Biology subjects

GAO, Y.

Publications and source records attributed to GAO, Y..

4 recordsLinked to original sources

bioRxiv2026

Cooperative Peripheral CB1 Inhibition by Extracellular Antibody Binding and Orthosteric Antagonism

The cannabinoid receptor CB1 is an important therapeutic target for obesity and metabolic disorders, yet centrally acting CB1 antagonists are limited by neuropsychiatric side effects. Although the anti-CB1 antibody Nimacimab has advanced to Phase 2 clinical trials for metabolic disorders, the molecular mechanisms underlying peripheral CB1 inhibition remain poorly understood. Here, we report cryo-EM structures of human CB1 bound to Nimacimab alone and in complex with the orthosteric antagonists Rimonabant and JD5037. Unlike previously characterized inhibitory GPCR antibodies that block ligand access through steric occlusion or directly engage orthosteric sites, Nimacimab functions through extracellular allosteric inhibition by stabilizing an inactive-like extracellular architecture of CB1. Antibody binding restricts extracellular conformational dynamics and allosterically stabilizes inactive-state signaling microswitches. Importantly, extracellular antibody engagement is structurally compatible with orthosteric antagonism and cooperatively enhances CB1 inhibition. Structural analysis further reveals how JD5037 remodels the extracellular vestibule to achieve peripheral-selective antagonism. Together, these findings establish extracellular allosteric inhibition as a distinct mechanism of GPCR regulation and provide a structural framework for the development of peripherally selective CB1 therapeutics.

pharmacology and toxicology↗

bioRxiv2025

Contrasting genomic routes to domestication in Occidental and Oriental pears

The domestication of perennial fruit trees remains poorly understood compared with annual crops, which were shaped by strong bottlenecks and elevated genetic load. Pears (Pyrus spp.) provide an ideal model for exploring how long-lived, outcrossing crops evolved under human selection. Here, we combined high-coverage whole-genome resequencing of 396 wild and cultivated accessions from Occidental and Oriental pears with analyses of nucleotide and transposable element (TE) polymorphisms to reconstruct the demographic and adaptive history of pear domestication. Demographic inferences revealed weak or no domestication bottlenecks and extensive gene flow between wild and cultivated populations. In the Occidental lineage, dessert and perry P. communis cultivars underwent independent domestications from the same wild progenitor, P. pyraster, with divergent selection linked to fruit use. In the Oriental lineage, regionally independent domestications gave rise to Chinese and Japanese P. pyrifolia cultivars, shaped by both environmental adaptation and human selection. Selection scans identified lineage- and use-specific targets related to fruit texture, metabolism, and immunity. Contrary to the classical "cost of domestication" hypothesis, cultivated pears carried fewer deleterious variants than their wild relatives, suggesting efficient purging through selection and introgression. TE insertions mirrored population structure and occasionally occurred near selected genes, indicating a limited but detectable adaptive role. Together, our findings go beyond confirming the dual origins of Pyrus domestication to reveal contrasting demographic and adaptive pathways in Occidental and Oriental pears, illustrating independent adaptive trajectories in perennial crops, where long lifespan, self-incompatibility, and recurrent introgression shape distinctive genomic outcomes.

genomics↗

bioRxiv2024

Elucidating the Diversity and Potential Function of Ribosomally Synthesized and Post-translationally Modified Peptides in the Human Microbiome

The human microbiome holds tremendous potential for generating specialized peptides, specifically ribosomally synthesized and post-translationally modified peptides (RiPPs), significantly affecting human health by mediating interactions with other microbes and the human host. However, the capacity of our microbiome to produce these peptides and their links with human health are poorly understood. This study systematically analyzes 306,481 human microbiota-associated genomes, uncovering a broad array of yet-to-be-discovered RiPPs. These RiPPs are distributed across various body sites but show a specific enrichment in the gut and oral microbiome. Big data omics analysis reveals that numerous RiPP families are inversely related to various diseases, suggesting their potential protective effects on health. For a proof of principle study, guided by biosynthetic prediction, nine autoinducing peptides (AIPs) were chemically synthesized for in vitro and ex vivo assay. Our findings revealed that five AIPs effectively inhibited the biofilm formation of disease-associated pathogens, with one demonstrating significant anti-inflammatory capabilities. Furthermore, when ex vivo testing gut bacteria from mice with inflammatory bowel disease, we observed that two AIPs could regulate the microbial community and reduce harmful species. These findings highlight the vast potential of human microbial RiPPs in regulating microbial communities and maintaining human health, emphasizing their potential for therapeutic development.

microbiology↗

bioRxiv2020

abPOA: an SIMD-based C library for fast partialorder alignment using adaptive band

SummaryPartial order alignment, which aligns a sequence to a directed acyclic graph, is now frequently used as a key component in long-read error correction and assembly. We present abPOA (adaptive banded Partial Order Alignment), a Single Instruction Multiple Data (SIMD) based C library for fast partial order alignment using adaptive banded dynamic programming. It can work as a stand-alone multiple sequence alignment and consensus calling tool or be easily integrated into any long-read error correction and assembly workflow. Compared to a state-of-the-art tool (SPOA), abPOA is up to 15 times faster with a comparable alignment accuracy. Availability and implementationabPOA is implemented in C. A stand-alone tool and a C/Python software interface are freely available at https://github.com/yangao07/abPOA. Contactydwang@hit.edu.cn or XINGYI@email.chop.edu

bioinformatics↗