Biology subjects

Ke, L.

Publications and source records attributed to Ke, L..

8 recordsLinked to original sources

bioRxiv2025

Epithelial FOXP3 Drives Pancreatic Fibrosis through O-glycosylated IL-6

BACKGROUND & AIMSThe transcription factor FOXP3, known for specifying regulatory T cell fate, is unexpectedly expressed in the epithelium of precancerous pancreatic lesions. Here we investigate its non-immune role in initiating pancreatic fibrosis, a process driving therapeutic resistance and organ failure in pancreatic ductal adenocarcinoma (PDAC) with unknown origins in early neoplasia. METHODSUsing human tissues and genetically engineered mouse models, we analysed FOXP3 expression in premalignant lesions. We employed epithelial-specific FOXP3 knockout and knock-in strategies to determine its functional impact on fibrogenesis and neoplasia progression. Mechanistic studies included chromatin immunoprecipitation, glycomic analyses, and signalling assays. RESULTSFOXP3 was consistently expressed in the epithelial compartment of human and murine precancerous pancreas. Epithelial-specific deletion of FOXP3 attenuated pancreatic fibrosis and delayed neoplasia, whereas its knock-in induced spontaneous stromal activation and accelerated PanIN progression. Mechanistically, epithelial FOXP3 directly transactivated the glycosyltransferase GALNT1. GALNT1, in turn, mediated O-glycosylation of interleukin (IL)-6, which was essential for its rapid secretion. CONCLUSIONSOur study establishes epithelial-derived FOXP3 as a master regulator of early pancreatic fibrocarcinogenesis. It drives a glycosylation-dependent amplification loop for IL-6 signalling, orchestrating sustained stromal activation. This pathway represents a promising target for intercepting pancreatic fibrosis and carcinogenesis at its origin.

cancer biology↗

bioRxiv2024

Andexanet alfa-associated heparin resistance in cardiac surgery: mechanism and in vitro perspectives

BackgroundAndexanet alfa (andexanet) is the only FDA-approved antidote for direct factor Xa (FXa) inhibitors but has been reported to cause resistance to unfractionated heparin (UFH). This has delayed anticoagulation for procedures requiring cardiopulmonary bypass (CPB). The mechanism, andexanet and UFH dose dependence, and thrombotic risk of andexanet-associated heparin resistance are unknown. MethodsThe effect of andexanet in vitro was determined using activated clotting times (ACT) and thromboelastography (TEG). Ex vivo CPB circuits were used to determine whether andexanet impaired anticoagulation for extracorporeal circulation. Kinetics of antithrombin (AT) inhibition of FXa and thrombin were measured in the presence of andexanet. Equilibrium modeling and thrombin generation assay (TGA) validation were used to predict the role of andexanet, AT, and UFH concentrations in andexanet-associated heparin resistance. ResultsAndexanet prevented UFH-mediated prolongation of ACT and TEG times. At lower concentrations of andexanet, heparin resistance could be overcome with suprapharmacologic doses of UFH, but not at higher andexanet concentrations. Andexanet rendered standard doses of UFH inadequate to prevent circuit thrombosis, and suprapharmacologic UFH doses were only partially able to overcome this. Scanning electron microscopy demonstrated coagulation activation in circuits. Andexanet prevented UFH enhancement of AT-mediated inhibition of FXa and thrombin. Equilibrium modeling and TGA validation demonstrated that andexanet creates a triphasic equilibrium with UFH and AT: initial UFH unresponsiveness, normal UFH responsiveness when andexanet is depleted, and finally AT depletion. Sufficient CPB heparinization can only occur at low therapeutic andexanet doses and normal AT levels. Higher andexanet doses or AT deficiency may require both AT supplementation and very high UFH doses. ConclusionsAndexanet causes heparin resistance due to redistribution of UFH-bound AT. If andexanet cannot be avoided prior to heparinization and direct thrombin inhibitors are undesirable, our in vitro study suggests excess UFH should be considered as a potential strategy prior to AT supplementation. HighlightsO_LIAndexanet alfa causes heparin resistance not by depleting antithrombin, but rather by sequestering heparin-bound antithrombin such that it cannot act as an anticoagulant. C_LIO_LIHeparin responsiveness in the presence of Andexanet alfa is triphasic such that the effect of a dose of heparin can now be predicted in vitro based on the relative concentrations of andexanet, heparin, and antithrombin. C_LIO_LIThe in vitro insights provided by this work provide a rational starting point for further clinical elucidation of the problem and management of andexanet-associated heparin resistance C_LI

