the contra-thermodynamic syn isomers. The reaction displays broad functional group compatibility, including acid, ester, 1 degrees, 2 degrees, and 3 degrees amide, carbamate, and pyridyl groups, and was effective for a range of differently substituted monocyclic and bicyclic lactams. Experimentally observed diastereoselectivities are consistent with the calculated relative stabilities of lactam diastereomers. Convergence to the same diastereomer ratio from the syn- and anti-diastereomers establishes that reversible epimerization provides an equilibrium mixture of diastereomers. Additionally, deuterium labeling and luminescence quenching studies shed further light on the mechanism of the reaction
La impresión conservadora: los hermanos Uribe y Alcalde y el campo tipográfico del primer conservadurismo mexicano, 1828-1836
No full text
Or, (2022) Image 06
No full textOr,December 8-11, 2022Irene and Alan Wurtzel Theater, Oberlin College
By Liz Duffy AdamsDirected by Chris Flaharty
More information about this productionhttps://digitalcommons.oberlin.edu/images_or/1005/thumbnail.jp
Which Limitations Block Requirements?
No full textOne of David Estlund\u27s key claims in Utopophobia is that theories of justice should not bend to human motivational limitations. Yet he does not extend this view to our cognitive limitations. This creates a dilemma. Theories of justice may ignore cognitive as well as motivational limitations-but this makes them so unrealistic as to be unrecognizable as theories of justice. Theories may bend to both cognitive and motivational limitations-but Estlund wants to reject this view. The other alternative is to find some non-ad hoc way to distinguish cognitive from motivational limitations. I argue that this strategy will not work. Just as a person\u27s cognitive limitations may block her motives no matter how much she perseveres, so too motivational limitations may be genuine inabilities. Even ideal theories of justice must bend to even ordinary motivational limitations when they truly cause us to be unable to comply with requirements