Biology subjects

li, j.

Publications and source records attributed to li, j..

10 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↗

bioRxiv2026

A Phospho-Switch for Cell Fate Control

Cell fate control is thought to be complex, likely involving both cell intrinsic and extrinsic factors, and remains ill-defined at the molecular level. Here we show a phospho-switch controls cell fate both in vitro and in vivo. We first show that SALL4 is phosphorylated at multiple sites, but only T903 as the primary one as SALL4T903A lost BAF interaction and [~]90% activity in reprogramming. Mechanistically, we demonstrate that SALL4pT903 is sensitive to BMP4 signaling through DUSP9 axis. Finally, we show by tetraploid embryo complementation that mESCs harboring SALL4T903A can sustain embryo development but with severe defects including cranial hypoplasia and flattened skull vault after birth. A genome wide search identifies 608 transcription factors harboring the same HTG motif sandwiched by two zinc fingers, suggesting that this phospho-switch may be a conserved mechanism to control cell fate. In briefA phosphorylation switch, pT903, in SALL4 governs cell fate by modulating BAF complex interaction in response to BMP4-DUSP9 signaling, as its dephosphorylation abrogates reprogramming and causes cranial defects in mice, suggesting that such switches may broadly regulate cell fate machinery. HighlightsO_LIA T903 phospho-switch in SALL4 gates BAF interaction to orchestrate gene activation and reprogramming C_LIO_LIBMP4-DUSP9 signaling converges on SALL4pT903 dephosphorylation to couple extracellular cues with cell fate determination C_LIO_LIDisrupting the SALL4-T903 phospho-switch causes severe postnatal developmental defects in mice. C_LIO_LIThe HTGE motif may function as a central switch on key transcription factors for sensing upstream signals C_LI

developmental biology↗

bioRxiv2025

FGF8 promotes lipid droplet accumulation via the FGFR1/p-p38 axis in chondrocytes

Chondrocytes store lipids in the form of lipid droplets (LDs) and maintain cartilage lipid metabolic homeostasis by consuming or regenerating LDs. This modulation is largely mediated by a series of biochemical factors. Fibroblast growth factor 8 (FGF8) is one of the most important factors involved in the proliferation, differentiation, and migration of chondrocytes, and has attracted increasing attention in the physiology and pathology of cartilage. However, the effect of FGF8 on LD accumulation in chondrocytes remains unclear. This study aimed to elucidate the role of FGF8 in LDs and explore the underlying biomechanism involved. The results showed that FGF8 promoted LD accumulation in chondrocytes by upregulating perilipin1 (Plin1) expression. FGF8 activates the cytoplasmic p-p38 signaling pathway via fibroblast growth factor receptor 1 (FGFR1) to increase LD accumulation in chondrocytes. Subsequent experiments with siRNAs and specific inhibitors further confirmed the importance of the FGFR1/p38 axis for LD accumulation in chondrocytes exposed to FGF8. These results increase our understanding of the role of FGF8 in the lipid metabolic homeostasis of chondrocytes and provide insights into the physiology and pathology of cartilage.

cell biology↗

bioRxiv2025

Genetic association between posterior parietal cortex and intelligence

The identification of intelligence-associated loci raises questions for functional association of brain regions and for different intelligence concepts of either a general capability or discrete abilities. By generating single-nucleus transcriptomic atlas of mouse posterior parietal cortex (PPC), which is implicated in quantification behavior, we find that human intelligence-associated gene homologs are significantly enriched in certain specific neurons within the PPC. We also find 73% of the human intelligence gene homologs are highly enriched in PPC. In addition to PPC, several regions at different locations, not cortex next to PPC, are also significantly associated with intelligence genes. The separate locations of these cortex regions and their regional-specific expressed intelligence genes raise the possibility for discrete intelligence capabilities. Animal behavior analysis reveals that mutations for two top intelligence-associated genes with specific expression in either PPC or entorhinal cortex (ENT) affect quantification or learning and memory, respectively. Finally, five patients with PPC resection in the left hemisphere also display quantification defects, but not other cognitive abilities. Together, our studies provide the first genetic and functional evidence for the involvement of PPC in intelligence. Our data also support the model of multiple intelligence over a general capability for intelligence.

