Biology subjects

Huang, Z.

Publications and source records attributed to Huang, Z..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Integrative spatial profiling of 3D genome organization and gene expression in tissue

The interplay between 3D genome architecture and transcriptional activity is fundamental to gene regulation. However, existing methodologies cannot simultaneously measure these modalities within intact tissues, limiting our understanding of how genome organization coordinates transcriptional programs across diverse cell types and spatial microenvironments. Here, we introduce Spatial Hi-C-RNA, a spatial multi-omics technology that enables the genome-wide co-mapping of chromatin conformation and transcriptome directly from the same tissue section at near- single-cell resolution. Applied to the mouse embryo and adult brains, Spatial Hi-C-RNA generated high-resolution tissue maps revealing that chromatin organization and gene expression jointly define spatially coherent domains aligned with histological structures. While concordant features were observed across modalities, distinct domain patterns also emerged, indicating that chromatin structure and transcription each contribute complementary layers of spatial regulation. We further demonstrated the robustness and biological insight of Spatial Hi-C-RNA in human melanoma, where both modalities delineated tumor boundaries and microenvironmental niches. Notably, chromatin maps revealed fine-scale tumor subdomains undetectable by transcriptomic profiling alone, highlighting the added resolution provided by spatial chromatin architecture. Integrated analysis revealed that multiscale 3D genome features, from A/B compartments and topologically associating domains to chromatin loops, are closely coupled with domain- and cell-type-specific transcriptional programs. In addition, Spatial Hi-C-RNA resolves spatiotemporal dynamics underlying embryonic lineage specification and tumor progression. Together, these capabilities extend the spatial omics landscape beyond transcriptome and epigenome profiling to the level of chromatin organization, establishing an integrative framework for understanding tissue biology across development and disease.

genomics↗

bioRxiv2026

An integrated single-cell atlas of human lung across the lifespan

The healthy adult lung is largely quiescent but can respond to injury and replace damaged or lost cells. However, the identities and origins of regenerative cell states remain poorly understood. Here we present the Human Developmental Lung Cell Atlas (HDLCA), a curated single-cell reference atlas of the respiratory system across the lifespan, integrating 253 datasets from 225 studies, and comprising over 18 million cells from 3,198 samples and 2,460 individuals across 34 anatomical locations in both health and disease. The HDLCA defines 142 consensus lung cell types, including 13 rare and 8 previously undescribed ones. Notably, we identify a rare intermediate alveolar epithelial progenitor (Int AP) population in normal lungs, with transcriptional signatures shared by alveolar type 2 (AT2) and alveolar type 1 (AT1) cells. Trajectory inference indicates that Int AP cells arise from both AT2 and SCGB1A1+ secretory cells and give rise to AT1 cells, with Hippo-YAP/TAZ signalling governing lineage specification. Int AP cells are associated with genetic susceptibility to idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, and their dysfunction may contribute to abnormal alveolar repair and regenerative failure in both diseases. The HDLCA provides a unified atlas-level reference for mapping respiratory cellular diversity, uncovering reparative cell dynamics and informing regenerative and cell-based therapeutic strategies.

bioinformatics↗

bioRxiv2026

Cerebral Encoding of Word Classes is Distributed and Context-Dependent

Word classes such as nouns, verbs, and adjectives are fundamental units of language, but their neural encoding remains unclear. Here, we investigate whether word classes are processed as invariant, context-independent lexical categories or depend on sentence context during language processing. We analyse source-localized magnetoencephalography (MEG) data from 200 native Dutch participants who read or listened to sentences and their scrambled counterparts (word lists) from the MOUS dataset. Time-resolved encoding models are used to predict neural responses from major word classes (noun, verb, adjective) and other linguistic variables including word frequency, surprisal, entropy, word length, and ordinal position. Across modalities, we observe a significant interaction between word class and context (sentences vs. word lists), manifest as dynamic modulation of neural responses in a widespread cortical network including bilateral perisylvian, frontal, and midline regions previously implicated in lexicosemantic, structural, and pragmatic processing. This interaction emerges early and reappears later in processing, with distinct temporal profiles for reading and listening. Within-condition effects reveal that word class contributes to neural responses at the level of individual words, but this contribution is context-dependent: it is robust in sentences across modalities and in word-list reading, but absent in auditory word lists. These results indicate that word-class encoding is shaped by the interaction between word-level properties and sentence context during real-time language processing.

