Biology subjects

Huo, Q.

Publications and source records attributed to Huo, Q..

7 recordsLinked to original sources

bioRxiv2025

Disruption of ADAMTSL4 Causes Ectopia Pupillae in Zebrafish via COL8A1-Driven Cell Migration

Congenital ectopia lentis (EL) poses a significant threat to visual outcomes in children. Although emerging causative genes have been identified, their biological functions remain poorly understood. In this study, we investigated the contribution of ADAMTSL4 variants to congenital EL in a cohort of 702 pedigrees. Pathogenic variants in ADAMTSL4 were identified in 23 probands (3.28%), comprising 29 distinct variants, with 14 being novel, making ADAMTSL4 the second most frequently mutated gene in the cohort. All affected individuals exhibited EL, and 26.09% also presented with ectopia pupillae (EP), also referred to as ectopia lentis et pupillae. To explore the functional consequences of ADAMTSL4 deficiency, we generated a CRISPR/Cas9-mediated adamtsl4-knockout zebrafish model, that faithfully recapitulated cardinal human disease features with an incidence comparable to that observed in affected patients. Histological and ultrastructural analysis revealed disrupted zonular fiber anchorage at the lens capsule, even in mutated eyes without overt EL or EP. Transgenic overexpression of adamtsl4 successfully reversed the ocular phenotypes, confirming the genes essential role in ocular development. Single-cell RNA-sequencing and fluorescence in situ hybridization demonstrated enriched ADAMTSL4/adamtsl4 expression in the equatorial lens epithelium, retinal pigment epithelium (RPE), iris anterior pigmented epithelium, and choroid fibroblast. Functional assays using zebrafish and human RPEs revealed that ADAMTSL4 deficiency compromised cell adhesion and promoted cell migration. Transcriptomic profiling revealed significant enrichment of extracellular matrix organization and cell adhesion pathways, with cross-species validation identifying consistent upregulation of COL8A1/col8a1b. Notably, COL8A1 knockdown in ADAMTSL4-deficient RPEs partially reversed the aberrant migratory phenotype, suggesting a functional interaction. Together, these findings establish ADAMTSL4 as a major causative gene in ectopia lentis et pupillae, highlight its role in orchestrating ocular integrity via regulation of extracellular matrix and cell behavior.

genetics↗

bioRxiv2025

Depicting pathogenesis of osteomyelitis by single cell RNA-sequencing and an involvement of Morrbid in the autoinflammatory disease

Autoinflammatory diseases (AIDs) are defined as abnormal activation of the innate immune system leading to spontaneous and uncontrolled inflammation. The AIDs affect bone tissue and lead to chronic recurrent multifocal osteomyelitis (CRMO). However, the etiology and treatment of CRMO remain elusive. A mouse strain, Pstpip2cmo/cmo (cmo: chronic multifocal osteomyelitis), exhibits phenotypic characteristics similar to human CRMO. Morrbid is a long non-coding RNA gene and has been indicated in leukemogenesis in our previous studies. In this study, we demonstrated that Morrbid and Pstpip2 are co-expressed in mature myeloid cells and hypothesized a role of Morrbid in osteomyelitis. The Pstpip2-/- mice have the same phenotype as Pstpip2cmo/cmo, mimicking CRMO, while loss of Morrbid in Pstpip2-/-mice significantly inhibited the initiation and progression of CRMO symptoms, as well as the dysregulated activation of myeloid cells and the excessive release of inflammatory cytokines. Furthermore, single-cell RNA-sequencing (scRNA-seq) analysis from the Pstpip2-/- mice and the compound mutant mice supports that reduction of osteoclasts and inflammatory cells caused by Morrbid loss. The study systematically profiles the etiology of CRMO by scRNA-seq and warrants that inhibiting the lifespan of inflammatory myeloid cells by targeting Morrbid is an effective therapeutic strategy for osteomyelitis. HighlightsO_LIWe generated a frameshift mutant mouse strain Pstpip2-/-, which have a classic CRMO-like phenotype as same as Pstpip2cmo/cmo and could be used for testing various anti-inflammation perturbations. C_LIO_LILoss of Morrbid significantly inhibited the autoinflammatory symptoms in Pstpip2-/- mice, suggesting that Morrbid is a novel target for mitigating CRMO. C_LIO_LIscRNA-seq analysis of the affected bone marrow cells in Pstpip2-/-revealed the abnormalities of osteoclasts (OC), neutrophils (NE) and granulocyte macrophage progenitors (GMP) in both their fractions and inflammatory activities. C_LIO_LIUpon loss of Morrbid, we observed reduced composition and proliferation of OC and decreased activity of Nfkb2 and Rela in the compound mutants. C_LI

immunology↗

bioRxiv2023

Cooperative progression of colitis and leukemia modulated by clonal hematopoiesis via PTX3/IL-1β pro-inflammatory signaling

