Biology subjects

Lu, M.

Publications and source records attributed to Lu, M..

At least 19 recordsLinked to original sources

bioRxiv2026

A Single-Cell Atlas of PVOD Across the Lifespan Reveals Cellular and Molecular Therapeutic Targets

Rationale Pulmonary veno-occlusive disease (PVOD) is a progressive and lethal disease cured only lung transplant. While genetic mutations in EIF2AK4 have been identified in some cases, 70% of PVOD patients have no known etiology. Objectives To construct a single-cell atlas to define the cellular and molecular constituents driving pathophysiology in PVOD. Methods Lung samples were collected from four idiopathic non-EIF2AK4 mutation pediatric and adult PVOD patients and age-matched controls. Analyses of single-cell RNA sequencing, Xenium spatial transcriptomics, and immunohistochemistry were performed to identify cell state changes and differential gene expression between controls and PVOD and subsequent transcriptome comparison between our PVOD and published pulmonary arterial hypertension (PAH) datasets. Measurement and Main Results The single-cell atlas reveals marked changes in the PVOD endothelium compared to controls. EndMT and ectopic COL15A1+ systemic venous shunts and pulmonary vein endothelium are hallmarks of PVOD. Molecular analyses reveal activation of the integrated stress response (ISR)/ATF4, TGF{beta} signaling, MAPK signaling, and BRD4 are potential key players in the pathophysiology of PVOD. While PVOD and PAH share both pathological and some molecular mechanisms, ISR and TGF{beta} signaling are more prominent in PVOD than PAH. Conclusions These data indicate that endothelial dysfunction is a primary etiology in the development of PVOD with activation of multiple pathways with druggable targets.

molecular biology↗

bioRxiv2026

Conserved molecular compatibility for MIZ1 function in cytokinin signaling in land plants

Plant roots adjust their growth direction toward water through hydrotropism, a process that in Arabidopsis thaliana requires the endoplasmic reticulum (ER)-associated protein MIZU-KUSSEI1 (MIZ1). Nonetheless, MIZ1 orthologues occur throughout land plants, including lineages lacking true roots, raising questions about the ancestral function of this protein family. Here, we investigated the evolutionary conservation and functional diversification of MIZ1-like proteins across land plants. MIZ1 orthologues from evolutionarily distant land plants failed to restore hydrotropism or cytokinin sensitivity in the Arabidopsis miz1 mutant, despite conserved protein structure and ER localization. In the liverwort Marchantia polymorpha, loss of MpMIZ1a led to altered cytokinin sensitivity and cytokinin-mediated development in both the sporophyte and gametophyte. These phenotypes and gene expression analyses imply a conserved role of MIZ1 in cytokinin-related processes. Despite this functional similarity, protein-protein docking and bimolecular fluorescence complementation revealed species-specific interactions between MIZ1 proteins and their cognate cytokinin histidine kinase receptors in Arabidopsis and Marchantia. Together, our findings indicate that MIZ1 proteins represent ancient land plant regulators of cytokinin-dependent development whose molecular compatibility and developmental outputs have diverged during evolution. We propose that the role of MIZ1 in root hydrotropism represents a derived recruitment of this ancestral module into root-specific environmental response pathways.

plant biology↗

bioRxiv2026

HIV-1 envelope glycan loss links receptor adaptation and innate immune escape in SHIVs

