Biomedical subjects

Yuan Gao

Publications and source records attributed to Yuan Gao.

13 recordsLinked to original sources

PubMed2026

Developmental and cellular vulnerabilities underlie genetic architecture of schizophrenia.

Schizophrenia (SZ) is a highly heritable neuropsychiatric condition with complex polygenic architecture. Elucidating the cellular and developmental substrates vulnerable to the genetic risk is essential for understanding the underlying neurobiological mechanisms. Here, we integrated genome-wide association study (GWAS) and whole-exome sequencing (WES) data with a developmental multi-omics atlas of the human cortex (including 5 cortical regions), comprising about 3 million single-nucleus RNA sequencing (snRNA-Seq) and single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-Seq) profiles across 8 neurodevelopmental processes, to map cell-type-specific enrichment of SZ genetic risk. Our enrichment analyses revealed that both common and rare genetic liabilities converged on broad excitatory and inhibitory neuronal classes. Across different statistical frameworks, we identified genetic enrichment within intratelencephalic (IT) projection neurons and layer 6b excitatory neurons (Ex-L6b) networks across multiple cortical regions. Stage-resolved developmental mapping in the frontal cortex showed that genetic liabilities, particularly the rare variants, are predominantly concentrated within early developmental processes, namely neurogenesis and neuronal migration. Differential expression analysis in postmortem frontal cortex snRNA-Seq datasets cross-validated the cellular substrates of the genetic liabilities. Collectively, our findings establish a high-resolution cellular and temporal framework of SZ susceptibility, implicating mature associative IT microcircuits, deep-layer thalamocortical-regulating networks, and early developmental specification windows as primary points of genetic convergence in SZ.

Journal Article↗

PubMed2026

Pediatric sarcomas: challenges and opportunities.

Pediatric sarcomas are a heterogeneous group of rare mesodermal malignancies. These cancers, which affect children from infancy through adolescence and young adulthood, are in general challenging to treat with currently available therapies. Biologically, many are characterized by quiet genomes, fusion oncoproteins, immune "cold" microenvironments, and vast epigenetic deregulation that contributes to diverse and complex mechanistic drivers. Multifaceted advancements in research strategies, including high-throughput screening, new model systems, surfaceome profiling, and study of oncogenic fusion condensates have led to new opportunities for understanding the biology of pediatric sarcomas. To continue to make progress for these difficult to treat cancers, it will be critical to continue to improve access to bioinformatic data, approach patient care using innovative clinical trial frameworks, and foster interdisciplinary partnerships among medicinal chemists, scientists, clinicians, advocates, and industry partners.

Humans↗

PubMed2026

Hepatic metabolic adaptation to endurance exercise: temporal and sex differences by multiomics integration and validation.

BACKGROUND: Although endurance exercise benefits liver health, sex-specific adaptive trajectories remain unclear. This study mapped dynamic liver adaptation in males and females during prolonged training and identified underlying molecular programs. METHODS: Using publicly available time-resolved liver multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we established a computational pipeline for differential analysis of transcriptomic, proteomic, phosphoproteomic, and metabolomic data with FDR correction, followed by FGSEA pathway enrichment. Kinase activities were inferred through ortholog mapping and PhosphoSitePlus. Cross-omics co-expression networks were constructed using WGCNA and topological overlap to link omics features with physiological phenotypes. For experimental validation, liver tissues were collected from endurance-trained Sprague-Dawley rats, and key nodes were confirmed by Western blotting, qRT-PCR, and immunofluorescence/immunohistochemical staining. Public scRNA-seq data were further integrated to map multi-omics signals to single-cell resolution and assess functional changes in specific cell types. RESULTS: The hepatic response to exercise stress was stage-specific, shifting from early transcriptional activation to later proteomic and metabolic remodeling. Multi-omics integration revealed distinct sex-associated adaptive trajectories: males were more strongly associated with energy metabolism, redox-related programs, and amino acid/organic acid catabolism, whereas females showed prominent membrane lipid remodeling, proteostasis -related programs, and mitochondrial/ribosomal translational features. Single-cell analysis showed that tissue remodeling occurred without major lineage turnover, instead involving altered communication among pre-existing cell communities. Validation of PPP1R3G identified a protein-dominant exercise-responsive marker, supporting the contribution of post-transcriptional or protein-level regulation. CONCLUSIONS: Hepatic adaptation to endurance stress follows a cross-omics evolutionary pattern with sex-specific reprogramming of energy supply and homeostatic maintenance. This time-resolved framework clarifies how exercise improves liver function and supports sex-oriented metabolic interventions and therapeutic target discovery.

