Biology subjects

Mu, Z.

Publications and source records attributed to Mu, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Mental replay rescales the subjective duration of past events via alpha and theta oscillations

Human memory recall is flexible in time, allowing past events to be mentally replayed at variable speeds. However, it remains unclear whether temporally rescaled replay distorts the perceived duration of remembered events, and whether such distortion is tied to changes in the retrieved content. Here we instructed participants to mentally replay previously encoded naturalistic videos at compressed, expanded, or self-paced (free) speeds while recording scalp electroencephalography (EEG). Replaying an event at an expanded pace lengthened participants' subsequent judgments of its original duration relative to free and compressed replay, and the longer an event had been replayed, the longer it was judged to have lasted. Crucially, recalled memory content was unaffected, with gist accuracy and recalled detail comparable across speed conditions. During replay, alpha and theta power were reduced under compression, and both interacted with the speed instruction in predicting reported duration. Specifically, alpha power exhibited a stronger positive relationship with duration judgments under compressed replay than under free or expanded replay. Conversely, the relationship between theta power and reported duration was significantly more positive under expanded replay than under free or compressed replay. Neural pattern similarity between instructed and later spontaneous replay varied with replay speed, yet this reinstatement neither predicted reported duration nor mediated the oscillatory effects. These findings suggest that remembered duration is not read out from the amount of content retrieved but reconstructed at retrieval through oscillatory dynamics, decoupling the subjective scaling of time from the content of memory.

neuroscience↗

bioRxiv2026

Sleep reactivation shapes memories of event and its temporal structure

Episodic memory provides a temporal scaffold that organizes past experiences according to their sequential occurrence. While memories are reactivated and consolidated during sleep, it remains unknown how exogenous reactivation reshapes memories of complex events, particularly the temporal structure that binds individual elements across time. In this preregistered study, 35 participants encoded neutral and aversive narratives composed of image sequences, with auditory context shifts defining event boundaries. During post-encoding slow-wave sleep, closed-loop targeted memory reactivation (TMR) delivered boundary-associated auditory cues time-locked to the up-state of slow oscillations. Reactivation led to faster, more confident, and more liberal recognition responses for cued than uncued memories. However, reactivation exerted a time-dependent effect on temporal-order memory, impairing it immediately after sleep but attenuating forgetting one week later. This behavioral dissociation was paralleled at the neural level: stronger cue-elicited theta activity predicted superior recognition of neutral, but not aversive event content, whereas greater theta responses were associated with poorer temporal-order memory for the same events. Together, these findings suggest that sleep reactivation does not uniformly strengthen episodic memories. Rather, it selectively prioritizes access to event content while reorganizing temporal relations among event elements, revealing distinct, time-dependent consequences of sleep reactivation for different components of complex experiences.

neuroscience↗

bioRxiv2026

FOCUS-3D: Robust, generalizable volumetric cell segmentation for three-dimensional fluorescence microscopy

Understanding how cells establish spatial organization within tissues is a fundamental question in life sciences. While modern three-dimensional fluorescence microscopy captures large-volume tissue architecture, extracting quantitative cellular insights from complex volumetric datasets remains a major barrier. Here, we introduce FOCUS-3D, a robust, broadly generalizable volumetric cell segmentation framework built on a large, diverse manually annotated cell resource and advanced AI designs. Integrating volumetric representation learning, multi-scale feature extraction, and query-based mask prediction, FOCUS-3D achieves state-of-the-art performance across diverse species, tissues, fluorescent reporters and imaging modalities. During zebrafish (Danio rerio) development, FOCUS-3D uncovers three successive phases of notochord morphogenesis. We disentangle early motility-driven rearrangements from later cell shape remodeling and tissue repacking, and further link these morphological states to spatial and developmental transcriptional programs across independent datasets.

bioinformatics↗

bioRxiv2026

Identifying the causal allele in the CD40 autoimmune locus enables discovery of context-specific trans-effects in B cells

