Biology subjects

Bai, J.

Publications and source records attributed to Bai, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Reversion to the Meta Body Form of Life after Complete Cell Death in Pure Liquid Water

The prevailing view holds that simpler animate beings predating the dawn of cellular life once existed, yet they have long since vanished from the present-day Earth. Our hypothesis posits that these animate beings persist to this day. To this end, we devised a long-term experiment spanning over a decade, keeping Staphylococcus aureus (S. aureus) within a sealed aqueous system of pure water. The findings illustrated that, upon the complete cell death (CCD) of the S. aureus, as cellular remnants progressively succumbed to dissolution, the aqueous solution underwent self-purification, bringing forth a class of lipid bilayer membrane microspheres containing RNA and proteins. These structures maintained long-term sustainable stability within the thermodynamic storm of water molecules and underwent dynamic size fluctuations over time - collectively exhibited phenomena indicative of being "alive". This study reveals that the cell, upon complete cell death, undergoes reversion to a living entity simpler than the cell itself - the Meta Body (MB). The discovery of MB opens an entire re-conceptualization of what death ultimately brings.

biophysics↗

bioRxiv2026

Cell-intrinsic regulation of presynaptic release site patterning

Functional neuronal connectivity depends not only on synaptic partner choice but also on the number, strength, and spatial distribution of release sites between partners. How these features are regulated remains poorly understood. Here, using the C. elegans DA9 motor neuron, we identify the immunoglobulin superfamily cell adhesion molecules SYG-1 and SYG-2 as cell-autonomous regulators of presynaptic release-site patterning. SYG-2 regulates presynapse number, size, and spacing, whereas SYG-1 primarily regulates spacing. Endogenous localization and cell-specific knockout analyses reveal that SYG-2 recruits SYG-1 to the presynaptic domain through previously unrecognized cis interactions. Endogenous structure-function studies further demonstrate that the SYG-2 intracellular domain is required for presynaptic organization and can promote presynapse formation independently of its extracellular domain. Genetic and targeted actin-disruption experiments implicate the adaptor protein NCK-1 and local actin remodeling in SYG-2 intracellular signaling. Together, these findings reveal how cell adhesion molecules can act cell-intrinsically to pattern presynaptic release sites after synaptic partners have been established.

neuroscience↗

bioRxiv2026

TRIM21 licenses pancreatic acinar fate by modulating BiP phase state through VCP-dependent retrotranslocation

The endoplasmic reticulum (ER) chaperone BiP/GRP78 sits at the center of the proteostasis network, coordinating unfolded protein response (UPR) signaling and supporting oncogenic programs of plasticity, metastasis, immune evasion, and chemoresistance. While BiP undergoes liquid-liquid phase separation in vitro, whether mammalian cells dynamically tune this physicochemical behavior to prevent functional exhaustion or pathological condensation under sustained ER stress has remained unclear. Here, we identify the E3 ubiquitin ligase TRIM21 as a phase-state regulator that suppresses BiP's liquid-to-solid phase separation, clearing, and preventing insoluble aggregates-thereby controlling BiP's localization and availability to sustain the adaptive UPR under ER stress. We found that during ER stress, BiP is prone to liquid-to-solid phase separation, a transition that renders the chaperone dysfunctional. TRIM21 is recruited to BiP, where it directly polyubiquitinates BiP at specific K547/553/554/556 sites with K6-, K27-, K33-, and K63-linked chains; VCP recognizes these marks and extracts BiP from the ER lumen via ER-associated degradation (ERAD), coupling ubiquitin tagging to retrotranslocation. This preserves chaperone availability and sustains adaptive UPR-a homeostatic mechanism broadly relevant to UPR-driven diseases. In vivo, genetic ablation of Trim21 in KrasG12D/+; Pdx1Cre/+ mice triggers aberrant BiP solidification while curtailing acinar-to-ductal transdifferentiation and tumorigenesis; notably, TRIM21 co-localizes with BiP condensates in pre-malignant human pancreatic lesions, underscoring the clinical relevance of this regulatory axis. Our findings define the TRIM21-BiP axis as a phase-control system at the interface of proteostasis and stress adaptation, offering a new framework with translational potential.