Simian-human immunodeficiency viruses (SHIVs) are widely used to model HIV-1 infection in macaques, yet most SHIVs encoding circulating HIV-1 envelope glycoproteins (Env) replicate poorly because of inefficient use of macaque CD4 and sensitivity to host antiviral responses. During adaptation to macaques, Env is therefore subject to multiple selective pressures to improve receptor utilization while maintaining function in the face of host immune restriction. Type I interferon (IFN) is a major component of the host antiviral response during acute infection, and IFN resistance increases during SHIV adaptation to macaques through serial passage. However, the viral determinants of this resistance have remained unclear. Here, we show that serial passage of a lineage of SHIVs in macaques selected Env variants with markedly increased resistance to IFN- and enhanced replication in macaque CD4+ T lymphocytes. IFN- resistance mapped principally to loss of two highly conserved N-linked glycans at N197 and N276 near the CD4-binding site. Glycan loss altered the conformational landscape of virus-associated Env, enhanced macaque CD4-dependent entry and membrane fusion without increasing human CD4-dependent entry, and reduced incorporation of the IFN-inducible restriction factors IFITM3 and IFITM3A into progeny virions. Depletion of IFITM3/3A rendered the parental SHIV highly resistant to IFN- and abolished differential IFN- sensitivity among parental, adapted, and glycan-loss viruses. These findings reveal that loss of receptor-proximal Env glycans can simultaneously improve utilization of a heterologous CD4 receptor and promote escape from IFN-mediated restriction, linking receptor adaptation and innate immune evasion during lentiviral adaptation to a new host.

microbiology↗

bioRxiv2026

Immune determinants of leuprolide-associated cardiovascular risk in prostate cancer

Leuprolide, a widely used androgen-deprivation therapy (ADT) for prostate cancer (PC), has been associated with increased cardiovascular events (CVE), although the underlying mechanisms remain unclear. Through integrated spatial transcriptomic analyses of murine heart and immune-stromal profiling in patient blood, we identified immune programs linked to leuprolide-associated CVE risk. Spatial analyses revealed the distinct organization of lymphoid (T+B cells) aggregates and inflammatory macrophages in the plaque following leuprolide exposure that accompanied by ventricular hypertrophy, relative to normal vasculature. Parallel profiling of circulatory soluble and cellular components in patients demonstrated CD8+T cell enriched pattern in ~44% of patients, including memory and type 1 cytotoxic subsets that linked to treatment-induced CVE, such as ventricular dysfunctions, but no contribution of adipocytokines. These translational findings highlight the stratification of leuprolide-associated CVE risk in PC patients based on circulating T cell profiling and could guide the risk mitigation with alternative ADT agents.

immunology↗

bioRxiv2026

Joint inference of paired dynamical gene regulatory networks reveals distinct cell-state landscapes of neutrophil reprogramming

Disease reprograms cells through changes in gene regulation, yet identifying these changes remains a major challenge. We introduce NetDes-Duo, a computational method that jointly infers transcription factor regulatory network models for two related conditions using scRNA-seq data. The networks are optimized to have minimal topological differences, while the associated ODE models recapitulate single-cell gene expression trajectories for both conditions. On synthetic benchmarks, NetDes-Duo outperformed methods that infer each network independently. NetDes-Duo was applied to neutrophil reprogramming in naive and tumor-bearing mice, and the network-simulated dynamics reproduced the observed cell state transitions. The naive landscape had two well-separated basins, whereas the tumor-bearing landscape was more continuous, with three shallower basins. Perturbation and driving simulations also identified Cebpb as a key driver of the tumor-bearing transition, consistent with emergency granulopoiesis literature. We expect NetDes-Duo to be a broadly applicable framework for uncovering the regulatory logic of disease-associated cell state transitions.

systems biology↗

bioRxiv2026

The transcription factor Ste12(1) from Nakaseomyces glabratus acts pheromone-responsive in S. cerevisiae but seems decoupled from its cognate upstream GPCR in its native host.