neuroscience↗

bioRxiv2026

SemVac: A Semantic Vaccinology Paradigm Powered by LLMs for Antigen Discovery

Reverse vaccinology identifies vaccine antigens from pathogen genomes, yet existing methods rely mainly on sequence and structure and overlook the functional and immunological knowledge recorded in the published literature. We introduce semantic vaccinology, a paradigm in which large language models (LLMs) reason over literature-derived protein descriptions to predict protective antigens. Implemented as SemVac, the workflow retrieves publications linked to each protein through PaperBLAST, condenses the evidence into a structured semantic profile, and prompts an LLM to return an antigenicity probability. Benchmarked against a curated 246-protein bacterial benchmark and the specialized protein-language and geometric-deep-learning predictor PLGDL, the best of 14 general-purpose LLMs matched or exceeded the precision of PLGDL; the open-weight Kimi K2 0905 offered the strongest performance-cost balance. Predictions were robust to masking of vaccine keywords, reproducible across repeated inference, and generalized to a 1,200-protein cross-pathogen dataset. Surprisingly, explicit chain-of-thought reasoning increased recall but lowered precision in every model tested, revealing over-reasoning in biological scoring. Applied to the mpox virus proteome, SemVac recovered the established mpox antigen repertoire and prioritized uncharacterized candidates. Two of these, A30L and C19L, received independent experimental support in recent orthopoxvirus vaccine development, providing external validation. For one candidate, B20R, the model generated a coherent but false TNF-decoy narrative unsupported by curated annotations, demonstrating that LLM confabulation can be detected when reasoning traces are cross-checked against curated resources. Semantic vaccinology therefore establishes the literature as an explicit, auditable third modality alongside sequence and structure, while making its failure modes transparent and correctable.

immunology↗

bioRxiv2026

An immunocompetent model of MCPyV-driven Merkel cell carcinoma reveals tumor evolution under immune selection

Merkel cell carcinoma (MCC) is a neuroendocrine skin tumor that is frequently driven by integration of Merkel cell polyomavirus (MCPyV). In MCC, the MCPyV genome is truncated, but expression of the viral tumor antigens, truncated large tumor antigen (LTT) and small tumor antigen (sT), is maintained and drives uncontrolled proliferation. We introduced constitutive expression of the MCPyV T antigens (TAs) into primary mouse dermal fibroblasts (MDFs) to determine whether these cells are susceptible to MCPyV-driven transformation. TA expression alone in MDFs induced key MCC markers, cytokeratin-20 (CK20) and Sry-box transcription factor 2 (SOX2), and promoted anchorage-independent growth indicative of cellular transformation. Subcutaneous implantation of TA-transformed fibroblasts produced high-grade MCC-like tumors that grew persistently in immunodeficient NSG mice but not in immunocompetent C57BL/6 mice. Serial in vivo passaging of the tumor cell line enhanced tumor growth, reduced expression of p53-target genes and MHC-1, and was accompanied by a shift in T antigen isoform expression, with decreased LTT and increased sT expression. Our data demonstrate that MCPyV-driven tumors acquire immune-evasive adaptions during tumor progression in vivo and suggest that the anti-tumor immune response exerts selective pressure in MCC that favors expression of sT rather than LTT. The model established in this study provides a unique platform for studying evolution of MCPyV-driven tumors under immune pressure and identifying mechanisms of immune evasion in MCC that could be used to develop new therapeutic strategies. Significance StatementMCPyV tumor antigen expression transforms mouse dermal fibroblasts to generate MCC-like tumors. Serial in vivo passaging reveals tumor evolution under immune pressure, providing a model to study immune evasion mechanisms in MCC.

cancer biology↗

bioRxiv2026

SALL2 constrains TEAD4 by maintaining repressive chromatin to restrict trophectoderm identity