cell biology↗

bioRxiv2026

An Artificial Intelligence Model for Longitudinal Assessment of TCR Repertoires in SARS-CoV-2 Vaccine Recipients

T cells play a crucial role in reducing disease severity during SARS-CoV-2 infection and in shaping long-term immune memory. However, the precise molecular immune responses, particularly involving T-cell receptor (TCR) repertoire changes after full vaccination, and the use of TCR analysis to evaluate vaccine efficacy, remain incompletely understood. In this study, we developed the DeepAir-Cov19 model (AUC=0.94), a large language model tailored to identify SARS-CoV-2-specific TCRs, and observed significant differences in the TCR profiles between antibody-negative and antibody-positive populations before and after vaccination, indicating that the immune status of pre-vaccine recipients can directly assess the efficacy of vaccination. Notably, SARS-CoV-2-specific TCRs expanded to peak levels after the second dose and remained detectable in most subjects up to 10 months post-vaccination. Meanwhile, we also identified three specific V genes, 20 V-J combinations, and 3 epitopes associated with these responses. Finally, by leveraging vaccine-specific TCRs as novel biomarkers, we developed a vaccine efficacy model that predicts antibody levels with a mean AUC of 0.96. These findings underscore the accuracy of the large model in predicting SARS-CoV-2-specific TCRs and reveal a strong correlation between SARS-CoV-2-specific TCR responses and antibody levels. This highlights the complementary and synergistic roles of T cells and antibodies in providing vaccine-mediated protection. Our results offer valuable insights into the longitudinal dynamics of SARS-CoV-2-specific TCRs and illustrate the potential for developing potency evaluation models based on these TCR insights.

bioinformatics↗

bioRxiv2026

PANDA: Protein All-atom Nested-tree Denoising Architecture for End-to-End Generation

Deep generative models have expanded the scope of computational protein design, yet most approaches still separate backbone generation from sequence assignment or rely on latent and torsional representations that do not operate directly on all atoms in Cartesian space. We present PANDA, an end-to-end generative architecture that performs denoising in a unified all-atom representation, recovering sequence identity directly from atomic occupancy patterns. By coupling global and local coordinate tracks and introducing a sampling strategy that preserves side-chain geometry, PANDA achieves the highest self-consistency design success across protein lengths among evaluated all-atom methods. For functional design it conditions on pairwise distances between motif atoms rather than fixing their coordinates, allowing the functional atoms to be positioned jointly with the scaffold. On the Atomic Motif Enzyme benchmark, PANDA preserves motif geometry and delivers substantially higher scaffolding success than previous approaches, particularly for larger motifs. PANDA thus provides an efficient route to high-quality all-atom generative design with flexible atomic-level control.

biochemistry↗

bioRxiv2026

Uncovering key genes related to potato tuber starch concentration from the tuber bulking, maturation stage to storage

Potato is the worlds fourth major staple crop, and tuber starch is a critical dietary energy source and a food processing raw material. In this study, hybrid progenies of the high-starch cultivar Huasheng No.7 and China main commercial varieties were used as materials, high-throughput sequencing was performed on tuber samples at tuber bulking, maturation and storage stages. Combined with bioinformatics analysis, parent-progeny resequencing, SNP screening, the regulatory mechanism of tuber starch metabolism was explored. The results showed significant stage-specific transcriptional reprogramming in potato tubers: few differentially expressed genes (DEGs) were identified at tuber bulking and maturation stages, but massive transcriptional changes occurred during storage. XET family genes regulated cell wall remodeling and carbon translocation across all stages, and WRKY transcription factors specifically controlled starch homeostasis in stored tubers. The DEGs at different stage were induced by the SNPs from their parent, and the allele from the high-starch parent, Huasheng 7 may contribute the high-starch allele to the offsprings. One key gene, Soltu.DM.02G019910, which encoded {beta}-glucosidase, have a negatively relationship with tuber starch concentration. The low-starch potato breeding tubers shown higher significantly {beta}-glucosidase activity than high-starch breeding population at maturation stage. This study clarifies the molecular regulatory network of potato tuber starch metabolism and screens core regulatory genes from the tuber bulking stage to tuber storage, thereby providing theoretical support and genetic resources for molecular breeding of high-starch and storage-resistant potato varieties.