Animals↗

PubMed2026

Delayed maturation of the milk microbiome in women with type 1 diabetes.

AIMS/HYPOTHESIS: The breastmilk microbiome plays a crucial role in gut microbial colonisation and immune development, but little is known about how it is influenced by type 1 diabetes. METHODS: We conducted a longitudinal 16S rRNA gene sequencing study of milk from women with type 1 diabetes (n=69 pregnancies; 174 samples) and women who did not have type 1 diabetes (n=49 pregnancies; 123 samples), collected at seven timepoints from birth to 15 months postpartum. Alpha diversity (richness, inverse Simpson evenness) was analysed by generalised linear mixed models, beta diversity was analysed by Bray-Curtis dissimilarities and PERMANOVA, and differential abundance was analysed by limma. Additionally, we examined associations with maternal genetic risk score (GRS), maternal HLA type, glycaemic management (HbA1c) and breastmilk secretory IgA (sIgA), and performed a parallel analysis for the infant stool microbiome. RESULTS: A significant interaction between type 1 diabetes status and timepoint was observed for alpha diversity, both richness (p=0.01) and inverse Simpson diversity (p=0.003), indicating distinct temporal trajectories between women with and without type 1 diabetes. In those without type 1 diabetes, richness increased significantly between birth and 1 week postpartum, but this early increase was delayed in women with type 1 diabetes to between 1 week and 3 months postpartum (p=0.002). Beta diversity analysis revealed earlier and more extensive compositional shifts in women without type 1 diabetes compared to those with type 1 diabetes. These differences persisted after adjusting for Caesarean delivery, BMI, parity and infant sex, and were not attributable to a delay in initiating breastfeeding. Taxa with delayed enrichment in women with type 1 diabetes included Streptococcus spp. and Rothia mucilaginosa, which metabolise human milk oligosaccharides to short-chain fatty acids to promote development of the infant's gut barrier and immune system. Maternal GRS, HLA, HbA1c or sIgA were not associated with milk microbiota diversity trajectories. In infant stool samples, alpha diversity did not differ between exposure groups, and showed no evidence of delayed maturation. Beta diversity revealed an early compositional shift between birth and 1 week postpartum only in infants born to women without type 1 diabetes. Similarly, significant taxonomic changes between birth and 1 week postpartum were detected only in infants born to women without type 1 diabetes, but with some taxa differing between exposure groups at 1 week. CONCLUSIONS/INTERPRETATION: Maternal type 1 diabetes is associated with delayed early maturation of the breastmilk microbiome. Early compositional differences in microbiota restructuring were also observed in the infant gut, partially mirroring the pattern in the milk microbiome; however, sustained differences in infant gut microbiota diversity were not detected. Further investigation could determine whether these changes affect development of the infant's gut and immune system.

Humans↗

PubMed2026

QCatch: a framework for quality control assessment and analysis of single-cell sequencing data.