Clonal hematopoiesis (CH) is considered an important risk factor for all-cause mortality and the development of multiple chronic diseases including hematological neoplasms, cardiovascular diseases, and potentially a range of autoimmune or immune-deficiency diseases. Mutations in TET2 are one of the first identified, most important, and prevalent genetic drivers of CH. However, cooperative factors and mechanisms underlying TET2-deficiency related CH (TedCH) remain largely unknown. Recently, it has been suggested that certain diseases occurred before TedCH and promote TedCH trajectory on the contrary, indicating that diseases in non-hematopoietic organs may act as environmental non-genetic drivers of CH. To clarify the relationships between immune-dysfunctional diseases and CH, here we tested the impact of various challenges on TedCH. We found that expedited TedCH depended on establishment of an inflammatory environment. Primary or chimeric Tet2-mutant mice spontaneously developed co-symptoms reminiscent of human chronic colitis and myeloid leukemia, which was exacerbated by feeding with DSS, an experimental inducer of ulcerative colitis. Single cell RNA-seq (scRNA-seq) analysis reveals in depth the damage of colon in the Tet2-mutant mice in physiological conditions or fed with DSS, along with increase of dysbacteriosis indicated by gut microbiome analysis. Results from colon scRNA-seq from both mouse and human highlight the important roles of PTX3/IL-1{beta} pro-inflammatory signaling in promoting colitis or leukemia. Finally, TedCH trajectory and inflammation in colon and bone marrow were ameliorated by treatment of IL-1R1 inhibitor Anakinra. Our study suggests that PTX3/IL-1{beta} signaling and clonal hematopoiesis cooperate and play important roles in gut-bone marrow axis and related diseases including colitis and leukemia. HighlightsO_LICertain environmental factors, such as Dextran Sulfate Sodium (DSS), an experimental inducer of ulcerative colitis, promote TedCH C_LIO_LIColitis and leukemia are spontaneously and simultaneously developed in Tet2-defficient primary or chimeric mice, along with increased pathogenic gut microbiomes, indicating an aberrant gut-bone marrow axis in the mutant mice. C_LIO_LISingle cell RNA-seq analysis reveals enhanced PTX3, a soluble pattern recognition molecule and IL-1{beta} pro-inflammatory signaling in colitis and leukemia. C_LIO_LIThe In vivo function of the PTX3/IL-1{beta} pro-inflammatory signaling in TedCH is indicated in human colitis and validated in experimental settings. C_LI

immunology↗

bioRxiv2022

Osteosarcoma-enriched transcripts paradoxically generate osteosarcoma-suppressing extracellular proteins

Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and osteosarcoma-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with Cisplatin. CM was enriched with proteins such as Calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of Calr transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein (APP), a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.

cancer biology↗

bioRxiv2021

Comparative genomics reveals evolutionary drivers of sessile life and left-right shell asymmetry in bivalves

Bivalves are species-rich mollusks with prominent protective roles in coastal ecosystems. Across these ancient lineages, colony-founding larvae anchor themselves either by byssus production or by cemented attachment. The latter mode of sessile life is strongly molded by left-right shell asymmetry during larval development of Ostreoida oysters such as Crassostrea hongkongensis. Here, we sequenced the genome of C. hongkongensis in high resolution and compared it to reference bivalve genomes to unveil genomic determinants driving cemented attachment and shell asymmetry. Importantly, loss of the homeobox gene antennapedia (Antp) and broad expansion of lineage-specific extracellular gene families are implicated in a shift from byssal to cemented attachment in bivalves. Evidence from comparative transcriptomics shows that the left-right asymmetrical C. hongkongensis plausibly diverged from the symmetrical Pinctada fucata in expression profiles marked by elevated activities of orthologous transcription factors and lineage-specific shell-related gene families including tyrosinases, which may cooperatively govern asymmetrical shell formation in Ostreoida oysters.

genomics↗

bioRxiv2020

Microglial activation results in neuron-type-specific increase in mPFC GABAergic transmission and abnormal behavior in mice

Neuroinflammation and synaptic dysfunction are two early symptoms of most neurological diseases. However, the mechanisms underlying microglia-associated neuroinflammation in the regulation of synaptic activity remain obscure. We report here that acute neuroinflammation induced by a single-dose proinflammatory cytokine inducer, lipopolysaccharide (LPS), results in enhanced inhibitory postsynaptic currents (IPSCs) of glutamatergic neurons, upregulated levels of GABAAR subunits, glutamine synthetase (GS) and vGAT, and downregulated BDNF and pTrkB levels, due to enhanced activation of microglia in the medial prefrontal cortex (mPFC). Blockage of microglial activation by minocycline ameliorated LPS-induced aberrant mIPSCs and associated aberrant protein expression and behavior. Exogenous application of BDNF prior to LPS challenge also ameliorated LPS-induced abnormal mIPSCs. Thus, this study elucidates a critical role for microglia in the neurobiology of GABAergic synaptic dysfunction induced by neuroinflammation, revealing a novel GABAergic signaling pathway that might be targeted therapeutically to treat neuroinflammation-induced abnormal synaptic activity and associated aberrant behavior.

neuroscience↗

bioRxiv2019

Bacterial and Archaeal Communities in Recycling Effluents from a Bauxite Flotation Plant

Recycling effluent has become a bottleneck and an environmental risk associated with the regular production of bauxite via flotation and the sustainable development of the aluminum industry in China. To find a practical direction for biotreatment, the bacterial and archaeal communities in recycling effluents containing concentrate and tailings from bauxite flotation plants were investigated by a metagenomic sequencing method in association with the evaluated geochemical properties. The results showed that Paracoccus, Desulfomicrobium, Exiguobacterium, Tindallia, Ercella and Anoxynatronum were the primary bacterial genera and Methanothrix, Methanobacterium, Nitrososphaera and Methanosarcina were the dominant archaeal genera. Upon combining the microbial diversity and the geochemical properties of the two sample types, the microbial community containing Desulfomicrobium, Paracoccus, Tindallia, Methanobacterium, Methanothrix and Nitrososphaera was better adapted to the biodegradation of flotation collectors, and the microbial community consisting of Paracoccus, Exiguobacterium, Methanothrix and Methanobacterium was more efficient at hydrolyzed polyacrylamide (HPAM) biodegradation. In addition, a large proportion of unclassified OTUs has indicated that recycling effluent is a worthy resource for isolating new strains from the Firmicutes phylum.

microbiology↗