The Rational Adolescent: Strategic Information Processing during Decision Making Revealed by Eye Tracking.

Adolescence is often viewed as a time of irrational, risky decision-making - despite adolescents' competence in other cognitive domains. In this study, we examined the strategies used by adolescents (N=30) and young adults (N=47) to resolve complex, multi-outcome economic gambles. Compared to adults, adolescents were more likely to make conservative, loss-minimizing choices consistent with economic models. Eye-tracking data showed that prior to decisions, adolescents acquired more information in a more thorough manner; that is, they engaged in a more analytic processing strategy indicative of trade-offs between decision variables. In contrast, young adults' decisions were more consistent with heuristics that simplified the decision problem, at the expense of analytic precision. Collectively, these results demonstrate a counter-intuitive developmental transition in economic decision making: adolescents' decisions are more consistent with rational-choice models, while young adults more readily engage task-appropriate heuristics.

Sleep deprivation biases the neural mechanisms underlying economic preferences.

A single night of sleep deprivation (SD) evoked a strategy shift during risky decision making such that healthy human volunteers moved from defending against losses to seeking increased gains. This change in economic preferences was correlated with the magnitude of an SD-driven increase in ventromedial prefrontal activation as well as by an SD-driven decrease in anterior insula activation during decision making. Analogous changes were observed during receipt of reward outcomes: elevated activation to gains in ventromedial prefrontal cortex and ventral striatum, but attenuated anterior insula activation following losses. Finally, the observed shift in economic preferences was not correlated with change in psychomotor vigilance. These results suggest that a night of total sleep deprivation affects the neural mechanisms underlying economic preferences independent of its effects on vigilant attention.

Separate neural mechanisms underlie choices and strategic preferences in risky decision making.

Adaptive decision making in real-world contexts often relies on strategic simplifications of decision problems. Yet, the neural mechanisms that shape these strategies and their implementation remain largely unknown. Using an economic decision-making task, we dissociate brain regions that predict specific choices from those predicting an individual's preferred strategy. Choices that maximized gains or minimized losses were predicted by functional magnetic resonance imaging activation in ventromedial prefrontal cortex or anterior insula, respectively. However, choices that followed a simplifying strategy (i.e., attending to overall probability of winning) were associated with activation in parietal and lateral prefrontal cortices. Dorsomedial prefrontal cortex, through differential functional connectivity with parietal and insular cortex, predicted individual variability in strategic preferences. Finally, we demonstrate that robust decision strategies follow from neural sensitivity to rewards. We conclude that decision making reflects more than compensatory interaction of choice-related regions; in addition, specific brain systems potentiate choices depending on strategies, traits, and context.

Boundary conditions on unconscious thought in complex decision making.

Should individuals delegate thinking about complex choice problems to the unconscious? We tested two boundary conditions on this suggestion. First, we found that in a decision environment similar to those studied previously, self-paced conscious thought and unconscious thought had similar advantages over conscious thought constrained to a long fixed time interval in terms of identifying the option with the highest number of positive outcomes. Second, we found that self-paced conscious thought performed better than unconscious thought in a second decision environment where performance depended to a greater extent on magnitudes of the attributes. Thus, we argue that it is critical to take into account the interaction of forms of processing with task demands (choice environments) when considering how to approach complex choice problems.

Enhanced susceptibility to antifungal oligopeptides in yeast strains overexpressing ABC multidrug efflux pumps.

The susceptibility to several oligopeptide and amino acid antifungals of a Saccharomyces cerevisiae strain carrying multiple deletions in yeast multidrug resistance genes was compared to transformants containing the CDR1, CDR2, or MDR1 genes that encode the major Candida albicans drug efflux pumps. Recombinant yeast strains overexpressing Cdr1p and Cdr2p showed enhanced susceptibilities to all tested oligopeptide antifungals. The enhanced susceptibilities of multidrug-resistant yeast strains to oligopeptide antifungals corresponded to higher rates of oligopeptide uptake. Yeast cells overexpressing Cdr1p or Cdr2p effluxed protons at higher rates than the reference cells lacking these ABC transporters. An increased plasma membrane electrochemical gradient caused by the functional overexpression of Cdr1p or Cdr2p appeared to increase cellular susceptibility to oligopeptide antifungals by stimulating their uptake via oligopeptide permeases.