Embryonic development is marked by the successive restriction of developmental potential and the specification of embryonic and extraembryonic lineages. Yet, how these lineage decisions are established, and how the epigenome is remodelled to promote and restrict cell fate transitions, remains poorly understood. Here, we demonstrate that SALL2 knockdown in primed human pluripotent stem cells (hPSCs) triggers a trophectoderm (TE)-like phenotype, characterized by palisade-like morphology and the up-regulation of TE-associated genes. Mechanistically, SALL2 physically interacts with the key TE driver TEAD4 and maintains bivalent, repressive chromatin (H3K4me3/H3K27me3) at TE-specific loci. Reduced SALL2 led to enhanced TEAD4 occupancy and disrupted H3K27me3 and increased active chromatin marks at TE genes. Importantly, depletion of TEAD4 abolished the TE-like phenotype induced by SALL2 knockdown, demonstrating that TEAD4 is required for the downstream effects of SALL2 loss. In support of this, blastoid-like aggregates can be generated from primed hPSCs with SALL2 knocked down. Together, our findings identify SALL2 as a key epigenetic barrier that restrains TE lineage commitment by limiting TEAD4-dependent activation of the trophoblast transcriptional program. Key findingsO_LISALL2 acts as a molecular barrier to trophectoderm differentiation. C_LIO_LISALL2 suppresses the trophectoderm by maintaining bivalent repressive chromatin at TEAD4-bound loci. C_LIO_LIBlastoid-like structures can be generated from primed-state media when SALL2 was knocked down. C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=91 SRC="FIGDIR/small/737659v1_ufig1.gif" ALT="Figure 1"> View larger version (20K): org.highwire.dtl.DTLVardef@42cafaorg.highwire.dtl.DTLVardef@11c040borg.highwire.dtl.DTLVardef@4d9ffborg.highwire.dtl.DTLVardef@42546a_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2026

Kidney medulla macrophages maintain a free flow of urine by sensing force

Blockade by sedimentary particles, such as mineral crystals, is a continuous risk the kidney tubule faces. To prevent that, kidney resident macrophages form transepithelial protrusions and remove intratubular sedimentary particles, a behavior particularly prevailing in the medulla over the cortex. However, the molecular mechanisms underlying this characteristic behavior of medulla macrophages are incompletely understood. In this study, we identified that the medulla had higher mechanical stiffness than the cortex in steady state, which was further elevated when kidney stone formed. Increased tissue rigidity was sensed by medulla macrophages via mechanoreceptor Piezo1, which promoted macrophage protrusion formation and their ability to clean the tubules. Loss of Piezo1 expression in kidney macrophages predisposed mice to intratubular accumulation of mineral crystal in steady state and accelerated kidney stone formation during oxalate intake challenge. Signaling via Piezo1 mobilized molecules involved in cell adhesion and protrusion assembly, including Talin2 and focal adhesion kinase (FAK). Finally, we developed a first-of-its-kind cell-based therapy for the treatment of experimental nephrolithiasis by exploiting macrophage Piezo1 activity, and this strategy shows great promise for future translational research.

physiology↗

bioRxiv2026

Ancient pyroptotic machinery via GSDMA/B cleavage by LPS-activated caspase-1 in cartilaginous fish

Gasdermins are pore-forming effectors that mediate pyroptosis, an inflammatory form of programmed cell death characterized by membrane permeabilization and the release of intracellular contents. Phylogenetically, gasdermin members can be broadly divided into two major branches, the GSDME/PJVK branch and the GSDMA/B/C/D branch. Whereas the GSDME mediated pyroptosis was traced back to metazoans, the functional origins of GSDMA/B/C/D branch remain poorly understood. As a basal representative of the GSDMA-D lineage in cartilaginous fish, Callorhinchus milii GSDMA/B (CmiGSDMA/B) provides essential information for the ancestral state of this branch. Here, we functionally characterized CmiGSDMA/B and identified CmiCASP1 as its upstream protease. Mechanistically, Lipopolysaccharide (LPS) activates CmiCASP1 via its CARD domain, leading to cleavage of CmiGSDMA/B into two functionally distinct products, N241 and N288. N241 binds cell membrane to drive pyroptosis, whereas N288 suppresses N241-triggered cell death. Interestingly, N241 exhibits bactericidal activity against Gram-negative bacteria in vitro, suggesting that antimicrobial activity may have been an early feature of the GSDMA-D lineage. Collectively, these findings provide insight into a non-canonical, LPS-responsive, caspase-driven pyroptosis pathway in cartilaginous fish and reveal the dual-fragment antagonistic regulation within this branch.