Thousands of genetic variants are associated with autoimmune diseases, but causal variants, their mechanisms, and the pathogenic context in which they act are elusive. Knowledge of pathogenic contexts may enable effective targeted therapies, instead of broad immunosuppressive approaches. First, to focus on the genetics of immune response, we used surface marker CITE-seq data from 1,055,857 peripheral blood mononuclear cells from 356 individuals. We defined genetic associations to 148 surface proteins across eight cell types. We observed a signal in the CD40 locus, implicated in rheumatoid arthritis (RA) and other autoimmune conditions. RA risk variants increased CD40 protein expression by [~]20% on B cells, but with minimal mRNA effects. Second, we deployed base-resolution genome editing, with CRAFT-seq, capturing genomic DNA sequence at the edited site and multimodal phenotypes at single-cell resolution. We defined a single causal allele, rs1883832, within the Kozak motif. Third, we edited this allele, in primary B cells and conducted CRAFTseq to demonstrate trans-effects in >200 genes. These effects were only in the light zone germinal center-like state. Importantly, these trans-effects were not seen in population-scale cohorts of unstimulated B cells. This represents a framework to define disease causal alleles, their cis- and trans-effects. It demonstrates the power of defining causal genetic variation to find trans-effects through editing, which cannot easily be found in population studies.

genetics↗

bioRxiv2026

Dissecting the Black Box of AlphaFold in Protein-Protein Complex Assembly

AlphaFold has revolutionized protein complex structure prediction, yet how it assembles intermolecular interfaces remains poorly understood. Contrary to the prevailing view that inter-protein coevolution drives complex prediction, we uncover a geometry-over-coevolution principle governing assembly in AlphaFold-Multimer and AlphaFold3. Through systematic perturbation of evolutionary and structural inputs and development of residue-level constraint propagation mapping to trace the emergence and propagation of geometric information within the network, we show that prediction accuracy is governed primarily by monomer-derived structural geometry and interface-specific sequence-geometry compatibility, rather than direct inter-protein coevolutionary signals. Our mapping reveals a hierarchical assembly mechanism in which monomer-level geometric representations are established first and progressively propagated to constrain cross-chain interfaces. This mechanism further explains why antigen-antibody complexes are predicted less accurately, as their intrinsic interface plasticity and non-canonical architectures limit the propagation of geometric constraints across interfaces. Together, these findings establish a mechanistic framework for understanding how artificial intelligence models assemble protein complexes and provide principles for improving next-generation structure prediction.

bioinformatics↗

bioRxiv2026

High-Fidelity Long-term Whole-embryo Lineage and Fate Reconstruction by Iterative Tracking with Error Correction

Reconstructing the complete cell lineages and fate maps of a living embryo has remained a central challenge in developmental biology. Here we introduce ITEC (Iterative Tracking with Error Correction), a fully unsupervised method that automatically reconstructs the lineage of every cell in the embryo with high fidelity. ITEC was validated with manually annotated lineages on four cross-species datasets including zebrafish, mouse, and Drosophila. We reconstructed the developmental lineages of a zebrafish embryo from terabyte-scale data of total 18.5 million cells with an estimated accuracy of over 99.7%. With ITEC, we revealed spatiotemporal dynamics of key morphogenetic processes such as somite boundary formation, demonstrated the various patterns of spatial sorting among adjacent organs or anatomical regions, and identified associations between cellular movement and spatial transcriptomics. ITEC provides a powerful platform for retrospective fate mapping and systematic exploration of developmental dynamics at the cellular scale and single-embryo level.

bioinformatics↗

bioRxiv2025

Hepatocyte FGFR2 Mediates the Antifibrotic Effects of FGF10 in Advanced Liver Fibrosis.