biochemistry↗

bioRxiv2024

Element accumulation in the tracheal and bronchial cartilages of monkeys

Compositional changes in the tracheal and bronchial cartilages can affect respiratory ventilation and lung function. We aimed to elucidate element accumulation in the tracheal and bronchial cartilages of monkeys and divided it into four sites: tracheal, tracheal bifurcation, left bronchial, and right bronchial cartilages. The elemental content was analyzed using inductively coupled plasma atomic emission spectrometry. The average calcium content was two to three times higher in the tracheal cartilage than in the other three cartilages. The trends of phosphorus and zinc were similar to those of calcium. The average calcium, phosphorus, and zinc contents were the highest in the tracheal cartilage and decreased in the following order: the left bronchial, right bronchial, and tracheal bifurcation cartilages. These findings revealed that differences existed in element accumulation between different sites within the same airway cartilage and that calcium, phosphorus, and zinc accumulation mainly occurred in the tracheal cartilage. A substantial direct correlation was observed between age and calcium content in the tracheal and bronchial cartilages and all such monkeys with high calcium content were > four years of age. These results suggest that calcium accumulation occurs in the tracheal and bronchial cartilages after reaching a certain age. An extremely substantial direct correlation was observed between calcium and phosphorus contents in the tracheal and bronchial cartilages. This finding is similar to the previously published calcium and phosphorus correlations in several other cartilages, suggesting that the calcium and phosphorus contents of cartilage exist in a certain ratio.

zoology↗

bioRxiv2023

A resource for probing influences of perinatal factors on neurodevelopment in 3-10-years-old Chinese children

Adverse perinatal factors can disrupt the normal development of the brain, with potential long-term impacts on childrens overall development. Currently, the neuropathological mechanisms by which these factors lead to various neurodevelopmental disorders (NDDs) remain largely unknown. An open resource that integrate perinatal factors with brain and mental health development is essential for investigating NDD-related aetiology. In this Data Descriptor, we introduce a multicentre database containing information on perinatal factors that influence childrens brain-mind development, namely, periCBD, that combines neuroimaging and behavioural phenotypes with perinatal factors associated with a high incidence of NDDs at county/region/central district hospitals. PeriCBD was designed to establish a platform for the investigation of individual differences in brain-mind development among children aged 3-10 years are associated with perinatal factors. Ultimately, our goal was to develop an early prediction and screening model for NDDs that leverages normative data to facilitate NDD aetiology research. Herein, we provide a systematic overview of the data acquisition/cleaning/quality control/sharing, processes of periCBD and present preliminary brain-mind associations.

neuroscience↗

bioRxiv2023

RNPS1 stabilizes NAT10 protein to facilitate translation in cancer via tRNA ac4C modification

NAT10 is dysregulated and plays an essential role in various types of cancers. However, the exact machenism of how NAT10 regulates cancer progression remains debatable. In this report, we show that NAT10 affects tumorigeneis mainly based on its acetylation function on tRNA. In addition, we found NAT10 regulate the ac4C of tRNA in cancer via interaction with RNPS1, which in turn protect NAT10 from degradation by E3 ubiquitin ligase ZSWIM6. We developed TRMC-seq method to compreshensively profile tRNA ac4C sites and uncovered the presence of ac4C in a broader range of tRNA isoacceptors than previous studies. Multi-omics analysis identified AP-1 signaling pathway as a major downstream mediator of NAT10. Mechanistically, we found NAT10 is responsible for the translation efficiency genes which contain higher ac4C-tRNA codon. Importantly, our genetic mouse model validated our in vitro findings of NAT10 in cancer. Our study highlights a role of NAT10 in mediating tRNA ac4C to regulate the translation and tumorigenesis of cancer.

molecular biology↗

bioRxiv2022

Fish oil Nano-emulsion Kills Macrophage: Ferroptosis and Autophagy Triggered by Catalase-catalysed Superoxide Eruption