G-protein-coupled receptor (GPCR)-mediated signalling pathways govern critical cellular responses in fungi, including mating, biofilm formation, and virulence. The mating pathway of Saccharomyces cerevisiae, in which peptide-sensing GPCRs (peptide GPCRs) activate a MAP kinase cascade and the transcription factor Ste12, has thereby served as the canonical model for fungal peptide GPCR signalling. Homologues of this pathway are conserved across many fungi, including the high-priority pathogen Nakaseomyces glabratus. Yet the function of this pathway in this mating-incompetent pathogen remains unclear. Here, we investigated whether the central transcription factor Ste12 of N. glabratus (NgSte12(1)) can act as a peptide GPCR-coupled transcription factor using a component-swapping strategy in which pathway elements from N. glabratus and S. cerevisiae were reciprocally exchanged and assessed using fluorescent and growth arrest readouts. We show that NgSte12(1) is in principle capable of supporting peptide-GPCR-dependent activation in S. cerevisiae, however, subtle and dependent on promoter identity. Ste12 chimaeras further demonstrate that all three NgSte12(1) subdomains are individually functional and compatible with their S. cerevisiae counterparts. Heterologous expression of ScSte12 in N. glabratus shows constitutive pathway activation, while NgSte12(1) does not show pathway activation in N. glabratus. Peptide-GPCR expression experiments indicate a block in N. glabratus signalling upstream of Ste12 (1): the S. cerevisiae peptide-GPCR Ste2 (ScSte2) activated the N. glabratus Ste12 GPCR-dependent downstream signalling constitutively, while NgSte2 failed to activate signalling in its native environment. Together, these results indicate that NgSte12(1) is a competent pheromone-responsive transcription factor that can couple to a heterologous GPCR in a heterologous context but is unresponsive to its own cognate upstream peptide/GPCR pair, either because it binds a yet unknown ligand or the signalling is rewired in this pathogen.

microbiology↗

bioRxiv2026

Peptide inhibitors recognize prefusion viral fusion proteins with heterogeneous stoichiometry and rapid kinetics

Peptide fusion inhibitors, an important class of antivirals, block viral entry by targeting fusion proteins required for membrane fusion. However, their interactions with intact trimeric fusion proteins remain elusive; direct observation of binding on virions or native-like trimers has been lacking. Here, we developed a single-molecule imaging platform to visualize peptide binding in real time. LP-98 bound HIV-1 Envelope (Env) trimers on virions and, unexpectedly, prefusion-stabilized soluble Env trimers, with higher affinity for virion-associated Env and, among soluble trimers, a mutant Env. RSV fusion-inhibiting T-118 and 4ca similarly engaged prefusion-stabilized fusion (F) trimers with rapid kinetics and high-nanomolar affinities. Binding to prefusion Env or F demonstrates that peptide inhibitors can act earlier than the canonical prehairpin-intermediate model suggests. Individual binding events revealed heterogeneous peptide-to-trimer stoichiometries, with single-peptide occupancy predominating, while stepwise and simultaneous events revealed multiple routes to higher occupancy. These findings expand the canonical model of peptide fusion inhibition and provide previously inaccessible mechanistic insights into how antiviral peptide fusion inhibitors act.

microbiology↗

bioRxiv2026

Melittin-induced membrane disruption in hepatocellular carcinoma involves mtROS/GSDME-mediated pyroptosis

Although melittin is classically regarded as a membrane-lytic peptide, it remains unclear whether its membrane-disruptive effects in tumour cells result exclusively from direct peptide-lipid interactions or are partly generated by pyroptosis. Here, we show that melittin markedly suppresses the viability and clonogenic growth of human Huh7 and murine Hepa1-6 HCC cells and rapidly induces characteristic features of pyroptosis, including cell swelling, balloon-like membrane protrusions, plasma-membrane permeabilization and lactate dehydrogenase release. In Hepa1-6 cells, melittin induced prominent GSDME cleavage and accumulation of its pore-forming N-terminal fragment, whereas GSDMD activation was not detected. Quantitative proteomics and ultrastructural analyses further revealed pronounced mitochondrial perturbation after melittin treatment, accompanied by loss of mitochondrial membrane potential and increased mitochondrial reactive oxygen species (mtROS). Importantly, scavenging mitochondrial oxidants with Mito-TEMPO markedly reduced mtROS accumulation, attenuated pyroptotic membrane damage and partially restored cell viability. Collectively, our findings provide, to our knowledge, the first evidence that melittin induces pyroptotic cell death in HCC cells through a mechanism involving mitochondrial oxidative stress and GSDME processing. These results extend the conventional view of melittin as a direct membrane-lytic peptide and uncover an mtROS/GSDME-associated pyroptotic mechanism underlying its antitumour activity in HCC.

