Biology subjects

Jiao, X.

Publications and source records attributed to Jiao, X..

At least 19 recordsLinked to original sources

bioRxiv2026

ATR is a master regulator of the oocyte meiotic prophase checkpoint

During meiotic prophase, programmed double-strand breaks (DSBs) initiate meiotic recombination, and defects in this process result in persistent DSBs and chromosome asynapsis, triggering checkpoint-mediated oocyte elimination before primordial follicle formation. However, how the oocyte meiotic prophase checkpoint is regulated remains unclear. ATR is a DNA damage response kinase essential for male meiosis, but its role in female meiosis is poorly characterized. Here, we identify ATR as a master regulator of the oocyte meiotic prophase checkpoint. ATR loss fully rescues the survival of Dmc1-/- oocytes, which exhibit persistent DSBs and extensive chromosome asynapsis. ATR loss also fully rescues the survival of asynaptic Spo11-/- oocytes and Trip13-/- oocytes with aberrant checkpoint activation, demonstrating an essential role for ATR in the chromosome asynapsis checkpoint. Mechanistically, BRCA1 is required for ATR localization to unsynapsed chromosome axes, whereas ATR is dispensable for BRCA1 localization, establishing a BRCA1-ATR regulatory hierarchy at unsynapsed chromosome axes that is conserved between oocytes and spermatocytes. Together, these findings place ATR at the center of the oocyte meiotic prophase checkpoint and define a BRCA1-ATR signaling axis that links chromosome asynapsis to oocyte elimination.

developmental biology↗

bioRxiv2026

A Cross-tissue Temporal Multi-omics Atlas Reveals the Molecular Architecture of Pressure Injury

Pressure injury induces progressive necrosis of skin and deep muscle, yet how mechanical loading reshapes molecular programs across tissues and time remains poorly defined. To address this gap, we established a rat pressure-injury model and performed longitudinal integrated profiling of skin and deep muscle across four stages, combining transcriptomics, proteomics and untargeted metabolomics with histological assessment. This multi-layered atlas revealed a staged injury program dominated by early transcriptional activation of innate immunity and complement-coagulation crosstalk, accompanied by neutrophil-associated responses and engagement of upstream regulatory networks. As injury advanced, a second axis of remodeling emerged, characterized by sustained suppression of mitochondrial energy metabolism and oxidative phosphorylation, particularly in muscle, together with extracellular matrix and adhesion rewiring. In parallel, skin preferentially activated barrier-repair and protein-homeostasis programs, including keratinization and autophagy-linked processes, indicating tissue-specific adaptation to the same mechanical insult. Temporal clustering and pathway-network analysis further showed that immune activation and metabolic collapse are not independent events but are dynamically coupled across stages, with muscle exhibiting broader molecular reprogramming and a stronger shift toward irreversible structural failure. Together, these data define a cross-tissue, stage-resolved molecular framework for pressure injury progression and identify pathway-level windows that may inform tissue-targeted and stage-specific intervention strategies.

systems biology↗

bioRxiv2026

Biosynthesis of bisbenzylisoquinoline alkaloids

Bisbenzylisoquinoline alkaloids (bisBIAs) are pharmacologically valuable plant metabolites with complex stereochemical architectures, yet the catalytic principles governing their assembly have remained largely unclear. Here, we elucidate the enzymatic pathway to cyclic bisBIAs and uncover a non-canonical redox-mediated mechanism for post-assembly stereochemical control. We identify cytochrome P450 enzymes that catalyze regioselective oxidative dimerization and macrocyclization of benzylisoquinoline monomers, establishing the macrocyclic scaffold. Subsequent stereochemical specification is achieved by a paired oxidase-reductase module that selectively epimerizes a single stereocenter through a transient imine formation, converting (R,S)-configured intermediates to (S,S)-products. Reconstitution of the pathway in yeast enabled production of both native bisBIAs and non-natural analogs, demonstrating pathway modularity and engineering potential. These results establish the biochemical principle underlying bisBIA biosynthesis and provide a framework for programmable biosynthesis of these complex natural products.

biochemistry↗

bioRxiv2025

Migration patterns and hybridization within the Asian stonechat complex in response to a major geographical barrier

