Biology subjects

Zhu, S.

Publications and source records attributed to Zhu, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Autophagy acts as a spatial organizer of cell-type-specific plant immunity

Effective plant immunity requires precise spatial coordination of immune responses across cell-types to restrict pathogens while preventing tissue damage, yet the intracellular pathways that organize this spatial architecture remain unknown. Here we show that autophagy serves as a spatial coordinator of immunity, partitioning and calibrating immune strategies across tissues during Pseudomonas syringae infection in Arabidopsis thaliana. Combining single-cell transcriptomics, cell-type-specific complementation, and live-cell imaging, we uncover distinct and opposing roles of autophagy across tissues. In guard cells, autophagy promotes pathogen-induced stomatal reopening by suppressing abscisic acid (ABA) signalling in part via autophagic turnover of the guard cell ABA receptor PYL4. In contrast, in mesophyll cells, autophagy restricts immune activation while simultaneously enabling effective immune execution: its loss enhances EDS1-PAD4-ADR1 pathway expression yet compromises PTI outputs. Mechanistically, bacterial infection triggers autophagic EDS1 turnover, supporting a model in which controlled EDS1 recycling facilitates HR elicitation. Cell-type-specific complementation reveals that PTI competence may involve coordinated autophagy across tissues, whereas mesophyll-autonomous autophagy is partially sufficient for HR execution. Together, these findings establish a framework in which spatial control of proteostasis orchestrates multicellular immune coordination, with broad implications for understanding how conserved degradation pathways regulate layered immunity across organisms.

plant biology↗

bioRxiv2026

Distribution, assembly and mechanism of GluN1/GluN3A excitatory glycine receptors

NMDA receptors play key roles in brain development, plasticity and diseases. While glutamate and glycine co-gated GluN2-containing NMDARs have been extensively characterized, little is known regarding GluN3A-containing NMDARs that form receptors gated by glycine only. Here, combining native purification, mass spectrometry, cryo-EM and electrophysiology, we provide key insights on the molecular logic of GluN3A-NMDARs. We demonstrate that native GluN3A receptors account for a sizeable fraction of total NMDARs, are enriched at extrasynaptic compartments in the adult brain, and assemble specifically as diheteromeric GluN1/GluN3A excitatory glycine receptors (eGlyRs) rather than as triheteromeric GluN1/GluN2/GluN3A receptors. The architecture of eGlyRs reveal splayed and loosely packed extracellular domains, strikingly different from conventional GluN1/GluN2 receptors. Through back-and- forth structural and functional validations, we demonstrate how the combined effects of a weak ligand-binding domain (LBD) dimer interface and high intrinsic mobility of the N-terminal domains (NTDs) shape the atypical gating of eGlyRs. These findings illuminate GluN3A-NMDAR physiology and mechanism, with implications for neuronal signaling and pharmacology.

neuroscience↗

bioRxiv2026

Shared brain basis for altered self-referential processing across psychiatric disorders? A systematic review and meta-analysis of neuroimaging studies

Self-referential processing is a fundamental cognitive function, and abnormalities in its neural implementation have been reported across a range of psychiatric disorders, leading to the proposal that such alterations may constitute a transdiagnostic neurobiological feature. Yet claiming transdiagnostic requires rigorous evidence. Here, we examined the evidence for such a hypothesis by conducting a systematic review and coordinate-based meta-analysis of psychiatric neuroimaging studies that employed self-referential tasks. The systematic review identified 36 neuroimaging studies across 9 broad categories of psychiatric disorders, suggesting that the neural aberrancy of self-referential processing is indeed of great interest across different diagnosis. Of these, 27 studies were eligible for the ALE meta-analysis. The ALE results revealed hypoactivation of the right precuneus in psychiatric groups relative to health controls, alongside hyperactivation of the right triangular part of the inferior frontal gyrus (IFGtri) during self-referential processing in psychiatric groups. Notably the precuneus and IFGtri are core nodes of the default mode network and the frontal-parietal control network, respectively, suggesting that aberrant self-referential processing across psychiatric disorders may be characterized by disrupted default mode network engagement accompanied by compensatory or maladaptive recruitment of control-related frontal regions. Together, our findings revealed a strong research interest in neural aberrancy of self-referential processing as a transdiagnostic feature. However, available evidence only provided preliminary evidence for such statement. To move forward, the field needs coordinated efforts to systematically accumulate data and collecting new datasets.

