Biology subjects

Ju, C.

Publications and source records attributed to Ju, C..

11 recordsLinked to original sources

bioRxiv2025

TRIO-AI: Hybrid temporal graph, ODE, and VAE modeling for high-resolution cellular trajectory inference in liver injury

Resolving dynamic cellular transitions at single-cell resolution is essential for understanding complex biological processes in development, disease, and regeneration. However, existing trajectory inference methods struggle to capture heterogeneous temporal dynamics, particularly for rare or transitional cell populations critical to injury and repair responses. Here, we present TRIO-AI, a hybrid computational framework that synergistically integrates three complementary approaches: Temporal Graph Neural Networks (Temporal GNN) for branching detection, Neural Ordinary Differential Equations (Neural ODEs) for continuous state flow modeling, and Time-Variational Autoencoders (Time-VAE) for density-based transitional state identification. We applied TRIO-AI to single-cell RNA sequencing data from mouse liver ischemia-reperfusion (IR) injury across multiple timepoints (days 0, 1, 3, and 5 post-injury), comprehensively characterizing major hepatic macrophage populations. TRIO-AI identified a distinct transitional macrophage population (MPs_3) that peaks at 48 hours post-injury and exhibits coordinated signatures for lipid handling (LRP1, LRP6, ABCA1, LDLR, SCARB1), efferocytosis (MARCO, MERTK, MSR1), and extracellular matrix engagement (ITGA9, ITGB1, SDC2). This population serves as a critical integrator of multicellular pro-reparative signals through APOE-LRP1 and FN1-ITGA9 signaling axes. Spatial transcriptomics validation confirmed MPs_3 localization to peri-necrotic borders with dramatic enrichment of APOE-LRP1 co-localization at 48 hours (19 pairs) compared to 24 hours (3 pairs). Comparative analysis against five state-of-the-art methods demonstrated TRIO-AIs superior performance in detecting transitional states, accurately reconstructing branching trajectories, and identifying off-path populations missed by conventional approaches. This framework provides a powerful platform for dissecting cellular dynamics in complex biological systems and reveals new insights into macrophage-mediated tissue repair mechanisms.

bioinformatics↗

bioRxiv2025

Ethylene receptors are functionally conserved in calcium permeability across the green lineage

The gaseous hormone ethylene plays a key role in regulating plant growth and stress responses. Although Ca{superscript 2} has long been implicated in ethylene signaling, the identity of molecules controlling Ca{superscript 2} permeability involved has remained elusive. Here we show that Arabidopsis ethylene receptors ETR1 and ERS1 are Ca2+ permeable, and that ETR1 mediates ethylene-induced cytosolic Ca2+ increase and regulates hypocotyl elongation. Homologs of ETR1 from eight land plant and algal species also exhibit Ca{superscript 2} permeability, suggesting an evolutionarily conserved function. We further demonstrate ethylene enhances the Ca2+ permeability of ETR1 and its homologue from the charophyte Klebsormidium flaccidum. These findings uncover a previously unrecognized but conserved role of ethylene receptors in Ca{superscript 2} permeability regulation in the green lineage, with broad implications for Ca{superscript 2} signaling in plant development and environmental adaptation.

plant biology↗

bioRxiv2025

Quantifying Protein-Protein Interaction with a Spatial Attention Kinetic Graph Neural Network

Accurate prioritisation of near-native protein-protein interaction (PPI) models remains a major bot-tleneck in structural biology. Here we present SAKE-PP, a physics-inspired, spatial-attention equivariant graph neural network that directly regresses interface RMSD (iRMSD) without any native references. Trained on docking decoys generated through our novel hierarchical sampling strategy applied to PDB-Bind dataset, SAKE-PP combines force-field-like attention with Laplacian-eigenvector orientation to couple local interaction forces with global topology. On the 2024PDB benchmark comprising 176 het-erodimers, SAKE-PP demonstrates effective optimization and selection of AF3 decoys, achieving improvements of 13.75% based on iRMSD statistics and 12.5% based on DockQ scores. It consistently outperforms the AF3 ranking score in multiple metrics, including overlap, hit rate, and correlation. In zero-shot evaluation of 139 antibody-antigen complexes, SAKE-PP improves the score-iRMSD correlation by 0.4. By unifying geometric deep learning with physics-based realism, SAKE-PP provides a robust, plug-and-play scoring function that streamlines reliable PPI evaluation and accelerates downstream structure-guided drug-design workflows.

bioinformatics↗

bioRxiv2025

Catastrophic drought effects on water quality and phytoplankton biomass in Nanwan Reservoir (Xinyang, China)

