Biomedical subjects

Xi Li

Publications and source records attributed to Xi Li.

8 recordsLinked to original sources

PubMed2026

Molecular epidemiology and genomic characteristics of clinical Acinetobacter baumannii isolates from patients with hospital-acquired pneumonia in China, 2019-2020: a multicentre retrospective study.

BACKGROUND: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a leading cause of hospital-acquired pneumonia (HAP) with high mortality. However, large-scale nationwide data of HAP-causing CRAB in China remain limited. METHODS: Here, we performed a nationwide multicentre retrospective study to characterise the molecular epidemiology and genomic features of 802 A. baumannii isolates from patients with HAP across 33 tertiary hospitals in China during 2019-2020. Antimicrobial susceptibility testing (AST), whole-genome sequencing (WGS), phylogenetic and comparative genomic analysis were used to investigate molecular epidemiology of HAP-causing CRAB strain. Clinical comparative analyses were carried out on data from 500 patients with HAP stratified by distinct antimicrobial susceptibility and genomic profiles, and a Galleria mellonella infection model was utilised for in vivo virulence assessment. FINDINGS: The overall carbapenem resistance rate of A. baumannii was 82.0% (658/802), with marked regional variations. CRAB exhibited high resistance to conventional agents but remained largely susceptible to polymyxin, tigecycline, cefiderocol and sulbactam-durlobactam. Among enrolled patients, CRAB infection was linked to substantially higher mortality (39.0% vs. 17.5%), and multivariate analysis confirmed ICU admission and advanced age as independent risk factors for patients with CRAB infection. Molecular typing revealed STPas2 (96.2%) as the absolutely predominant type; STOxf208, STOxf195, STOxf540, and STOxf369 were the most prevalent Oxford sequence types with obvious geographic stratification and divergent comorbidity profiles among corresponding patients. A total of 654 CRAB isolates harboured carbapenemase genes, with blaOXA-23 dominating at 98.8%. Genomic analysis revealed lineage-specific features: STOxf208 carried more virulence genes, while STOxf540 harboured a broader antimicrobial resistance genes (ARGs). The STOxf208 clone mainly belonged to KL2 (62.1%) and KL7 (36.8%) serotypes, with KL2 strains possessing richer ARGs and virulence factors, and in vivo virulence assays further validated that KL2 strains possessed higher pathogenicity than KL7 strains. INTERPRETATION: This study demonstrates the extremely high prevalence and clonal dominance of CRAB in Chinese patients with HAP, providing critical evidence for clinical treatment, antimicrobial stewardship, and targeted infection control. FUNDING: National Key Research and Development Program of China (2024YFE0106200), National Natural Science Foundation of China (U22A20338, 82502763, W2621007), Zhejiang Provincial Natural Science Foundation of China (LQN25H190006), Zhejiang Provincial Postdoctoral Science Foundation (ZJ2025058).

Acinetobacter baumannii↗

PubMed2026

Genomic epidemiology and ceftazidime-avibactam resistance mechanism of KPC-3-producing Pseudomonas aeruginosa: A decade retrospective study in China.

OBJECTIVES: Carbapenem-resistant Pseudomonas aeruginosa (CRPA), especially KPC-producing P. aeruginosa, is rapidly expanding and posing a serious public health threat. Here, we aim to characterise the epidemiology of KPC-3-producing P. aeruginosa in a tertiary hospital over a 10-year period and elucidate the mechanism of ceftazidime-avibactam (CZA) resistance driven by blaKPC-3 to blaKPC-267 mutations in CRPA, along with conducting a global phylogeographic analysis of KPC-3-producing P. aeruginosa. METHODS: 11 non-duplicate KPC-3-producing CRPA isolates collected over a 10-year period were characterized by antimicrobial susceptibility testing and whole-genome sequencing (WGS). The genetic context and transferability of blaKPC-3/267 and the mechanism of KPC-267-mediated CZA resistance were investigated. Global phylogenomic analysis was performed to characterize the geographic distribution and population structure of blaKPC-3-carrying P. aeruginosa. RESULTS: All 11 KPC-3-producing CRPA strains in this study belonged to ST1076 and exhibited multidrug resistance. The blaKPC-267-positive CZA-resistant strain SRMPA3523 was isolated from patient 1 after blaKPC-3-positive P. aeruginosa SRMPA1139 and SRMPA1630 were treated with CZA. WGS indicated that blaKPC-3/267 was located on the Tn6296 transposon contained in the transferable IncP-2 plasmid. KPC-267 mediates resistance to CZA by reducing the inhibitory effect of avibactam and increasing affinity for ceftazidime. Global analysis indicated that blaKPC-3-carrying P. aeruginosa were predominantly in China, America, and Colombia, with ST1076 and ST111 as dominant clones. CONCLUSIONS: This study characterised the global phylogeography of blaKPC-3-carrying P. aeruginosa and identified KPC-267 as a KPC-3-derived variant associated with CZA resistance. This finding highlighted the risk of developing CZA resistance in KPC-producing P. aeruginosa strains under therapeutic pressure.