neuroscience↗

bioRxiv2026

Med12 and Med13 prevent tumorigenic dedifferentiation of intermediate neural progenitors and premature loss of neural stem cells

Med12 and Med13 are components of the kinase module of the mediator complex. Mutations of Med12 and Med13 have been associated with neurodevelopmental disorders and various cancers. However, their functions in neural development are not well understood. Here we show that in the developing Drosophila brain, Med12 and Med13 are required to prevent tumorigenic dedifferentiation of intermediate neural progenitors (INPs) and maintain neural stem cell (NSC) self-renewal. We further demonstrate that Med12 and Med13 prevent INP dedifferentiation by coordinating with a subset of core mediator complex subunits to mediate the activation of genes required for INP fate commitment. In contrast, during the maintenance of NSC self-renewal, Med12 and Med13 antagonize the function of a different subset of core mediator complex subunits. Together, our findings reveal that Med12 and Med13 perform two distinct functions in neural progenitors by coordinating with one subset of core mediator complex subunits while antagonizing another. HighlightsO_LILoss of Med12 and Med13 causes dedifferentiation of intermediate neural progenitors C_LIO_LIMed12 and Med13 mediate the activation of target genes of PntP1 C_LIO_LILoss of Med12 and Med13 leads to premature loss of neural stem cells C_LIO_LIMed12 and Med13 act with one subset of core mediator subunits but oppose another C_LI eTOC blurbZhu and his colleagues show that Med12 and Med13 promote cell fate commitment of intermediate neural progenitor cells and self-renewal of neural stem cells. Med12 and Med13 perform these two distinct functions by coordinating with one subset of core mediator complex subunits while opposing another to regulate the expression of different target genes.

developmental biology↗

bioRxiv2026

Early proteomic signatures of Alzheimer`s disease in the retina and brain of 3xTg-AD mice

Visual dysfunction and retinal structural alterations often precede brain pathology and cognitive decline in Alzheimers disease (AD), yet the molecular basis of these early changes and their relationship to the brain pathology remain unclear. Here, we performed quantitative proteomic profiling of retina and brain from 1-month of age triple-transgenic (3xTg-AD) mice harboring human PS1M146V, APPSwe, and tauP301L mutations, preceding detectable morphological abnormalities. Proteomic analysis identified 92 significantly altered proteins in the retina and 130 in the brain, with eight overlapping proteins between tissues. These shared proteins included three hemoglobin subunits (HBB1, HBB2, A8DUK4) and five proteins involved in metabolic regulation and intracellular transport. In addition to individual protein changes, pathway analysis demonstrated that mitochondrial metabolism and intracellular transport were commonly dysregulated in both tissues. Brain proteome was characterized by broad changes in mitochondrial-associated proteins, including respiratory chain components and mitochondrial ribosomal subunits, as well as proteins related to autophagy and synaptic vesicle pathways. In contrast, the retinal proteome was characterized by downregulation of vision-related proteins, altered small molecule transporters, and a marked reduction of the mitochondrial enzyme succinate-CoA ligase subunit {beta} (SUCB2). As SUCB2 links mitochondrial metabolism to epigenetic regulation through succinylation and lactylation, its depletion may promote mitochondria-to-nucleus signaling and early transcriptional reprogramming in the AD retina. Together, these findings demonstrate early metabolic and transport dysregulation in both retina and brain and highlight selective alterations of visual proteins in the retina. These early retinal proteomic changes provide valuable insight into understanding early metabolic disturbances in the eye and brain for AD detection.

biochemistry↗

bioRxiv2026

p300/CBP-Driven Acetylation Stabilizes PARP7 to Reinforce Negative Feedback on IFN-I Signaling