evolutionary biology↗

bioRxiv2026

Evolutionary Origins of Molecular Programs Underlying Brain Circuitry

The vertebrate pallium harbors independently evolved structures that, nevertheless, support strikingly similar sensory and cognitive circuit architectures. The mechanisms and evolutionary timing driving the emergence of these parallel pallial circuits remain unelucidated. Here, we integrated spatial transcriptomic and single-nucleus RNA-seq datasets from eight representative vertebrate species spanning approximately 500 million years of evolution to reconstruct the evolutionary assembly of the primary sensory-allocortical (Pr-Al) molecular axis, a conserved cortical hierarchical axis defined in our prior work. We uncovered that Pr- and Al-like neuronal identities are deeply conserved across sarcopterygians, encompassing all tetrapods and lobe-finned fishes. Intriguingly, this ancestral neuronal homology is uncoupled from spatially partitioned patterning: only tetrapods further compartmentalized these Pr- and Al- neurons into distinct pallium regions. Functional enrichment of Pr- and Al- gene programs uncovered a conserved tetrapod genetic core suite including MAPK signaling and axon guidance pathways. This core toolkit underwent sequential functional refinement from amphibians through mammals. Notably, mammals and birds convergently evolved association-cortical molecular profiles enriched for synaptic regulatory genes to support advanced cognitive functions. Collectively, this work delineates a stepwise vertebrate pallium evolutionary paradigm that explains how conserved molecular modules shape spatially organized brain circuitry across deep evolutionary time.

evolutionary biology↗

bioRxiv2026

Coral settlement module designs for scalable reef restoration

The global coral reef crisis has prompted restoration initiatives worldwide. Targeting the coral larval stage is among the most scalable approaches as recruitment operates over large spatial scales. It thus represents one of the best levers for coral population recovery. Active coral larval seeding has shown considerable success, and passive substrate engineering has emerged as a promising complementary strategy. Coral settlement modules featuring helix recesses have increased settlement and survival by up to 80-fold on small experimental units, but whether these results translate to tools deployable at the scale of thousands of units, remains yet an open question. Here, we transferred structural features from successful experimental coral settlement designs into production-ready concrete modules to (i) evaluate coral recruitment on five designs at four reef sites differing in flow regime and coral cover over one year; (ii) compare production-scale performance against experimental clay modules and natural reef substrate; and (iii) identify key parameters for large-scale production. The helix recess geometry of coral settlement modules outperformed the featureless control design approximately 20-fold and exceeded natural reef recruitment at least 3- to 32-fold. The helix features were successfully transferred from experimental clay to production-scale concrete modules, yielding comparable settlement densities when standardized to crevice length, which proved to be the biologically relevant unit of available habitat. Production feasibility was demonstrated by producing 690 modules for deployment on a hybrid reef on the west side of Oahu, Hawaii. The passive coral larval recruitment approach presented here could substantially improve the logistical and economic feasibility of large-scale coral reef restoration. This approach requires neither coral larval rearing, handling, nor coral fragmenting, and is compatible with active larval seeding where genetic diversity or larvae supply are limiting factors. The coral settlement modules can be cast in standardized concrete molds at precast facilities. Modules have demonstrated consistent coral recruitment enhancement across reef environments with contrasting flow and coral cover. Deploying mixed arrays of helix-recess structures with designs offering multi-level complexity and three-dimensional rugosity maximizes outcomes for coral, fish, and invertebrate communities simultaneously. Site selection is the most critical deployment decision and should consider larval supply, hydrodynamics, and substrate stability which drive recruitment outcomes more than design choice alone. The modules offer a range of application potential, ranging from integration into existing coastal infrastructure over stand-alone reef restoration approaches, to substrate-consolidating interconnected arrangements.

ecology↗

bioRxiv2026

A GPX4 phosphorylation switch by FGFR1 guards against ferroptosis

Ferroptosis is driven by lipid peroxidation, yet the mechanisms by which cells rapidly adjust their sensitivity to ferroptosis in response to extracellular cues remain elusive. We identify a direct phosphorylation switch controlling the activity of glutathione peroxidase 4 (GPX4), the core ferroptosis regulator. The receptor tyrosine kinase FGFR1 directly binds and phosphorylates GPX4 at Tyr180/Tyr196 in a kinase-dependent manner, requiring its Tyr730 as a docking site. This phosphorylation enhances GPX4s catalytic activity and suppresses ferroptosis. In cardiac ischemia/reperfusion injury, the FGFR1-GPX4 axis is suppressed, and a selective FGFR1 agonist (FGF-1{Delta}NT) reactivates it to protect against ferroptosis-mediated damage. Critically, a phosphorylation-deficient GPX4 knock-in mouse exhibits hypersensitivity to injury and non-responsive to this agonist, proving that GPX4 phosphorylation is essential. Our findings reveal a rapid mechanism for regulating ferroptosis via GPX4 tyrosine phosphorylation, directly linking receptor tyrosine kinase signaling to ferroptosis, and offering new strategies for treating ischemic-and other ferroptosis-associated diseases.

