Biology subjects

Bird, G.

Publications and source records attributed to Bird, G..

3 recordsLinked to original sources

bioRxiv2025

Targeting NEDD9-SH3 with a Covalent Peptide Controls Endothelial Phenotype

Src homology 3 (SH3) proteins regulate numerous fibroproliferative pathophenotypes including pulmonary arterial hypertension (PAH) but are challenging to target therapeutically. We innovated a peptidomimetic that occupies the canonical focal adhesion kinase (FAK) binding site on the SH3 domain of the neural precursor cell expressed, developmentally down-regulated 9 (NEDD9) protein, a pro-PAH regulator. Peptidomimetic derivatization with a bromoacetamide group alkylated a NEDD9 cysteine positioned uniquely among SH3 domains (Cys18), which stabilized the RT loop, prevented FAK binding, and inhibited human pulmonary artery endothelial cell (HPAEC) migration. When linked to a thalidomide moiety, the peptide showed degrader activity of NEDD9 protein and, therefore, we next investigated therapeutic application of NEDD9 inhibition. In HPAECs, si-NEDD9 downregulated sulfatase-1, which increased podosome rosette formation and cell migration via 6-O-desulfation of glycocalyx-forming heparan sulfate proteoglycans, and reversed vascular remodeling and PAH in vivo. Whereas sulfatase-1 overexpression decreased pulmonary endothelial podosome formation, cell migration, and tube formation and increased collagen III synthesis, sulfatase-1 knockdown prevented fibroproliferative remodeling and pulmonary hypertension in PAH in vivo. These data leverage cysteinyl thiol reactivity to establish an SH3 domain-targeting structure-validated covalent peptide and identify two convergent mechanisms through NEDD9 that control endothelial phenotype, including reverse remodeling via sulfatase-1 transcriptional control. Overall, this study advances an SH3-specific therapeutic approach with relevance to PAH and other fibroproliferative pathophenotypes.

molecular biology↗

bioRxiv2022

Neural representations of vicarious rewards are linked to interoception and prosocial behaviour

Every day we constantly observe other people receiving rewards. Theoretical accounts posit that vicarious reward processing might be linked to peoples sensitivity to internal body states (interoception) and facilitates a tendency to act prosocially. However, the neural processes underlying the links between vicarious reward processing, interoception and prosocial behaviour are poorly understood. Previous research has linked vicarious reward processing to the anterior cingulate gyrus (ACCg) and the anterior insula (AI). Can we predict someones propensity to be prosocial or to be aware of interoceptive signals from variability in how the ACCg and AI process rewards? Here, participants monitored rewards being delivered to themselves or a stranger during functional magnetic resonance imaging. Later, they performed a task measuring their willingness to exert effort to obtain rewards for others, and a task measuring their propensity to be aware and use interoceptive signals. Using multivariate similarity analysis, we show that peoples willingness to be prosocial is predicted by greater similarity between self and other representations in the ACCg. Moreover, greater dissimilarity in self-other representations in the AI is linked to interoceptive propensity. These findings highlight that vicarious reward is linked to bodily signals in AI, and foster prosocial tendencies through the ACCg.

neuroscience↗

bioRxiv2021

Egocentric Biases are Determined by the Precision of Self-related Predictions.

According to predictive processing theories, emotional inference involves simultaneously minimising discrepancies between predictions and sensory data relating to both ones own and others states, achievable by altering either ones own state (empathy) or perception of anothers state (egocentric bias) so they are more congruent. We tested a key hypothesis of these accounts, that predictions are weighted in inference according to their precision (inverse variance). If correct, more precise self-related predictions should bias perception of anothers emotional expression to a greater extent than less precise predictions. We manipulated predictions about upcoming own-pain (low or high magnitude) using cues that afforded either precise (a narrow range of possible magnitudes) or imprecise (a wide range) predictions. Participants judged pained facial expressions presented concurrently with own-pain to be more intense when own-pain was greater, and precise cues increased this biasing effect. Implications of conceptualising interpersonal influence in terms of predictive processing are discussed.

neuroscience↗