Climate change has led to increasingly frequent and unpredictable droughts and high-temperature events, creating extreme conditions that profoundly impact the productivity of freshwater ecosystems. This study investigates the Nanwan Reservoir, a large and deep reservoir in Xinyang, China, to evaluate the effects of extreme drought events on water quality and phytoplankton production. Field investigations were conducted during both high-temperature and drought (HTD) conditions in 2019, and during non-high-temperature and drought (NHTD) conditions in 2020. Results showed that HTD conditions significantly disrupted the thermocline and oxycline structures, leading to prolonged stratification during the HTD period. Although phosphorus concentrations remained relatively stable across both periods, nitrogen levels were markedly lower during HTD events--likely due to uptake by phytoplankton--indicating a shift in nutrient limitation from phosphorus to nitrogen. Additionally, a complex relationship between environmental variables and phytoplankton biomass was observed under HTD conditions. These findings advance our understanding of primary production responses to extreme weather events in the Nanwan Reservoir and highlight the importance of incorporating such knowledge into water resource management and ecological conservation strategies.

ecology↗

bioRxiv2025

Non-mutated human tau stimulates Alzheimer's disease-relevant neurodegeneration in a microglia-dependent manner

The accumulation of abnormal, non-mutated tau protein is a key pathological hallmark of Alzheimers disease (AD). Despite its strong association with disease progression, the mechanisms by which tau drives neurodegeneration in the brain remain poorly understood. Here, we selectively expressed non-mutated or mutated human microtubule-associated protein tau (hMAPT) in neurons across the brain and observed neurodegeneration in the hippocampus, especially associated with non-mutated human tau. Single-nuclei RNA sequencing confirmed a selective loss of hippocampal excitatory neurons by the wild-type tau and revealed the upregulation of neurodegeneration-related pathways in the affected populations. The accumulation of phosphorylated tau was accompanied by cellular stress in neurons and reactive gliosis in multiple brain regions. Notably, the lifelong absence of microglia significantly and differentially influenced the extent of neurodegeneration in the hippocampus and thalamus. Therefore, our study established an AD-relevant tauopathy mouse model, elucidated both neuron-intrinsic and neuron-extrinsic responses, and highlighted critical and complex roles of microglia in modulating tau-driven neurodegeneration.

neuroscience↗

bioRxiv2021

The production of 4,182 mouse lines identifies experimental and biological variables impacting Cas9-mediated mutant mouse line production

The International Mouse Phenotyping Consortium (IMPC) systematically produces and phenotypes mouse lines with presumptive null mutations to provide insight into gene function. The IMPC now uses the programmable RNA-guided nuclease Cas9 for its increased capacity and flexibility to efficiently generate null alleles in the C57BL/6N strain. In addition to being a valuable novel and accessible research resource, the production of 3,313 knockout mouse lines using comparable protocols provides a rich dataset to analyze experimental and biological variables affecting in vivo gene engineering with Cas9. Mouse line production has two critical steps - generation of founders with the desired allele and germline transmission (GLT) of that allele from founders to offspring. A systematic evaluation of the variables impacting success rates identified gene essentiality as the primary factor influencing successful production of null alleles. Collectively, our findings provide best practice recommendations for using Cas9 to generate alleles in mouse essential genes, many of which are orthologs of genes linked to human disease.

genetics↗

bioRxiv2021

Chitinase 3-like-1 Contributes to Acetaminophen-induced Liver Injury by Promoting Hepatic Platelet Recruitment

Hepatic platelet accumulation contributes to acetaminophen (APAP)-induced liver injury (AILI). However, little is known about the molecular pathways involved in platelet recruitment to the liver and whether targeting such pathways could attenuate AILI. The present study unveiled a critical role of chitinase 3-like-1 (Chi3l1) in hepatic platelet recruitment during AILI. Increased Chi3l1 and platelets in the liver were observed in patients and mice overdosed with APAP. Compared to wild-type (WT) mice, Chi3l1-/- mice developed attenuated AILI with markedly reduced hepatic platelet accumulation. Mechanistic studies revealed that Chi3l1 signaled through CD44 on macrophages to induce podoplanin expression, which mediated platelet recruitment through C-type lectin-like receptor 2. Moreover, APAP treatment of CD44-/- mice resulted in much lower numbers of hepatic platelets and liver injury than WT mice, a phenotype similar to that in Chi3l1-/- mice. Recombinant Chi3l1 could restore hepatic platelet accumulation and AILI in Chi3l1-/- mice, but not in CD44-/- mice. Importantly, we generated anti-Chi3l1 monoclonal antibodies and demonstrated that they could effectively inhibit hepatic platelet accumulation and AILI. Overall, we uncovered the Chi3l1/CD44 axis as a critical pathway mediating APAP-induced hepatic platelet recruitment and tissue injury. We demonstrated the feasibility and potential of targeting Chi3l1 to treat AILI.

pharmacology and toxicology↗

bioRxiv2020

Pyronaridine and artesunate are potential antiviral drugs against COVID-19 and influenza