genetics↗

bioRxiv2024

Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+ TAMs and CD8+ T cells

Administration of selective serotonin reuptake inhibitors (SSRIs) is associated with a reduced cancer risk and shows significant anti-tumor effects across multiple tumor types, suggesting the potential for repurposing SSRIs in cancer therapy. Nonetheless, the specific molecular target and mechanism of action of SSRIs remain to be fully elucidated. Here, we reveal that citalopram exerts an immune-dependent anti-tumor effects in hepatocellular carcinoma (HCC). Interestingly, the anti-HCC effects of citalopram are not reliant on its conventional target, the serotonin transporter. Through various drug repurposing approaches, including global reverse gene expression profiling, drug affinity responsive target stability assay, and molecular docking, the complement component 5a receptor 1 (C5aR1) is identified as a new target of citalopram. C5aR1 is predominantly expressed by tumor-associated macrophages (TAMs), and citalopram treatment enhances local macrophage phagocytosis and elicits CD8+ T anti-tumor immunity. C5aR1 deficiency or depletion of CD8+ T cells hinders the anti-HCC effects of citalopram. Collectively, our study reveals the immunomodulatory roles of citalopram in inducing anti-tumor immunity, and provides a basis for considering the repurposing of SSRIs as promising anticancer agents for HCC treatment.

cancer biology↗

bioRxiv2023

Identification of a recombinant human astrovirus type 5 strain from an acute gastroenteritis outbreak in Beijing, China

Two samples positive for the same strain (2103CP) of human astrovirus (HAstV) were identified during an acute gastroenteritis outbreak in Beijing, China. A full genomic analysis showed that for both samples, open reading frame 1a (ORF1a) clustered with HAstV-1, whereas ORF1b and ORF2 clustered with HAstV-5. The recombination site was detected upstream of the region where ORF1a and ORF1b overlapped. Recombinant HAstV-5 strains were reported previously in China in 2013 and 2021. Our results indicate the need for continuous surveillance of the prevalence and evolution of this recombinant HAstV-5 in China.

evolutionary biology↗

bioRxiv2022

Genetic structure analysis on leopard cat reveals the effects of habitat fragmentation on subpopulation differentiation in Beijing

In the face of habitat shrinkage and segregation, the survival of wild cats looks bleak. Interpreting the population genetic structure during habitat fragmentation is critical to planning effective management strategies. To reveal the segregation effects of road construction and human settlement on population genetic structure, we noninvasively analyzed fecal DNA samples from leopard cats (Prionailurus bengalensis) from five nature reserves in mountainous areas around Beijing. We focused on molecular microsatellite markers and the mitochondrial control region. A total of 112 individual leopard cats were identified among 601 samples of scat, and generally moderate population genetic diversity was detected. Microsatellite marker-based gene flow (Nm) and STRUCTURE analyses showed no obvious discrepancies among the subpopulations; however, the calculation of genetic distance and construction of a phylogenetic tree of the mitochondrial control region revealed a trend toward differentiation from the other subpopulations in the Songshan subpopulation, which indicates habitat fragmentation effects. Because the isolated Songshan subpopulation may evolve independently, we suggest that its genetic structure be monitored every 5 years to detect any changes and that individuals be introduced as needed to maintain the viability of this subpopulation.

genetics↗

bioRxiv2019

Aquaculture potential of Bohai Red and its hybrid with Agropecten irradians concentricus in southern China

