Biology subjects

Ai, Z.

Publications and source records attributed to Ai, Z..

7 recordsLinked to original sources

bioRxiv2025

Study on Early pregnancy diagnosis in sows based on joint analysis of vaginal secretion metabolomics and machine learning

ObjectiveMetabolic transformations in female mammals throughout gestation manifest in the metabolite profiles of bodily fluids, potentially serving as biomarkers for the diagnosis of pregnancy. This investigation concentrated on sows 18 days post-mating, with the objective of identifying biomarkers pertinent to early pregnancy diagnosis through the analysis of variations in metabolic molecules within vaginal secretions. MethodsVaginal secretion samples were procured from both pregnant and non-pregnant sows 18 days post-mating, subsequently subjected to untargeted metabolomic analysis utilizing liquid chromatography-mass spectrometry (LC-MS). The samples were partitioned into training and testing datasets, and machine learning algorithms--specifically, Random Forest (RF) and support vector machine (SVM)--were integrated with metabolite weight ranking to identify key biological markers. ResultsA total of 3,249 metabolic molecules were identified, among which 534 exhibited significant differential expression in the vaginal secretions of pregnant versus non-pregnant sows. Notably, three hormones that correlate with the pregnant status of the sow were discerned: Progesterone, 3-Deoxyestradiol, and Prostaglandin E1. KEGG pathway analysis revealed that the differentially expressed metabolites were predominantly enriched in nucleotide metabolic pathways. The RF model demonstrated an impressive accuracy of 1.00 in the training dataset and 0.88 in the testing dataset, while the SVM model maintained an accuracy of 1.00 across both datasets. Utilizing model weights and differential expression data, three pivotal metabolites were identified: Indolepropionic acid, cis-Aconitate, and 4-p-Coumaroylquinic acid, which exhibited ROC curve AUC values of 0.90, 0.89, and 0.79, respectively. ConclusionThis study validates the viability of utilizing vaginal secretions for the early diagnosis of pregnancy in sows, thereby establishing a foundation for the advancement of non-invasive diagnostic methodologies.

zoology↗

bioRxiv2024

Dynamic p21-dependency during quiescence arrest unveiled by a rapid p21 depletion system

Stress- or developmentally-induced signals can trigger G0/G1 cell cycle arrest through the upregulation of p21, a key inhibitor that halts proliferation. While p21 is widely recognized as essential for establishing this arrest, its degradation is generally assumed to be a prerequisite for the exit from arrest and cell cycle re-entry. Using a rapid p21 degradation system that allows for both endogenous p21 tracking and controlled depletion, we uncovered an extended role for p21 during the exit from G0/G1 arrest. Our results showed that removal of the arrest inducing signals did not lead to an immediate decline of p21 during the exit process; instead, p21 levels continued to maintain for a period before its gradual down-regulation. Importantly, premature depletion of p21 during this process weakened the capacity of cell cycle re-entry, particularly in cells with high levels of pre-existent p21. We found that during the release from arrest, cells with high levels of pre-existent p21 but a premature p21 depletion exhibited reduced capacity to restore KRAS/ERK activity, and supplementing KRAS/ERK activity rescued the failure of cell cycle re-entry in these cells. These findings reveal a previously unappreciated function for p21 during the exit from G0/G1 arrest, aside and distinct from its role in initiating the arrest. This new paradigm extends across multiple cell lines and stress-induced arrest contexts, offering a new framework for understanding p21 function in response to anticancer therapies and in development.

cell biology↗

bioRxiv2024

Zfp263 is a transcriptional checkpoint of neutrophil development

During development neutrophils undergo extensive changes in nuclear morphology, gene expression programmes, and acquire specific effector functions. However, molecular mechanisms controlling neutrophil development remain largely unknown. Here we systematically analysed changes in gene expression and chromatin landscape across stages of neutrophil differentiation, to construct a network of transcription factors, predicted to control neutrophil development and acquisition of functions. Zinc finger protein 263 (Zfp263) emerged at the apex of this network. Neutrophil maturation ex vivo and in vivo was blocked in cells lacking Zfp263 and accelerated if its levels were induced. Mechanistically, Zfp263 acts as a direct transcriptional repressor of the ERK1/2 pathway, that supports the proliferative capacity of neutrophil progenitors and limits their differentiation into mature cells. Blocking ERK1/2 signalling in the Zfp263 deficient cells using chemical inhibitors, rescues neutrophil differentiation. Other targets of Zfp263 include genes involved in neutrophil migration, cytokine and chemokine expression, reactive oxygen species and formation of neutrophil extracellular traps. Thus, our study outlines a framework for modulation of neutrophil development and / or function, aimed at neutrophil-mediated diseases.

genomics↗

bioRxiv2023

Comprehensive Assessment of Isoform Detection Methods for Third-Generation Sequencing Data