MOTIVATION: Single-cell sequencing data analysis requires robust quality control (QC) to mitigate technical artifacts and ensure reliable downstream results. While tools like alevin-fry and simpleaf (and augmented execution context for the alevin-fry), offer flexibility and computational efficiency to process single-cell data, this ecosystem will further benefit from a standardized QC reporting tailored for its outputs. RESULTS: We introduce QCatch, a Python-based command-line tool that generates comprehensive and interactive HTML QC reports designed specifically for single-cell quantification results. Taking the output directory of alevin-fry or simpleaf as the input, QCatch is able to perform essential processing steps, like cell calling, and generate detailed QC reports that contain informative visualizations and statistics, including unique molecular identifier (UMI) count distributions, sequencing saturation estimates, and splicing status information, for QC assurance. Built for seamless integration into downstream analysis workflows, QCatch exports the processed results in a richly-annotated H5AD format file, a widely used data format common among many downstream single-cell data analysis tools. AVAILABILITY AND IMPLEMENTATION: The source code and documentation of QCatch are available on GitHub at https://github.com/COMBINE-lab/QCatch. QCatch can be installed via both Bioconda and PyPI.

Single-Cell Analysis↗

PubMed2025

The Complete Chloroplast Genome and the Phylogenetic Analysis of Panicum bisulcatum (Thumb.) (Poaceae).

The chloroplast (cp) genome of Panicum bisulcatum (Thumb.), a significant agricultural weed, was sequenced and characterized to elucidate its genomic architecture, evolutionary dynamics, and phylogenetic relationships. The complete cp genome was assembled as a circular DNA molecule of 138,489 bp, exhibiting a typical quadripartite structure comprising a large single-copy (LSC, 82,260 bp), a small single-copy (SSC, 12,569 bp), and a pair of inverted repeats (IR, 21,830 bp each) regions. It encodes 135 genes, including 89 protein-coding genes, 49 tRNAs, and 8 rRNAs. Functional annotation revealed that most genes are involved in photosynthesis and genetic system. A total of 51 simple sequence repeats (SSRs) and 62 long repeats (LRs) were identified, providing potential molecular markers. Comparative analysis of IR boundaries highlighted both conserved features and species-specific expansion/contraction events among Panicum species. Phylogenomic analysis robustly placed P. bisulcatum within the genus Panicum, showing a closest relationship with P. incomtum and confirming the monophyly of the genus. Furthermore, single nucleotide polymorphism (SNP) analysis with its closest relative, P. incomtum, revealed 4659 SNPs, with a dominance of synonymous substitutions, indicating the action of purifying selection. This study provides the first comprehensive cp genomic resource for P. bisulcatum, which will facilitate future studies in species identification, phylogenetic reconstruction, population genetics, and the development of sustainable management strategies for this weed.

Phylogeny↗

PubMed2025

The new frontier in understanding human and mammalian brain development.

Neurodevelopmental disorders that cause cognitive, behavioural or motor impairments affect around 15% of children and adolescents worldwide1, with diagnoses of profound autism and attention deficit hyperactivity disorder increasing in the USA and contributing to a major economic burden2,3. Yet the origins and mechanisms of these conditions remain poorly understood, limiting progress in therapies. Comprehensive cell atlases of the developing human brain, alongside those of model organisms such as mice and non-human primates, are now providing high-resolution measures of gene expression, cell-type abundance and spatial distribution. In this Perspective, we highlight recent studies that have identified novel developmental cell populations, revealed conserved and divergent patterns of cell genesis, migration and maturation across species, and begun testing hypotheses that link them to processes ranging from transcriptional control of cell fate specification to the emergence of complex behaviours. We present remaining conceptual and technical challenges and provide an outlook on how further studies of human and mammalian brain development can empower a deeper understanding of neurodevelopmental and neuropsychiatric disorders. Future efforts expanding to additional developmental stages, including adolescence, as well as whole-brain, multimodal and cross-species integration, will yield new insights into how development shapes the brain. These atlases promise to serve as essential references for unravelling mechanisms of brain function and disease vulnerability, and for advancing precision medicine.

Humans↗

PubMed2025

Detecting and quantifying circular RNAs in terabyte-scale RNA-seq datasets with CIRI3.

To address recent challenges in circular RNA (circRNA) analysis, we present CIRI3, a tool for circRNA detection and quantification in terabyte-scale RNA-sequencing datasets. Using dynamic multithreaded task partitioning and a blocking search strategy for junction reads, CIRI3 is an order of magnitude faster than existing tools, while providing increased accuracy. We identified differentially spliced circRNAs across 2,535 cancer-related samples, and constructed a pretraining model and a biomarker network provided as the CIRIonco database.

