Biology subjects

Zhu, M.

Publications and source records attributed to Zhu, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Charting sex divergence in the human brain across the lifespan

Biological sex fundamentally shapes human brain organization, but sex-specific normative neuroanatomical trajectories across the lifespan remain largely uncharted. Here, we constructed independent, sex-specific lifespan brain charts using structural neuroimaging data from 59,915 healthy individuals (29,760 males and 30,155 females) ranging in age from 266 postconception days to 100 years. By examining 296 structural phenotypes across global, cortical, and subcortical measures, these models revealed widespread sex differences in maturational timing, with males reaching peak milestones later than females. These trajectories demonstrate that sex differences evolve dynamically, with phenotype-specific windows of emergence and maximal separation. Compared with conventional sex-pooled references, sex-specific models achieved superior predictive accuracy and reduced misestimation of individual deviations in healthy populations. Across five neuropsychiatric conditions, sex-specific models improved the detection of extreme deviations and revealed both shared and sex-dependent patterns of disorder-related neuroanatomical abnormalities. These sex-specific charts establish tailored normative references for assessing brain development, ageing, and disease.

neuroscience↗

bioRxiv2026

Stressed alga-free coral cells can initiate coral bleaching

Coral bleaching is driving the rapid decline of coral reefs worldwide, yet a fundamental question remains unresolved: does the bleaching cascade begin in the coral host or in its intracellular algal symbionts, Symbiodiniaceae? Resolving where this process starts is critical for understanding how symbiosis collapses and where early intervention might be effective. Here we use transient stress to create a temporal window between the early cellular response and subsequent symbiosis breakdown. Across transient menthol and thermal stress in soft and stony corals, bleaching developed after the stress had ended. In Xenia sp., single-cell transcriptomics revealed a broad host response before detectable symbiont loss, including coordinated redox changes consistent with conditions favouring reactive oxygen species (ROS) accumulation. Cell-resolved imaging showed that alga-free coral cells were the first to become ROS-positive, whereas Symbiodiniaceae showed no detectable ROS signal. This early host response was transmissible. Conditioned medium from stressed cultures induced the emergence of ROS-positive host cells and subsequent symbiosis breakdown in unstressed recipients. Purified ROS-positive alga-free coral cells alone were sufficient to trigger symbiosis breakdown in recipient cultures without direct stress exposure. Suppressing the early emergence of ROS-positive coral cells markedly reduced later bleaching, whereas intervention after stress was substantially less effective. These findings identify a host-initiated, intercellularly propagating route to coral bleaching and reveal an early host response that can determine the subsequent fate of the symbiosis.

cell biology↗

bioRxiv2026

Stress triggers global histone synthesis in the liver

Despite extensive drug development targeting DNA synthesis, there have been few efforts to inhibit histone synthesis, which occurs jointly with DNA synthesis in S-phase. A major roadblock is the lack of tools to quantitatively measure histone synthesis due to the high abundance and stability of histone proteins. Here we present chemical labeling methodologies to produce the first in vivo measurements of histone synthesis rates. Under basal conditions, histone synthesis tracks closely with tissue proliferation. However, multiple systemic and liver-specific stresses induce a previously uncharacterized surge of hepatocyte nucleosome production that is uncoupled from DNA replication. Tracing of newly synthesized nucleosomes detected promoter deposition, which was required to buffer transcriptional output. These results may inform strategies to modulate histone production to influence stress responses or disease.

molecular biology↗

bioRxiv2026

A cross-modal generative model for incomplete and degradedprostate MRI with multicentre clinical validation

Missing or degraded sequences can limit prostate multiparametric MRI. We developed MSCNet, a sequence-conditioned cross-modal generative framework for reconstructing unavailable contrasts and restoring degraded acquisitions. Across ten completion tasks, task-specific MSCNet achieved mean structural similarity of 0.818 versus 0.798 for the strongest task-matched comparators; matched-capacity analyses showed larger differences in lesion fidelity and boundary preservation. In a blinded 1,000-case reader study, overall image quality met the prespecified non-inferiority criterion for DWI, ADC and T2W completion, but not T1W. In a separate 200-case diagnostic assessment, AUCs for clinically significant cancer were 0.860 with acquired images, 0.841 with MSCNet and 0.797 with baseline-generated images. A locked 186-case three-hospital cohort supported multicentre transportability. These retrospective results support quality-controlled cross-modal reconstruction as an adjunct to acquired prostate MRI.