Immune suppression within the tumor microenvironment (TME) remains a major barrier to effective immunotherapy, yet the molecular mechanisms that constrain type I interferon (IFN-I) signaling in tumor cells are incompletely understood. PARP7 (also known as TIPARP), a mono-ADP-ribosyltransferase, has been reported to suppress IFN-I signaling by modifying TBK1. Here, we identify PARP7 as a previously unrecognized acetylation substrate of the histone acetyltransferases p300 and CBP. We show that p300/CBP-mediated acetylation of PARP7 at lysine 32 markedly enhances its stability, thereby reinforcing repression of the TBK1-IRF3-STAT1 axis and suppressing IFN-{beta}-induced expression of interferon-stimulated genes, including CXCL10. Beyond their established function as transcriptional co-activators that support tumor cell proliferation, our findings uncover a direct role for p300/CBP in shaping innate antitumor immunity. Pharmacological inhibition of p300/CBP catalytic activity by A-485 abolishes PARP7 acetylation, accelerates its proteasomal turnover, and restores IFN-I signaling. In immunocompetent tumor models, this is accompanied by enhanced CD8+ T-cell infiltration and effector function. Together, these findings define a p300/CBP-PARP7 regulatory axis, uncover a non-canonical role for p300/CBP in innate immune suppression, and nominate this pathway as a tractable target for restoring antitumor immunity.

cancer biology↗

bioRxiv2026

Programming T cells for Early Cancer Detection with Customized Protease-Activatable Receptors

Early cancer detection has the potential to reduce cancer mortality, yet endogenous tumor-shed biomarkers lack sensitivity for early-stage disease. We report OncoSCOUT, a cancer detection strategy using T cells engineered with protease-activatable receptors (PARs) that conditionally recognize tumor cells and release a synthetic biomarker for detection in urine. These PARs comprise masked synthetic Notch receptors in which antigen binding is blocked by a peptide mimotope tethered via a protease-cleavable linker. We demonstrate that requiring both extracellular protease activity and tumor antigen recognition improves spatial specificity and minimizes off-tumor activation of PAR T cells in vivo. To identify tumor-selective PARs, we adoptively transferred a HER2-targeted PAR library displaying [~]160,000 unique 4-mer amino acid linkers and discovered multiple variants significantly enriched in a HER2-positive cancer xenograft model. Using a single customized PAR, we show that OncoSCOUT can detect total tumor burdens as small as 10-30 mm3 with significantly improved sensitivity than the protein biomarker CA 15-3 or a 20-plex circulating tumor DNA (ctDNA) assay.

bioengineering↗

bioRxiv2026

Poly(A)-tail-length-dependent surveillance of viral RNA by PABPC1 orchestrates broad-spectrum antiviral defense

RNA processing and modification are critical for virus replication and pathogenesis, yet how the host exploits viral RNA features--particularly the poly(A) tail--for antiviral defense remains unclear. Through multi-omics integration and systematic functional screening, we identify the poly(A)-binding protein PABPC1 as a broad-spectrum restriction factor against multiple coronaviruses. We demonstrate that PABPC1 preferentially binds viral RNAs bearing short poly(A) tails--distinct from the longer and more heterogeneous host poly(A) tails--and, in a poly(A)-length-dependent manner, recruits the mitochondrial exonuclease EXD2 to assemble a degradative RNA-protein complex. Both the recognition and subsequent degradation of viral RNA strictly depend on poly(A) tail length, enabling selective decay of short-tailed viral transcripts while sparing host mRNAs. Importantly, inflammatory signaling enhances the expression of PABPC1 and EXD2, suggesting its role as an inducible host defense pathway activated during viral infection. Capitalizing on this discovery, we engineered a synthetic fusion protein mimicking the PABPC1-EXD2 complex and achieved efficient delivery using lipid nanoparticles (LNPs). This rationally designed therapeutic exhibits robust suppression of coronavirus replication in both cellular and murine models. Collectively, our findings uncover a novel host antiviral strategy that targets a conserved viral RNA structural element and provide a conceptual framework for developing host-derived and broad-spectrum anti-coronavirus therapeutics.

microbiology↗

bioRxiv2026

EOLA1, a novel mitochondria-localized protein critical for heart functions via regulating mitochondrial translation