cancer biology↗

bioRxiv2026

The mitochondrial RNA extrusion-induced innate immunity is regulated by N6-methyladenosine machinery

Mitochondrial RNA (mtRNA) released into the cytosol functions as a damage associated molecular pattern that activates pattern-recognition receptor (PRR)-mediated inflammation, yet its release mechanisms and cytoplasmic fate remain poorly understood. Here we report that chemical Abt-373-treatment and Vesicular stomatitis virus (VSV) infection induce mtRNA extrusion through Bax/Bak and VDAC1 channels, accompanied by mtDNA release. Extruded mtRNA in A549 cells activates multiple cytosolic PRRs, including RIG-I, MDA5, TLR3/7/8, and PKR, each contributing differentially to the innate immune signaling. Analysis of GEO datasets and methylated RNA immunoprecipitation (MeRIP) assays further reveals that mtRNA carries methyladenosine (m6A) modification. m6A machinery proteins are involved in the cytoplasmic retention time of mtRNA and its interaction with RIG-I, thereby modulating mtRNA-induced innate immunity. Thus, our work establishes in vitro models of mtRNA extrusion, and highlights m6A-dependent modulation as a potential therapeutic target for mtRNA-driven inflammation.

immunology↗

bioRxiv2026

Avs2 drives non-canonical tetrameric assembly of trypsin-like domain for anti-phage defense

Bacteria have evolved diverse anti-phage defense systems, with the antiviral STAND family (Avs) representing one of the most diverse and widespread, encompassing at least 90 distinct families, yet only Avs3, Avs4, Avs5 and Avs7 have been well characterized. Here, we elucidated the molecular mechanism of Avs2-trypsin-MBL system, where phage terminase recognition by Avs2 triggers coupled activation of the protease and nuclease activities of trypsin-MBL. Cryo-EM structure of Avs2-trypsin-terminase and biochemical analysis reveal that the binding of terminase ATPase domain triggers the assembly of Avs2 into tetramer, with two unique ATP molecules bridging ATPase active-site recognition by TPR domain. This tetramerization drives the fused trypsin into an active C4-symmetric assembly, an architecture distinct from the conventional non-defense trypsin. Our study unravels the activation mechanism of Avs2-trypsin-MBL system, expanding our understanding on commonality and diversity of widespread Avs-mediated anti-phage immunity, alongside the structural and functional adaption of trypsin.

microbiology↗

bioRxiv2026

A Time-Resolved Single-Cell Atlas Reveals Infection-Status, Age-, and Sex-Dependent Immune Responses Drive Viral Disease Severity

The majority of mortality during viral infections occurs in older males; however, underlying mechanisms by which age and sex shape antiviral immunity and pathological inflammatory responses remain incompletely understood. Here, we performed time-resolved single-cell RNA sequencing across 16 conditions spanning age, sex, and four stages of influenza infection in mice, generating a high-resolution atlas. Aged mice demonstrate delayed antiviral and inflammatory responses in multiple myeloid cells, impairing viral clearance, which delays recovery. Similarly, endothelial cells from aging mice show prolonged inflammatory and antiviral gene signatures. Altered gene signatures in immune and endothelial cells result in a shift in endothelial-immune interactions in the aged lung. Further, the infection status of the cell is a major driver of transcriptional state, with infected myeloid cells exhibiting broad upregulation of genes, including interferon-stimulated, inflammatory, complement, and oxidative stress-related genes. To assess whether these age-associated transcriptional patterns are conserved in humans, we examined BAL cells obtained from healthy individuals and COVID-19 patients, and found that immune cells from aged COVID-19 patients had elevated antiviral and pro-inflammatory gene expression compared to cells from young patients. Our analyses of sex differences identified that multiple myeloid cell types in aged male mice, but not in young male mice, show persistent inflammatory responses at later stages of infection, a likely mechanism contributing to elevated mortality in older males. These data reveal how infection status of the cell, age, and sex interact to drive persistent inflammation and impaired resolution, providing a foundational resource for designing age- and sex-specific therapeutic strategies.