CRPA↗

PubMed2026

A Novel Long Noncoding RNA-LNC000133 Associated With Steroid-Induced Osteonecrosis of the Femoral Head Promotes Osteoblast Differentiation Through Bone Marrow Mesenchymal Stem Cells-Derived Exosomes Pathway: A Bioinformatics Validation and Detailed Mechanistic Study.

Steroid-induced osteonecrosis of the femoral head (SONFH) is a debilitating disease caused by glucocorticoid abuse, characterized by complex pathogenesis and unclear molecular mechanisms. Dysfunction of bone marrow mesenchymal stem cells (BMSCs) and their exosome-mediated signalling is a key contributor to SONFH, although the precise mechanisms remain to be elucidated. In this study, the differential expression profiles of long noncoding RNAs (lncRNAs), microRNAs (miRNAs) and messenger RNAs (mRNAs) in exosomes derived from human BMSCs (hBMSCs) obtained from patients with SONFH compared to controls with femoral neck fractures were identified. Through next-generation sequencing, a novel lncRNA, LNC000133, associated with SONFH was discovered. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and competing endogenous RNA (ceRNA) network construction, the LNC000133/miR-362-5p/TGF-β3/SMAD3/BMP2 signalling axis was established. The definitive expression, localization and full-length sequence of LNC000133 in BMSCs were subsequently validated by Northern blot, quantitative real-time polymerase chain reaction (qRT-PCR), fluorescence in situ hybridization (FISH) and rapid amplification of cDNA ends (RACE). Most notably, mechanistic studies demonstrated that LNC000133-modified BMSCs-derived exosomes were efficiently taken up by osteoblasts, which promoted proliferation and osteogenic differentiation by targeting the miR-362-5p/TGF-β3/SMAD3/BMP2 signalling pathway.

Humans↗

PubMed2025

Global emergence and transmission dynamics of carbapenemase-producing Citrobacter freundii sequence type 22 high-risk international clone: a retrospective, genomic, epidemiological study.