Fish oil is increasingly utilized in the form of nano-emulsion as nutrient and function fortifier. The nano-emulsions high polyunsaturated fatty acids content and electron donors at oil/water interface could be a potential site of redox reaction, if a previously unrecognised trigger was provided. Here we report that a vigorous superoxide production occurred in fish oil nano-emulsion in the presence of mammalian catalase in both acellular and cellular systems. Furthermore, the resulting superoxide increased cytosolic ROS and membrane lipid peroxidation of murine macrophage, and eventually caused fatal oxidative damage, which involves autophagy and ferroptosis but not apoptosis. The cell death was significantly inhibited by a catalase-specific inhibitor. The ferroptosis was independent of protease Caspase-3 activation or glutathione peroxidase suppression. Our findings discover a hidden risk factor of the widely acclaimed fish oil emulsion and suggest a novel mechanism of cellular damage by dietary lipids on mucosal layer of the alimentary tract.

cell biology↗

bioRxiv2021

Quantitative model suggests both intrinsic and contextual features contribute to the transcript coding ability determination in cells

Gene transcription and protein translation are two key steps of the "central dogma". It is still a major challenge to quantitatively deconvolute factors contributing to the coding ability of transcripts in mammals. Here, we propose Ribosome Calculator (RiboCalc) for quantitatively modeling the coding ability of RNAs in human genome. In addition to effectively predicting the experimentally confirmed coding abundance via sequence and transcription features with high accuracy, RiboCalc provides interpretable parameters with biological information. Large-scale analysis further revealed a number of transcripts with a variety of coding ability for distinct types of cells (i.e., context-dependent coding transcripts, CDCTs), suggesting that, contrary to conventional wisdom, a transcripts coding ability should be modeled as a continuous spectrum with a context-dependent nature.

bioinformatics↗

bioRxiv2020

Molecular surveillance of HIV, HBV, and HCV amongst blood donors in five Chinese regions

Hepatitis B (HBV), hepatitis C (HCV) and human immunodeficiency virus (HIV) are transfusion transmissible infections (TTIs) agents that threaten the safety of the blood supply. Surveillance of the variance of those viruses is an important way to monitor their diversity and evolution to improve safety in blood transfusion. In this study, we characterized the specimens of blood donors from 13 blood centers located in 5 Chinese regions. Samples collected between 2014 and 2017 were screened with serological and molecular tests conducted on Abbott ARCHITECT and m2000 platforms. Sequencing was used to determine the classifications. The HBV immune escape mutations were also analyzed for assessing vaccine breakthrough risks and challenges for diagnostic tests. For HIV, 11 genotypes or recombinants were identified. The predominant genotype was C, which accounts for 42%. For HBV, the genotypes of B, C and D were identified, with B and C predominating. The major subgenotype was B2, comprising 84.1% of all infections. 79 out of 113 (69.9%) samples carried escape mutations in the "a" determinant region with 69 (87.3%) multiple mutants and 15 (19%) escape mutants which will affect HBsAg detection. For HCV, 7 genotypes or subtypes were identified. The major genotype was 1b (48%), followed by 6a (16.7%) and 2a & 3a (10%). This study provides the information of diversity of HBV, HCV and HIV strains circulating in blood centers from 5 regions in China. These data can also be scientific basis for development of detection assays that mitigate the impact of viral diversity on performance. ImportanceThe prevalence of TTIs in blood donations is important for evaluating blood safety and it can also reflect the burden of these disease among populations. Virus variance is threat to blood safety due to it may affect assays detection by nucleic acid, antigen and antibody-based methods in blood donors. HIV, HBV and HCV exhibit high degrees of genetic diversity, with different strains predominating in different geographic locations. The aim of this study is to assess the diversity of HBV, HCV and HIV among blood donors in China. In this study, 13 blood centers located in 5 Chinese regions were involved and the most informative phylogenetic regions of each virus had been sequenced. This will benefit for viral monitoring by subtype/genotype analyses to determine whether the distributions of variants are changing over time and geographically, and to speculate whether previously rare subtypes are becoming established in blood donors in China.

genetics↗