plant biology↗

bioRxiv2026

Diaphragmatic EMG Uncovers Left-Right Diaphragmatic Imbalance After Ischemic Stroke with Implications for Motor Recovery

BackgroundStroke-associated respiratory dysfunction has been increasingly recognized, yet whether diaphragmatic impairment after stroke involves lateralized neuromuscular imbalance remains unclear. MethodsIn this controlled experimental study, transient left middle cerebral artery occlusion and reperfusion (tMCAO) was performed in mice, followed by multimodal assessment of treadmill-based peak oxygen uptake testing, diaphragm ultrasonography, bilateral diaphragmatic electromyography (dEMG) with simultaneous respiratory flow monitoring, behavioral assessment, and whole-mount immunofluorescence imaging of the diaphragm. ResultsIschemic stroke reduced exercise capacity and diaphragmatic excursion without detectable diaphragm thinning, indicating functional impairment rather than overt atrophy. Bilateral dEMG revealed a subacute left-right asymmetry in inspiratory activation, with the ipsilesional hemidiaphragm exhibiting reduced amplitude, decreased area under the curve, and altered burst duration, consistent with a relative contralateral-dominant pattern rather than frank hyperactivation. Whole-mount imaging demonstrated asymmetric nerve remodeling, characterized by a nadir in ipsilesional nerve fiber density at 1 week and partial recovery by 2 weeks after stroke. These structural changes closely paralleled the dEMG alterations, suggesting a neural substrate for lateralized dysfunction. Exploratory analyses further linked dEMG parameters with motor recovery. ConclusionsThese findings provide novel evidence that ischemic stroke induces a left-right diaphragmatic neuromuscular imbalance, with structural and functional correlates in diaphragmatic innervation. The study further supports the utility of bilateral dEMG as a functional marker for assessing diaphragmatic dysfunction and monitoring recovery after stroke. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/737872v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@10001a4org.highwire.dtl.DTLVardef@16bc3d5org.highwire.dtl.DTLVardef@5e40aorg.highwire.dtl.DTLVardef@be53b7_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Allele-specific correction of dominant Best vitelliform macular dystrophy in patient-derived retinal pigment epithelium

Autosomal dominant Best vitelliform macular dystrophy (BVMD) caused by variants in the BEST1 gene is characterized by dysfunction of the macular retinal pigment epithelium (RPE) and secondary degeneration of the photoreceptors. There are currently no approved treatments for BVMD, and owing to its dominant nature, there remains uncertainty regarding the utility of traditional gene augmentation. Here we evaluated whether a dominant pathogenic BEST1 allele can be corrected by base editing in differentiated RPE cells. We identified a patient with a likely pathogenic BEST1 c.851A>G (p. Tyr284Cys) variant that was amenable to cytidine base editing. After establishing patient-derived induced pluripotent stem cells (iPSCs), we corrected the pathogenic variant in the iPSCs to obtain corrected iPSCs with the same genetic background. Corrected iPSC-derived RPE exhibited normalized monolayer appearance, improved barrier integrity, reduced cell death, and restored RPE-specific transcriptome. We then used a dual adeno-associated virus (AAV) split-intein system to deliver a CRISPR-associated protein 9 cytidine base editor (SpCas9-CBE) to BEST1 c.851A>G mutant RPE monolayers and achieved editing of the pathogenic allele with a maximum efficiency of 13.42 {+/-} 3.64% (mean {+/-} SD). Together, these results demonstrate progress towards allele-specific base editing in a dominantly inherited retinal disorder.

neuroscience↗

bioRxiv2026

HnRNPAB-targeted antisense oligonucleotides ameliorate tau pathology and cognitive deficits by modulating Alzheimers disease-associated alternative splicing