BACKGROUND: Carbapenemase-producing Citrobacter (CPC) species have recently been recognised as emerging pathogens associated with nosocomial infections in humans. The increased rate of Citrobacter freundii infections is a public health concern and there is a paucity of genomic data regarding its global transmission dynamics. We aimed to characterise the genetic features of CPC species, and their associated carbapenemase-encoding plasmids, obtained from hospitalised patients in China and from publicly available global data, with a particular focus on high-risk clones. METHODS: This was a retrospective, genomic epidemiological study of CPC species obtained from a tertiary hospital in Zhejiang Province, China, from March 5, 2013, to March 5, 2023. We used antimicrobial susceptibility testing, short-read and long-read whole-genome sequencing, phylogenomic analysis, and plasmid structure analysis. A global dataset of complete plasmid sequences encoding blaKPC, blaNDM, and blaIMP was constructed from the National Center for Biotechnology Information (NCBI) RefSeq database to provide insights into their diversity and distribution. All carbapenemase-producing Citrobacter freundii genomes from the NCBI GenBank database were incorporated in the comparative genomic analyses. Bayesian phylogeographical analysis and growth rate assays were carried out to characterise the high-risk C freundii sequence type (ST) 22 clone. FINDINGS: 1724 Citrobacter species isolates were collected from diverse clinical specimens, with 48 identified as CPC species. Citrobacter koseri (22 [46%] of 48) and C freundii (20 [42%]) were the predominant CPC species. Comparative analysis found C freundii carried significantly higher median numbers of plasmid replicons (5·0 [IQR 3·3-6·0] vs 2·0 [2·0-3·0]; p<0·0001) and acquired antimicrobial resistance genes (12·0 [7·3-15·8] vs 3·0 [3·0-5·3]; p<0·0001) than did C koseri. Molecular characterisation identified Inc-type plasmids, In823::Kl.pn.I3/In1589-like/In837-like integrons, Tn6296/Tn125/Tn5060 transposons, and insertion sequences (eg, IS26, IS3000, IS5, ISAba125, ISCR1), collectively facilitating the dissemination of carbapenemase genes. Global analysis of 3126 carbapenemase-encoding plasmids found epidemic plasmids with broad host ranges and global diversity. Phylogenetic investigation of predominant carbapenemase-encoding plasmids showed their persistence across geographical regions, temporal spans, and Enterobacterales species, exhibiting high genetic similarity to our clinical plasmids. A phylogenetic tree of 726 global carbapenemase-producing C freundii genomes showed that ST22 (227 [31·3%]) represents the predominant multidrug-resistant clone across community, health-care, and environmental niches. Transmission across continents contributes to the global predominance of the ST22 clone, which carries a high load of resistance genes (median 15·0 [IQR 11·0-17·0] vs 12·0 [3·0-16·0]; p<0·0001) and enhanced plasmid maintenance capacity (median replicons 5·0 [IQR 4·0-7·0] vs 4·0 [3·0-6·0]; p<0·0001) relative to non-ST22 clones. INTERPRETATION: Our study provides evidence to suggest that Citrobacter species are emerging carriers of carbapenem-resistance genes. These findings provide insight into the population structure of CPC species and highlight C freundii ST22 as a prominent high-risk international clone. FUNDING: National Natural Science Foundation of China, National Health Commission Scientific Research Fund-Zhejiang Provincial Major Health Science and Technology Plan Project, Zhejiang Province Natural Science Foundation Project, Outstanding Youth Foundation of Jiangsu Province of China, the Priority Academic Program Development of Jiangsu Higher Education Institutions, and Postgraduate Research and Practice Innovation Program of Jiangsu Province.

Citrobacter freundii↗

PubMed2024

Angiopoietin-like protein 8 directs DNA damage responses towards apoptosis by stabilizing PARP1-DNA condensates.

Upon genotoxic stresses, cells employ various DNA damage responses (DDRs), including DNA damage repair or apoptosis, to safeguard genome integrity. However, the determinants among different DDRs choices are largely unknown. Here, we report angiopoietin-like protein 8 (ANGPTL8), a secreted regulator of lipid metabolism, localizes to the nucleus and acts as a dynamic switch that directs DDRs towards apoptosis rather than DNA repair after genotoxin exposure. ANGPTL8 deficiency alleviates DNA damage and apoptosis in cells exposed to genotoxins, as well as in the liver or kidney of mice injured by hepatic ischemia/reperfusion or cisplatin treatment. Mechanistically, ANGPTL8 physically interacts with Poly (ADP-ribose) polymerase 1 (PARP1), in a PARylation-independent manner, and reduces the fluidity of PARP1-DNA condensates, thereby enhancing the pro-apoptotic accumulation of PARP1 and PAR chains on DNA lesions. However, the transcription of ANGPTL8 is gradually decreased following genotoxin treatment, partly due to downregulation of CCAAT enhancer binding protein alpha (CEBPA), presumably to avoid further cytotoxicity. Together, we provide new insights by which genotoxic stress induced DDRs are channeled to suicidal apoptosis to safeguard genome integrity.

Animals↗

PubMed2024

Phase Transition of Wax Enabling CRISPR Diagnostics for Automatic At-Home Testing of Multiple Sexually Transmitted Infection Pathogens.

