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Chen, X. R.

Publications and source records attributed to Chen, X. R..

2 recordsLinked to original sources

A specific computational role for early-life unpredictability, and not lifelong stressful experience, in decision-making under uncertainty.

It has been shown that early-life adversity (ELA) shapes how individuals learn, remember, and make decisions, yet the precise computations altered by these experiences remain unclear. Here, we combine a structured foraging task with computational modeling to test a recently developed theory for how a particular kind of ELA, early-life unpredictability (ELU), specifically influences choice under uncertainty. Adult participants (N=297) performed a sequential foraging task requiring continuous trade-offs between exploiting depleting resources and exploring alternatives. Subsets also completed assessments of early-life unpredictability (QUIC) and for trauma symptoms arising from lifelong stressors (PCL). We fit participants behavior with a Bayesian learning-and-planning model in which uncertainty modulates the valuation of leaving a current resource patch. Critically, the subjective influence of local uncertainty was allowed to vary freely between participants. Consistent with theoretical proposals, computational model fits and mediation analyses revealed a robust indirect pathway: ELU predicted increased discounting in the face of uncertainty, which in turn predicted greater overharvesting. This pattern was consistent across environmental conditions, indicating that early-life unpredictability primarily influences behavior through a general influence on uncertainty processing. Importantly, although PCL scores were also correlated with uncertainty adaptation, these effects were fully accounted for by shared variance with ELU, offering a clear dissociation between developmental unpredictability and lifelong traumatic experience. Together, our results show that early-life unpredictability causes long-lasting changes in decision-making by amplifying the subjective experience of uncertainty.

neuroscience↗

Mechanisms by Which Small Molecule Inhibitors Arrest Sec14 Phosphatidylinositol Transfer Protein Activity

Phosphatidylinositol transfer proteins (PITPs) promote phosphoinositide signaling by enhancing phosphatidylinositol (PtdIns) 4-OH kinase activities in producing signaling pools of PtdIns-4-phosphate. As such, PITPs are key regulators of lipid signaling in eukaryotic cells. While the PITP phospholipid exchange cycle is the engine that stimulates PtdIns 4-OH kinase activity, the protein and lipid dynamics associated with this critical process are not understood. Herein, we use an integrative structural approach that takes advantage of small molecule inhibitors (SMIs) directed against the major yeast PITP (Sec14) to gain new insights into the mechanics of the Sec14 phospholipid exchange cycle from the perspective of protein, phospholipid and SMI dynamics. Moreover, as Sec14 has emerged as an attractive target for next-generation antifungal drugs, the structures of Sec14 bound to SMIs of four different chemotypes reported in this study provide critical information required for structure-based design of next-generation lead compounds that target Sec14 PITPs of virulent fungi.

biophysics↗