Enzymatic degradation and transport of endothiopeptides into Escherichia coli K12 mutant strains.

Transport of three synthesized endothiopeptides: AlaPsi[CSNH]Ala, AlaPsi[CSNH]Leu, and AlaPsi[CSNH]Phe, into Escherichia coli K12 mutant strains and enzymatic degradation studies were carried out. These compounds, well transported by permeases, but significantly more resistant to enzymatic cleavage than the corresponding natural peptides, seem to be useful as enzyme inhibitor carriers.

Structure-activity relationships for a series of peptidomimetic antimicrobial prodrugs containing glutamine analogues.

Synthetic glutamine analogues such as N3-(4-methoxyfumaroyl)-l-2,3-diaminopropanoic acid (FMDP) inhibit purified glucosamine-6-phosphate synthase, an intracellular enzyme that is essential for microbial cell wall synthesis, but they are inactive against intact organisms because they cannot enter the cell. However, when the analogues are linked to a peptide they can be actively transported, and FMDP peptidomimetics show broad-spectrum antimicrobial activity. To characterize this process in more detail, the antibacterial activities of various synthetic peptidomimetics containing glutamine analogues have been determined against isogenic strains of Escherichia coli in which one or more of its three peptide transporters Dpp, Opp and Tpp have been mutated. In addition, their affinities for DppA and OppA, the binding-protein components of the transporters, have been measured. In general, antibacterial activities against the various transport mutants correlated with binding to DppA and OppA. Xaa-FMDP compounds have greater activities than FMDP-Xaa analogues. To explore structure-activity relationships for the peptidomimetics, molecular modelling was used to determine the conformational forms they adopt in solution. The relative bioactivities of the peptidomimetics correlated with the percentage of conformers that had backbone torsions matching those previously defined for the molecular recognition templates of the peptide transporters. However, the large size of the N-terminal residue in the FMDP-Xaa analogues appears to interfere with transport and thus to limit antibacterial activity. Overall, the results provide the structural rationale for the identification in silico of analogues with optimal bioactivities, which decreases the need for extensive chemical syntheses and testing.

Conformational analysis of bacterial cell wall peptides indicates how particular conformations have influenced the evolution of penicillin-binding proteins, beta-lactam antibiotics and antibiotic resistance mechanisms.

Our aim was to use a conformational analysis technique developed for peptides to identify structural relationships between bacterial cell wall peptides and beta-lactam antibiotics that might help to explain their different actions as substrates and inhibitors of penicillin binding proteins (PBPs). The conformational forms of the model cell wall peptide Ac-L-Lys(Ac)-D-Ala-D-Ala are described by just a few backbone torsion combinations: three C-terminal carboxylate regions, with Tor8 (psi(i+1)) ranges of D3 region (50 degrees to 70 degrees ), D6 region (140 degrees to 170 degrees ) and D9 region (-50 degrees to -70 degrees ) are combined with either of two Tor6 (phi(i))-Tor4 (psi(i)) combinations, C4 region (-50 degrees to -80 degrees ) with B8 region (-40 degrees to -70 degrees ) or C11 region (30 degrees to 50 degrees ) with B2 region (30 degrees to 70 degrees ). From these results, and comparisons with conformational analyses of various beta-lactams and Ac-L-Lys(Ac)-D-Ala-D-Lac, it is concluded that molecular recognition of cell wall peptide substrates by PBPs requires conformers with backbone torsion angles of D3C4B8. beta-Lactam antibiotics are constrained compounds with fewer conformational forms; these match well the backbone torsions of cell wall peptides at D3C4, allowing their recognition and acylation by PBPs, whereas their unique Tor4 produces differently orientated CO and N atoms that appear to prevent subsequent deacylation, leading to their action as suicide substrates. The results are also related to the selective pressures involved in evolution of beta-lactamases from PBPs. From analysis of conformers of Ac-L-Lys(Ac)-D-Ala-D-Ala and the vancomycin-resistant analogue Ac-L-Lys(Ac)-D-Ala-D-Lac, it is concluded that vancomycin may recognise D6C11B2 conformers, giving it complementary substrate specificity to PBPs. This approach could have applications in the rational design of antibiotics targeted against PBPs and their substrates.