Fibroblast growth factor 10 (FGF10) supports epithelial repair, but its role in liver fibrogenesis remains uncertain. Here we found that hepatic FGF10 and its receptor FGFR2 decline with progression to advanced fibrosis in patient biopsies and in carbon tetrachloride (CCl4)- and diet-induced mouse models. Restoring hepatic FGF10 with recombinant human FGF10 or adeno-associated virus mediated liver-targeted expression attenuated and partially reversed established advanced bridging fibrosis, reduced inflammation, and decreased hepatocyte apoptosis, and these benefits required hepatocyte FGFR2 because hepatocyte-specific Fgfr2 deletion abolished protection. In primary hepatocytes, FGF10 activated FGFR2-FRS2, increased inhibitory GSK3{beta}(Ser9) phosphorylation, and suppressed NF-{kappa}B activation, reducing TGF-{beta}1 and other cytokines and thereby limiting paracrine hepatic stellate cells activation. The molecular and histologic benefits extended to metabolically primed steatohepatitis, supporting translatability beyond toxicant injury. Mechanistic signaling readouts confirm FGFR2 engagement, while the main text centers on the hepatocyte FGF10-FGFR2 axis as an intrinsic brake on fibrogenesis. Together, these data identify a hepatocyte-centric FGF10-FGFR2 axis as a negative regulator and potential regressor of fibrogenesis, highlighting it as a tractable therapeutic target in advanced liver fibrosis.

pharmacology and toxicology↗

bioRxiv2025

Mechanism-Aware Protein-Protein Interaction Prediction via Contact-Guided Dual Attention on Protein Language Models

Robust prediction of protein-protein interactions (PPIs) requires models that generalize beyond the training distribution. Here, we present PLMDA-PPI, a mechanism-aware framework that incorporates biophysical inductive biases into a dual-attention architecture with residue-level contact supervision applied to protein language model embedded geometric representations. This design enables the model to jointly learn global interaction likelihoods and the residue pairs mediating interactions, producing interpretable, mechanism-grounded predictions. PLMDA-PPI demonstrates strong out-of-distribution generalization, substantially outperforming lightweight deep learning models (D-SCRIPT, Topsy-Turvy, TT3D, and TUnA) and achieving comparable or even superior performance to computationally intensive methods (AF2Complex, RF2-Lite, and RF2-PPI) derived from AlphaFold2 and RoseTTAFold2, while requiring orders of magnitude fewer computational resources. These results show that incorporating mechanistic priors as architectural inductive biases enhances generalization, interpretability, and computational efficiency, providing a principled foundation for AI-driven prediction of complex biological interactions.

bioinformatics↗

bioRxiv2023

Mechanism of ozone alleviation of malignant ascites in hepatocellular carcinoma through inhibition of NETs

Malignant ascites in hepatocellular carcinoma is usually a sign of advanced disease and poor prognosis and is also thought to be associated with chronic inflammation mediated by neutrophil extracellular trap networks (NETs). Whereas ozone, a strong oxidant, has significant antibacterial and anti-inflammatory effects, its effectiveness in treating malignant liver ascites is unclear.cOzone showed significant anti-peritoneal fluid production properties in H22 tumor-bearing mice, and ozone reduced peritoneal fluid production by activating AMPK and up-regulating SR-A phagocytosis damage-associated molecular patterns (DAMPs) to reduce the production of NETs. This suggests that ozone could be used as a new drug for the treatment of malignant ascites in hepatocellular carcinoma.

cancer biology↗

bioRxiv2022

Structure-based stabilization of SOSIP Env enhances recombinant ectodomain durability and yield

The envelope glycoprotein (Env) is the main focus of HIV-1 vaccine development due to its critical role in viral entry. Despite advances in protein engineering, many Env proteins remain recalcitrant to recombinant expression due to their inherent metastability, making biochemical and immunological experiments impractical or impossible. Here we report a novel proline-stabilization strategy to facilitate the production of prefusion Env trimers. This approach, termed "2P", works synergistically with previously described SOSIP mutations and dramatically increases the yield of recombinantly expressed Env ectodomains without altering the antigenic or conformational properties of native Env. We determined that the 2P mutations function by enhancing the durability of the prefusion conformation and that this stabilization strategy is broadly applicable to evolutionarily and antigenically diverse Envs. These findings provide a new Env stabilization platform to facilitate biochemical research and expand the number of Env variants that can be developed as future HIV-1 vaccine candidates.

biochemistry↗

bioRxiv2022

Epigenetic variation impacts ancestry-associated differences in the transcriptional response to influenza infection