RNA, Circular↗

PubMed2025

Validation of caprine H11 and the Rosa26 platform for transgene integration via CRISPR-based system: investigations on stable transgene expression and genetic biosafety.

CRISPR/Cas9 technology is an efficient tool for site-specific livestock gene editing. However, to minimize potential disruption of host genome function, exogenous genes should be integrated into well-characterized genomic loci, such as H11 or Rosa26, which have been empirically validated for stable transgene expression. This study established a multi-dimensional assessment system to evaluate the biological applicability of the H11 locus and the widely used Rosa26 targeting platform as sites for targeted integration of exogenous genes in goats. Donor cells carrying the enhanced green fluorescent protein (EGFP) reporter gene at the H11 and Rosa26 loci were generated via CRISPR/Cas9-mediated homology-directed repair; this was followed by somatic cell nuclear transfer to produce transgenic cloned embryos and healthy offspring. Multi-dimensional analyses revealed the following. At the cellular level, there was stable and efficient EGFP expression at integration sites, with donor cells maintaining normal cell cycle progression, proliferation capacity, and apoptosis levels, and with no alterations in the transcriptional integrity of adjacent genes. At the embryonic level, there was sustained EGFP expression across pre-implantation embryonic stages, with developmental metrics statistically indistinguishable from wild-type embryos. Finally, at the individual level, cloned offspring exhibited growth phenotypes consistent with wild-type counterparts, and EGFP showed broad-spectrum expression in eight tissues. This study establishes the first CRISPR/Cas9-based crossscale (cellular-embryonic-individual) validation in goats, demonstrating that the H11 and Rosa26 loci support efficient and stable transgene integration in goats. These results provide a precise and predictable technical framework for livestock genetic improvement.

Animals↗

PubMed2024

DGKH-mediated phosphatidic acid oncometabolism as a driver of self-renewal and therapy resistance in HCC.

BACKGROUND AND AIMS: HCC is characterized by metabolic pathway aberrations, which enable cancer cells to meet their energy demands and accelerate malignant progression. Identifying novel metabolic players governing therapy resistance and self-renewal in HCC is crucial, as these properties are likely responsible for tumor recurrence. APPROACH AND RESULTS: Clinical traits and RNA-seq of patients with HCC in The Cancer Genome Atlas were used for weighted gene coexpression network analysis, where 1 module was significantly correlated with advanced pathological stage and stem cell population maintenance. Further analysis of this module by integrating data obtained from HCC patient nonresponders to tyrosine kinase inhibitors identified 361 commonly deregulated genes. Intriguingly, these genes are significantly enriched in the intracellular signal transduction pathway, with diacylglycerol kinase eta (DGKH) ranked as the most enriched gene in poorly differentiated HCC tumors. Clinically, DGKH was elevated in tumor tissues compared to nontumor tissues. Patients with higher DGKH expression exhibited a more undifferentiated state and were less responsive to tyrosine kinase inhibitors. Functional assays using DGKH-manipulated HCC cell lines demonstrated that DGKH augmented aggressive features, including cancer stemness, therapy resistance, and metastasis. Upstream of DGKH , we discovered that the E1A-associated protein p300 (EP300) binds to DGKH's promoter region, thereby increasing its transcriptomic expression. Mechanistically, DGKH promotes mTOR signaling by producing phosphatidic acid. In an immunocompetent mouse model, cotreatment with sorafenib and liver-directed AAV8-mediated Dgkh depletion significantly reduced tumor burden, self-renewal, phosphatidic acid production, and mTOR signaling. CONCLUSIONS: Our research demonstrated that DGKH is a crucial oncometabolic regulator of cancer stemness and therapy resistance, suggesting that inhibiting DGKH may lead to more effective HCC treatment.

Humans↗

PubMed2024

NQO1 polymorphism and susceptibility to ischemic stroke in a Chinese population.

