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Abstract: The tertiary structure of the Leu308Val mutant of human 20α-hydroxysteroid dehydrogenase (AKR1C1) in complex with the inhibitor 3,5-dichlorosalicylic acid (DCL) has been determined. Structures and kinetic properties of the wild-type and mutant enzymes indicate that Leu308 is a selectivity determinant for inhibitor binding. The Leu308Val mutation resulted in 13-fold and 3-fold reductions in the inhibitory potencies of DCL and 3-bromo-5-phenylsalicylic acid (BPSA), respectively. The replacement of Leu308 with an alanine resulted in 473-fold and 27-fold reductions in the potencies for DCL and BPSA, respectively. In our attempts to optimize inhibitor potency and selectivity we synthesized 5-substituted 3-chlorosalicylic acid derivatives, of which the most potent compound, 3-chloro-5-phenylsalicylic acid (K i = 0.86 nM), was 24-fold more selective for AKR1C1 relative to the structurally similar 3α-hydroxysteroid dehydrogenase (AKR1C2). Furthermore, the compound inhibited the metabolism of progesterone in AKR1C1-overexpressed cells with an IC50 value equal to 100 nM. [ABSTRACT FROM AUTHOR]

Task demand type (e.g., competitive, cooperative, conjunctive) is an important factor influencing learning motivation and performance in a group. Limited research is available regarding conjunctive task demand for learning tasks, especially for the lower performing individuals. Additionally, group composition or social categorization diversity in a group is another important yet relatively understudied factor. To fill the research gap, this study attempted to examine the effects of task demand and social categorization diversity in a group on motivation and performance in a computer-based foreign language learning game. Seven conditions were included: 2 (social categorization diversity: in-group or out-group) x 3 (group task demand: competitive, conjunctive, or cooperative) plus an individual task demand control condition. A total of 102 undergraduates without prior Italian language background were randomly assigned to one of the seven conditions to play an Italian learning game on the computer in the laboratory for about 15 min. We found that for inferior group members, a conjunctive task was the most effective for the performance of learning Italian vocabulary. Significant interaction effects between social categorization diversity and task demand were found for both task performance and enjoyment. Implications for serious games and mediated educational tool design are discussed. [ABSTRACT FROM AUTHOR]