Humans display remarkable inter-individual variation in immune response when exposed to identical immune challenges. Yet, our understanding of the genetic and epigenetic factors contributing to such variation remains limited. Here we carried out in-depth genetic, epigenetic, and transcriptional profiling on primary macrophages derived from a panel of European and African-ancestry individuals before and after infection with influenza A virus (IAV). We show that baseline epigenetic profiles are strongly predictive of the transcriptional response to IAV across individuals, and that ancestry-associated differences in gene expression are tightly coupled with variation in enhancer activity. Quantitative trait locus (QTL) mapping revealed highly coordinated genetic effects on gene regulation with many cis-acting genetic variants impacting concomitantly gene expression and multiple epigenetic marks. These data reveal that ancestry-associated differences in the epigenetic landscape are genetically controlled, even more so than variation in gene expression. Lastly, we show that among QTL variants that colocalized with immune-disease loci, only 7% were gene expression QTL, the remaining corresponding to genetic variants that impact one or more epigenetic marks, which stresses the importance of considering molecular phenotypes beyond gene expression in disease-focused studies.

genetics↗

bioRxiv2022

Protection from Omicron and other VOCs by Bivalent S-Trimer COVID-19 Vaccine

The Omicron variant of SARS-COV-2 (GISAID GRA clade [B.1.1.529, BA.1 and BA.2]) is now the single dominant Variant of Concern (VOC). The high number of mutations in the Omicron Spike (S) protein promotes humoral immunological escape. Although a third homologous boost with S, derived from the ancestral strain, was able to increase neutralizing antibody titers and breadth including to Omicron, the magnitude of virus neutralization could benefit from further optimization. Moreover, combining SARS-COV-2 strains as additional valences may address the current antigenicity range occupied by VOCs. Using Trimer-Tag platform we have previously demonstrated phase 3 efficacy and safety of a prototypic vaccine SCB-2019 in the SPECTRA trial and have submitted applications for licensure. Here, we successfully generated a bivalent vaccine candidate including both Ancestor and Omicron variant S-proteins. Preclinical studies demonstrate this SARS-CoV-2 bivalent S-Trimer subunit vaccine elicits high titers of neutralizing antibodies against all VOCs, with markedly enhanced Omicron specific neutralizing antibody responses.

immunology↗

bioRxiv2022

Near telomere-to-telomere nuclear phased chromosomes of the dikaryotic wheat fungus Rhizoctonia cerealis

Rhizoctonia cerealis (Rce), which causes sharp eyespot, is one of the most destructive wheat pathogens. However, the genetic and molecular virulence mechanisms of Rce have not been elucidated. As a dikaryotic organism, the haplotype phasing of this fungus has not been completed so far. We applied a haplotype phasing algorithm to generate a high-quality near telomere-to-telomere nuclear-phased genome sequence of Rce strain R0301. Sixteen pairs of chromosomes were assigned to the A and B genomes with a total size of 83 Mb. Based on a dual-time course RNA-seq, 25308 genes were predicted. Genes for steroid biosynthesis and starch and sucrose metabolism were significantly enriched, together with many genes encoding carbohydrate-active enzymes (CAZymes) and secreted effector proteins, which should be involved in infection of wheat plants. Population genomic analysis of 31 isolates collected in China during the last forty years suggests that this population has not undergone substantial differentiation over time. ImportanceThe finished genome reference is the basis of revealing pathogens biology base. Many efforts have been made to produce the chromosome-scale assembly of fungi. However, the reference of many pathogenic fungi is highly fragmented, which prevents the analysis of genome structure variation, evolution and import pathogenicity genes. Here, we assembly the only chromosome-scale haplotype-phased reference of dikaryotic fungus so far. This assembly achieves the gold standard based on many evaluation software, which indicates that the pipeline developed in this study can be applied to assemble references for other dikaryotic organisms. This work can also promote the research on the globes destructive wheat pathogens, sharp eyespot, caused by R. cerealis.

genomics↗

bioRxiv2021

Ability of nucleoside-modified mRNA to encode HIV-1 envelope trimer nanoparticles