Cell Biology↗

bioRxiv2026

Lack of ancestral SARS-CoV-2 imprinting promotes BA.3.2.2 infection in children

The ongoing evolution of SARS-CoV-2 is heavily constrained by population-level immune imprinting. Recent genomic surveillance reveals an unexpected demographic shift: the highly mutated BA.3.2.2 sublineage is significantly enriched in paediatric populations globally, unlike concurrent variants XFG and NB.1.8.1. Here, the evidence demonstrates that this paediatric susceptibility arises from the absence of ancestral Wuhan-strain immune imprinting. Serological analyses reveal a profound failure to neutralise BA.3.2.2 in young children with no ancestral strain exposure. Concurrently, single-B-cell sequencing analyses demonstrate that BA.3.2.2 completely evades Omicron-specific Class 1/4 neutralising antibodies, encoded by IGHV2-5 and IGHV5-51, which dominate the repertoires of weakly imprinted individuals such as young children. Conversely, BA.3.2.2 remains uniquely susceptible to broadly cross-reactive Class 1 antibodies, encoded by IGHV3-53/66, typically enriched in adults with strong ancestral imprinting, such as mRNA vaccine recipients. Critically, sustained transmission of BA.3.2.2 in paediatric populations may catalyse the emergence of secondary variants that combine the paediatric-evading features of BA.3.2.2 with adult-evading Class 1 mutations. This could allow the lineage to breach the imprinted immunity of the adult population, potentially driving widespread global transmission. Together, these findings show that legacy immune imprinting paradoxically provides superior protection against a highly divergent saltation variant, directly explaining the age-biased transmission of BA.3.2.2, and informing future paediatric vaccination strategies.

immunology↗

bioRxiv2026

Tracing the Evolutionary Origin of Interferon to Basal Chordates and Unveiling Its Antiviral Functionality in Jawless Vertebrates

Interferons (IFNs) are essential mediators of antiviral defense in vertebrates, having gradually replaced the RNA interference (RNAi) antiviral mechanism that predominates in invertebrates and plants. To date, IFNs have been identified exclusively in jawed vertebrates, leaving the origin of IFN-based antiviral mechanisms largely mysterious. In this study, by conducting a genome-wide screening of IFN homologs accross various species, we successfully identified seveal IFN homologs from agnatha and lancelet, but not other invertebrates. Notably, both agnatha and lancelet IFN homologs have ability to induce a set of interferon-stimulated genes (ISGs)-like genes, thus tracing the origin of IFN to basal chordate. Using VSV infected peripheral blood mononuclear cells (PBMCs) of Japanese lampreys, we found that lamprey IFNs have antiviral functionality by inducing the expression of hundreds of ISGs through interacting with a heterodimeric complex composed of CRFB7 and CRFB14. In addition to robustly mediating antiviral responses in monocytes, lamprey IFNs exert their effects on variable lymphocyte receptor B (VLRB)+ cells by remodeling the cytokine/chemokine networks to orchestrate antiviral innate and adaptive immunity. Furthermore, cross-species functional comparison of Dicer revealed that changes in residues essential for dsRNA processing occurred concurrently with the evolution of the IFN system. Collectively, these findings uncover the evolutionary origin of IFN and underscore its ancient roles in antiviral response and immune regulation, especially in the takeover of the RNAi antiviral mechanism during the early evolution of vertebrates. Significance StatementInterferons (IFNs) represent a hallmark of vertebrate antiviral immunity, yet their origin has remained elusive. Here, we reported bona fide IFN ligands and cognate receptors in both lamprey and lancelet, two key species placed at the transition from invertebrates to vertebrates. Using the VSV infection model, we further demonstrated the roles of lamprey IFN in antiviral defense and immune regulation. We also found that substitutions in residues essential for Dicer mediated dsRNA processing coincided with the emergence of the IFN system. Collectively, our findings provide key insights into the evolutionary origin of IFN-based immunity and its gradual replacement of RNAi as the dominant antiviral strategy in vertebrates.