bioengineering↗

bioRxiv2026

Adolescent stress recruits a latent amygdala-dopamine circuit to drive punishment-resistant reward-seeking

Adolescent stress is a lifelong risk factor for addiction, but the underlying neural circuit changes remain unknown. Here, we show that chronic unpredictable stress in adolescent mice causes a prominent increase in punishment-resistant reward-seeking - behavior tightly linked to the diagnostic criteria for addiction - establishing a model for mechanistic investigation. Using this model, we find a "gain-of-function" in reward processing wherein persistent hyperexcitability in a subset of central amygdala (CeA) neurons projecting to the substantia nigra pars lateralis (SNL) disinhibits dopamine release in the tail of the striatum (TS), newly recruiting TS to participate in punishment-resistant reward-seeking. Normalizing circuit-specific CeA hyperexcitability or optogenetically counteracting excessive TS dopamine release prevented the increase in punishment resistance. These results identify a novel circuit mediator for the lifelong effects of adolescent stress on a core feature of addictive disorders, opening a new avenue for interventions targeted to at-risk populations with specific formative experiences.

neuroscience↗

bioRxiv2026

Single-cell lineage tracing of human neuromesoderm organoids reveals TBX6-mediated posterior mesoderm fate diversification

Neuromesodermal progenitors (NMPs) drive vertebrate posterior axis elongation, but the lineage hierarchy of human NMP derivatives remains poorly defined. Here, we integrated a CRISPR/Cas9-based single-cell lineage tracing system with paired multiomics profiling--including scRNA-seq and scATAC-seq--in human pluripotent stem cell-derived neuromesodermal organoids (NMOs) to reconstruct high-resolution lineage relationships spanning 50 days of differentiation. Our data analysis reveal that intermediate mesoderm (IM) and paraxial mesoderm (PM) originate from a shared presomitic mesoderm (PSM) progenitor downstream of NMPs, whereas lateral plate mesoderm (LPM) segregates early from committed mesodermal progenitors. Notably, TBX6 ablation disrupts both IM and somite development, demonstrating that TBX6 functions as an upstream regulator of these two lineages. Mechanistically, TBX6 loss arrests PSM at the progenitor stage and abolishes activation of development programs required for IM maturation. We further delineate neural crest differentiation pathways from NMPs, identifying pre-bifurcation molecular signatures that predict neural crest fate. This work provides a clonal-resolution lineage map of human NMP differentiation and advances our understanding of human posterior trunk development and the etiology of TBX6-associated congenital disorders affecting both the spine and the kidney.

developmental biology↗

bioRxiv2026

Integrative AI-Enabled Virtual Cell Modeling Reveals a Clinically Relevant Latent Effector State of Human CD8 T Cells Undetectable by Conventional Analyses

Understanding how immune checkpoint inhibitors (ICIs) reshape human T-cell responses requires models that move beyond static transcriptomic snapshots and discrete cell-state classifications. Here, we present an integrative AI-enabled virtual cell framework that represents human CD8 T-cell responses as dynamic and computable systems during ICI therapy. By integrating single-cell RNA sequencing with paired T-cell receptor sequencing within the C2S-scale foundation model, we construct a virtual representation of individual T cells, in which each cell is encoded by a unique functional identity that captures its transcriptional, signaling, and clonal characteristics. Using this framework, we identify a previously unrecognized dynamic latent effector state of CD8 T cells characterized by intermediate expression of effector genes, distinct signaling activity, and ongoing clonal expansion. Across independent patient cohorts, the virtual cell model consistently indicates that ICI therapy mainly acts by unmasking pre-existing effector potential rather than inducing de novo effector differentiation. Notably, this latent effector population remains transcriptionally restrained despite active signaling and clonal expansion, revealing a hidden reservoir of antitumor immune capacity. More broadly, our study demonstrates how AI-enabled virtual cell modeling can reconstruct latent cellular states and their dynamic transitions from multidimensional single-cell data. By incorporating functional identity into virtual cell model, this framework uncovers biologically meaningful yet non-obvious T-cell effector program during cancer immunotherapy and provides a generalizable approach for studying immune dynamics in human disease.

