Effects of outcomes and random arbitration on emotions in a competitive gambling task.

Research on self-serving biases in judgments and decision-making suggests that individuals first evaluate the outcomes they get, and then the procedures by which these outcomes were obtained. Evidence also suggests that the appraisal of the former (outcome favorability) can bias the appraisal of the latter (procedural fairness). We investigated the nature of the emotions that are elicited by these appraisals by using a new paradigm in which participants performed a choice task between pairs of competing gambles against a virtual opponent. Conflicts (when the participant selected the same gamble as his virtual opponent) were resolved by a neutral arbitrator who either confirmed the participant's choice ("pro-self") or attributed his gamble to the virtual opponent ("pro-competitor"). Trials in which the participant and his virtual opponent selected different gambles ("no-conflict") served as a control condition. In order to validate this new task, emotional reactions to the outcomes of the gambles were measured using self-reports, skin conductance responses, and facial electromyography (zygomaticus, corrugator, and frontalis). In no-conflict trials, effects of counterfactual thinking and social comparison resulted in (i) increased happiness as well as SCR and zygomaticus activity for wins compared to losses (valence effect) and for high compared to low gains (magnitude effect), and (ii) increased anger, regret, disappointment, and envy for losses compared to wins (valence effect). More importantly, compared to no-conflict trials and to pro-self awards with similar outcomes, pro-competitor awards increased subjective reports of anger for unfavorable outcomes, and increased happiness and guilt for favorable outcomes. Although the outcomes were independent from the arbitrators' decisions, and both the arbitrators' decisions and the outcomes were kept equally likely, individuals tended to attribute their outcomes to unfair arbitrators, reacting emotionally, especially when the modification of their initial choice for a gamble led to a negative outcome.

Solution structure of the third TB domain from LTBP1 provides insight into assembly of the large latent complex that sequesters latent TGF-beta.

Almost all TGF-beta is secreted as part of a large latent complex. This complex is formed from three molecules, a latent transforming growth factor-beta binding protein (LTBP), which plays roles in targeting and activation, a latency associated peptide (LAP), which regulates latency, and the TGF-beta cytokine. LAP is the TGF-beta pro-peptide that is cleaved intracellularly prior to secretion, and TGF-beta binds non-covalently to LAP. Formation of the large latent complex is important for the efficient secretion of TGF-beta. Previous studies have revealed that the LTBP-LAP interaction is mediated by intracellular exchange of a single disulphide bond within the third, and only the third, TB domain (TB3) with LAP. We have previously reported the structure of a homologous TB domain from fibrillin-1. However, TB3 contains a two amino acid insertion, not found in fibrillin-1 TB domains, which is not amenable to molecular modelling. In order to clarify the basis of TB domain function, we have determined the solution NMR structure of TB3(LTBP1). Comparison with the fibrillin-1 TB domain reveals that the two-residue insertion is associated with a significant increase in solvent accessibility of one of the disulphide bonds (linking the second and sixth cysteine residues). Site-directed mutagenesis and NMR studies indicate that this is the only disulphide bond that can be removed without perturbing the TB domain fold. Furthermore, a ring of negatively charged residues has been identified that surrounds this disulphide bond. Homology modelling suggests that the surface properties of TB3 domains from different LTBP isoforms correlate with binding activities. This research provides testable hypotheses regarding the molecular basis of complex formation between LTBPs and LAPs.

Effects of the N2144S mutation on backbone dynamics of a TB-cbEGF domain pair from human fibrillin-1.

The calcium-binding epidermal growth factor-like (cbEGF) module and the transforming growth factor beta-binding protein-like (TB) module are the two major structural motifs found in fibrillin-1, the extracellular matrix (ECM) protein defective in the Marfan syndrome (MFS). An MFS-causing mutation, N2144S, which removes a calcium ligand in cbEGF32, does not detectably affect fibrillin-1 biosynthesis, rate of secretion, processing, or deposition of reducible fibrillin-1 into the ECM. Since the residue at position 2144 is normally engaged in calcium ligation, it is unable to mediate intermolecular interactions. We have shown previously that this mutation does not affect the folding properties of the TB or cbEGF domains in vitro, but does decrease calcium-binding in cbEGF and TB-cbEGF domain constructs. Here, we use NMR spectroscopy to probe the effects of the N2144S mutation on backbone dynamic properties of TB6-cbEGF32. Analysis of the backbone (15)N relaxation data of wild-type TB6-cbEGF32 has revealed a flexible inter-domain linkage. Parallel dynamics analysis of the N2144S mutant has shown increased flexibility in the region joining the two domains as well as in the calcium-binding site at the N terminus of cbEGF32. This research demonstrates that a small change in peptide backbone flexibility, which does not enhance proteolytic susceptibility of the domain pair, is associated with an MFS phenotype. Flexibility of the TB-cbEGF linkage is likely to contribute to the biomechanical properties of fibrillin-rich connective tissue microfibrils, and may play a role in the microfibril assembly process.