Dataset2: Individual level analyses

Dataset used to test (1) if individual males were more likely to participate after receiving social incentives than before, and (2) if individuals who received social incentives participated above their personal base-line level (i.e. the proportion of aggressive episodes participated in during intergroup fights where they were not the male to receive social incentives)

Dataset3: spatio-temporal variability in the occurrence of social incentives

Dataset used in the GLMM testing the spatio-temporal variability in the occurrence of social incentives (punishment and/or rewards). The summer season (when high quality fruits were available) was indexed by the NDVI, the birth season was indexed by the number of small infants (<3 months old) in the group, and the mating season was a dichotomous variable. The spatial distribution of food in the different areas (mapping units) of each home range was determined by mapping the distribution of important tree species and monitoring their fruit abundance on a monthly basis

Dataset1: Population level analysis

Dataset used (1) to determine if females who used social incentives were more likely to direct aggression at males who had recently defected, but groom males who had recently cooperated, and (2) if target males were more likely to participate after receiving social incentives than before

Wnt Inhibition Correlates with Human Embryonic Stem Cell Cardiomyogenesis: A Structure–Activity Relationship Study Based on Inhibitors for the Wnt Response

Human embryonic stem cell-based high-content screening of 550 known signal transduction modulators showed that one “lead” (<b>1</b>, a recently described inhibitor of the proteolytic degradation of Axin) stimulated cardiomyogenesis. Because Axin controls canonical Wnt signaling, we conducted an investigation to determine whether the cardiogenic activity of <b>1</b> is Wnt-dependent, and we developed a structure–activity relationship to optimize the cardiogenic properties of <b>1</b>. We prepared analogues with a range of potencies (low nanomolar to inactive) for Wnt/β-catenin inhibition and for cardiogenic induction. Both functional activities correlated positively (<i>r</i>² = 0.72). The optimal compounds induced cardiogenesis 1.5-fold greater than <b>1</b> at 30-fold lower concentrations. In contrast, no correlation was observed for cardiogenesis and modulation of transforming growth factor β (TGFβ)/Smad signaling that prominently influences cardiogenesis. Taken together, these data show that Wnt signaling inhibition is essential for cardiogenic activity and that the pathway can be targeted for the design of druglike cardiogenic molecules

Synthesis and SAR of <i>b</i>‑Annulated 1,4-Dihydropyridines Define Cardiomyogenic Compounds as Novel Inhibitors of TGFβ Signaling

A medium-throughput murine embryonic stem cell (mESC)-based high-content screening of 17000 small molecules for cardiogenesis led to the identification of a <i>b</i>-annulated 1,4-dihydropyridine (1,4-DHP) that inhibited transforming growth factor β (TGFβ)/Smad signaling by clearing the type II TGFβ receptor from the cell surface. Because this is an unprecedented mechanism of action, we explored the series’ structure–activity relationship (SAR) based on TGFβ inhibition, and evaluated SAR aspects for cell-surface clearance of TGFβ receptor II (TGFBR2) and for biological activity in mESCs. We determined a pharmacophore and generated 1,4-DHPs with IC₅₀s for TGFβ inhibition in the nanomolar range (e.g., compound <b>28</b>, 170 nM). Stereochemical consequences of a chiral center at the 4-position was evaluated, revealing 10- to 15-fold more potent TGFβ inhibition for the (+)- than the (−) enantiomer. This stereopreference was not observed for the low level inhibition against Activin A signaling and was reversed for effects on calcium handling in HL-1 cells