Since the first human case was reported in Wuhan Province, China in December 2019, SARS-CoV-2 has caused millions of human infections in more than 200 countries worldwide with an approximately 4.01% case-fatality rate (as of 27 July, 2020; based on a WHO situation report), and COVID-19 pandemic has paralyzed our global community. Even though a few candidate drugs, such as remdesivir (a broad antiviral prodrug) and hydroxychloroquine, have been investigated in human clinical trials, their therapeutic efficacy needs to be clarified further to be used to treat COVID-19 patients. Here we show that pyronaridine and artesunate, which are the chemical components of anti-malarial drug Pyramax(R), exhibit antiviral activity against SARS-CoV-2 and influenza viruses. In human lung epithelial (Calu-3) cells, pyronaridine and artesunate were highly effective against SARS-CoV-2 while hydroxychloroquine did not show any effect at concentrations of less than 100 M. In viral growth kinetics, both pyronaridine and artesunate inhibited the growth of SARS-CoV-2 and seasonal influenza A virus in Calu-3 cells. Taken together, we suggest that artesunate and pyronaridine might be effective drug candidates for use in human patients with COVID-19 and/or influenza, which may co-circulate during this coming winter season.

microbiology↗

bioRxiv2020

Ultra-sensitive nanozyme-based chemiluminescence paper test for rapid diagnosis of SARS-CoV-2 infection

The recently emerged coronavirus disease COVID-19 has now evolved into a global pandemic. Early detection is crucial for its effective control. Nucleic acid testing for viral pathogen and serological testing for host antibodies are playing important roles in current COVID-19 diagnosis. However, while nucleic acid testing is complicated, facility-restricted and time-consuming, antibody testing may result in high rates of false-negative diagnoses, especially during the early stages of viral infection. Thus, a more rapid and reliable test for both early COVID-19 diagnosis and whole-population screening is urgently needed. Here, we developed a novel nanozyme-based chemiluminescence paper assay for rapid and high-sensitive testing of SARS-CoV-2 spike antigen. Our paper test uses a newly established peroxidase-mimic Co-Fe@hemin nanozyme instead of natural HRP that catalytically amplifies the chemiluminescent signal, allowing for target concentrations to be as low as 0.1 ng/ml. Furthermore, our nanozyme-based chemiluminescence test exhibits a linear range that is 32-fold wider compared to ELISA tests. Importantly, testing is completed in less than 16 min, compared to 1-2 h required for ELISA or nucleic acid tests. Critically, signal detection is feasible using a smartphone camera. Ingredients for our test are simple and readily available, rendering overall cost considerably lower than those used in current diagnoses. In conclusion, our novel test provides a high-sensitive, point-of-care testing (POCT) approach for SARS-CoV-2 antigen detection, which should greatly increase current early screening capacities for suspected infections, and considerably lower demand for national healthcare resources.

microbiology↗

bioRxiv2018

Neurons of the inferior olive respond to broad classes of sensory input while subject to homeostatic control

Cerebellar Purkinje cells integrate sensory information with motor efference copies to adapt movements to behavioural and environmental requirements. They produce complex spikes that are triggered by the activity of climbing fibres originating in neurons of the inferior olive. These complex spikes can shape the onset, amplitude and direction of movements as well as the adaptation of such movements to sensory feedback. Clusters of nearby inferior olive neurons project to parasagittally aligned stripes of Purkinje cells, referred to as "microzones". It is currently unclear to what extent individual Purkinje cells within a single microzone integrate climbing fibre inputs from multiple sources of different sensory origins, and to what extent sensory-evoked climbing fibre responses depend on the strength and recent history of activation. Here we imaged complex spike responses in cerebellar lobule crus 1 to various types of sensory stimulation in awake mice. We find that different sensory modalities and receptive fields have a mild, but consistent, tendency to converge on individual Purkinje cells. Purkinje cells encoding the same stimulus show increased events with coherent complex spike firing and tend to lie close together. Moreover, whereas complex spike firing is only mildly affected by variations in stimulus strength, it strongly depends on the recent history of climbing fibre activity. Our data point towards a mechanism in the olivo-cerebellar system that regulates complex spike firing during mono- or multisensory stimulation around a relatively low set-point, highlighting an integrative coding scheme of complex spike firing under homeostatic control.

neuroscience↗

bioRxiv2018

Adaptation of Whisker Movements Requires Cerebellar Potentiation

Cerebellar plasticity underlies motor learning. However, how the cerebellum operates to enable learned changes in motor output is largely unknown. We developed a sensory-driven adaptation protocol for reflexive whisker protraction and recorded Purkinje cell activity from crus 1 and 2 of awake mice. Before training, simple spikes of individual Purkinje cells correlated during reflexive protraction with the whisker position without lead or lag. After training, simple spikes and whisker protractions were both enhanced with the spiking activity now leading the behavioral response. Neuronal and behavior changes did not occur in two cell-specific mouse models with impaired long-term potentiation at parallel fiber to Purkinje cell synapses. Consistent with cerebellar plasticity rules, increased simple spike activity was prominent in cells with low complex spike response probability. Thus, potentiation at parallel fiber to Purkinje cell synapses may contribute to reflex adaptation and enable expression of cerebellar learning through increases in simple spike activity.\n\nImpact statementRomano et al. show that expression of cerebellar whisker learning can be mediated by increases in simple spike activity, depending on LTP induction at parallel fiber to Purkinje cell synapses.

neuroscience↗