Do arousal and valence have separable influences on attention across time?

Previous research has shown that emotions differentially influence attention across time, especially when the valence of the attended stimuli is congruent with the emotion of observer. Sadness produces a larger attentional blink while fear and happiness produce smaller attentional blinks. We report on four dual-task rapid serial visual presentation experiments in which participant emotion and the affective features of the first target (T1) were systematically varied to determine whether arousal and valence have unique and consistent influences on attention performance. All T1s connoted affect. Results showed that the emotional experience of negative affect with high arousal led to better second target (T2) detection than negative affect with low arousal. In conditions where positive affect was the experienced emotion, low arousal resulted in better T2 detection than high arousal. When participant arousal was held constant at a low level there were no differences in performance. When participant arousal was high, a cross-over effect was observed in which negative affect produced better performance than positive affect at early positions and negative affect produced better performance at late. The first targets in these experiments varied in arousal and valence to test for emotion congruent effects, but none were found. It was concluded that the experience of varied levels of arousal and types of valence do not have separable influences on attention across time. Rather, their influence is more consistent with emotion-specific mechanisms.

Small molecule targeting of the STAT5/6 Src homology 2 (SH2) domains to inhibit allergic airway disease.

Asthma is a chronic inflammatory disease of the lungs and airways and one of the most burdensome of all chronic maladies. Previous studies have established that expression of experimental and human asthma requires the IL-4/IL-13/IL-4 receptor α (IL-4Rα) signaling pathway, which activates the transcription factor STAT6. However, no small molecules targeting this important pathway are currently in clinical development. To this end, using a preclinical asthma model, we sought to develop and test a small-molecule inhibitor of the Src homology 2 domains in mouse and human STAT6. We previously developed multiple peptidomimetic compounds on the basis of blocking the docking site of STAT6 to IL-4Rα and phosphorylation of Tyr641 in STAT6. Here, we expanded the scope of our initial in vitro structure-activity relationship studies to include central and C-terminal analogs of these peptides to develop a lead compound, PM-43I. Conducting initial dose range, toxicity, and pharmacokinetic experiments with PM-43I, we found that it potently inhibits both STAT5- and STAT6-dependent allergic airway disease in mice. Moreover, PM-43I reversed preexisting allergic airway disease in mice with a minimum ED50 of 0.25 µg/kg. Of note, PM-43I was efficiently cleared through the kidneys with no long-term toxicity. We conclude that PM-43I represents the first of a class of small molecules that may be suitable for further clinical development against asthma.