BACKGROUND: Ischemic stroke (IS) is a major cause of death and disability worldwide. Genetic factors are important risk factors for the development of IS. The quinone oxidoreductase 1 gene (NQO1) has antioxidant, anti-inflammatory, and cytoprotective properties. Thus, in this study, we investigated the relationship between NQO1 gene polymorphism and the risk of IS. METHODS: Peripheral blood was collected from 143 patients with IS and 124 the control groups in Yunnan, China, and NQO1 rs2917673, rs689455, and rs1800566 were genotyped. Logistic regression was used to analyze the relationship between the three NQO1 loci and IS susceptibility. The difference in the expression levels of NQO1 between the control groups and IS groups was verified using public databases and enzyme-linked immunosorbent assay. RESULTS: The rs2917673 locus increased the risk of IS by 2.375 times in TT genotype carriers under the co-dominance model compared with CC carriers and was statistically associated with the risk of IS (OR = 2.375, 95% CI = 1.017-5.546, P = 0.046). In the recessive model, TT genotype carriers increased IS risk by 2.407 times compared with CC/CT carriers and were statistically associated with the risk of IS (OR = 2.407, 95% CI = 1.073-5.396, P = 0.033). CONCLUSIONS: NQO1 rs2917673 polymorphism is significantly associated with IS. Mutant TT carriers are risk factors for IS.

Aged↗

PubMed2024

Phased telomere-to-telomere reference genome and pangenome reveal an expansion of resistance genes during apple domestication.

The cultivated apple (Malus domestica Borkh.) is a cross-pollinated perennial fruit tree of great economic importance. Earlier versions of apple reference genomes were unphased, fragmented, and lacked comprehensive insights into the apple's highly heterozygous genome, which impeded advances in genetic studies and breeding programs. In this study, we assembled a haplotype-resolved telomere-to-telomere (T2T) reference genome for the diploid apple cultivar Golden Delicious. Subsequently, we constructed a pangenome based on 12 assemblies from wild and cultivated species to investigate the dynamic changes of functional genes. Our results revealed the gene gain and loss events during apple domestication. Compared with cultivated species, more gene families in wild species were significantly enriched in oxidative phosphorylation, pentose metabolic process, responses to salt, and abscisic acid biosynthesis process. Our analyses also demonstrated a higher prevalence of different types of resistance gene analogs (RGAs) in cultivars than their wild relatives, partially attributed to segmental and tandem duplication events in certain RGAs classes. Structural variations, mainly deletions and insertions, have affected the presence and absence of TIR-NB-ARC-LRR, NB-ARC-LRR, and CC-NB-ARC-LRR genes. Additionally, hybridization/introgression from wild species has also contributed to the expansion of resistance genes in domesticated apples. Our haplotype-resolved T2T genome and pangenome provide important resources for genetic studies of apples, emphasizing the need to study the evolutionary mechanisms of resistance genes in apple breeding.

Malus↗

PubMed2024

DNA polymerase delta governs parental histone transfer to DNA replication lagging strand.

Chromatin replication is intricately intertwined with the recycling of parental histones to the newly duplicated DNA strands for faithful genetic and epigenetic inheritance. The transfer of parental histones occurs through two distinct pathways: leading strand deposition, mediated by the DNA polymerase ε subunits Dpb3/Dpb4, and lagging strand deposition, facilitated by the MCM helicase subunit Mcm2. However, the mechanism of the facilitation of Mcm2 transferring parental histones to the lagging strand while moving along the leading strand remains unclear. Here, we show that the deletion of Pol32, a nonessential subunit of major lagging-strand DNA polymerase δ, results in a predominant transfer of parental histone H3-H4 to the leading strand during replication. Biochemical analyses further demonstrate that Pol32 can bind histone H3-H4 both in vivo and in vitro. The interaction of Pol32 with parental histone H3-H4 is disrupted through the mutation of the histone H3-H4 binding domain within Mcm2. Our findings identify the DNA polymerase δ subunit Pol32 as a critical histone chaperone downstream of Mcm2, mediating the transfer of parental histones to the lagging strand during DNA replication.

DNA Polymerase III↗