The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared to trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor VH + VL knock-in mice. Next generation sequencing demonstrated acquisition of critical mutations, and monoclonal antibodies that neutralized heterologous HIV-1 isolates were isolated. Thus, mRNA- LNP can encode complex immunogens and are of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.

immunology↗

bioRxiv2020

Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates

Development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we found that mRNA-LNP immunization compared to protein immunization elicited either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope (prM-E) or HIV-1 Env gp160 induced durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 g were immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.

immunology↗

bioRxiv2020

Single-cell RNA-sequencing reveals pervasive but highly cell type-specific genetic ancestry effects on the response to viral infection

Humans vary in their susceptibility to infectious disease, partly due to variation in the immune response following infection. Here, we used single-cell RNA-sequencing to quantify genetic contributions to this variation in peripheral blood mononuclear cells, focusing specifically on the transcriptional response to influenza infection. We find that monocytes are the most responsive to influenza infection, but that all cell types mount a conserved interferon response, which is stronger in individuals with increased European ancestry. By comparing European American and African American individuals, we show that genetic ancestry effects on expression are common, influencing 29% of genes, but highly cell type-specific. Further, we demonstrate that much of this population-associated expression variation is explained by cis expression quantitative trait loci, which are enriched for signatures of recent positive selection. Our findings establish common cis-regulatory variants--including those that are differentiated by genetic ancestry--as important determinants of the antiviral immune response.

genomics↗

bioRxiv2020

Quadratic Mutual Information estimation of mouse dLGN receptive fields reveals asymmetry between ON and OFF visual pathways

The longstanding theory of "parallel processing" predicts that, except for a sign reversal, ON and OFF cells are driven by a similar pre-synaptic circuit and have similar visual field coverage, direction/orientation selectivity, visual acuity and other functional properties. However, recent experimental data challenges this view. Here we present an information theory based receptive field (RF) estimation method - quadratic mutual information (QMI) - applied to multi-electrode array electrophysiological recordings from the mouse dorsal lateral geniculate nucleus (dLGN). This estimation method provides more accurate RF estimates than the commonly used Spike-Triggered Average (STA) method, particularly in the presence of spatially correlated inputs. This improved efficiency allowed a larger number of RFs (285 vs 189 cells) to be extracted from a previously published dataset. Fitting a spatial-temporal Difference-of-Gaussians (ST-DoG) model to the RFs revealed that while the structural RF properties of ON and OFF cells are largely symmetric, there were some asymmetries apparent in the functional properties of ON and OFF visual processing streams - with OFF cells preferring higher spatial and temporal frequencies on average, and showing a greater degree of orientation selectivity.

neuroscience↗

bioRxiv2020

IgM Natural Antibodies Bind HLA-E-Leader Peptide Complexes and Modulate NK Cell Cytotoxicity

HLA-E is a non-classical class Ib molecule that has limited polymorphism and binds HLA class Ia leader peptides (VL9). HLA-E-VL9 complexes interact with the natural killer (NK) cell receptors NKG2A-C/CD94 and regulate NK cell-mediated cytotoxicity. Here we isolated a murine IgM antibody 3H4, that specifically recognized HLA-E-VL9 bound complexes and enhanced killing of HLA-E-VL9-expressing cells by an NKG2A+ NK cell line. Structural analysis revealed how 3H4 prevents CD94/NKG2A docking on HLA-E-VL9 by binding with an overlapping footprint. Upon in vitro maturation, an affinity-optimized 3H4 IgG showed enhanced NK killing of HLA-E-VL9-expressing cells. Remarkably, HLA-E-VL9-specific IgM autoantibodies with similar specificity and functions to 3H4 were subsequently isolated from naive B cells of cytomegalovirus (CMV)-negative, healthy male human donors. Thus, a repertoire of germline low affinity HLA-E-VL9-reactive antibodies are present in both naive human and murine B cell repertoires. These antibodies can enhance NK cell cytotoxicity and therefore have potential for therapeutic modulation of NK cell function.

immunology↗