Long-distance avian migration is thought to be under strong natural selection. Facing geographical barriers, migrants display various patterns considered to be adaptive. For example, they may detour along either side around the barrier or cross it, requiring specialized behavioral adaptations. Variations within closely related taxa are excellent sources for understanding the evolutionary background of migration and how barriers are shaping migration routes. In Asia, some species are assumed to have a migratory divide in response to the major geographical barrier, the Qinghai-Tibet Plateau (QTP), including the stonechat taxa (Siberian Stonechat Saxicola maurus maurus and Amur Stonechat S. stejnegeri). As they detour along either side of the QTP, these taxa are believed to disfavor a crossing over the highland. However, the more southernly distributed Tibetan Stonechat (S. m. przewalskii) breeds on the QTP, suggesting adaptation to high elevation. To investigate migration patterns and the potentially associated genetic differences, we studied migration routes and population genetics of four populations around the assumed migratory divide in Russia and Mongolia, and of one from the QTP in China. Our results confirmed the existence of a migratory divide between maurus and stejnegeri, albeit with extensive hybridization. We observed both the hypothesized western and eastern routes, but also found individuals employing intermediate routes crossing the QTP, of which two-thirds were clear hybrids. Meanwhile, przewalskii followed a highland-crossing route and was genetically differentiated from maurus and stejnegeri. The diverse migration routes among Asian stonechats show differential responses towards the geographical barrier. The intermediate route may be associated with hybridization, and its conditional viability may facilitate gene flow between maurus and stejnegeri. The Asian stonechat complex thus offers great opportunities for novel research of the genetics and evolution of migration. The specific evolutionary background associated with inhabiting and crossing the QTP can offer new perspectives in this field. Teaser textMigratory divides can arise in birds because alternative routes around migratory barriers would select for behaviors to restrict hybridization. Hybrids of parental types that employ alternative routes are hypothesized to embark on intermediate routes that would expose them to suboptimal conditions, resulting in post-zygotic reproductive isolation. However, this hypothesis is challenged when a sister taxon actually breeds on the geographical barrier. This is the case in the Asian stonechat complex that breeds near or on the Qinghai-Tibet Plateau (QTP), the roof of the world. We demonstrated a migratory divide in central Siberia to Mongolia for race maurus and stejnegeri, yet showed also evidence for extensive hybridization. Hybrids migrated along a newly discovered intermediate route, seemingly viable and overlaps with the migration trajectory of race przewalskii over the eastern part of the QTP. The Asian migratory divide relative to the QTP thus provided new insights to the evolution of landbird migration.

evolutionary biology↗

bioRxiv2025

Bayesian inference of introgression between sister lineages using genomic data

Inference of interspecific gene flow using genomic data is important to reliable reconstruction of species phylogenies and to our understanding of the speciation process. Gene flow is harder to detect if it involves sister lineages than nonsisters; for example, most heuristic methods based on data summaries are unable to infer gene flow between sisters. Likelihood-based methods can identify introgression between sisters but the test exhibits several nonstandard features, including boundary problems, indeterminate parameters, and multiple routes from the alternative to the null hypotheses. In the Bayesian test, those irregularities pose challenges to the use of the Savage-Dickey (S-D) density ratio to calculate the Bayes factor. Here we develop a theory for applying the S-D approach under nonstandard conditions. We show that the Bayesian test of introgression between sister lineages has low false-positive rates and high power. We discuss issues surrounding the estimation of the rate of gene flow between sister lineages, especially at very low or very high rates, and suggest that evidence for gene flow between sisters be assessed via a Bayesian test. We find that the species split time has a major impact on the information content in the data, with more information at deeper divergence. We use a genomic dataset from Sceloporus lizards to illustrate the test of gene flow between sister lineages.

evolutionary biology↗

bioRxiv2025

Improved flux profiling in genome-scale modeling of human cell metabolism

Understanding human cell metabolism through genome-scale flux profiling is of interest to diverse research areas of human health and disease. Metabolic modeling using genome-scale metabolic models (GEMs) has the potential to achieve this, but has been limited by a lack of appropriate input data as model constraints. Here we show that GEM-based flux profiling simulations can be improved with an appropriate input data collection procedure and exo-metabolite exchange flux calculation method, called regression during exponential growth phase (REGP). Our results show that the GEM-simulated feasible flux space is constrained to a biologically meaningful region, allowing an exploration of the basic organizing principles of the feasible flux space. These improvements help to fulfil the promise of GEMs as a valuable tool in the study of human metabolism and future development of translational applications.