Aberrant alternative splicing alters multiple disease-associated splicing events, including MAPT exon 10 inclusion linked to tau pathology, and thereby impacts Alzheimers disease (AD) progression. Heterogeneous nuclear ribonucleoprotein AB (hnRNPAB) functions as a splicing regulator, yet its roles in AD remain poorly defined. Here, we identified AB332, the full-length isoform of hnRNPAB, as a novel repressor of MAPT exon 10 inclusion. AB332 binds a conserved AAUAU motif and recruits RBMX and RBMXL1 through its RRM and glycine-rich domains to assemble a complex. Beyond MAPT, AB332 modulates a network of splicing events in multiple AD-associated genes, including STAG2, ApoER2, MCL-1, PICALM, and zDHHC7. Importantly, the exon 7-skipping isoform AB285 lacks these activities. Transcriptomic analysis of post-mortem brain tissues from AD patients revealed reduced expression of hnRNPAB, while selective downregulation of AB332 was confirmed in the hippocampus of 3xTg AD mice. We performed a systematic antisense oligonucleotide-tiling screen targeting hnRNPAB exon 7 and its flanking intronic regions, identifying ASO30 that specifically upregulated AB332 expression. In 3xTg AD mice, ASO30 restored hippocampal AB332 levels, reduced pathological tau phosphorylation, and rescued cognitive deficits. These findings define a molecular mechanism by which AB332 regulates AD-associated splicing events, thereby providing a therapeutic strategy targeting hnRNPAB for AD. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/736008v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@621096org.highwire.dtl.DTLVardef@2f01b1org.highwire.dtl.DTLVardef@182e6forg.highwire.dtl.DTLVardef@190afd3_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2026

Entanglement-governed protein networks enable mechanically adaptive artificial skin for transplantation-scale skin replacement

Artificial skin substitutes that simultaneously achieve mechanical robustness, regenerative bioactivity, and transplantation-scale tissue integration remain challenging to engineer. Here we report a mechanically adaptive bilayer artificial skin based on entanglement-mediated protein networks. By integrating protein chain entanglement, flexible molecular linkers, and photo-triggered intermolecular crosslinking, we establish a hierarchically organized protein matrix with enhanced toughness, structural adaptability, and regenerative compatibility. Spatial biofunctionalization further enables integration of an antibacterial Zn{superscript 2}-coordinated epidermal layer and a regenerative CLP-EGF-functionalized dermal layer within a unified construct. The engineered skin promotes cellular proliferation through PI3K-AKT-mTOR activation, exhibits sustained antibacterial activity, and supports large-area full-thickness skin replacement covering approximately 40% of the dorsal skin surface in mice. The construct further accelerates diabetic wound repair and extracellular matrix remodeling in vivo. These findings establish entanglement-mediated protein engineering as a strategy for mechanically adaptive regenerative biomaterials and provide a platform for transplantation-scale skin regeneration.

bioengineering↗

bioRxiv2026

FERONIA-Dependent Translational Buffering of Ribosome-Associated Genes in Salt-Stressed Tomato Roots

Salt stress limits tomato productivity, yet how translational regulation contributes to root salt adaptation remains poorly understood. We integrated RNA-seq and ribosome profiling in wild-type (WT) and fer tomato roots under control and 150 mM NaCl conditions. In WT roots, the salt response was predominantly transcript-driven, but a 29-gene ribosome-associated module showed reduced RNA abundance alongside increased translational efficiency (TE), indicating selective translational buffering. FER deficiency disrupted this balance: it constitutively elevated ribosome occupancy of ribosome-associated genes while reducing basal expression of stress- and ion-transport-related genes. Under salt treatment, fer further showed stronger ion-transport transcriptional responses but weaker ribosome-associated TE responses, consistent with impaired translational selectivity. WT salt stress also shifted ribosome allocation away from the 5'UTR toward the CDS, an effect attenuated in fer; upstream open reading frame (uORF) and coding sequence (CDS) translational efficiency were also positively coupled during salt treatment. Feature modelling confirmed established features associated with uORF translation and further identified weaker local RNA folding around the uORF start codon, proline and charged amino acid enrichment, and TAG or TGA stop codon identity as positive predictors. Together, these results reveal FER-dependent changes in ribosome-associated translational buffering during tomato root salt responses.

