Biology subjects

Yu, R. C.

Publications and source records attributed to Yu, R. C..

4 recordsLinked to original sources

bioRxiv2025

Cannabinoid Receptor 2 Activating Antibodies: A Promising Therapeutic Strategy for Macrophage-Driven Fibro-Inflammatory Diseases

Fibrotic diseases, often fueled by chronic inflammation, represent a major unmet medical need. A critical driver of this process is the activation of macrophages, which secrete pro-inflammatory cytokines and chemokines, leading to immune cell recruitment and collagen deposition by myofibroblasts. Agonizing the cannabinoid receptor 2 (CB2), expressed on macrophages, offers a potential therapeutic avenue to suppress this activation. Despite widespread interest in CB2 modulation, challenges remain in the development of small molecule agonists, including insufficient specificity and poor drug-like properties. Antibodies are highly specific with favorable pharmacokinetics and bioavailability, but GPCR agonist antibodies have been difficult to discover. Here we present first-in-class CB2 agonist antibodies, AB120 and AB150. These antibodies are CB2 specific, G-alpha biased, and effectively decrease the expression of macrophage activation markers and key pro-inflammatory cytokines, including IL-6, IL-1{beta} and TNF-. Furthermore, using an ex vivo human precision-cut liver slice (hPCLS) model of liver fibrosis, we observe that treatment with these CB2 agonist antibodies not only reduces inflammatory markers but also decreases collagen expression, indicating a potential to halt or reverse fibrosis. These novel CB2-specific agonist antibodies hold promise as therapeutics for a range of fibrotic and inflammatory conditions driven by chronic macrophage activation and demonstrate the potential of GPCR antibody agonists to drug this challenging class of targets. Significance StatementFibrotic diseases driven by chronic inflammation lack effective treatments. CB2 agonism modulates macrophage activation to reduce pro-inflammatory cytokines suggesting a novel avenue of treatment, but small molecule CB2 agonists have faced substantial limitations due to off-target effects. We introduce two novel CB2-specific agonist antibodies with potent anti-inflammatory and anti-fibrotic effects in vitro and in a human ex vivo liver fibrosis model. These antibodies provide a promising new therapeutic strategy and highlight the advantages of antibodies as GPCR agonist drugs.

pharmacology and toxicology↗

bioRxiv2024

Persistent Neurological Deficits in Mouse PASC Reveal Antiviral Drug Limitations

Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, as found in human neurodegenerative diseases. Early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titers and lung inflammation but failed to prevent neurological abnormalities, as observed in patients. Together these results show that chronic deficiencies in neuronal function in SARS-CoV-2-infected mice are not directly linked to ongoing olfactory epithelium dysfunction. Rather, they bear similarity with neurodegenerative disease, the vulnerability of which is exacerbated by chronic inflammation.

microbiology↗

bioRxiv2016

Cell-to-cell variability in the yeast pheromone response: high throughput screen identifiesgenes with different effects on transmitted signal and response

Populations of isogenic cells often respond coherently to signals despite differences in protein abundance and cell state. Our previous work in the Saccharomyces cerevisiae pheromone response system (PRS) uncovered processes that reduced cell-to-cell variation in signal and response. To understand these and other processes that controlled variation, we generated a whole-genome collection of haploid strains with deletions in non-essential genes and used high-throughput flow cytometry to screen more than 1000. We identified 50 \"variation genes\" required for normal cell-to-cell variability in signal and response. Some genes affected only signal variability, signal strength, or system output, defining these quantities as separable \"axes\" of system behavior. Two genes affected cytoplasmic microtubule function.

systems biology↗

bioRxiv2016

Cell-to-cell variability in the yeast pheromone response: Cytoplasmic microtubule functionstabilizes signal generation and promotes accurate fate choice

In a companion paper, we carried out a high-throughput screen to identify genes that suppressed cell-to-cell variability in signaling in yeast. Two genes affected cytoplasmic microtubules that can connect the nucleus to a signaling site on the membrane. Here, we show that microtubule perturbations that affected polymerization and depolymerization, membrane attachment, and force generation increased variability. For some perturbations, \"outlier\" cells drove the increased variability. Bypass experiments that activated the PRS ectopically at downstream points indicated that microtubule-dependent processes might stabilize the membrane-recruited scaffold protein Ste5. The variability caused by microtubule perturbations required the MAP kinase Fus3. Microtubule perturbations hindered stable scaffold formation and decreased the accuracy of a polarity-dependent fate choice. Our experiments suggest that membrane-attached microtubules stabilize signaling by scaffold-bound Fus3, and are consistent with a model in which signaling irregularities from changes in microtubule function are amplified by cross-stimulatory feedbacks among PRS proteins. The fact that microtubule perturbations also cause aberrant fate and polarity decisions during embryonic development and cancer initiation suggests that similar variation-reducing processes might also operate in metazoans.

systems biology↗