systems biology↗

bioRxiv2024

Defective DcpS Decapping Manifests in Creatine Deficiency Syndrome and Neurological impairment

Biallelic mutations in the DCPS gene disrupting the decapping activity of the scavenger decapping protein DcpS, leads to neurodevelopmental deficiencies and intellectual disability. However, the molecular basis for the neurogenesis defects in these individuals remains unknown. Here we show that cells derived from individuals with a DCPS mutation harbor a creatine deficiency and a corresponding elevation of the creatine precursor, guanidinoacetate (GAA). The altered metabolite levels are a consequence of a reduction in both the mRNA and protein levels for the enzyme that converts GAA into creatine, guanidinoacetate methyltransferase. Importantly, the compromised neurogenesis and neurite outgrowth phenotypes observed during the differentiation of DcpS mutant patient derived induced pluripotent stem cell differentiation into neurons was reversed upon supplementation of creatine monohydrate. These findings suggest creatine deficiency as the major underlying factor for the neurogenetic defect detected in DcpS mutant cells and a potential driver of the neurological deficiencies in affected individuals.

cell biology↗

bioRxiv2024

Extracellular Exosomal RNAs are Glyco-Modified

Epitranscriptomic modifications play pivotal roles in regulating RNA function, encompassing base alterations and the addition of both canonical m7G and noncanonical nucleotide metabolite caps. Recently, the spectrum of modifications has extended to include glyco modification at the 5 cap or within the RNA. Despite this expansion, the functional implications of glyco modification on RNA remain elusive. Our study reveals that mammalian cells labeled with N-azidoacetylgalactosamine-tetraacylated (Ac4GalNAz) produce small noncoding and nonpolyadenylated glyco-modified RNA (glycoRNA), primarily localized within exosome vesicles. The resistance of glycoRNA-containing exosomes to RNase treatment suggests that Ac4GalNAz-derived glycoRNA constitutes intraluminal cargo, distinct from recently reported cell surface glycoRNAs. Furthermore, we demonstrate that exosome cargo can be transferred to naive cells, underscoring exosome-mediated intercellular communication of glycoRNAs. Inhibition of exosome biogenesis leads to the accumulation of intracellular glycoRNA while blocking glycan transfer to proteins concomitantly reduced the targeting of glycoRNA within exosomes. These findings highlight a correlation between protein and RNA glycosylation, suggesting that the accumulation of glycoRNAs within exosomes is a regulated process. Our results support a functional role for glyco-modification in mediating RNA targeting into exosomes, offering new insights for enhancing recent advances in exosome-directed diagnostics and therapeutic applications.

cell biology↗

bioRxiv2024

The Glutamatergic Projection from the Substantia Nigra Pars Reticulata to the Dorsal Raphe Nucleus Facilitates Social Hierarchy in Mice

Social hierarchy constitutes a fundamental organizational characteristic among various social species, significantly influencing individual survival, health, and reproductive success within these societies. Neurons in the substantia nigra pars reticulata (SNr) exhibit extensive connectivity with the dorsal raphe nucleus (DRN), a critical structure implicated in social interaction, reward processing, and the establishment of social rank. However, the specific neuronal types within the SNr, as well as the associated neural circuits that regulate social dominance, remain inadequately characterized. This study aims to elucidate the crucial role of SNr glutamatergic neurons in the establishment and maintenance of social hierarchy in mice. Employing fiber photometry, we observed that the activation of SNr glutamatergic neurons increased during the initiation of effortful behaviors in the tube test. Further investigations revealed that optogenetic activation or chemogenetic inhibition of the glutamatergic neural circuit connecting the SNr to the DRN induced upward or downward shifts in social ranks, respectively. Additionally, our findings indicate that the activation of SNr glutamatergic terminals in the DRN reduces anxiety levels in mice. Collectively, these results underscore the critical role of the glutamatergic pathway from the SNr to the DRN in regulating social hierarchy. This work enhances our understanding of the functions of SNr glutamatergic neurons in both physiological contexts and neurological disorders.