Mitochondria possess their own mRNA translation system, mediated by specialized mitoribosomes. Dysregulation of mitochondrial translation disrupts metabolic homeostasis and is linked to various pathologies, including metabolic syndromes, neurological disorders, and cardiac diseases. Using CRISPR/Cas9 screening, we identified EOLA1 (endothelial-overexpressed lipopolysaccharide-associated factor 1) as a novel mitochondrial matrix protein essential for metabolic homeostasis. Knockout of Eola1 severely affects mitochondrial translation and consequently the oxidative phosphorylation in mammalian cells. Mechanistically, EOLA1 physically interacts with mitochondrial 12S ribosomal RNA (12S mt-rRNA) and the mitochondrial Tu translation elongation factor (TUFM), facilitating efficient translation elongation of mitochondrial-encoded mRNAs. Furthermore, genetic ablation of Eola1 in mice induced severe cardiac dysfunction, demonstrating its indispensable role in maintaining heart function through mitochondrial translation control. Together, our findings establish EOLA1 as a key regulator of mitochondrial translation via its interactions with 12S mt-rRNA and TUFM, highlighting its importance in cellular metabolism and a potential role in cardiac disease pathogenesis.

molecular biology↗

bioRxiv2026

BiomeGPT: A foundation model for the human gut microbiome

The human gut microbiome encodes rich information about host health, yet current analysis pipelines remain narrowly optimized for individual tasks. This limits our ability to gain a thorough view of how the microbiome impacts health and disease. Here we introduce BiomeGPT, a transformer-based foundation model pretrained on over 13,300 human gut metagenomes spanning 32 phenotypes--including healthy and 31 diverse diseases--to learn context-aware, species-level gut microbiome representations. The model captures quantitative compositional structure and intricate cross-species dependencies embedded within community profiles. When fine-tuned for predicting host health status, BiomeGPT accurately distinguishes healthy from diseased microbiomes and resolves individual disease states across a broad clinical spectrum. Furthermore, its attention patterns reveal biologically plausible microbial signatures, highlighting both shared and disease-specific microbial species linked to host phenotypes. By providing a unified, scalable framework for species-level gut microbiome representation learning and prediction, BiomeGPT enables new avenues for biomarker discovery, disease stratification, and microbiome-driven precision medicine.

bioinformatics↗

bioRxiv2026

A System for Live Sorting of Neuronal Spiking Activity from Large-scale Recordings

Online monitoring of neuronal activity has tremendous value for closed-loop control in both experimental and clinical settings, yet established methods rely primarily on thresholded neural activity, rather than sorted single-neuron spikes. The recent introduction of large-scale electrophysiological tools has greatly expanded single-neuron recording capacity in animals and humans highlighting the need to sort spikes during data collection. Here, we describe a system for live spike sorting (LSS) populations of hundreds of neurons with millisecond-scale latency. Using neurophysiological recordings from macaque visual cortex with Neuropixels probes, we show that LSS closely replicates the temporal responses and tuning of single neurons obtained using offline sorting. We further show that decoding neural signals with LSS achieves the same performance as that obtained from offline sorting. Lastly, we demonstrate the capacity of LSS to enable closed-loop interventions based on the activity of specific neuronal subclasses.

neuroscience↗

bioRxiv2025

Ensemble Coding of Hidden Objects in Visual Cortex

Many species exhibit the understanding that visual objects that become hidden by others nonetheless still exist, a property known as object permanence. Previous studies in human and nonhuman primates have provided evidence that neurons within visual cortex encode objects that are remembered but not seen. However, past neurophysiological studies have generally failed to find evidence of visual cortical representations of hidden objects. We measured the activity of large populations of neurons within dorsal extrastriate cortex of macaques trained to monitor the identity of visual objects that moved behind an irrelevant occluder. We found that although the firing rates of neuronal populations signaled the trajectory of hidden objects throughout the occlusion period, coding of object identity in the same activity decayed to chance before the behavioral trial ended. Nevertheless, information about the hidden object was present in the coordinated activity of neuronal populations. Specifically, the strength and presence of pairwise cross-correlations reliably depended on the identity of the hidden object. These results demonstrate that ensembles of visual cortical neurons preserve information about hidden objects independent of single neuron firing rates.