immunology↗

bioRxiv2026

K63-linked ubiquitin chains mark inactive Smoothened for packaging into ciliary extracellular vesicles

Signaling receptors can exit cilia either by retrieval back into the cell or by secretion in extracellular vesicles (EVs), a process known as ectocytosis. The mechanisms that govern ectocytosis remain poorly understood. Here, we leverage quantitative proteomic profiling to identify the Hedgehog signaling receptor Smoothened (SMO) as a major cargo of cilia-derived EVs. Surprisingly, ligands that promote ciliary accumulation of SMO strongly suppressed its packaging into EVs, indicating that ectocytosis selectively packages specific conformational states of SMO. We further find that SMO packaged into EVs is extensively modified with K63-linked ubiquitin chains. Preventing SMO ubiquitination or selectively removing K63-linked ubiquitin chains from SMO markedly reduced its secretion into EVs and caused SMO accumulation within cilia. Together, these results identify K63-linked ubiquitin chains as a sorting signal for ciliary ectocytosis and indicate that ubiquitin-dependent packaging of inactive SMO contributes to the dynamic redistribution of SMO during Hedgehog signaling.

cell biology↗

bioRxiv2026

Decoding Immune Reconstitution Failure in People Living with HIV through Single-cell Genomics

Immune non-responders (INRs), a subset of people living with HIV (PLWH), fail to achieve full immune reconstitution and remain at increased risk of morbidity, mortality, and non-AIDS-related illnesses. As the mechanisms underlying this impaired immune recovery remain poorly understood, we performed single-cell multi-omics profiling on peripheral blood mononuclear cells from 43 INRs, 47 immune responders and 53 healthy donors. Our dataset comprises 2,744,009 transcriptomes and 1,226,658 chromatin-accessibility profiles across 58 identified immune cell types. INRs exhibited markedly elevated inflammatory signaling, increased apoptotic activity, and dysregulation of immune-activating ligand-receptor interactions. Additionally, we identified 2,996 interaction cis-eGenes and 5,938 cis-caPeaks, and validated key cell type-specific cis-xQTL effects associated with immune reconstitution failure. Furthermore, we identified 3,551 sc-eQTLs and 872 cell-state interaction eQTLs (ieQTLs) in CD4+ T cells. A genotype-specific upregulation of OAS3 in INRs, likely regulated by STAT1, was identified based on these results. We developed scPRISM (single cell Predictive Reconstitution Immune Status Model), a multi-modal framework that integrates scRNA-seq and scATAC-seq data to perform the dual tasks of differentiating disease states and predicting gene expression from chromatin accessibility, thereby deciphering the cell type-specific cis-regulatory basis of the disease. Our study delineates the transcriptional and epigenomic landscape of immune dysregulation in INRs and provides new genetic insights into HIV-associated immune reconstitution failure. These findings offer a foundation for developing biomarkers and precision therapies to restore immune function in PLWH.

genetics↗

bioRxiv2026

Molecular underpinning of Hydra viridissima-algal facultative symbiosis and vertical algal transmission

The symbiosis between algae and animals represents a relatively recent evolutionary innovation, and exemplified by species in the Cnidaria phylum. Cnidaria can harbor algae within a modified cellular organelle called the symbiosome in a process called endosymbiosis. This animal-algal symbiosis can be facultative or obligate. Algae acquisition occurs either by horizontal transmission, where free-swimming planula gain algae through feeding, or by algae deposition into the developing oocyte in vertical transmission[1-5]. Most studies focus on anthozoans that perform obligate endosymbiosis and transmit algae horizontally. How facultative endosymbiosis in combination with vertical algal transmission impacts the evolutionary adaptation between host and symbiont remains unclear. By studying Hydra viridissima, which performs facultative endosymbiosis and transmits its Chlorella algae vertically, we define different cell types and identify the endoderm cell lineage that gives rise to three major cell types hosting algae. Compared to obligate endosymbiosis[6, 7], Hydra viridissima algal host cells exhibit distinct features, including algal uptake, elevated oxidative phosphorylation and redox activities, and express genes that can provide ammonium for their algal symbionts. We further show when and how the developing Hydra oocytes may take up algae and where oocytes may obtain lipids. Since Hydra is amenable to genetic manipulations, our findings should enable mechanistic studies of how facultative endosymbiosis and vertical transmission evolve and adapt in a changing climate.