neuroscience↗

bioRxiv2024

DDX3 regulates the cap-independent translation of the Japanese encephalitis virus via its interactions with PABP1 and the untranslated regions of the viral genome

The translation of global cellular proteins is almost completely repressed in cells with flavivirus infection, while viral translation remains efficient. The mechanisms of flaviviruses evade host translational shutoff are largely unknown. Here, we identified viral elements and host factors associated with JEV evasion of host shutoff. JEV 5'UTR lacked IRES or IRES-like activity, while noncapped 5'UTR initiated translation in the presence of 3'UTR. Furthermore, the elements DB2 and sHP-SL within 3'UTR were involved in the regulation of cap-independent translation, which is conserved in the genus Orthoflavivirus. By RNA affinity purification and mass spectrometry analysis, cellular DDX3 and PABP1 were identified as key factors in regulating cap-independent translation of JEV via their interactions with DB2 and sHP-SL RNA structures. Mechanistically, we revealed that DDX3 could bind to both 5'UTR and 3'UTR of the JEV genome to establish a closed-loop architecture, recruit eIF4G/eIF4A to form the DDX3/PABP1/eIF4G/eIF4A tetrameric complex via its interaction with PABP1, thereby recruiting 43S PIC to the 5'-end of the JEV genome to start translation. Our findings demonstrated a noncanonical translation strategy employed by JEV and further revealed the regulatory roles of DDX3 and PABP1 in this mechanism. These results expand our knowledge of the translation initiation regulation in flaviviruses under the state of host translational shutoff, which provides a conserved antiviral target against orthoflavivirus.

microbiology↗

bioRxiv2024

Single Distal Mutation Enhances Activity of known PETases via Stabilisation of PET-binding

As a major source of plastic pollution, PET has attracted significant interest for biodegradation due to its potential in the circular economy. Finding effective enzymes still remains a challenge as screening methods are limited by either the low throughput or dependence on alternative non-PET substrates due to PETs insolubility. Here, we report a highly active, stable and robust enzyme, Fast_2.9, identified while directly screening for PET-degrading activity in mesophilic conditions using droplet-based encapsulation of PET nanoparticles with the throughput above 1 kHz. We identified a distal S269T mutation that improves activity in the majority of all known PETases with up to 400 times over wildtype, and more than twice of known engineered PETases, as tested on untreated post-consumer plastics. Microsecond time scale molecular dynamics analyses indicate that this distant mutation possibly influences residues near the substrate-binding cleft via a common mechanism across PETases. Compared to the state-of-the-art FastPETase and LCCICCG enzymes, the engineered Fast_2.9 enzyme requires up to 8 and 42 times lower enzyme concentrations to reach the same enzymatic activity, ultimately requiring significantly less enzyme. As such our engineered enzyme degrades multiple post-consumer PET substrates, including polyester textiles, within as least as just 2 days with up to nearly 100% terephthalic acid conversion using as little as 0.72 mgenzyme/gPET at 50. Our study presents a universal methodology for direct screening of insoluble substrates at ultra-high-throughput and highlights the techno-economic potential of Fast_2.9 for PET depolymerisation.

synthetic biology↗

bioRxiv2024

iVirP: An integrative, efficient, and user-friendly pipeline to annotate viral contigs from raw reads of metagenome or VLP sequencing

Metagenome sequencing and virus-like particles sequencing make it possible to explore the virome in the humans and other organisms. One way to analyze the sequencing data is to assemble reads into contigs according to the overlapping regions, and then the predicted viral contigs are screened out to conduct deeper dives. iVirP (integrative virome pipeline) is a user-friendly pipeline that includes the whole process of viral contigs discovery from the quality control of raw data to the filter of high quality viral contigs. This pipeline also features a branching function that can estimate the abundance of known eukaryotic viruses in a short period, while reducing host contamination. It is suitable for the rapid diagnosis of pathogens. Throughout iVirP, many details that might affect the experience of users are optimized carefully to reduce the time spent on dealing with usage and errors. iVirP was tested on a published, high-quality VLP sequencing dataset and was able to well reproduce the conclusions of the corresponding research. The benchmark indicates that iVirP could accurately assemble viral contigs from real sequencing data. iVirP is easy to install and currently available at https://github.com/li-bw18/iVirP.