immunology↗

bioRxiv2026

Hybridisation and herbivory fuel Amazonian tree radiations

Tropical rainforests, and Amazonia in particular, contain more tree species than anywhere else, most of which arose through rapid evolutionary radiations 1-3. Rapid radiations are often catalysed by ecological opportunity 4-6, which in rainforest trees is presented by intense insect herbivore pressure, spurring the evolution of novel plant defence chemistry to escape it 7. However, we do not understand how long-lived trees can adapt quickly enough to keep pace with rapidly-evolving insect herbivores. Here we show that hybridisation in rainforest trees, which was considered rare, allows exchange of gene clusters used in chemical defence against herbivore attack, facilitating rapid adaptation and diversification. Using genome sequencing for 461 individuals from the genus Inga, a characteristic Amazonian tree radiation, we find that regional tree communities form syngameons - networks of closely related, co-occurring species connected by gene flow. Integrating these genomes with herbivore abundance data from the same communities across the tropical Americas, we show that herbivore compositional turnover coincides with local, recurrent interspecific transfer of defence gene clusters that are retained by balancing selection, consistent with fluctuating selective pressure imposed by shifting herbivore communities. Together, our results demonstrate that hybridisation allows long-lived tropical trees to rapidly evolve chemical defences, fuelling adaptation to the relentless insect herbivory that structures the worlds most species-rich forests.

evolutionary biology↗

bioRxiv2026

LIN-44/Wnt controls developmental neurite pruning via UNC-43/CaMKII and PKC-2/PKC in C. elegans

During development, many neurons prune their neurites. While many pruning events are activity-dependent, some neurons undergo stereotyped and developmentally regulated neurite pruning, and our understanding of the signaling pathways that mediate this form of pruning remains limited. In this study, using the PDB motor neuron in C. elegans, we show that the Wnt-calcium signaling pathway is required for stereotyped neurite pruning during development. We found that mutants of itr-1/IP3 receptor and two calcium-dependent kinases, unc-43/CaMKII and pkc-2/PKC, exhibit neurite pruning defects. Genetic analysis suggested that they function downstream of lin-44/Wnt in neurite pruning. Human CaMKIIA can induce neurite pruning in C. elegans, and mutations in CaMKII genes in patients with intellectual disabilities affect its pruning function. In vivo calcium imaging revealed that PDB neurites exhibit calcium transients during neurite pruning, which are regulated at least in part by lin-44 and itr-1. Furthermore, we demonstrate that pkc-2 regulates neurite pruning through clathrin-mediated endocytosis. Together, our work reveals the critical functions of Wnt-calcium signaling in neurite pruning.

neuroscience↗

bioRxiv2026

Coupled intracellular redox and extracellular respiration sensing for quantitative oxidative stress profiling