molecular biology↗

bioRxiv2026

Thalamus orchestrates local acetylcholine-dependent dopamine release in the learning striatum

Dopamine is essential for striatal function and learning. Striatal dopamine release can be triggered by dopamine cell firing, but also by coordinated cholinergic interneuron activity, which stimulates dopamine release via presynaptic nicotinic acetylcholine receptors on dopamine axons. While acetylcholine-dependent dopamine release is well-documented ex vivo and under artificial optogenetic stimulation in vivo, its role during natural behavior has remained unclear. One possible endogenous driver of acetylcholine-dependent dopamine release is thalamic input, which provides strong excitatory drive to cholinergic interneurons. To examine whether thalamic input provokes acetylcholine-dependent dopamine release during behavior, we performed simultaneous fiber photometry recordings of striatal dopamine (GRAB-rDA3m) and thalamic axon activity (gCaMP8m) in the dorsomedial (DMS) and dorsolateral striatum (DLS) of mice learning the accelerating rotarod, a striatal-dependent task that demands precise and effortful motor control. Recordings were obtained on- and off-task and across days of training to capture the full arc of learning. Dopamine transients in DMS, but not DLS, were frequently coupled to peaks in thalamic axon activity via an acetylcholine-dependent mechanism. The occurrence of these thalamic-evoked DMS dopamine transients depended on learning, task engagement, and the recent history of dopamine activity, but did not contribute to motor error signals. Together, these findings establish thalamic input as a physiological driver of acetylcholine-dependent dopamine release in DMS. Moreover, they reveal that striatal sensitivity to this local release mechanism is dynamically gated by dopaminergic history, providing a compelling framework for understanding how local and soma-triggered dopamine signals are coordinated to support learning.

neuroscience↗

bioRxiv2026

Role of Alanine Transaminase in Retinal Metabolic Homeostasis: Potential therapeutic target in retinal diseases

PurposeAlanine transaminases (ALT), encoded by the GPT gene, catalyzes the reversible conversion of pyruvate and glutamate to alanine and alpha-ketoglutarate, thereby correlating carbohydrate and amino acid metabolism. However, its role in the human neural retina remains unclear. This study aimed to explore the expression, localization, and metabolic function of ALT in the human neural retina and its potential involvement in retinal diseases. MethodsALT1 and ALT2 expression and localization were examined in the retinas of healthy and diabetic retinopathy (DR) donors via immunoblotting and immunofluorescence. ALT function was assessed in ex vivo human retinal explants using pharmacological inhibition with beta-chloro-L-alanine (BCLA), followed by the analyses of enzyme activity, tissue injury, and transcriptomic responses. Stable-isotope tracing with 13C-and 15N-labelled substrates combined with GC-MS was used to define ALT-dependent carbon and nitrogen fluxes in macular and peripheral retinas. Redox level (NADPH/NADP+) was also evaluated under tert-butyl hydroperoxide-induced oxidative stress. ResultsALT1 and ALT2 were both expressed in the human neural retina, with prominent localization in Muller glia and photoreceptor inner segments. ALT1 displayed a diffuse cytoplasmic distribution, whereas ALT2 demonstrated a punctate pattern consistent with mitochondrial localization. In DR retinas, ALT1 expression was spatially disorganized and heterogeneous, while ALT2 remained comparatively preserved. Inhibition of ALT with BCLA markedly reduced ALT activity without causing overt cytotoxicity or major transcriptional changes. Isotope tracing demonstrated that retinal ALT predominantly channels pyruvate-derived carbon into alanine, whereas alanine was minimally contributed to pyruvate production under basal conditions. ALT inhibition suppressed alanine synthesis and release, redirected nitrogen flux towards glutamate, glutamine, and aspartate, and uncovered distinct metabolic adaptations in macular but not peripheral retinas. Under oxidative stress, ALT inhibition induced the decrease of NADP+/NADPH ratio and LDH release, indicating improved redox balance and reduced tissue injury. ConclusionsALT is previously unrecognized as a regulator of carbon and nitrogen partitioner in the human neural retina, contributing to redox homeostasis under stress. The altered distribution of ALT1 in DR retina and the protective metabolic effects of ALT inhibition suggest ALT as a potential contributor to retinal metabolic vulnerability and a candidate therapeutic target in retinal diseases.

