Biomedical subjects

Chao Liu

Publications and source records attributed to Chao Liu.

15 recordsLinked to original sources

PubMed2026

Hypervirulence-associated pseudo-compound transposons as fundamental mobile units driving cross-species virulence dissemination in Enterobacteriaceae.

BACKGROUND: The rapid global spread of hypervirulence in Enterobacteriaceae, particularly in carbapenem-resistant Klebsiella pneumoniae, poses a significant public health threat. However, the key genetic vehicles and mechanisms driving horizontal transfer of hypervirulence-associated genes (iucA, iroB, rmpA, rmpA2, and peg-344) remain poorly defined, limiting effective surveillance. METHODS: We performed a large-scale genomic survey of 2,869 virulence-associated plasmid sequences and 2,337 complete Enterobacteriaceae chromosomes. Using comparative genomics and evolutionary analyses, we systematically identified and characterized Hypervirulence-associated Pseudo-Compound Transposons (Hva-PCTs), defined as structured mobile elements in which hypervirulence-associated genes are flanked by insertion sequences. RESULTS: Our results demonstrate that hypervirulence-associated genes are transmitted primarily as discrete IS-bounded units, which we term Hva-PCTs. We identified 29 distinct plasmid-borne Hva-PCTs (pHva-PCTs) and 30 chromosomal Hva-PCTs (cHva-PCTs). These modules show clear species-specific patterns: iucA/iroB-associated Hva-PCTs mainly originate in Escherichia coli and spread through IncFIB-containing multi-replicon plasmids (commonly combined with IncFIC(FII) and/or IncFII, while rmpA/rmpA2/peg-344-containing modules originate in K. pneumoniae and are disseminated via IncHI1B/repB plasmids. Three Hva-PCTs were detected on both plasmids and chromosomes (xHva-PCTs). In one clinical K. pneumoniae isolate (LS356), the identical composite module was present on both replicons. Simpler sub-modules, such as ISKqu3-rmpA2-iucA_1-IS102 and IS102-rmpA-peg-344-iroB_1-IS1A, frequently co-occur on the same plasmid; when positioned in tandem, they reconstitute the full composite structure. This assembly pattern is further supported by a partial duplication event in plasmid pP901. CD-HIT clustering (80% nucleotide identity and 90% coverage) showed that 13 of 22 major clusters contained both plasmid and chromosomal copies, with intra-cluster identities >80% across multiple sequence types and host species. CONCLUSION: Hypervirulence-associated genes in Enterobacteriaceae are disseminated mainly as IS-flanked Hva-PCTs rather than solely through intact virulence plasmids. These modules exhibit strong but not absolute host specificity. The presence of identical Hva-PCTs on plasmids and chromosomes suggests inter-replicon mobility, while their stepwise assembly from simpler sub-modules highlights modular accretion as a key evolutionary process. Tracking Hva-PCTs as distinct mobile units may complement existing plasmid- and gene-centric surveillance approaches for hypervirulent and convergent strains. Experimental validation of their transposition activity and phenotypic effects is still required.

Virulence↗

PubMed2026

AI proteomics: from protein identification to virtual cells.

Artificial intelligence (AI) is transforming scientific research, including proteomics. In this Perspective, we highlight key mass spectrometry (MS)-based proteomics areas where AI is driving innovation, ranging from protein identification to building AI virtual cells. These include improving peptide and protein identification and quantification; characterizing protein-protein interactions and protein complexes; advancing spatial and perturbation proteomics; integrating multi-omics data; and, ultimately, enabling AI virtual cells. Finally, we call for global collaboration among data producers, data consumers and other stakeholders to establish an AI-friendly ecosystem for MS-based proteomics, laying the foundation for transformative advancements in proteomics driven by AI.

Proteomics↗

PubMed2026

CRISPR-Cas regulates expression of embedded anti-phage defence systems.

