Debbie J. Beard

The role of the N-terminal and mid-region residues of substance P in regulating functional selectivity at the tachykinin NK1 receptor

Previous studies have shown that tachykinin peptide ligands of the tachykinin NK1 receptor exhibit functional selectivity with respect to signal activation and desensitization. The differences are most dramatic between the naturally occurring peptides substance P (RPKPQQFFGLM-NH2) and ranatachykinin C (HNPASFIGLM-NH2). To understand the structural features of the peptides that underlie these differences, four peptide analogs have been designed and tested. The analogs were designed to assess the major structural differences between substance P and ranatachykinin C, including the role of the N-terminal Arg and the substitution of the mid-region Glns with Ala and Ser (Q5 replaced with A and/or Q6 replaced with S). Receptor binding, receptor activation of intracellular calcium fluxes, and receptor desensitization of the rat tachykinin NK1 receptor were quantified for each ligand. All of the peptides bound to the rat tachykinin NK1 receptor with high affinity, produced robust calcium signal activation, and led to agonist-induced receptor desensitization. It was found that deletion of the N-terminal Arg of substance P or replacement of either or both Q5 and Q6 altered the functional selectivity of substance P based on the relationship of receptor binding to receptor activation and activation to desensitization. When considered in light of our previously published nuclear magnetic resonance structure data, the data presented herein suggest that the one, five and six positions of the substance P backbone are key structural residues that govern the relative degree of tachykinin peptide-mediated receptor signaling and desensitization.

Theoretical study of geometry and nucleophilicity of the exocyclic methylene in five-membered ring cyclic ketene acetals, neutral and protonated, containing pnictogen and chalcogen heteroatoms

A series of neutral and protonated five-membered ring cyclic ketene acetals have been examined computationally for any trends in nucleophilicity in the exocyclic methylene and for their ground state geometries. A total of 58 different species were examined, 29 neutral molecules and the corresponding 29 protonated species. The heteroatoms that were used in the heterocyclic ring were a combination of nitrogen, phosphorus, and arsenic from the pnictogen family and oxygen, sulfur, and selenium from the chalcogen family. All geometries were initially optimized at using density functional theory and all stationary points were confirmed to be either minima or transition states through vibrational analysis. All the geometries were consequentially optimized using Møller–Plesset second order perturbation theory with a polarized triple zeta basis set. The main focus of the study was the nucleophilicity of the exocyclic methylene carbon atom and its dependence on heteroatom substitution. As probes for nucleophilicity, the proton affinities of the neutral species, the bond lengths of the exocyclic double bond, and atomic charges were used. The study also resulted in some interesting molecular geometries.

Four-membered ring cyclic ketene –O,O–, –O,S–, –O,N–, –S,S–, –S,N–, and –N,N–acetals and their corresponding cations: a computational study

A systematic computational study of four-membered cyclic ketene –O,O–, –O,S–, –O,N–, –S,N– and –N,N-acetals as well as their protonated analogs have been performed at the second order Möller Plesset level with a polarized triple zeta basis set. The main purpose of this study was to make predictions about the nucleophilicity of these systems and the variations in nucleophilicity with the hetero atoms. Our calculations suggest that all six target molecules are good nucleophiles, and that the N,N analog is the strongest and the S,S analog the weakest nucleophile. Our results include molecular geometries, bond lengths, proton affinities, vibrational frequencies, and calculated charges.

Optimizing Online Content Instruction for Effective Hybrid Teacher Professional Development Programs

ABSTRACT The Teacher Academy in the Natural Sciences (TANS) provided middle school (U.S. Grades 6–8) teachers (N = 81) with intensive professional development in chemistry, geosciences, and physics through 13 days of face-to-face instruction that was extended with 2 online science modules per discipline. Because we administered online module assessments before the summer academy (pretest), after the summer academy (Post 1), and after the online module was assigned (Post 2), we were able to analyze via dependent t tests the learning components contributed by the online module. Only 1 geosciences module resulted in significant gains after it was assigned. Other modules (2 physics, 1 geosciences) resulted in gains before module assignments, at the end of the 10-day summer academy. Although the 2 chemistry modules exhibited positive score increases, no significant gains were made. Calculated Pearson correlation coefficients revealed no association between participants’ online access times and science content gains. This research documents benefits of hybrid teacher professional development programs and offers recommendations for their optimized effectiveness, including more consistent instructor/participant online access.