Biology subjects

Xie, J.

Publications and source records attributed to Xie, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Characterization of expression elements for an AAV delivered antibody in nonhuman primates when co-delivered with PD-L1

Successful AAV-expressed antibody therapy for HIV-1 requires broadly neutralizing antibody (bNAbs) concentrations and reduced immune responses to sustain viral suppression without ART. We have previously demonstrated that co-delivery of AAV-expressed PD-L1 reduces immune responses against HIV-1 bNAbs in rhesus macaques. Here we systematically evaluated six AAV9 transgene cassettes encoding 10-1074 with different promoter/intron combinations (CMV, CMV/R, CBA, CASI, CB7, EF1) across in vitro systems, immune-deficient mice, and in rhesus macaques. We show that both promoter and species selection, leads to differences in 10-1074 concentrations with the CB7 promoter leading to greatest expression in mice and CMV/R promoter in macaques. In addition to differences observed, loss of 10-1074 serum concentrations in macaques resulted in higher anti-drug antibody responses and antigen specific IFN-y T cell responses were focused on the 10-1074 heavy-chain variable region. Furthermore, inclusion of the WPRE greatly impacted 10-1074 expression leading to higher concentrations in both mice and nonhuman primates. Lastly, circulating 10-1074 in macaques retained neutralizing activity against diverse HIV-1 pseudovirus isolates. Together these results demonstrate how expression elements influence AAV-expressed antibodies in the context of co-delivery and highlight the need for further improvements to AAV transgene cassettes when co-delivered with AAV expressed PD-L1.

microbiology↗

bioRxiv2026

Intron 13 retention expands the ADAR1 isoform repertoire to rewire PKR signaling and promote tumorigenesis

For decades, the biology of ADAR1 has been framed around two major isoforms: the nuclear-enriched p110 and the predominantly cytoplasmic p150. Here, we reveal an unexpected repertoire expansion of ADAR1 isoforms that is driven by intron retention. Specifically, intron 13 (I13) can be retained in ADAR1 transcripts, conferred by an evolutionarily conserved weaker 5SS. In addition, we found that the I13 retention (I13R) is negatively autoregulated by ADAR1 through antagonizing the binding of hnRNPA1 to I13 in an editing-independent manner. Despite being sensitive to nonsense-mediated decay, I13R generates two previously uncharacterized truncated isoforms - p90 and p130, that both lack the C-terminal portion of the deaminase domain. Intriguingly, ADAR1p90 - a derivative of the canonical nuclear-enriched p110 isoform - is predominantly cytoplasmic, that effectively represses PKR and eIF2 activation through the sequestration of immunogenic double-stranded RNA (dsRNA) substrates. Furthermore, in a colorectal cancer (CRC) cohort, p90 levels are increased in most tumors relative to matched normal tissues that positively correlates with hnRNPA1 expression. Functionally, xenografts expressing ADAR1p90 grow significantly faster and larger than those expressing ADAR1p110, indicating enhanced tumorigenic potential. These findings revise the canonical view of ADAR1 isoforms, demonstrating that intron retention can generate alternative isoforms with augmented functions that tumors readily exploit. One Sentence SummaryThe conserved retention of I13 in ADAR1 transcripts gives rise to previously uncharacterized C-terminal truncated cytoplasmic ADAR1 isoforms, p90 and p130, which, although devoid of catalytic activity, sequester immunogenic dsRNA substrates, thereby preventing PKR binding and downstream activation of eIF2.