Bacteria utilize diverse defence systems to protect against harmful foreign DNA such as bacteriophages1,2, but how these systems coordinate with each other remains poorly understood. Here we uncover CRISIS (CRISPR-supervised immune system), a widespread regulatory paradigm whereby type I CRISPR-Cas loci embed and transcriptionally modulate diverse innate defences. Small non-canonical CRISPR RNA (crRNA)-like RNAs guide the I-C CRISPR-associated complex for antiviral defence (Cascade) effector complex to inhibit promoters of diverse immune cassettes-including composite multi-system clusters-enabling their basal expression for antiviral activity while mitigating fitness costs associated with hyperactivation, such as host growth impairment or exclusion of beneficial plasmids. When CRISPR-Cas is compromised by mutation or anti-CRISPR proteins, there is a burst in transcription of these embedded defence systems, leading to higher-level innate immunity at the expense of host fitness. Together, adaptive CRISPR-Cas systems orchestrate diverse innate immune systems into a layered defence network, comprising a prokaryotic 'immunity guard' strategy.

Bacteriophages↗

PubMed2026

Transcriptome sequencing provides novel insights into larval development and sexual dimorphism in the firefly Aquatica leii (Coleoptera: Lampyridae).

Fireflies are regarded as one of the most charismatic beetles due to their bioluminescence and ecological importance as bioindicators of freshwater quality. However, molecular mechanisms of larval development and sexual dimorphism in aquatic species remain poorly understood. Here, we performed multi-stage transcriptomic analysis of the aquatic firefly Aquatica leii across larval instars from L2 to L6, together with adult females and males, with three biological replicates per stage. Using time-series expression clustering, differential expression analysis, and weighted gene co-expression network analysis (WGCNA), we characterized the transcriptional dynamics of continuous larval development and the onset of sex-biased gene expression. We identified a critical transcriptional transition occurred at L5-L6, marked by downregulation of early morphogenetic genes and upregulation of juvenile hormone metabolism, oxidoreductase activity, and muscle contraction genes, indicating a shift from growth to metamorphic preparation. WGCNA identified a module strongly correlated with L6 (R = 0.97) enriched for the same functions, confirming a coordinated late-larval program. Notably, genes exhibiting sex-biased expression in adults were already expressed during late larval stages (L5 and L6), and 123 genes progressively upregulated from L2 to L6 showed enrichment in chitin biosynthesis, heart contraction, and ion transport; among these, six genes maintained high expression in adults with clear male-biased (Alei052192, Alei006658, and Alei087054) or female-biased (Alei003725, Alei096818, and Alei074026) patterns. These findings establish that transcriptional foundations for sexual dimorphism and adult tissue formation are laid during late larval stages, providing the first multi-stage transcriptomic resource for aquatic firefly conservation and breeding.

Animals↗

PubMed2026

Differentiating hemorrhagic shock and organophosphate poisoning through integrated skin microbiome-metabolome signatures.

Accurate determination of cause of death and estimation of postmortem interval (PMI) are critical yet challenging tasks in forensic science, particularly in cases with rapid demise and absence of obvious morphological abnormalities. We employed an integrative multi-omics approach to characterize postmortem microbial succession and metabolic alterations on facial skin in mouse models of hemorrhagic shock (HS) and organophosphorus poisoning (OP) across three decomposition stages: bloating (2 days), active decay (8 days), and advanced decay (16 days). Metagenomic profiling revealed significantly reduced α-diversity in HS compared with OP throughout all stages (p < 0.001), accompanied by stage-dependent compositional shifts, including early enrichment of Firmicutes in HS and Proteobacteria in OP. A total of 237 differential taxa were identified, with Providencia and Morganella predominating in OP, whereas Staphylococcus and Corynebacterium dominated bloating stage of HS. Untargeted metabolomics uncovered distinct cause-of-death-linked metabolites, notably elevated 2'-deoxycytidine-5'-diphosphate in early OP and persistent cholic acid/cholate accumulation in HS at later PMI. Functional analysis highlighted histidine and phosphate/phosphonate metabolism as key discriminatory pathways, exhibiting stage-specific oscillations and strong correlations with characteristic taxa. These findings demonstrate that skin-based metagenomic-metabolomic integration provides robust, mechanistically informed biomarkers for both PMI estimation and cause-of-death differentiation, offering a minimally invasive and temporally dynamic tool for forensic investigations.

