Biology subjects

Warman, A.

Publications and source records attributed to Warman, A..

5 recordsLinked to original sources

bioRxiv2026

Human see, human do? Viewing tool pictures evokes tool-use action information in hand-selective occipitotemporal cortex

Amongst all the objects we encounter, tools are unique because they are tightly linked to predictable actions. Neuroimaging studies have reported selective responses in occipitotemporal and parietal cortices when viewing pictures of tools or hands. Whether these responses contain information about specific tool-use actions (e.g., rotation for keys), and whether such information shares a neural format with action execution, remains unclear. Here, we used fMRI and multivoxel pattern analysis to ask whether specific actions associated with viewed tools could be decoded and whether action-specific information generalised across viewing and acting. Participants (N=18; 11 females) viewed tool pictures and, in separate runs, pantomimed tool-use actions in response to tool names. Familiar tools differed in their associated action (rotate or squeeze) but were matched for grip type. Viewing tool pictures elicited tool-use action information in lateral occipitotemporal cortex (LOTC), parietal cortex, and even somatosensory cortex. Notably, hand-selective LOTC was the only region in which action decoding exceeded tool-identity decoding during both viewing and pantomime, suggesting sensitivity to learned relationships between objects and characteristic hand actions. However, neither region-of-interest nor whole-brain searchlight analyses yielded reliable cross-task decoding. Thus, although overlapping cortical regions contained information about tool-use actions during perception and production, we found no evidence that this information was represented in a shared multivoxel format. These findings suggest that seeing familiar tools evokes distributed information about their associated actions and sensory consequences, but that such information may be expressed in task-dependent formats rather than simply reinstating the neural patterns engaged during action production.

neuroscience↗

bioRxiv2023

Phosphorylation barcodes direct biased chemokine signaling at CXCR3

G protein-coupled receptor (GPCR) biased agonism, the activation of some signaling pathways over others, is thought to largely be due to differential receptor phosphorylation, or "phosphorylation barcodes." At chemokine receptors, ligands act as "biased agonists" with complex signaling profiles, which contributes to the limited success in pharmacologically targeting these receptors. Here, mass spectrometry-based global phosphoproteomics revealed that CXCR3 chemokines generate different phosphorylation barcodes associated with differential transducer activation. Chemokine stimulation resulted in distinct changes throughout the kinome in global phosphoproteomic studies. Mutation of CXCR3 phosphosites altered {beta}-arrestin conformation in cellular assays and was confirmed by molecular dynamics simulations. T cells expressing phosphorylation-deficient CXCR3 mutants resulted in agonist- and receptor-specific chemotactic profiles. Our results demonstrate that CXCR3 chemokines are non-redundant and act as biased agonists through differential encoding of phosphorylation barcodes and lead to distinct physiological processes.

biochemistry↗

bioRxiv2022

Single-Cell Analysis Identifies Distinct Immune and Smooth Muscle Cell Populations that Contribute to Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is a sequelae of acute pulmonary embolism (PE) in which the PE remodels into a chronic scar in the pulmonary arteries. This results in vascular obstruction, small vessel arteriopathy and pulmonary hypertension. Our current understanding of CTEPH pathobiology is primarily derived from cell-based studies limited by the use of specific cell markers or phenotypic modulation in cell culture. Here we used single cell RNA sequencing (scRNAseq) of tissue removed at the time of pulmonary thromboendarterectomy (PTE) surgery to identify the multiple cell types, including macrophages, T cells, and smooth muscle cells, that comprise CTEPH thrombus. Notably, multiple macrophage subclusters were identified but broadly split into two categories, with the larger group characterized by an upregulation of inflammatory signaling predicted to promote pulmonary vascular remodeling. Both CD4+ and CD8+ T cells were identified and likely contribute to chronic inflammation in CTEPH. Smooth muscle cells were a heterogeneous population, with a cluster of myofibroblasts that express markers of fibrosis and are predicted to arise from other smooth muscle cell clusters based on pseudotime analysis. Additionally, cultured endothelial, smooth muscle and myofibroblast cells isolated from CTEPH thrombus have distinct phenotypes from control cells with regards to angiogenic potential and rates of proliferation and apoptosis. Lastly, our analysis identified protease-activated receptor 1 (PAR1) as a potential therapeutic target that links thrombosis to chronic PE in CTEPH, with PAR1 inhibition decreasing smooth muscle cell and myofibroblast proliferation and migration. These findings suggest a model for CTEPH similar to atherosclerosis, with chronic inflammation promoted by macrophages and T cells driving vascular remodeling through smooth muscle cell modulation, and suggest new approaches for pharmacologically targeting this disease.

pathology↗

bioRxiv2022

Location bias contributes to functionally selective responses of biased CXCR3 agonists

Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" which preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the chemokine GPCR CXCR3. The signaling profile of CXCR3 changed as it trafficked from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling was critical for biased activation of G proteins, {beta}-arrestins, and ERK1/2. In CD8+ T cells, the chemokines promoted unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, {beta}-arrestin-biased CXCR3-mediated inflammation was dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs.

biochemistry↗

bioRxiv2020

Biased agonists of the chemokine receptor CXCR3 differentially drive formation of Gαi:β-arrestin complexes

G-protein-coupled receptors (GPCRs), the largest family of cell surface receptors, signal through the proximal effectors G proteins and {beta}-arrestins to influence nearly every biological process. Classically, the G protein and {beta}-arrestin signaling pathways have largely been considered separable. Recently, direct interactions between G protein and {beta}-arrestin have been described and suggest a distinct GPCR signaling pathway. Within these newly described G:{beta}-arrestin complexes, Gi/o, but not other G protein subtypes, have been appreciated to directly interact with {beta}-arrestin, regardless of canonical GPCR G protein subtype coupling. However it is unclear how biased agonists differentially regulate this newly described Gi:{beta}-arrestin interaction, if at all. Here we report that endogenous ligands (chemokines) of the GPCR CXCR3, CXCL9, CXCL10, and CXCL11, along with two small molecule biased CXCR3 agonists, differentially promote the formation of Gi:{beta}-arrestin complexes. The ability of CXCR3 agonists to form Gi:{beta}-arrestin complexes does not correlate well with either G protein signaling or {beta}-arrestin recruitment. Conformational biosensors demonstrate that ligands that promoted Gi:{beta}-arrestin complex formation generated similar {beta}-arrestin conformations. We find these Gi:{beta}-arrestin complexes can associate with CXCR3, but not with ERK. These findings further support that Gi:{beta}-arrestin complex formation is a distinct GPCR signaling pathway and enhance our understanding of biased agonism.

biochemistry↗