Quantitative assessment of cellular oxidative stress requires simultaneous measurement of intracellular redox state and extracellular respiratory activity, yet integrated sensing approaches remain limited. Here, we present a dual-fluorescent sensing platform combining a genetically encoded redox biosensor (roGFP2{square}Tsa2{Delta}CR) with an optical oxygen sensor embedded in microwell plates for parallel, non-invasive quantification of intracellular reactive oxygen species (ROS) and oxygen consumption rates (OCR) in industrial yeast systems. The roGFP2-based sensor was stably expressed in Saccharomyces cerevisiae (S. cerevisiae) and Yarrowia lipolytica (Y. lipolytica), enabling dynamic monitoring of oxidative stress at population, single-cell, and subcellular levels, while oxygen-sensitive films provided real-time respiration measurements. Using this platform, we identified distinct redox-respiration phenotypes between the two yeasts. Crabtree-positive S. cerevisiae exhibited low OCR and mitochondrial ROS during glucose cultivation, whereas growth on glycerol increased OCR and mitochondrial ROS by ~2.5-fold and 12%, respectively. In contrast, the obligate respiratory yeast Y. lipolytica displayed 3-fold higher OCR and 16% lower mitochondrial ROS than respiring S. cerevisiae, indicating differences in respiratory oxidative burden. Antimycin A treatment reduced OCR by 60% in respiring S. cerevisiae while increasing mitochondrial ROS by 35%, whereas Y. lipolytica showed greater resistance to respiratory and oxidative perturbations. By integrating intracellular redox sensing with extracellular oxygen measurements, this platform enables quantitative coupling of redox state and respiration in living cells. The approach provides a scalable framework for evaluating cellular fitness, stress tolerance, and metabolic state in biomanufacturing and synthetic biology.

bioengineering↗

bioRxiv2026

Identification, optimization, and structural elucidation of chloroacetamide scaffold as covalent inhibitors for Ubiquitin C-terminal Hydrolase L3

The deubiquitinating enzyme, ubiquitin C-terminal hydrolase L3 (UCHL3), has been implicated as a potential therapeutic target for cancer with a role in regulating the DNA damage response pathways. While the target has been studied using genetic methods there is a lack of reliable chemical probes to selectivity target UCHL3. In this study we report hit identification and optimization of a new chemical scaffold that irreversibly inhibits UCHL3. The observed structure-activity relationships are corroborated by ligand-bound crystal structures that confirm covalent adduct formation with the catalytic cysteine of the enzyme. Finally, through gel-shift assays using a ubiquitin activity-based probe we demonstrate on-target engagement with UCHL3 in two cell lines. The work as a whole presents a comprehensive evaluation of the new scaffold that can be utilized to probe UCHL3 in different biological contexts.

pharmacology and toxicology↗

bioRxiv2026

Genomic Decoding of Specialized Aromatic Hydrocarbon Degradation in Mangrove-Derived Gordonia sp. B7 2

Petroleum pollution has increased worldwide, driving the search for microorganisms with efficient hydrocarbon-degrading capabilities. Here, we report a novel bacterium, Gordonia sp. B7-2, isolated from mangrove sediments in Hainan, China. Phylogenetic analysis based on the 16S rRNA gene and whole-genome sequences, together with digital DNA-DNA hybridization and average nucleotide identity values, supported its classification as a new species within the genus Gordonia. The complete genome of strain B7-2 consists of a single circular chromosome of 5.39 Mb with a G+C content of 65.99%, and encodes 4,887 protein-coding genes. Genomic annotation revealed a complete pathway for aromatic hydrocarbon degradation, including genes encoding protocatechuate 3,4-dioxygenase and biphenyl-2,3-diol 1,2-dioxygenase, whereas genes involved in the initial oxidation of alkanes were absent. Consistent with these genomic predictions, strain B7-2 degraded 64.33% of crude oil (300 mg/L) within 28 days, with rapid degradation during the initial 14 days, followed by a slower phase thereafter, reflecting the dynamics of complex hydrocarbon mixtures. Together, these results demonstrate that strain B7-2 is specialized for the degradation of aromatic hydrocarbons and highlight its potential for targeted petroleum bioremediation. IMPORTANCEMangrove ecosystems are highly vulnerable to petroleum contamination, yet the microorganisms responsible for hydrocarbon turnover in these environments remain poorly characterized. This study describes a new bacterial species, Gordonia sp. B7-2, that exhibits a strong metabolic specialization for aromatic hydrocarbon degradation. Unlike many known oil-degrading bacteria that preferentially utilize alkanes, strain B7-2 targets aromatic components of crude oil, which are among the most persistent and toxic fractions.Its ability to efficiently degrade crude oil highlights its potential in the bioremediation of contaminated coastal environments and expands our understanding of microbial contributions to hydrocarbon cycling in mangrove sediments

microbiology↗

bioRxiv2026

Targeting the APRIL-BAFF axis in IgA nephropathy: preclinical insights from influenza challenge and single-cell spatial profiling