Animals↗

PubMed2026

Age-stratified associations of glycemia, blood pressure, and cholesterol with mortality in diabetes: A prospective cohort study.

BACKGROUND: Optimization of HbA1c, blood pressure and cholesterol, referred to as the "ABCs", is central to the management of diabetes. However, the age-specific associations of these factors with mortality in patients with diabetes remains unclear. METHODS: In this prospective cohort study, 43,732 Chinese adults aged ≥ 40 years with diabetes were included from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Participants were stratified by age (< 55, 55-<65, 65-<75, ≥ 75 years). Cox proportional hazards regression and Fine-Gray competing risk models were employed to estimate the associations of HbA1c, systolic blood pressure (SBP), and low-density lipoprotein cholesterol (LDL-C) with all-cause, cardiovascular, and non-cardiovascular mortality across age groups. Relative importance and population attributable fractions (PAFs) were computed for each metabolic factor. RESULTS: During a median follow-up of 10.1 years, 3,975 deaths were documented. Age significantly modified the associations of HbA1c, SBP, and LDL-C with all mortality outcomes (all P for interaction < 0.05). Among participants aged < 75 years, HbA1c showed graded positive associations with all-cause, cardiovascular, and non-cardiovascular mortality. The SBP thresholds associated with increased mortality risk were 140 mmHg in those aged < 65 years and 160 mmHg in those aged 65-<75 years. Among those aged ≥ 75 years, however, the patterns of these associations differed markedly. Elevated mortality risk was observed only at HbA1c ≥ 9%, with a hazard ratio (HR) of 1.51 (95% confidence interval [CI]: 1.19-1.91) for all-cause mortality and a subdistribution hazard ratio (SHR) of 1.70 (95% CI: 1.23-2.36) for cardiovascular mortality, while SBP showed no significant association with any mortality outcome in this age group. Moreover, LDL-C emerged as a significant risk factor for cardiovascular mortality. Compared with participants with LDL-C < 1.8 mmol/L, those with LDL-C of 1.8-<2.6 mmol/L exhibited a significantly higher risk (SHR: 1.86; 95% CI: 1.11-3.11). Additionally, LDL-C had the largest PAF for cardiovascular mortality (9.6%) within this age group. CONCLUSIONS: The impacts of ABC factors on mortality risk vary substantially by age among adults with diabetes. In patients aged ≥ 75 years, less stringent glycemic and blood pressure targets may be appropriate, whereas lipid management remains critically important for reducing cardiovascular mortality.

Humans↗

PubMed2026

Structural genomics sheds light on protein functions and remote homologs across the insect tree of life.

Protein structure bridges the sequence-function relationship, enabling deep exploration of biological processes across diverse organisms. Insects, the most diverse animal lineage, accounting for over 50% of all described animal species, provide an exceptional system for exploring sequence-structure-function relationships. Here, we reconstructed a comprehensive and well-resolved phylogeny of 4854 insects, spanning all orders. Leveraging this framework, we created an atlas of 13.29 million predicted protein structures from 824 representative species, including 11.63 million newly predicted structures. Structural clustering revealed that proteins with divergent sequences but similar structures could be effectively grouped together. Structural similarity searches against proteins with well-characterized functions yielded annotations for 7.61 million insect proteins, including up to 14% of previously unannotated proteins. We further identified 750 million remote homologs between insect proteins, many of which trace back to ancient branches of the insect phylogeny. Remarkably, despite extensive sequence divergence, cGAS-like receptors (cGLRs) were structurally conserved across all 824 insects. Experimental assays demonstrated that these structurally identified cGLRs play a crucial role in antiviral defense in the yellow fever mosquito. Our findings highlight the significance of structural genomics for understanding protein function and evolution across the tree of life.

Animals↗

PubMed2026

Integrated Bulk and Single-Cell RNA-Seq Analysis Reveals Transcriptional Activation of PTGS2 by FOS in Progression From T2DM to T2DM-Associated NAFLD.