cell biology↗

bioRxiv2026

Striatal Cholinergic Interneurons Signal Aversion and Drive Avoidance

Seeking reward and avoiding punishment are essential for survival. However, how the brain learns aversive value and generates avoidance remains poorly understood. We investigate acetylcholine-releasing striatal cholinergic interneurons (ChIs), which exhibit prominent excitation to salient behavioral cues but have largely been postulated to play a permissive role in reinforcement learning. Using voltage imaging in mice performing aversive versus reward conditioning tasks, we reveal learning-mediated changes in both subthreshold membrane voltage and suprathreshold spiking of individual ChIs. Across tasks, ChIs exhibit stronger immediate excitation to conditioned cues predicting negative outcomes than positive outcomes. This valence-dependent response augmentation reflects a learning-induced network change specific to cues predicting negative outcomes. Furthermore, brief optogenetic silencing of this immediate excitation selectively impairs conditioned avoidance, but not conditioned approach. Together, these results reveal that ChIs actively signal evidence for aversion and play a critical role in driving avoidance, highlighting a cholinergic mechanism underlying aversive learning.

neuroscience↗

bioRxiv2026

Optimisation of OptoDrum protocol for measuring optomotor response in juvenile & adult zebrafish

Zebrafish (Danio rerio) are an important vertebrate model for vision and neuroscience research. In the larval stages, the aquatic species begins to elicit the optomotor response (OMR) to stabilize themselves in water -- a behaviour that may be exploited in the laboratory to measure visual acuity. However, up to now, the measurement of the OMR in juvenile and adult zebrafish has been limited due to their behavioural complexity. Here, we optimize a protocol to assay zebrafish aged between 4 and 9 weeks-post-fertilization, by displaying sinusoidal gratings parallel to the zebrafish eye to elicit a robust OMR. We assessed the visual spatial-frequency tuning function of an environmentally induced myopia model to confirm the sensitivity and robustness of the protocol. Additionally, we show the OMR is sensitive to the contrast and temporal resolution of the sinusoidal gratings. Furthermore, we found that the time between stimulus presentations impact the spatial-frequency tuning function likely as time is required for zebrafish to return to baseline swimming after eliciting the OMR. Finally, we found that the OMR after ten versus twenty seconds of stimulus onset appears comparable; indicating that robust OMR responses in zebrafish can be elicited through relatively short stimulus presentations. Through the experiments conducted, we present an optimized protocol specific to zebrafish. The protocol may be used to follow the progression or treatment efficacy of progressive neurological disorders including specific visual disorders and higher brain functions with visual endophenotypes. Ultimately, this protocol allows for high-throughput robust measures of visual and neural function in zebrafish.

neuroscience↗

bioRxiv2026

A natural soil-derived microbiota reshapes nitrogen form and plant mineral nutrition

Nitrogen form in soil has a major influence on plant growth and mineral nutrition, yet whether and how nitrogen form is controlled by microbiota in natural soils remains poorly understood. Here we show that, in a high-organic-matter soil from Danish nature, the native soil microbiota determines nitrogen form and thereby controls plant mineral nutrition. Eliminating the microbiota by sterilization disrupted nitrification, causing ammonium accumulation and loss of nitrate, which resulted in impaired growth and a pronounced reduction in shoot Mg and Ca associated with chlorosis. Reintroduction of a simplified soil-derived microbiota restored nitrification and re-established a balanced NO{square}{square}/NH{square}{square} regime, which rescued Mg and Ca accumulation, alleviated chlorosis, and promoted plant growth. Metagenomic analyses of bulk soil, rhizosphere, and root-associated communities revealed enrichment of nitrogen-cycling functions, including nitrification-related genes, supporting the capacity of the restored microbiota to modulate nitrogen form in soil and the rhizosphere. Moreover, this microbiota alleviated mineral deficiency symptoms in an organic agricultural soil. Together, our findings reveal a natural microbiota-dependent mechanism by which soil microbes determine nitrogen form and thereby regulate plant mineral nutrition, particularly Mg and Ca homeostasis.

plant biology↗

bioRxiv2026

Bridging LLM Reasoning and Chemical Knowledge via an Evolutionary Multi-Agent Framework for Molecular Synthesis