neuroscience↗

bioRxiv2026

Coronavirus envelope protein drives iron sensing disorder by hijacking the TAp73-FDXR axis

Iron overload is increasingly recognized as a critical contributor to coronavirus pathogenesis1, yet the underlying induction mechanisms remain unclear. Here, we uncover a fundamental pathway by which coronavirus drives IRP1 RNA-binding activity to induce iron accumulation2 via targeting the TAp73-FDXR axis. Specifically, coronavirus infection represses transcription of FDXR (encoding the key rate-limiting enzyme in host iron-sulfur cluster synthesis3), thereby impairing host iron-sulfur cluster generation to trigger the functional conversion of the cytosolic aconitase 1 (ACO1) into iron-regulatory protein 1 (IRP1)4, ultimately leading to the hosts persistently false perception of iron deficiency. We identify TAp73 as the primary transcription factor governing FDXR expression, and demonstrate that the coronavirus envelope protein (CoV-E) orchestrates TAp73 nuclear export. Subsequently, CoV-E binds TAp73 through a critical valine residue within its C-terminal PBM domain, inducing the K48-linked ubiquitination and proteasomal degradation of TAp73. Furthermore, we developed a CoV-E-targeting molecule, DPTP-FC, which blocks CoV-E-TAp73 interaction via forming steric hindrance and effectively alleviates iron accumulation and tissue damage caused by PEDV, PDCoV, and SARS-CoV-2 infection. Our study reveals the central role of the TAp73-FDXR axis in CoV-induced iron accumulation, highlighting CoV-E as an attractive antiviral target and DPTP-FC as a promising therapeutic candidate.

microbiology↗

bioRxiv2026

A Novel Bioprocess Control Strategy Under Uncertainty via Operational Space Identification

Bioprocesses are critical for sustainable industrial development but face challenges from their inherent uncertainties that affect efficiency and scalability. This study in-troduces a worst-case operational space design framework, integrating symbolic optimization with scenario-based validation, to preemptively mitigate uncertainties so that key performance indicators are consistently satisfied even under adverse conditions. The methodology is demonstrated through two case studies: a lab-scale fermentation for astaxanthin production and a site-scale anaerobic digestion for biogas production. Process uncertainty is quantified through model parameter variations (2% - 13%) to reflect real-world scenarios. The results indicate that highly flexible operational spaces are identified in both case studies, with control variables able to vary by up to 25% and 15% in the respective systems, while consistently adhering to system constraints. Validation over 10,000 scenarios confirmed 0 violation per case study. The proposed framework delivers validated operational flexibility with modest computational requirements, making it practical for lab-to-site deployment.

microbiology↗

bioRxiv2026

Injury-transduced SerpinOLs modulate neuroinflammation and glial activation in the diseased and non-diseased CNS

Oligodendroglial dysfunction is common in CNS diseases and injuries, but the molecular and functional responses of oligodendroglia to CNS pathologies remain poorly defined. Here, we report that oligodendrocytes (OLs) respond to demyelinating diseases by dysregulating serine protease inhibitor clade A member 3N (SERPINA3N). Homeostatic OLs transition to Serpina3n-expressing OLs (SerpinOLs) under other diseased conditions including stroke, endotoxicity, neurodegeneration, neurotrauma, and non-diseased healthy aging conditions. Mechanistically, general neuroinflammation or inflammatory mediators is insufficient for SerpinOL transition. Instead, oligodendrocyte damage/injury, even in the absence of neuroinflammation or glial activation, is sufficient for the transition. Phenotypically, SerpinOLs are characterized by molecular signatures of inflammatory and immune regulation and STAT3 signaling activation. Functionally, SerpinOLs exacerbate neuroinflammation and promote glial activation toward pro-inflammatory and neurodegenerative states. Together, our findings suggest SerpinOLs are a common population of injury-transduced OLs that amplify neuroinflammation and glial activation in the diseased and non-diseased CNS through SERPINA3N secretion. Our findings provide new insights into myelination-independent role of OLs in regulating CNS pathophysiology.