The advancement of Third-Generation Sequencing (TGS) techniques has significantly increased the length of sequencing to several kilobases, thereby facilitating the identification of alternative splicing (AS) events and isoform expressions. Recently, numerous computational methods for isoform detection using long-read sequencing data have been developed. However, there is lack of prior comparative studies that systemically evaluates the performance of these software tools, implemented with different algorithms, under various simulations that encompass potential influencing factors. In this study, we conducted a benchmarking analysis of eleven methods implemented in eight computational tools capable of identifying isoform structures from TGS RNA sequencing data. We evaluated their performances using simulated data, which represented diverse sequencing platforms generated by an in-house simulator, as well as experimental data. Our comprehensive results demonstrate the guided mode of StringTie2 and Bambu achieved the best performance in sensitivity and precision, respectively. This study provides valuable guidance for future research on AS analysis and the ongoing improvement of tools for isoform detection using TGS data.

bioinformatics↗

bioRxiv2023

Dissecting peri-implantation development using cultured human embryos and embryo-like assembloids

Studies of cultured embryos have provided insights into human peri-implantation development. However, detailed knowledge of peri-implantation lineage developments as well as underlying mechanisms remain obscure. Using 3D-cultured human embryos, herein we report a complete cell atlas of the early post-implantation lineages and decipher cellular composition and gene signatures of the epiblast and hypoblast derivatives. In addition, we develop an embryo-like assembloid (E-assembloid) by assembling naive hESCs and extraembryonic cells. Using human embryos and E-assembloids, we reveal that WNT, BMP and Nodal signaling synergistically, but functionally differently, orchestrate human peri-implantation lineage development. Specially, we dissect mechanisms underlying extraembryonic mesoderm and extraembryonic endoderm specifications. Finally, an improved E-assembloid is developed to recapitulate the epiblast and hypoblast developments and tissue architectures in the pre-gastrulation human embryo. Our findings provide insights of the human peri-implantation development, and the E-assembloid offers a useful model to disentangle cellular behaviors and signaling interactions that drive human embryogenesis.

developmental biology↗

bioRxiv2022

Plasma iron controls neutrophil production and function

Low plasma iron (hypoferremia) induced by hepcidin is a conserved inflammatory response that protects against infections but inhibits erythropoiesis. How hypoferremia influences leukocytogenesis is unclear. Using proteomic data, we predicted that neutrophil production would be profoundly more iron-demanding than generation of other white blood cell types. Accordingly in mice, hepcidin-mediated hypoferremia substantially reduced numbers of granulocytes but not monocytes, lymphocytes or dendritic cells. Neutrophil rebound after anti-GR1-induced neutropenia was blunted during hypoferremia, but was rescued by supplemental iron. Similarly, hypoferremia markedly inhibited pharmacologically-stimulated granulopoiesis mediated by GCSF and inflammation-induced accumulation of neutrophils in the spleen and peritoneal cavity. Furthermore, hypoferremia specifically altered neutrophil effector functions, suppressing antibacterial mechanisms but enhancing mitochondrial ROS-dependent NETosis associated with chronic inflammation. Notably, antagonising endogenous hepcidin during acute inflammation enhanced production of neutrophils. We propose plasma iron modulates the profile of innate immunity by controlling monocyte-to-neutrophil ratio and neutrophil activity in a therapeutically targetable system.

immunology↗

bioRxiv2020

PYK2 controls intestinal inflammation via activation of IRF5 in macrophages

Inflammatory bowel disease (IBD) is a group of inflammatory disorders of the gastro-intestinal tract caused by a complex combination of genetic and environmental factors. Interferon regulating factor 5 (IRF5) is a multifunctional regulator of immune responses, which plays a key pathogenic role in mouse colitis models and is a genetic risk factor for IBD. A screen of a protein kinase inhibitor library in macrophages revealed a list of putative IRF5 kinases. Among the top hits validated in multiple in vitro assays, protein-tyrosine kinase 2-beta (PTK2B or PYK2) was identified as the only IBD genetic risk factor, known to impact gene expression in myeloid cells1,2. Phospho-proteomics and mutagenesis analyses established that PYK2 directly phosphorylates and activates IRF5 at tyrosine (Y) 171. IRF5 nuclear translocation and recruitment to target genes was impaired in PYK2-deficient cells or in cells treated with PYK2 inhibitors. Importantly, macrophage transcriptomic signature under PYK2 inhibition phenocopied IRF5 deficiency. Treatment with a PYK2 inhibitor reduced pathology and inflammatory cytokine production in Helicobacter hepaticus + anti-IL-10R antibody induced colitis model. It also decreased levels of pro-inflammatory cytokines in human colon biopsies taken from patients with ulcerative colitis. Thus, we have identified a major role for PYK2 in regulating the inflammatory response and mapped its activity to the IRF5 innate sensing pathway, opening opportunities for therapeutic interference with it in IBD and other inflammatory conditions.

immunology↗