MotivationMolecular design faces the dual challenge of navigating a vast chemical space while ensuring experimental synthesizability. Traditional models are constrained by small datasets, restricting their scalability and broader chemical context. In contrast, Large Language Models (LLMs) encapsulate extensive synthesis protocols derived from vast scientific literature, yet they struggle to leverage this potential due to severe hallucinations and a superficial grasp of rigorous chemical logic. ResultsWe propose EvoSyn, an evolutionary multi-agent framework that synergizes LLM reasoning with domain experts for preference-aware molecular synthesis. EvoSyn orchestrates a dual-process evolutionary paradigm: a co-evolving process that collaboratively aligns linguistic capabilities with multi-objective constraints, and a self-evolving process formulated as a Markov Game. Through evolution and reinforcement learning, agents actively learn from mistakes, utilizing domain feedback to penalize invalid proposals and ground generation in feasible reaction pathways. Extensive evaluations on comprehensive benchmarks demonstrate that EvoSyn significantly outperforms state-of-the-art baselines. These results highlight that by integrating LLM-guided self-evolution with rigorous domain validation to mitigate hallucinations, EvoSyn effectively yields molecules that are both bioactive and synthetically actionable. Availability and implementationImplementation code is available as supplementary material. Contactyangyd25@mail.sysu.edu.cn Supplementary informationSupplementary data are available at Bioinformatics online.

bioinformatics↗

bioRxiv2026

NEURA: An agentic system for autonomous neuroimaging workflows

Neuroimaging research depends on heterogeneous software, multimodal data and multistage statistical workflows. Large language model (LLM)-based agents offer a route to automate these workflows, but their susceptibility to hallucination limits their credibility in scientific use. Here we introduce NEURA, a proof-carrying framework for hallucination-resistant neuroimaging automation. NEURA converts free-text research questions and neuroimaging datasets into executable analysis plans, validated outputs and structured reports. The system combines disease- and tool-aware planning with a deterministic verification layer inspired by formal proof: before any claim is retained for reporting, it must be checked against tool-derived evidence and domain axioms. On NeuroEval, an expert-curated benchmark of 110 neuroimaging tasks, NEURA achieved 89.5% planning accuracy, a 30.5% improvement over direct LLM queries. In a controlled hallucination-injection experiment, the verification layer detected all the injected error classes under the specified axiom bank and trust assumptions, with no false positives. In case studies of spinocerebellar ataxia type 3, NEURA reproduced cerebellar atrophy and abnormal diffusion patterns consistent with established pathology and independent expert analyses. Together, these findings show that coupling domain-grounded agency with proof-carrying verification can turn LLM-driven workflow automation from probabilistic self-checking into auditable scientific computation.

neuroscience↗

bioRxiv2026

CellChem: Cellular transcriptional responses reshape molecular representation space for efficient and multi-scale drug discovery

Despite decades of progress in computational drug discovery, deep learning-based molecular representation models remain largely structure-centric, assuming that chemical similarity approximates functional similarity. However, drug effects in cells are shaped not only by chemical similarity but also by molecular interactions in the cellular context. To capture this complexity, we introduce CellChem, a cellular-chemical representation-learning framework that learns cell-guided molecular representations of small-molecule actions within cells. By incorporating large-scale cellular transcriptional profiles during pretraining, CellChem reshapes molecular representation space from structure-centric to a balanced integration of structure and function. The learned CellChem molecular representations exhibit biologically meaningful geometric organization, such that distances between molecules encode not only structural similarity but also similarity in the cellular responses they elicit, independent of downstream tasks. Using downstream derivative models such as cell-guided compound-protein interaction prediction and drug-induced transcriptional response profile generation, CellChem supports highly efficient, multi-scale drug discovery, achieving significantly better performance than traditional models.

molecular biology↗

bioRxiv2026

Durable protection against SIV challenge by adeno-associated virus delivery of Env-specific antibodies