neuroscience↗

bioRxiv2026

Advancing Protein Design via Multi-Agent Reinforcement Learning with Pareto-Based Collaborative Optimization

Protein design is revolutionizing biotechnology, yet existing approaches struggle to balance structural foldability with functional performance. Structure-based models excel at generating stable protein backbones but often overlook critical functional properties, while protein language models capture evolutionary and functional signals but frequently predict sequences lacking structural stability. Integrating these complementary approaches remains challenging due to their inherently conflicting objectives. We present MAProt, a multiagent framework that synergistically combines structure-based and protein language model-based methods for protein design. Each agent specializes in a distinct aspect of the design objective: the structure-based agent (e.g., ProteinMPNN) ensures compatibility with the target backbone, while protein language model-based agents (e.g., ESM, SaProt) capture evolutionary plausibility and functional potential. To reconcile conflicts and achieve optimal trade-offs, we introduce a Pareto-based negotiation module that enables effective multi-objective coordination and consensus among agents. Extensive experiments on benchmark datasets demonstrate that MAProt achieves a remarkable improvement over state-of-the-art baselines, and generalizes robustly across a range of tasks, including thermodynamic folding stability design, functional protein design, and high-affinity antibody design. These results highlight the power of collaborative optimization for advancing rational protein engineering. Codehttps://github.com/biomed-AI/MAProt

bioinformatics↗

bioRxiv2025

Chronic stress abnormalize microglial-vascular interaction via AT1R signaling and microglia activation to drive depression-like behaviors

Depression entails a range of pathological processes in the brain, typically characterized by microglia activation, neural dysfunction, and vascular dysregulation. While it is well established that activated microglia inflict damage to neurons through direct and indirect microglia-neuron interactions, their interaction with vasculature and the associated regulation of vascular structure and function in depression remain poorly understood. Here, using a mouse model of depression induced by chronic unpredictable stress (CUS), we find that in stressed mice, activated microglia present reduced motility and decreased contact area with vasculature, which is accompanied by pathological vascular structure and function, marked by reduced vessel density, narrowed vascular diameters, and sluggish blood flow velocity. We observe that vascular structure in the stressed mice is rapidly modified by the vascular-contacted microglia. These vascular-contacted microglia show upregulated angiotensin II type 1 receptor (AT1R) expression, which is not present in the vascular-uncontacted microglia. Furthermore, we demonstrate that AT1R signaling together with microglia activation under chronic stress are critical mediators for the altered microglial-vascular contact situation, vascular dysregulation, as well as the depression-like behaviors. Together, our findings reveal that under CUS, the aberrant microglial-vascular interaction, including the dysregulated microglial vasoregulation arising from AT1R signaling and microglia activation, leads to depression, forging a new link between chronic stress and depression.

neuroscience↗

bioRxiv2025

Neocortical temporal patterning by a two-layered regulatory network

In the developing neocortex, a diverse array of neurons with defined types and abundances are systematically generated by a limited population of radial glial progenitors (RGPs) as they undergo successive fate changes. The molecular regulation behind this intricate temporal patterning remains elusive. We undertook in-depth single-cell multi-omics analyses, discovering a two-layered regulatory framework at the core of this process. Central to this are global temporal regulators positioned above a temporal network, consisting of series of transcriptional factor (TF) hub groups under sequential state transitions. This temporal network operates not by restricting TF expressions to discrete temporal windows, but through coordinated transcriptional and chromatin-accessibility dynamics that modulate transient TF regulatory activity. Moreover, global temporal regulators specify the duration of each cascading stage and, consequently, the number of progenies generated at each stage. Loss of global temporal regulators protracts RGP lineage progression, whereas their increased activity accelerates it. These findings suggest a two-layer temporal regulatory system controlling RGP lineage progression and neural progeny output duality in mammalian neocortical development.

neuroscience↗