neuroscience↗

bioRxiv2025

Systematic profiling of growth interactions in human gut microbiome species

Microbial interactions shape the composition and stability of the human gut microbiome. Yet, the molecular mechanisms underlying these relationships remain poorly understood. Here, we systematically profiled 1,224 pairwise growth interactions among 36 representative gut bacterial strains using a spent medium assay. Most interactions were inhibitory and largely explained by resource depletion or medium acidification. We investigated further the molecular basis of a positive interaction, showing that Clostridium perfringens promotes the growth of Mediterraneibacter gnavus through extracellular vesicles. Additionally, we identified Veillonella parvula as a key species capable of modulating environmental pH, thereby enabling the growth of Parabacteroides merdae, a strain highly sensitive to acidic conditions. This pH-buffering effect was enhanced by guanine supplementation and persisted in multi-species communities containing different pH-lowering strains from diverse bacterial phyla. This demonstrates the ecological relevance of V. parvula, a species that, despite being commonly present in human gut microbiomes, is generally found at low levels. Overall, the comprehensive dataset and mechanistic insights presented here provide a foundation for rational strategies to manipulate microbiome composition and function.

microbiology↗

bioRxiv2025

Subtype-Specific Dependencies and Drug Vulnerabilities Enable Precision Therapeutics in Head and Neck Cancer

Molecular heterogeneity in head and neck squamous cell carcinoma (HNSCC) is well recognized, yet existing subtype frameworks remain largely descriptive and have not translated into therapeutic decision-making. Here, we establish a mechanistic platform that converts transcriptomic diversity into drug-actionable tumor states. Integrating multi-cohort RNA-seq from 727 tumors across five independent datasets, genome-scale CRISPR dependency maps, and pharmacologic screening, we define distinct tumor survival circuits across HPV-negative HNSCC and nominate subtype-matched therapeutic strategies. These circuits encompass a proliferative axis (MYC, MET/FAK, inflammatory and translational programs), an epithelial-differentiated/adhesion program, an EMT-like state with stromal activation, and mitochondrial/oxidative metabolic states, each mapping to selective liabilities (e.g., mitotic/autophagy control, ERBB/PI3K and cadherin signaling, OXPHOS/mitochondrial translation, and G2/M-integrin-Notch pathways, respectively). We then develop a transcriptomic predictor of EGFR-inhibitor response using machine learning and validate it in prospectively collected, fresh patient-derived 3D microtumors. The resulting 13-gene signature identifies erlotinib-responsive tumors (R = 0.93) and maps biologically to an epithelial-differentiated state, outperforming EGFR expression alone. Our study establishes a subtype-to-dependency-to-therapy framework, enabling precision stratification and providing a clinically feasible path for prospective biomarker deployment.

bioinformatics↗

bioRxiv2025

Dissecting sequence determinants of DNA methylation and in silico perturbation

DNA methylation shapes cellular identity and genome function, yet the sequence logic that governs its establishment remains largely unresolved. Here we present MethylAI, a cross-species-pretrained and human-specialized deep learning framework that predicts single-CpG methylation states directly from genomic sequence with high fidelity. Through quantitative attribution, MethylAI uncovers intrinsic cis-regulatory principles embedded in DNA, revealing conserved transcription factor (TF) motifs whose influence extends beyond CpG composition. Activated motifs demarcate gene-body CpG islands, encode lineage-defining methylation states, and align with TF occupancy and diverse histone modifications, thereby linking sequence syntax to local chromatin regulation. CTCF perturbation experiments validated MethylAI-predicted methylation shifts at activated motifs, showing strong concordance with in silico perturbations. Mapping genetic variants onto methylation-linked active motifs further uncovered widespread connections to zinc-finger TF families, providing mechanistic insight into how noncoding variation contributes to human traits and diseases. By transforming DNA sequence into interpretable methylation grammar, MethylAI establishes a generalizable framework for decoding the regulatory architecture of the human epigenome.

genomics↗

bioRxiv2025

Gut Microbiota-derived Adenosine Determines the Efficacy of Electroconvulsive Therapy for Depression