Conventional vaccines have so far failed to elicit the types of antibodies needed for protection against HIV. As an alternative, we evaluated adeno-associated virus (AAV) delivery of rhesus macaque antibodies to the SIV envelope glycoprotein for protection against SIV challenge. AAV vectors encoding a broadly neutralizing antibody (bnAb) and an antibody that only mediates antibody-dependent cellular cytotoxicity (ADCC) were administered individually or together to separate groups of rhesus macaques. Antibody expression was sustained for more than a year with minimal anti-drug antibody responses. All animals that received a control antibody or the ADCC-only antibody became infected after five low-dose, intrarectal challenges with SIVmac239. In contrast, 14 of 16 animals that received the bnAb resisted two rounds of twelve SIVmac239 challenges more than a year apart. Thus, AAV delivery of a single bnAb can afford durable protection against a pathogenic SIV strain that is notoriously difficult to protect against by vaccination.

immunology↗

bioRxiv2026

A transcriptomics-native foundation model for universal cell representation and virtual cell synthesis

Current single-cell foundation models rely on language-model architectures that ignore transcriptomic data distributions, often underperforming specialized methods. We introduce xVERSE, a transcriptomics-native foundation model coupling batch-invariant representation learning with the probabilistic generation of expression profiles. xVERSE outperforms the leading foundation and batch-effect correction methods in representation learning by 17.9% and 11.4%, respectively, successfully preserving biological heterogeneity while diminishing batch effects. Furthermore, xVERSE surpasses the second-best spatial imputation method by 34.3% and uniquely synthesizes virtual cells indistinguishable from biological data (AUROC{approx} 0.5). As a powerful data-augmentation engine, xVERSE utilizes these high-fidelity virtual cells to enable accurate clustering and marker detection in tiny datasets--resolving rare cell types with as few as four cells--while improving the generalizability of cross-modality predictions across diverse pathological states. These results establish xVERSE as a transformative framework unlocking analytical capabilities beyond conventional models.

cell biology↗

bioRxiv2026

STING suppresses migration of murine triple-negative breast cancer cells E0771 and 4T1 in vitro

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks effective therapies. The stimulator of interferon genes (STING) has been shown to both suppress and promote migration in various cancer types, but its role in TNBC remains unclear. To investigate this, we established STING-overexpressing murine TNBC cell lines and assessed their migratory and proliferative behavior. STING overexpression significantly suppressed cell migration without affecting cell proliferation. Furthermore, STING overexpression in E0771 cells upregulated expression levels of Itgb1 and Itga6 significantly, but not Icam1, Cxcl3, Itgb2, Lama5, or Rhoa. These findings highlight the potential anti-migratory role of STING beyond immunomodulatory functions.

cancer biology↗

bioRxiv2026

Systemic Cysteine Elevation Sustains T-Cell Activation to Potentiate PD-1 Blockade

Resistance to immune checkpoint inhibition remains a major barrier in pancreatic cancer treatment. Here, we show that concurrent administration of probiotics restores sensitivity to anti-PD-1 therapy in pancreatic cancer mouse models. Mice treated with the combination of anti-PD-1 and probiotics demonstrate robust tumor control, accompanied by enrichment of microbial pathways governing cysteine biosynthesis, elevated serum cysteine levels, and increased T cell function. Serum cysteine levels, rather than intratumoral cysteine concentrations, inversely correlate with tumor burden. Functionally, cysteine directly promotes T cell survival, activation, and cytotoxicity while its restriction induces uncoupled transcriptional-translational stress and impairs T cell function. Oral cysteine supplementation synergizes with anti-PD-1 therapy in pancreatic cancer mice, reducing tumor burden and enhancing intratumoral T cell activation, phenocopying probiotics-mediated immune restoration. These findings suggest systemic cysteine availability as a tractable metabolic target to enhance cancer immunotherapy.

cancer biology↗

bioRxiv2026

Synergistic Inhibition of Notch Signaling and Forced Cell Cycle Re-entry Drive Müller Glia Reprogramming in Uninjured Mouse Retina