evolutionary biology↗

bioRxiv2026

Linezolid Acts as a Selective Inhibitor of the JAK2V617F Mutation

The JAK2V617F (JAK2VF) driver mutation is found in 95% of patients with polycythemia vera (PV), a progressive myeloproliferative neoplasm. Current treatments suppress excessive hematopoiesis but lack specificity for targeting JAK2VF cells, are unable to deplete mutant stem/progenitor cells and ultimately result in drug resistance. We discovered that the FDA-approved antibiotic, linezolid (LZD), ameliorates the PV phenotype across multiple model systems. LZD suppressed cell proliferation and STAT5 signaling, altered the cell cycle, and increased apoptosis of JAK2VF-harboring human erythroleukemia cells, but not in wild-type acute leukemia cells. Computational modelling indicated that LZD interacts specifically with mutant JAK2VF but not with wild-type JAK2 protein. We further showed that, in JAK2VF mice that faithfully recapitulate human PV, LZD mitigates disease burden by selectively targeting JAK2VF stem cells thereby normalizing spleen size and blood counts. LZD also inhibited hematopoietic colony formation by patient-derived peripheral blood mononuclear cells, with the more primitive progenitors being preferred targets. Importantly, LZD selectively decreased JAK2VF+ colony numbers, without impacting wild-type JAK2 colonies. In all, the data provide a firm foundation for evaluating LZD-like molecules as an effective therapy for PV and other myeloproliferative neoplasms. Key pointsO_LILinezolid acts as a JAK2V617FIZselective inhibitor in PV mouse models and PV patient samples while sparing wildIZtype hematopoiesis. C_LIO_LILinezolid acts directly on JAK2V617F hematopoietic stem cells. C_LI

cancer biology↗

bioRxiv2026

Repurposing of the assembly chaperone PAC1-PAC2 defines a specialized proteasome landscape in mature mammalian sperm

Mature mammalian sperm rely on active proteasomes containing the testis-specific subunit 4s for capacitation, acrosomal exocytosis and fertilization, but how these proteasomes are structurally specialized remains unclear. We determine the endogenous proteasome landscape of mature bovine spermatozoa and testis using cryo-electron microscopy. We resolve five sperm proteasome assemblies: PA200-20S, free 20S, a previously unrecognized PA200-20S-PAC1/2 hybrid, and PAC1/2-20S complexes capped at one or both ends. Unexpectedly, the PAC1/2-bound complexes are mature and POMP-free, selectively incorporated for 4s, lack 2, and adopt a PAC1/2 orientation and gate configuration distinct from known assembly intermediates. Together with elevated proteolytic activity, these features indicate that PAC1/2 is repurposed from a transient assembly chaperone into a stable post-assembly regulator in mature sperm. 4s-containing proteasomes assemble through the canonical PAC1-PAC4/POMP pathway yet may follow {beta}2-{beta}3-{beta}1 incorporation ordering; functionally, 4s incorporation remodels the sCP surface and enhances peptidase activities, definining the spermatoproteasomes as a hyperactive 20S variant. PAC1/2-bound proteasomes are absent from testis, where PA200-20S and 26S proteasomes are present, while 26S proteasomes are nearly lost in mature sperm. Our findings define a sperm-specific, ATP-independent proteasome landscape, expand the functional repertoires of 4s and PAC1/2, and provide a structural framework for proteasome specialization in male fertility.