Sexually transmitted infections (STIs) significantly impact women's reproductive health. Rapid, sensitive, and affordable detection of these pathogens is essential, especially for home-based self-testing, which is crucial for individuals who prioritize privacy or live in areas with limited access to healthcare services. Herein, an automated diagnostic system called Wax-CRISPR has been designed specifically for at-home testing of multiple STIs. This system employs a unique strategy by using the solid-to-liquid phase transition of wax to sequentially isolate and mix recombinase polymerase amplification (RPA) and CRISPR assays in a microfluidic chip. By incorporating a home-built controlling system, Wax-CRISPR achieves true one-pot multiplexed detection. The system can simultaneously detect six common critical gynecological pathogens (CT, MG, UU, NG, HPV 16, and HPV 18) within 30 min, with a detection limit reaching 10-18 M. Clinical evaluation demonstrates that the system achieves a sensitivity of 96.8% and a specificity of 97.3% across 100 clinical samples. Importantly, eight randomly recruited untrained operators performe a double-blinded test and successfully identified the STI targets in 33 clinical samples. This wax-transition-based one-pot CRISPR assay offers advantages such as low-cost, high-stability, and user-friendliness, making it a useful platform for at-home or field-based testing of multiple pathogen infections.

Sexually Transmitted Diseases↗

PubMed2024

ALDH1A1 promotes immune escape of tumor cells through ZBTB7B-glycolysis pathway.

The primary impediment to the success of immunotherapy lies in the immune evasion orchestrated by tumors, contributing to the suboptimal overall response rates observed. Despite this recognition, the intricacies of the underlying mechanisms remain incompletely understood. Through preliminary detection of clinical patient tissues, we have found that ALDH1A1 was a key gene for the prognosis of cancer patients and tumor glycolysis. In vitro experiments and tumor formation in nude mice suggested that targeting ALDH1A1 could inhibit tumor growth. Through further analysis of xenograft tumor models in immune-normal mice and flow cytometry, we found that deficiency in ALDH1A1 could promote immune system suppression of tumors in vivo. Specifically, RNA-seq analysis, combined with qPCR and western blot, identified the transcription factor ZBTB7B as downstream of ALDH1A1. The binding sites of the transcription factor ZBTB7B on the LDHA promoter region, which is responsible for regulating the rate-limiting enzyme gene LDHA in glycolysis, were determined using luciferase reporter gene detection and Chip-qPCR, respectively. In addition, the increased SUMOylation of ZBTB7B stabilized its transcriptional activity. Further in vivo and in vitro experiments confirmed that the combination of targeting ALDH1A1 and ZBTB7B with immune checkpoint inhibitors could synergistically inhibit tumors in vivo. Finally, after conducting additional verification of patient tissue and clinical data, we have confirmed the potential translational value of targeting ALDH1A1 and ZBTB7B for tumor immunotherapy. These results emphasize the potential translational significance of targeting ALDH1A1 and ZBTB7B in the realm of tumor immunotherapy. The convergence of ALDH1A1 inhibition and immune checkpoint blockade, particularly with PD-L1/PD-1 mAb, presents a compelling avenue for curtailing tumor immune escape.

Animals↗

PubMed2014

Upregulation of TLR2 expression is induced by estrogen via an estrogen-response element (ERE).

TLR2 and estrogen are both thought to be involved in the pathogenesis of RA; however, it is unknown if there is an association between estrogen and TLR2. In this report, we treated PMA-differentiated THP-1 cells with 17β-estradiol (E2) and observed increases in TLR2 mRNA and protein levels by real-time quantitative PCR and western blot. Transfection of THP-1 cells with a series of 5'-deleted TLR2 promoter-luciferase constructs revealed that E2 enhanced TLR2 transcriptional activity in an estrogen receptor alpha (ERα)-dependent pattern. An estrogen receptor response element (ERE) was identified 251 bases upstream of the TLR2 promoter, and electrophoretic mobility shift assay and chromatin immunoprecipitations showed ERα binding was increased by E2. In summary, this work demonstrated that TLR2 is a new estrogen-regulated gene whose expression is upregulated through the interaction of ERα with an ERE in the promoter region.

Cell Line↗