Plant Biology↗

bioRxiv2026

Cell-type-resolved RNP topologies reveal dynamic structural mechanisms of splicing and therapeutic targets

Resolving RNA conformations in native ribonucleoprotein (RNP) complexes remains a fundamental challenge. Here, we introduce spatial hydroxyl acylation reversible crosslinking with immunoprecipitation (SHARCLIP) to simultaneously capture RNA-RNA, RNA-protein and protein-protein contacts in cells. SHARCLIP profiling of HNRNPC-associated RNA conformations established a global phased map of ribonucleosomes, resolving a decades-old debate on heterogenous nuclear (hn)RNP assembly. We built a dynamic structural atlas across seven cell lineages for >10,000 RNAs, generating ~200 million contacts, and identifying millions of dynamic loops, steric blockers and conformational switches that control splicing outcome. Deciphering the structural logic of mutually exclusive exons (MXEs) enabled rational design of structure-breaking and stabilizing antisense oligonucleotides (ASOs). We demonstrate effective isoform swapping in 12 genes linked to genetic disorders. SHARCLIP provides a comprehensive roadmap for cellular RNA structural biology and structure-guided RNA therapeutics.

molecular biology↗

bioRxiv2026

Deep learning models for chemical perturbation prediction do not yet utilise drug molecular features

Recent deep learning models for L1000 chemical perturbation prediction incorporate dedicated drug molecular encoders. We retrained seven such models from scratch with zeroed or shuffled drug inputs, and compared them with a multilayer perceptron that uses only cell-line basal expression. Under drug-blind evaluation, ablation caused negligible performance changes and the drug-free baseline matched all models. Current architectures do not yet utilise drug molecular features for generalisation to unseen compounds.

bioinformatics↗

bioRxiv2026

Patient CACNA1A variant uncouples calcium channel conductance from synaptic output

Channelopathies are a class of neurodevelopmental disorders with often devastating consequences, and effective therapies depend on understanding how patient variants alter channel function. These effects are typically assessed by biophysical characterization in heterologous expression systems. Mutations in CACNA1A, which encodes the P/Q-type calcium channel CaV2.1, underlie a spectrum of neurological disorders in which symptoms are generally classified as loss-of-function (LoF) or gain-of-function (GoF). However, some patients present with overlapping phenotypes that defy this binary framework. Here we describe a CACNA1A variant for which heterologous assays fail to capture a key in vivo functional effect. We characterize a de novo variant of a highly conserved residue, D1634N, identified in a patient with a mixed clinical presentation that includes both LoF- and GoF-associated symptoms. Biophysical characterization in HEK293T cells supports a classic and severe LoF effect, including reduced current density and a right-shifted current-voltage relationship. In contrast, in vivo analysis of the corresponding endogenous variant in the C. elegans homolog reveals a paradoxical increase in spontaneous synaptic vesicle release, despite reduced channel expression. Molecular dynamics simulations predict that the mutation prolongs dwell time in a partially open state, potentially increasing calcium influx at rest. This model is supported by biophysical recordings of the human channel showing increased current at hyperpolarized potentials and by rescue of the C. elegans phenotype through genetic elevation of resting membrane potential. Together, these findings reconcile the patients clinical presentation by describing a complex, mixed-function variant, highlight the importance of cellular context in variant interpretation and therapeutic development, and establish C. elegans as a powerful in vivo platform for evaluating the functional consequences of pathogenic ion channel variants.

neuroscience↗

bioRxiv2026

mGluR6 coordinates cone terminal targeting and synaptic layer assembly during human retinal development

The metabotropic glutamate receptor 6 (mGluR6), encoded by GRM6, is a core component of the ON-bipolar signaling cascade in the retina, but its role in human retinal development remains unclear. Here, we used temporally controlled CRISPR-based genetic ablation in human induced pluripotent stem cell-derived retinal organoids to define the developmental functions of mGluR6. Unexpectedly, we found that mGluR6 is expressed not only in depolarizing ON-bipolar cells but also transiently in cone photoreceptors during human retinal development, a pattern not observed in the mouse retina. Early loss of GRM6 prior to synaptogenesis disrupted cone pedicle architecture, leading to mislocalization of synaptic proteins including Bassoon, ELFN2, and TRPM1, and ultimately resulting in widening or duplication of the outer plexiform layer (OPL). In contrast, deletion after synapse formation did not alter OPL synapses or morphology, revealing a temporally restricted requirement for mGluR6 during circuit assembly. These findings uncover a previously unrecognized role for mGluR6 in coordinating cone terminal targeting and synaptic layer assembly during human retinal development and highlight the power of temporally controlled genetic manipulation in organoid systems to reveal species-specific mechanisms of neural circuit formation.