bioinformatics↗

bioRxiv2023

Targeting CD74-positive macrophages improves neoadjuvant therapy in cervical cancer as revealed by single-cell transcriptomics analysis

Uterine cervical cancer (UCC) has the second-highest mortality rate among malignant tumors of the female reproductive system. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapeutic strategy for cervical cancer. However, the efficacy of PD-1 (programmed cell death protein 1) blockade combined with neoadjuvant chemotherapy (NACT) and the ensuing alterations within the tumor microenvironment need further investigation. We conducted single-cell RNA sequencing using 46,950 cells from nine sequential human cervical cancer tissues representing different stages of NACT and PD-1 blockade combination therapy. We delineated the trajectory of cervical epithelial cells and unveiled crucial factors involved in the combination therapy. Cell communication analysis revealed the inferred interaction strength decreased between T cell-cancer cells, while the communication between macrophage-cancer cells intensified after NACT therapy. We verified that macrophages are necessary for PD-1 blockade combination to exert antitumor effects in vitro. Detailed analysis unraveled the CD74-positive macrophages frequently interacted with the immunoreactive Epi 3 subgroup during neoadjuvant combination therapy. CD74 upregulation limited phagocytosis and stimulated M2 polarization. The CD74 blockade enhanced macrophage phagocytosis, resulting in decreased viability of cervical cancer cells in vitro and in vivo. This study unveils the dynamic microenvironment of UCC influenced by NACT and PD-1 blockade combination therapy, and targeting CD74 was a potential strategy to augment the therapy efficacy.

cancer biology↗

bioRxiv2023

Analysis of the heterogeneity and complexity of murine extraorbital lacrimal gland via single-cell RNA sequencing

PurposeThe lacrimal gland is essential for maintaining ocular surface health and avoiding external damage by secreting the aqueous layer of the tear film. However, a healthy lacrimal glands inventory of cell types and heterogeneity remains understudied. MethodsHere, 10X genome-based single-cell RNA sequencing was used to generate an unbiased classification of cellular diversity in the extraorbital lacrimal gland (ELG) of C57BL/6J mice. From 48,077 high-quality cells, an atlas of cell heterogeneity was produced, and cell types were defined by classic marker genes. The possible functions of these cells and the pseudotime trajectories for certain cell populations were analyzed through bioinformatics. In addition, a preliminary analysis of the cell-cell communication network in ELG was performed. ResultsOver 41 subclasses of cells were identified, including 9 kinds of glandular epithelial cells, 7 kinds of fibroblasts, 10 kinds of myeloid-derived immune cells, at least 10 kinds of lymphoid-derived immune cells, 3 kinds of vascular-associated cell subsets, and 2 kinds of Schwann cells. Analysis of cell-cell communication networks revealed that innate lymphoid cells were closely associated with other cells. ConclusionsThis study provides the first comprehensive transcriptome atlas and related database of mouse ELG. This resource can aid in a deeper understanding of lacrimal gland biology and pathophysiology of its related diseases.

bioinformatics↗

bioRxiv2023

Quorum sensing inhibits Type III-A CRISPR-Cas system activity through repressing positive regulators SarA and ArcR in Staphylococcus aureus

CRISPR-Cas is an adaptive immune system that protects prokaryotes from the invasion of foreign genetic elements. The components and immunity mechanisms of CRISPR-Cas have been extensively studied, but the regulation of this system in Staphylococci remains unclear. Here, we show that in the S. aureus Type III-A CRISPR-Cas system, the Pcas of 300 bp located in cas1 displays as a critical regulatory node that initiates the transcription of cas gene clusters. We discovered two transcriptional regulators, SarA and CRP-like ArcR, promote the expression and activity of the CRISPR-Cas system by directly binding to the novel promoter Pcas. Furthermore, we demonstrated that the cell-cell communication, known as quorum sensing (QS), inhibits the activity of CRISPR-Cas system by repressing the positive regulators SarA and ArcR. Bioinformatic analyses suggest that Pcas is conserved in many Type II and III CRISPR-Cas systems in Firmicutes. Our data reveal a new regulatory mechanism for QS-mediated repression of the Type III-A CRISPR-Cas system, which may allow S. aureus to acquire foreign genetic elements encoding antibiotic resistance or virulence factors specifically at high cell density.