Type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD) frequently coexist, exacerbating disease burden. However, the molecular mechanisms underlying the progression from T2DM to T2DM-associated NAFLD remain unclear. This study investigated the regulatory function of FOS-mediated PTGS2 activation in this transition. We integrated bulk RNA-seq data from GEO, single-cell transcriptomic data and transcriptomes from patients with T2DM-associated NAFLD. Differentially expressed genes were identified using the limma package, and T2DM-related gene modules were defined by weighted gene co-expression network analysis. LASSO regression and random forest identified 14 candidate genes, with PTGS2 and FOS prioritised. Single-cell analysis showed increased FOS and PTGS2 expression in monocytes, CD8+ T cells and Kupffer cells. Transcription factor prediction and dual-luciferase assays confirmed that FOS directly binds the PTGS2 promoter and drives its transcription. In vitro, FOS silencing decreased PTGS2 expression, cytokine secretion and apoptosis under high-glucose and free fatty acid conditions, whereas PTGS2 overexpression exacerbated inflammation and apoptosis independently of FOS expression. These findings demonstrate that FOS transcriptionally activates PTGS2, contributing to hepatic inflammation and apoptosis during the progression from T2DM to NAFLD. PTGS2 may serve as a promising biomarker and therapeutic target for T2DM-associated NAFLD.

Single-Cell Gene Expression Analysis↗

PubMed2025

Global epidemiology of diabetes and prediabetes in lean or non-obese patients with NAFLD: a systematic review and meta-analysis.

BACKGROUND: The presence of diabetes increases the risk of adverse outcomes of patients with non-alcoholic fatty liver disease (NAFLD) even in those with lean or non-obese NAFLD. However, the epidemiological data regarding the prevalence of diabetes and prediabetes in lean or non-obese NAFLD populations remain limited. We assessed the global epidemiology of diabetes and prediabetes in lean or non-obese patients with NAFLD. METHODS: Published studies were searched in PubMed, EMBASE, Cochrane Library, and Web of Science databases from the inception of the databases to October 2024. The pooled global prevalence of diabetes or prediabetes in patients with NAFLD was evaluated using random-effects meta-analysis. Subgroup meta-analysis and meta-regression were used to investigate potential sources of heterogeneity. RESULTS: A total of 54 studies involving 146,714 patients with non-obese or lean NAFLD were included. The pooled global prevalence of diabetes among patients with lean or non-obese NAFLD was 15.6% (95% CI 10.8%-22.7%). Studies from South America reported the highest prevalence (41.3%, CI 39.1%-43.5%). Meta-regression models showed that geographic region and mean age (p < 0.05) were associated with the were associated with the prevalence of diabetes, jointly accounting for 51.61% of the heterogeneity. The global prevalence of prediabetes among patients with lean or non-obese NAFLD was 22.9% (95% CI 12.5%-41.9%) with the highest prevalence reported in studies from Europe (34.4%, CI 23.0%-51.4%). Meta-regression models showed that geographic region and country (p < 0.05) were associated with the prevalence of prediabetes, jointly accounting for 73.65% of the heterogeneity. CONCLUSION: The pooled global prevalence of diabetes and prediabetes were 15.6% and 22.9% in lean or non-obese patients with NAFLD, respectively. These findings suggest the importance of diabetes screening in these patients.

Humans↗

PubMed2025

Noninvasive detection and differentiation of gastric malignancy using cell-free DNA biomarkers.

INTRODUCTION: Gastric cancer remains a major global health burden, with high mortality driven by late-stage diagnoses that limit treatment options and reduce survival. Current diagnostic methods such as endoscopy and biopsy are invasive, resource-intensive, and impractical for large-scale early detection. OBJECTIVES: This study aimed to develop and validate an ensemble machine learning model integrating four cell-free DNA (cfDNA) fragmentomic feature classes derived from 5 × whole genome sequencing (WGS) data to non-invasively differentiate malignant gastric cancer from benign gastric lesions in high-risk or symptomatic patients. METHODS: A total of 681 plasma samples were prospectively collected, comprising 329 from patients with gastric cancer or high-grade intraepithelial neoplasia (HGIN) and 352 from individuals with benign gastric conditions. The dataset was divided into a training cohort (n = 333) and a temporally independent validation cohort (n = 348). An external validation cohort of 305 participants was also included. RESULTS: The ensemble model achieved an AUROC of 0.920 in cross-validation testing on the training cohort, 0.912 in the independent validation cohort, and 0.896 (95% CI 0.860-0.932) in the external cohort. At a pre-specified prediction threshold of 0.402, the model demonstrated 93.3% sensitivity and 71.9% specificity in the validation cohort, yielding a PPV of 71.3% and an NPV of 93.5%. In the external cohort, sensitivity and specificity were 91.7% and 69.1%, respectively (PPV 75.7%, NPV 88.8%). Model scores correlated with clinical stage, tumor grade, and histopathological subtype. Approximately 71% of non-cancer patients could have been spared unnecessary endoscopy. CONCLUSIONS: The cfDNA fragmentomics-based ensemble model enables accurate, non-invasive differentiation between gastric cancer and benign gastric lesions in high-risk or symptomatic patients. This approach demonstrates strong potential as a pre-endoscopy triage tool, supporting earlier detection and more efficient use of diagnostic resources.