In regenerative species, such as teleost fish, Muller glia (MG) autonomously re-enter the cell cycle after injury and give rise to functional retinal neurons. In contrast, the loss of retinal neurons in mammals is irreversible due to the limited proliferative and regenerative ability of MG. Various strategies have been developed to induce proliferation of mature mouse MG with or without injury, yet most MG daughter cells retain glial cell fate. Here, we found that MG progenies maintain high Notch signaling, which may constrain their neurogenic potential. Conditional deletion of Rbpj, the central transcriptional effector of Notch, induced limited MG-to-neuron conversion in mature MG without proliferation. However, Rbpj deletion, combined with forced MG proliferation by overexpressing cyclin D1 and suppressing p27Kip1, significantly promoted MG dedifferentiation and ectopic expression of the neuronal marker Otx2 in MG daughter cells in uninjured mouse retina. Combining Notch inhibition with MG cell cycle re-activation not only increased the numbers of bipolar- and amacrine-like cells generated from MG but also promoted the further differentiation toward ON-cone, OFF-cone, and rod-bipolar subtypes. Single-nucleus RNA and ATAC sequencing data revealed that Notch inhibition facilitated the formation of MG-derived progenitor-like cells while MG proliferation increased chromatin accessibility of neurogenic genes. Notably, most MG-derived cells survived long term despite incomplete maturation. Together, our findings delineate how Notch inhibition and MG proliferation, alone or in combination, influence the regenerative potential of MG in the mammalian retina.

cell biology↗

bioRxiv2026

Potential risk for hearing from prolonged exposure to sound at conversation levels

Prolonged exposure to loud and moderate noise impairs hearing; the lower the noise level, the lower risk of hearing loss is. To date, little is known about how low the noise level can be safe to hearing. This study investigated the risk of exposure to tone at typical conversational levels by measuring auditory brainstem response (ABR). We show that exposing C57 mice to continuous pure tone at 65 dB SPL for 1 hour (TE65) leads to an increase in ABR threshold that is specific to the exposure frequency. Tone exposure also increased the latencies and decreased the amplitude in Waves I and II but not in Waves III and V. Significantly, the changes in amplitude and latency were highly correlated in Wave I and such correlation gradually degraded from Wave I through to Wave V. Our findings suggest that exposure to low level sound can impair hearing and alter the auditory information process in the brain if it is persistent and presented over a sufficient period of time. Significant StatementOur findings established the risk of hearing impairment following the exposure to continuous tone at normal or conversational voice levels. This finding challenges current public health guidelines for hearing protection. Although further clarification is required, our studies prompt that the regular use of ABR testing is a potential protocol for diagnosing hearing impairment in patients experiencing hidden hearing loss (HHL).

neuroscience↗

bioRxiv2026

Metformin Stabilizes the Abdominal Aorta in Aneurysm by Restoring VSMC Mitochondrial Homeostasis via the AMPK-SIRT1-PGC-1α Axis

BACKGROUNDAbdominal aortic aneurysm (AAA) is a life-threatening condition with >80% mortality upon rupture and no effective pharmacotherapy available. Despite epidemiological evidence linking metformin use to reduced AAA progression, its mechanism remains elusive. Notably, peroxisome proliferator-activated receptor {gamma} coactivator 1 (PGC-1, encoded by Ppargc1a) is downregulated in human AAA, yet its functional role in metformins protection is unknown. METHODSWe employed porcine pancreatic elastase (PPE)-induced murine AAA, VSMC-specific Ppargc1a knockout (Ppargc1aVSMC-KO), primary VSMC senescence models, and pharmacological inhibition (Compound C for AMPK; Ex-527 for SIRT1) to define the AMPK-SIRT1-PGC-1 axis. RESULTSMetformin significantly inhibited AAA expansion, suppressed VSMC senescence (p53/p21{downarrow}, SA-{beta}-gal{downarrow}), and preserved contractile phenotype (SMTN{uparrow}, IL-6/TNF-{downarrow}). Crucially, all benefits were abrogated in Ppargc1aVSMC-KO mice, which exhibited accelerated aneurysm growth, mitochondrial fragmentation, ATP depletion, and ROS accumulation. Mechanistically, metformin activated AMPK/SIRT1 to upregulate PGC-1; AMPK or SIRT1 inhibition blocked this cascade and reversed protection. CONCLUSIONMetformin restrains AAA by restoring VSMC mitochondrial homeostasis via the AMPK/SIRT1[->]PGC-1 axis, positioning PGC-1 as a non-redundant, cell-autonomous guardian against vascular degeneration. These findings provide a mechanistic foundation for repurposing metformin and developing PGC-1-targeted therapies in AAA.