cell biology↗

bioRxiv2026

Reorganization of Human Brain Waves Across Diverse States of Consciousness

Brain waves are ubiquitous phenomena of human brain activity. As they propagate, they coordinate neural communication, shaping conscious perception. Understanding how brain waves unfold across space and time is thus critical for uncovering the neural mechanisms that support and suppress consciousness. Here, we analyzed data from the Human Connectome Project alongside multiple independent human datasets of various states of consciousness collected during non-rapid eye movement sleep, propofol anesthesia, and psychedelic states produced by lysergic acid diethylamide, N,N-dimethyltryptamine, psilocybin, nitrous oxide, and ketamine. We then applied complex principal component analysis to map spatiotemporal propagation patterns of blood oxygen level-dependent activity across the human brain, under these diverse states of consciousness. We identified four dominant motifs of wave propagation: a global synchronized wave supporting unimodal-transmodal propagation, an anti-correlated unimodal-transmodal wave, an anti-correlated task-positive/task-negative wave, and an anti-correlated visual-somatomotor wave. Among them, the global wave exhibited the most pronounced state-dependent reconfiguration: in diminished states (sleep and anesthesia), the time needed for the wave to propagate across brain regions consistently increased and the distribution of regional contributions to the waves power became more spatially concentrated and heterogeneous across individuals, indicating slower, more fragmented, and less stereotyped dynamics. In contrast, propagation duration decreased under psychedelic states, reflecting accelerated global wave dynamics alongside a trend towards more spatially distributed and uniform regional contributions, consistent with a more integrated global wave propagation pattern. Beyond this global mode, diminished states slowed propagation primarily along the unimodal-transmodal axis, whereas psychedelic states selectively accelerated propagation along the task-positive/task-negative axis. Together, our findings reveal that diminished (sleep and anesthesia) and psychedelic states alter the spatiotemporal structure of wave propagation across the brain in opposite and distinct ways, providing a unifying account of how macroscale brain dynamics are dynamically reshaped under pharmacological and endogenous perturbations of consciousness.

neuroscience↗

bioRxiv2026

Eyewire II - A connectomic resource for resolving cell types and circuits of the mouse retina

Comprehensive wiring diagrams from electron microscopy (EM) are a powerful tool to understand the inner workings of the brain. The retina is an easily accessible part of the brain that performs complex visual computations. Its thin, layered structure offers a unique opportunity to decipher neural cell types and map their connectivity. A major obstacle has been the limited size of existing retinal EM datasets, which could not resolve rare cell types and neurons with large dendritic arbors. Here, we describe Eyewire II, a large-scale EM dataset covering nearly 1 mm2 of the adult mouse retina - roughly 10-100 times larger than previous retinal EM volumes. Human proofreading of an automated reconstruction has so far yielded more than 8, 000 bipolar cells, 13, 000 amacrine cells, and 4, 000 retinal ganglion cells. Automated detection is complete for synaptic ribbons and in progress for conventional synapses. Prior to EM imaging, visual responses to diverse stimuli - including natural movies - were recorded in a subset of neurons using two-photon Ca2+ imaging, enabling direct alignment of morphological and functional cell type identity. To enable high-throughput, automatic cell typing, we devised a human-in-the-loop approach that combines deep learning with human expert annotations. As a proof-of-principle, we show that morphological features of reconstructed bipolar cells are sufficient to recover all 15 known bipolar cell types with regular, non-overlapping mosaics. Together, these data and tools establish Eyewire II as a shared resource for the field of retina research. Already now, more than 30 laboratories worldwide are contributing proofreading, expert annotations, and software tools, advancing Eyewire II towards a complete cell type catalog and synaptic wiring diagram of a mammalian retina.

neuroscience↗

bioRxiv2026

Temporal structure of task engagement organizes infra-slow BOLD dynamics

Task-based fMRI has traditionally characterized cognitive engagement through spatial patterns of BOLD activation, leaving open whether tasks also organize activity along the frequency dimension. Here we tested whether temporally structured task engagement reshapes infra-slow BOLD dynamics, asking whether task responses are simply superimposed onto ongoing activity or instead redistribute power across the infra-slow spectrum. Across three independent fMRI datasets, task timing systematically reorganized the BOLD power spectrum. In the main visual attention dataset, periodic stimulation produced sharp stimulus-locked peaks at 0.083 and 0.125 Hz; critically, these gains were matched by a reduction concentrated within the dominant intrinsic infra-slow range (0.01-0.04 Hz), indicating redistribution rather than a simple local increase. Independent auditory and visual-motion datasets showed analogous task-frequency responses at their respective timescales, indicating that this reorganization generalizes across modalities and stimulation frequencies. The peaks were spatially related to GLM-derived activation but persisted after removal of the GLM-modeled response, indicating that this frequency-specific organization is not fully reducible to conventional task-evoked activation. These features were functionally informative: task-imposed frequencies distinguished cognitive states, predicted individual reaction time, and preserved subject-specific signatures across runs more effectively than broader spectral ranges or GLM-derived features. Finally, Jansen-Rit simulations coupled to a Balloon-Windkessel model reproduced the peaks, showing that their expression depends on balanced excitatory, inhibitory, and filter-gain regimes rather than simple amplification of input. Together, these findings indicate that task-fMRI reveals not only where cognition is localized, but how temporally structured engagement redistributes infra-slow dynamics across timescales.

neuroscience↗