Humans↗

PubMed2025

Rapid replacement of blaKPC variant in ST11 carbapenem-resistant and hypervirulent Klebsiella pneumoniae contributed to ceftazidime/avibactam resistance during severe in vivo infection.

OBJECTIVES: Hypervirulent ceftazidime/avibactam (CAZ/AVI)-resistant Klebsiella pneumoniae (Kp) has emerged; however, its dynamic within-host evolution and competitive features are uncharacterized. This study aimed to clarify the systematic microevolution characteristics of the rapid transformation of blaKPC variants during long-term infection. METHODS: Thirty-nine Kp strains were isolated from a single patient with severe recurrent osteomyelitis during a 2-year period. Whole-genome sequencing and in vitro evolution assay was performed. Microbiological characteristics were examined through antimicrobial susceptibility testing, plasmid stability, growth curve, in vitro competition and Galleria mellonella larvae lethality assays. RESULTS: Among all the clinical Kp isolates, 37 were carbapenem-resistant Kp (CRKP), including 25 CAZ-/AVI-resistant Kp. All isolates belonged to the ST11-K47. During in vivo evolution, the blaKPC variant and its amplification emerged. Twenty-four isolates (24/39, 61.5%) harboured a novel blaKPC variant, blaKPC-144. All five Kp isolates carried blaKPC-2 in 2021. Surprisingly, 24 blaKPC-144-harbouring isolates (70.6%, 24/34) and 10 blaKPC-2-harboring isolates were identified in 2023, indicating rapid changing of blaKPC. Kp4 carried two copies of blaKPC-2, and Kp10-1 exhibited a 1.94-fold increase in the blaKPC-144 copy number. Similarly, in vitro, the blaKPC copy number increased upon exposure to low CAZ/AVI concentrations. However, at higher concentrations (4/1 mg/L), the blaKPC copy number increased significantly, and blaKPC mutations emerged simultaneously. The competition assay indicated that the blaKPC-144-harboring isolates exhibited a superior competitive capacity. CONCLUSIONS: The blaKPC amplification and mutation emerged simultaneously or sequentially during in vivo and in vitro evolution. Kp isolates harbouring blaKPC-144, conferring resistance to CAZ/AVI, exhibited a competitive advantage, promoting the rapid replacement of blaKPC-2.

Klebsiella pneumoniae↗

PubMed2025

Largest-Scale Genomic Resource Reconstructing the Genetic Origin, Population Structure, and Biological Adaptations of the Hui People.