Electroconvulsive therapy (ECT) is a final procedure for major depressive disorders (MDD). However, the effectiveness of ECT in treating MDD patients varies. Here we identified gut microbiota as a potential restraining factor of ECT efficacy. By using a 5-day electroconvulsive shock (ECS) in depression mouse model of chronic restraint stress (CRS), it was observed that the antidepressant effect of ECS was suppressed after antibiotics (ABX)-induced microbiota dysbiosis, which also resulted in elevated c-Fos expression of CRH neurons in paraventricular nucleus of hypothalamus (PVN) and increased serum corticosterone levels after ECS. Metabolomic analysis revealed the critical involvement of microbiota associated purine metabolism, and the supplement of gut microbiota-derived adenosine was able to recover the antidepressant effect of ECS in ABX-treated CRS mouse model. Based on the neural tracing from colon to brain and the immunofluorescence staining, it was surmised a gut-brain axis originated from Adora1-expressing cells in colon mediate this biological process. Furthermore, adenosine supplement alleviated the further deterioration of post-ECS memory loss and impairment of synaptic plasticity induced by ABX-treatment as well. Our findings suggest a potential role of microbial adenosine metabolism in ECT efficacy determination and side effect protection, highlights potential application of adenosine supplement in antidepressant therapies of those depression patients with microbiota dysbiosis.

systems biology↗

bioRxiv2025

De novo design of phospho-tyrosine peptide binders

Phosphorylation on tyrosine is a key step in many signaling pathways. Despite recent progress in de novo design of protein binders, there are no current methods for designing binders that recognize phosphorylated proteins and peptides; this is a challenging problem as phosphate groups are highly charged, and phosphorylation often occurs within unstructured regions. Here we introduce RoseTTAFold Diffusion 2 for Molecular Interfaces (RFD2-MI), a deep generative framework for the design of binders for protein, ligand, and covalently modified protein targets. We demonstrate the power and versatility of this method by designing binders for four critical phosphotyrosine sites on three clinically relevant targets: Cluster of Differentiation 3 (CD3{varepsilon}), Epidermal Growth Factor Receptor (EGFR), Insulin Receptor (INSR) and Signal Transducer and Activator of Transcription 5 (STAT5). Experimental characterization shows that the designs bind their phosphotyrosine containing targets with affinities comparable to native binding sites and have negligible binding to non-phosphorylated targets or phosphopeptides with different sequences. X-ray crystal structures of generated binders to CD3{varepsilon} and EGFR are very close to the design models, demonstrating the accuracy of the design approach. A designed binder to an EGFR intracellular region phosphorylated upon EGF activation co-localizes with the receptor following EGF stimulation in single-particle tracking (SPT) experiments, demonstrating pY specific recognition in living cells. RFD2-MI provides a generalizable all-atom diffusion framework for probing and modulating phosphorylation-dependent signaling, and more generally, for developing research tools and targeted therapeutics against post-translationally modified proteins.

bioengineering↗

bioRxiv2025

IRF8 deficiency causes anxiety-like behavior in a sex-dependent manner

Anxiety disorder is a serious psychiatric disease that affects women twice more than men and disrupts patients daily lives. It is often comorbid with major depression and other mental diseases. Various underlying mechanisms have been proposed, such as neurotransmitters and neuroanatomical disruptions, and more recently, oxidative stress; however, much remained unclear, including the role of glial cells. Here, we investigated the role of IRF8 in anxiety disorders in the mouse model. IRF8 is a transcription factor expressed primarily in microglia in the brain. A battery of behavioral tests revealed that female IRF8 knockout (IRF8KO) mice show increased anxiety relative to male IRF8KO and wild-type mice. Female IRF8KO mice also exhibited a higher tendency for obsessive-compulsive disorder. However, these behavioral abnormalities were not observed when IRF8 was deleted postnatally, indicating that it acts during the fetal stage to control anxiety. Transcriptome analysis revealed that IRF8 deficiency leads to redox dysregulation. Further, 2,7-dichlorofluorescin diacetate (DCFDA) staining for microglia demonstrated that female IRF8KO microglia produce higher levels of reactive oxygen species (ROS) compared to WT and male IRF8KO counterparts. Detailed RNA-seq analysis, however, did not reveal specific genes that cause high ROS production in female cells. In sum, this work demonstrates that IRF8 in microglia plays a major role in controlling anxiety in a sex dependent manner.

neuroscience↗