BackgroundAPRIL and BAFF are TNF superfamily cytokines that regulate B-cell development, survival, and antibody production, and are emerging therapeutic targets for IgA nephropathy (IgAN). Selective APRIL and dual APRIL/BAFF inhibitors both reduce IgA and proteinuria in IgAN clinical trials, but whether their broader immunological consequences differ has not been systematically characterized. MethodsWe compared selective APRIL and dual APRIL/BAFF inhibition using influenza vaccination and lethal challenge, KLH immunization, serological profiling, and flow cytometry in mice, alongside human B-cell survival assays in vitro. Single-cell CITE-seq and in situ spatial transcriptomics were applied to characterize molecular and tissue-level changes in the spleen. ResultsBoth modes of inhibition reduced serum IgA by [≥]60% in mice. However, dual APRIL/BAFF inhibition nearly abolished vaccine-mediated protection against lethal influenza challenge (10% versus 70% survival in controls; p < 0.01), whereas selective APRIL inhibition had limited impact on protective immunity. This functional divergence was underpinned by broad cellular disruption under dual blockade, including >80% depletion of splenic B cells, loss of T follicular helper cells, and impaired antigen-specific IgM and IgG responses. Selective APRIL inhibition left these populations and responses largely intact. Consistent with these findings, human B-cell survival in vitro was dependent on BAFF, not APRIL. Single-cell and spatial transcriptomics revealed that dual blockade collapsed follicular architecture, eliminated germinal centers, and disrupted chemokine organization, whereas these structures remained intact under selective APRIL inhibition. At the molecular level, dual blockade, but not selective APRIL inhibition, downregulated NF-{kappa}B survival signaling and antigen presentation programs and shifted surviving germinal center B cells toward a pro-apoptotic state. ConclusionsSelective APRIL and dual APRIL/BAFF inhibition both reduce IgA, the pathologically relevant isotype in IgAN, but only dual blockade disrupts B-cell maturation, germinal center function, tissue architecture, and protective immunity. These findings inform the benefit-risk assessment of chronic B cell-targeting therapies in IgAN.

immunology↗

bioRxiv2026

Multiscale transcriptomic organization of the human brain with DigitalBrain

The human brain varies across anatomical regions, cell types, development, aging and disease states, yet existing single-cell transcriptomic resources remain fragmented and difficult to integrate into a unified biological model. Here we present DigitalBrain, a human brain-specific atlas and foundation-model framework for organizing diverse and fragmented human brain transcriptomic data across scales. We first built DigitalBrain-Atlas, a harmonized whole-brain single-cell resource comprising 16.35 million transcriptomes from 2,143 donors across 165 brain regions, spanning the human lifespan and multiple neurological and clinical conditions. We then developed DigitalBrain-M1, a Transformer-based model that jointly encodes gene identity and expression magnitude to learn a shared embedding space for cells and genes. Across held-out datasets, DigitalBrain supported robust single-cell integration, clustering and cell-type annotation while preserving major biological structure and reducing technical fragmentation. Beyond these benchmarks, the learned embeddings revealed emergent large-scale hierarchical organization of the human brain, linking anatomically distinct regions into higher-order patterns consistent with known functional systems. Applied to human hippocampal aging, DigitalBrain identified cell-type-specific aging sensitive gene sets, highlighted dentate gyrus granule cells as a particularly age-sensitive population, and discovered selective reorganization of gene programs related to synaptic transmission, postsynaptic structure, membrane excitability and axon guidance during aging. Cross-dataset convergence was strongest at the level of functional modules and recurrent aging sensitive genes. Together, these results demonstrate that DigitalBrain is a brain-specific framework for mapping human brain organization across scales, and as an early step towards a complete virtual organ for the human brain.

bioinformatics↗