Historical and archaeological records indicate that the Maritime and Land Silk Roads played a pivotal role in facilitating Trans-Eurasian migrations and cultural exchanges. However, the extent to which population movements or the spread of ideas shape Chinese Hui populations remains debated. We present the largest genomic resource to date, including 2,280 Hui individuals sequenced or genotyped from 30 diverse regions, to examine the genetic origins, population structure, and biological adaptations of this underrepresented group in global human genome research. We identified a detailed population structure characterized by five distinct genetic lineages of the Hui, influenced by geography and varying gene flow. The admixture history and demographic events suggest that the northwestern and northern Hui lineages emerged from demic diffusion during the Tang and Yuan Dynasties via the Land Silk Road. In contrast, the southern and island Hui lineages reflect cultural diffusion along the Maritime Silk Road, while the mixed southern-northern lineage likely developed through a combination of demic and cultural diffusion. Our findings support a hybrid model for Hui formation, indicating that both demographic processes and sociocultural transmissions contributed to their population history. We identified east-west highly differentiated variants and pre- and post-admixture adaptations in Hui genomes, demonstrating that admixture-driven adaptive or neutral variants impacted susceptibility to cardiovascular diseases and immune- and diet-related traits. These adaptive signatures include post-admixture signals of SLC24A5 and ECHDC1 in the Hui, as well as pre-admixture signals of the HLA region, BCL2A1, and KCNH8 in the East Asian source. Overall, our study suggests that Han-related genetic components helped the Hui population rapidly adapt to new local environments. Additionally, the frequency spectrum of clinically essential variants differed significantly between Hui and Han individuals, emphasizing the importance of including underrepresented populations in genomic research to promote health equity.

Humans↗

PubMed2025

Adult bi-paternal offspring generated through direct modification of imprinted genes in mammals.

Imprinting abnormalities pose a significant challenge in applications involving embryonic stem cells, induced pluripotent stem cells, and animal cloning, with no universal correction method owing to their complexity and stochastic nature. In this study, we targeted these defects at their source-embryos from same-sex parents-aiming to establish a stable, maintainable imprinting pattern de novo in mammalian cells. Using bi-paternal mouse embryos, which exhibit severe imprinting defects and are typically non-viable, we introduced frameshift mutations, gene deletions, and regulatory edits at 20 key imprinted loci, ultimately achieving the development of fully adult animals, albeit with a relatively low survival rate. The findings provide strong evidence that imprinting abnormalities are a primary barrier to unisexual reproduction in mammals. Moreover, this approach can significantly improve developmental outcomes for embryonic stem cells and cloned animals, opening promising avenues for advancements in regenerative medicine.

Animals↗

PubMed2025

The chromosome-level genome of Stylosanthes guianensis provides insights into genome evolution and environmental adaptation.

Stylosanthes guianensis is a leguminous forage crop of significant economic importance, primarily distributed in tropical and subtropical regions. It exhibits strong adaptability to various stresses, yet the genetic basis underlying this trait remains unclear. In this study, we constructed the first chromosome-scale reference genome of S. guianensis using a combination of Nanopore and Hi-C sequencing technologies. The assembled genome size is 1254 Mb, with 10 pseudochromosomes. Using Nanopore full-length transcriptome data, we generated high-quality transcript-level gene annotations, identifying 36 585 gene models and 110 601 transcripts. The repetitive sequences in S. guianensis account for 79.16% of the genome, with the extensive expansion of Gypsy elements in long terminal repeats contributing to its genome size enlargement. Comparative genomic and transcriptomic analyses revealed that flavonoid metabolism plays a pivotal role in stress adaptation, providing new insights into the genetic basis of stress tolerance. Additionally, we generated whole-genome methylation profiles under cold treatment and control conditions, offering valuable data for future epigenomic research. These findings provide essential molecular resources for understanding stress resilience in S. guianensis and advancing its molecular breeding.

Genome, Plant↗

PubMed2022

Multiplexed microfluidic chip for cell co-culture.

Paracrine signaling is challenging to study in vitro, as conventional culture tools dilute soluble factors and offer little to no spatiotemporal control over signaling. Microfluidic chips offer potential to address both of these issues. However, few solutions offer both control over onset and duration of cell-cell communication, and high throughput. We have developed a microfluidic chip designed to culture cells in adjacent chambers, separated by valves to selectively allow or prevent exchange of paracrine signals. The chip features 16 fluidic inputs and 128 individually-addressable chambers arranged in 32 sets of 4 chambers. Media can be continuously perfused or delivered by diffusion, which we model under different culture conditions to ensure normal cell viability. Immunocytochemistry assays can be performed in the chip, which we modeled and fine-tuned to reduce total assay time to 1 h. Finally, we validate the use of the chip for co-culture studies by showing that HEK293Ta cells respond to signals secreted by RAW 264.7 immune cells in adjacent chambers, only when the valve between the chambers is opened.

Microfluidics↗