cell biology↗

bioRxiv2026

Metabolic exchange and siderophore sharing underlie emergent biofilm synergism

Biofilm communities exhibit emergent properties that exceed the sum of contributions from individual members of the community. Here, we describe a multilayered metabolic interaction that drives enhanced biofilm formation among three bacterial species from the plant rhizosphere. Comparative metatranscriptomic and metabolomic analyses reveal that Bacillus velezensis-secreted 5-aminovaleric acid promotes the growth of the other community members, Burkholderia contaminans and Acinetobacter baumannii. In return, B. contaminans supplies branched-chain amino acids for B. velezensis. Branched-chain amino acids and cell-cell signaling acyl-homoserine lactones from B. contaminans induce biosynthesis of the siderophore bacillibactin in B. velezensis, that is further enhanced by A. baumannii. In exchange, the B. velezensis-secreted siderophore promotes the growth of B. contaminans in iron-limited conditions, which benefits the multispecies biofilm community in vitro and promotes plant growth performance in iron-depleted soil. Our study reveals the molecular mechanisms underlying an emergent rhizosphere biofilm community function and demonstrates its importance in plant-microbe interactions.

microbiology↗

bioRxiv2026

rRNA Expansion Segments Mediate Ribosome Dimerization as a Conserved Stress Response

Inhibition of mRNA translation is a common feature in proteostatic stress cellular responses. Puromycin, a widely used compound for studying translation, disrupts protein synthesis by mimicking the 3 end of aminoacyl-tRNAs. Despite its extensive use as a research tool to probe the connection between translation activity and various physiological and pathological states, the cellular response associated with puromycin-induced translation stress remains incompletely understood. Utilizing in situ cellular electron tomography and topology analysis, we visualized the translation machinery at high resolution. Our analysis revealed that puromycin-treated neuronal cells exhibit an accumulation of "idle ribosomes" characterized by the binding of eIF5A, indicating a close association of this factor with translationally inactive ribosome states under stress. Additionally, the idle ribosomes formed dimeric complexes mediated by ribosomal RNA expansion segments, suggesting an evolved mechanism involving these regions in translation hibernating and protecting idle ribosomes. We show that the hibernating disome formation is not unique to puromycin administration but represents a conserved mechanism as a response to different cellular stressors including those associated with endoplasmic reticulum (ER) stress and amino acid depletion. Altogether, our findings shed light on previously unexplored aspects regarding unique states of mammalian ribosome hibernation, and collectively offers new avenues for understanding the correlation of cellular stress response and the regulation of protein synthesis.

molecular biology↗

bioRxiv2026

Multi-agent reasoning enables predictive design of living materials

Artificial intelligence is increasingly used to accelerate scientific discovery, but most successful frameworks operate within well-defined molecular, protein or materials spaces. Living materials present a more formidable computational problem because functions emerge from context dependent coupling among cells, matrices, fabrication processes and evaluation conditions. Here we introduce LiveMat, a multi-agent reasoning framework that transforms unstructured literature into a computable design space for living materials. LiveMat standardizes 34,215 living material records, integrating 16,769 microorganism and 17,446 polymer entries into a knowledge graph linking living components, abiotic matrices, functional outputs, evaluation contexts and performance metrics. Benchmarking across five large language models shows that living material reasoning is limited mainly by cross-domain feature integration rather than coarse classification. LiveMat overcomes this limitation through constraint decomposition, provenance-aware extraction, consistency checking and expert-anchored ranking. In a prospective wound-healing task, it prioritizes a four-component design with state-of-the-art in vivo performance, establishing a scalable infrastructure for interpretable, evidence-grounded living material discovery.

biochemistry↗