Argopecten irradians concentricus (Say), one of four geographic subspecies of the bay scallop, has become the major cultured species in southern China since its introduction in 1995. However, its population has been significantly reduced due to high mortality.Also, poor growth rate has been observed following decades of culture.Therefore, the introduction or creation of new varieties is an urgent need. This study describes the first introduction of the new strain, Bohai Red, from the north to southern China. Hybridization trials were conducted between the recently introduced new strain and the local specie, A. irradians concentricus (Say). The success of hybridization was confirmed by SSR maker.The adult and juvenile Bohai Red cannot tolerate high temperatures compared to A. irradians concentricus (Say), whether in natural waters or under laboratory conditions. Fertilization rate for A. irradians concentricus (Say) x Bohai Red exceeded 80%, and hatching rate was 70%. The hybrids exhibit heterosis in survival rate, growth rate, and high-temperature tolerance, demonstrating substantial potential to replace A. irradians concentricus (Say) in southern China.

zoology↗

bioRxiv2019

Jasmonate-regulated ERF109-MYB51-MYC3 ternary complexes control indolic glucosinolates biosynthesis

Jasmonates (JAs) are plant hormones which regulate biosynthesis of many secondary metabolites, such as glucosinolates (GLSs), through JAs-responsive transcription factors (TFs). The JAs-responsive CYP83B1 gene, has been shown to catalyze the conversion of indole-3-acetaldoxime (IAOx) to indolic glucosinolates (IGLSs). However, little is known about the regulatory mechanism of CYP83B1 gene expression by JAs. In yeast one-hybrid screens using the CYP83B1 promoter as bait we isolated two JAs-responsive TFs ERF109 and MYB51 that are involved in JAs-regulated IGLS biosynthesis. Furthermore, using a yeast two-hybrid assay, we identified ERF109 as an interacting partner of MYB51, and Jasmonate ZIM-domain (JAZ) proteins as interactors of MYB51, and BTB/POZ-MATH (BPM) proteins as interactors of ERF109. Both JAZ and BPM proteins are necessary for the full repression of the ERF109-MYB51-MYC3 ternary complex activity on CYP83B1 gene expression and JA-regulated IGLS biosynthesis. Biochemical analysis showed that the 26S proteasome-mediated degradation of ERF109 protein is mediated by a CRL3BPM E3 ligase independently of JA signaling. Genetic and physiological evidence shows that MYB51 acts as an adaptor and activator to bridge the interaction with the co-activators MYC3 and ERF109, for synergistically activating the CYP83B1 gene expression, and all three factors are essential and exert a coordinated control in JAs-induced IGLS biosynthesis. Overall, this study provides insights into the molecular mechanisms of JAs-responsive ERF109-MYB51-MYC3 ternary complexes in controlling JAs-regulated GLSs biosynthesis, which provides a better understanding of plant secondary metabolism. One-sentence summaryThe JA-responsive ERF109-MYB51-MYC3 ternary complex controls JAs-regulated GLSs biosynthesis.

bioengineering↗

bioRxiv2018

MetaPGN: a pipeline for construction and graphical visualization of annotated pangenome networks

Pangenome analyses facilitate the interpretation of genetic diversity and evolutionary history of a taxon. However, there is an urgent and unmet need to develop new tools for advanced pangenome construction and visualization, especially for metagenomic data. Here we present an integrated pipeline, named MetaPGN, for construction and graphical visualization of pangenome network from either microbial genomes or metagenomes. Given either isolated genomes or metagenomic assemblies coupled with a reference genome of the targeted taxon, MetaPGN generates a pangenome in a topological network, consisting of genes (nodes) and gene-gene genomic adjacencies (edges) of which biological information can be easily updated and retrieved. MetaPGN also includes a self-developed Cytoscape plugin for layout of and interaction with the resulting pangenome network, providing an intuitive and interactive interface for full exploration of genetic diversity. We demonstrate the utility of MetaPGN by constructing Escherichia coli (E. coli) pangenome networks from five E. coli pathogenic strains and 760 human gut microbiomes respectively, revealing extensive genetic diversity of E. coli within both isolates and gut microbial populations. With the ability to extract and visualize gene contents and gene-gene physical adjacencies of a specific taxon from large-scale metagenomic data, MetaPGN provides advantages in expanding pangenome analysis to uncultured microbial taxa. MetaPGN is available at https://github.com/peng-ye/MetaPGN.

genomics↗