neuroscience↗

bioRxiv2026

Quantifying data reuse in proteomics using PRIDE downloads statistics and a semi-supervised LLM-based framework

Understanding how scientific datasets are accessed and reused is essential for resource planning and impact assessment. Here we present the PRIDE Archive download tracking infrastructure and a comprehensive analysis of 159.3 million download records from the PRIDE proteomics database (2021-2025), spanning 35,528 datasets accessed from 235 locations. The infrastructure includes nf-downloadstats, a scalable Nextflow pipeline for processing download logs, and DeepLogBot, a machine-learning framework that classifies traffic into bots, institutional download hubs, and independent user downloads. DeepLogBot combines heuristic seed selection with multi-LLM annotation (Claude and Qwen3) to produce gold-standard training labels, achieving 92.2% bot classification accuracy on a held-out test set. After separating bot traffic, analysis reveals downloads from 214 countries/regions, 249 institutional download hubs, and a concentrated reuse distribution, with the top five countries (United States, United Kingdom, Germany, China, and Canada) accounting for over 54% of independent user downloads. These findings provide actionable insights for repository infrastructure planning and highlight the importance of distinguishing automated from individual access in scientific data resources.

bioinformatics↗

bioRxiv2026

FoTO1 is an epoxide isomerase in paclitaxel biosynthesis

Paclitaxel biosynthesis is limited by the instability of taxadiene-4(5)-epoxide, which readily diverts to the non-productive byproduct 5(12)-oxa-3(11)-cyclotaxane (OCT) instead of rearranging to taxadiene-5-ol. Although FoTO1 suppresses OCT accumulation, its molecular function has been unclear. Here we identify FoTO1 as a dedicated epoxide isomerase that directs productive rearrangement. Biochemical characterization, site-directed mutagenesis, and QM/MM calculations reveal a pre-organized D68-D149 dyad that electrostatically activates epoxide ring opening and stereospecific rearrangement. Modular dissection of the C-terminal extension further reveals a functional partition between catalytic integrity and productive coupling with T5OH, mediated by specific hydrophobic contacts that enforce precise geometric complementarity at the binary complex interface. These results demonstrate how electrostatic activation and enzyme association cooperate to control the fate of a highly reactive intermediate in paclitaxel biosynthesis.

biochemistry↗

bioRxiv2026

The Risk of Gulf Birds Functional Diversity Loss with Climate Change Uncovered Using Deep Learning Population Models

Climate change and sea-level rise (SLR) pose increasing threats to coastal ecosystems and biodiversity in the Gulf of America. Most efforts to anticipate these threats focus on species counts or range shifts, while changes in species functional diversity remain uncovered. We estimated the impacts of climate change and sea-level rise on hundreds of bird species populations and corresponding shifts in functional diversity. We used the generative deep learning method, Variational Gaussian Mixture Autoencoder (GMVAE), and Trait Probability Density analysis to study such impacts. We found that a generative GMVAE model uncovered species unobserved ranges, and that climate change reduced coastal ecosystem resilience and caused biodiversity loss across multiple dimensions, including functional richness, redundancy, evenness, and divergence. Surprisingly, the most impacted areas are not the exposed shoreline but the landward coastal transition zones. Specifically, shoreline functional diversity turned out to increase with climate change and sea level rise, whereas uplands showed declining functional diversity and increasing redundancy, indicating contraction of functional trait space. Furthermore, avian biodiversity expanded in coastal protected areas, serving as refugia embedded in a surrounding landscape where unique combinations of species traits are lost.

bioinformatics↗