microbiology↗

bioRxiv2022

Functional characterization of multidomain protein Vip3Aa from Bacillus thuringiensis reveals a strategy to increase its insecticidal potency

Microbially derived, protein-based biopesticides offer a more sustainable pest management alternative to synthetic pesticides. Vegetative insecticidal proteins (Vip3), multidomain proteins secreted by Bacillus thuringiensis, represent a second-generation insecticidal toxin that have been used in transgenic crops. However, the molecular mechanism underlying Vip3s toxicity is poorly understood. Here, we determine the distinct functions and contributions of the domains of the Vip3Aa protein to its toxicity against Spodoptera frugiperda larvae. Vip3Aa domains II and III (DII-DIII) bind the midgut epithelium, while DI maintains the tetrameric state of the Vip3Aa protoxin, which is essential for its stability and toxicity. DI-DIII can be activated by midgut proteases, and exhibits ex vivo cytotoxicity similar to full-length Vip3Aa. We also determine that DV binds the peritrophic matrix via its glycan-binding activity, which is essential for Vip3Aa insecticidal activity. We further show that Vip3Aa has multiple protease activation sites and that introducing additional cleavage sites between DI and DII can increase the proteolysis efficiency and boost Vip3Aa insecticidal potency. This study provides insights into Vip3Aas mode-of-action and demonstrates a proof-of-concept strategy to enhance the insecticidal potency of Vip3Aa, which should significantly improve its application and development as a biopesticide.

microbiology↗

bioRxiv2022

Mechanism of treatment-free remission in patients with chronic myeloid leukemia revealed by a computational model of CML evolution

In the past few years, international treatment guidelines for chronic myeloid leukemia (CML) have incorporated recommendations for attempting discontinuation of treatment with tyrosine kinase inhibitors (TKIs) outside of the setting of a clinical trial with the aim of treatment-free remission (TFR). Multiple clinical studies have shown consistent results that 40%-50% patients can achieve long-term TFR after TKI discontinuation, and most relapse patients undergo molecular recurrence within 6 months after TKI discontinuation, however the underling mechanisms remain unclear. To understand the mechanism of TFR in patients with CML, we consider the competition between leukemia stem cell and bone marrow microenvironment, and develop a mathematical model to investigate the CML progression dynamics. Model simulations are consistent with clinical observation of CML progression, and reveal a mechanism of dimorphic response after TKI discontinuation. Our model predicts that neoplasitic microenvironment is significant for CML occurrence and progression. We furthermore discuss the prediction of TFR based on the change rates of microenvironment index and leukemia stem cells ratio prior TKI discontinuation.

cancer biology↗

bioRxiv2021

Perfluorononanoic acid impedes mouse oocyte maturation by inducing mitochondrial dysfunction and oxidative stress

Perfluorononanoic acid (PFNA), a member of PFAS, is frequently detected in human blood and tissues, even in follicular fluid of women. The exposure of PFNA, but not PFOA and PFOS, is positively correlated with miscarriage and increased time to pregnancy. Toxicological studies indicated that PFNA exposure is associated with immunotoxicity, hepatotoxicity, developmental toxicity, and reproductive toxicity in animals. However, there is little information regarding the toxic effects of PFNA on oocyte maturation. In this study, we investigated the toxic effects of PFNA exposure on mouse oocyte maturation in vitro. Our results showed that 600 M PFNA significantly inhibited germinal vesicle breakdown (GVBD) and polar body extrusion (PBE) in mouse oocytes. Our further study revealed that PFNA induced abnormal metaphase I (MI) spindle assembly, evidenced by malformed spindles and mislocalization of p-ERK1/2 in PFNA-treated oocytes. We also found that PFNA induced abnormal mitochondrial distribution and increased mitochondrial membrane potential. Consequently, PFNA increased reactive oxygen species (ROS) levels, leading to oxidative stress, DNA damage, and eventually early-stage apoptosis in oocytes. In addition, after 14 h culture, PFNA disrupted the formation of metaphase II (MII) spindle in most PFNA-treated oocytes with polar bodies. Collectively, our results indicate that PFNA interferes with oocyte maturation in vitro via disrupting spindle assembly, damaging mitochondrial functions, and inducing oxidative stress, DNA damage, and early-stage apoptosis.

cell biology↗