Biology subjects

Zhou, X.

Publications and source records attributed to Zhou, X..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

SPICE: A Robust Computational Framework for Identifying Copy Number Variations in Spatial Transcriptomics

Copy number variation (CNV), which alters the number of genomic segments, is a major driver of intratumor heterogeneity, characterized by spatially organized and genetically distinct cell populations. Recent advances in spatially resolved transcriptomic (SRT) technologies, which profile gene expression across thousands of spatially indexed tissue locations, offer a powerful opportunity to reconstruct the CNV architecture and dissect the spatial organization of cancer subclones. Here, we introduce SPICE (spatial inference of CNV events), a probabilistic method for identifying somatic CNVs and allele-specific copy number (ASCN) profiles from SRT data. A key feature of SPICE is its ability to integrate multiple complementary information available in SRT data, including gene expression, spatial coordinates, and heterozygous SNPs inferred from transcriptomic reads, to substantially enhance the accuracy and power of CNV detection. Using datasets generated across different SRT platforms, we first assess the reliability of SNPs derived from SRT data to ensure robust downstream inference. We then demonstrate that SPICE effectively integrates these modalities to deliver accurate and spatially coherent reconstruction of CNV landscapes and subclonal architecture, while maintaining excellent control of false discoveries. Together, SPICE provides a robust and effective solution for dissecting genomic heterogeneity in SRT studies of cancer.

genomics↗

bioRxiv2026

Micafungin exposure drives multidrug resistance in Clavispora lusitaniae

Fungal infections are an escalating global health concern, with rare Candida species posing an urgent threat due to emerging multidrug resistance. Clavispora (Candida) lusitaniae is an uncommon pathogen in which multidrug resistance has been documented during antifungal therapy, yet the selective forces driving this phenotype remain unclear. Here, we show that exposure to the echinocandin micafungin (MCF) alone can select for multidrug resistance in C. lusitaniae. Through controlled evolution experiments we identified individual point mutations in genes encoding ergosterol biosynthesis enzymes (ERGs), sterol trafficking proteins (OSH2), and the echinocandin drug target (FKS1) that confer a significant fitness benefit to one or more classes of antifungals. We find that ERG3 loss-of-function is the primary and independent driver of pan-antifungal resistance to echinocandins, azoles and polyenes. The ERG3 mutants have <1% ergosterol, increased levels of non-toxic sterol intermediates, and increased chitin content, consistent with both cell membrane and cell wall remodeling that enables the fungal pathogen to evade all three drug classes. The convergence of sterol reprogramming and compensatory cell wall remodeling that occurs during adaptation to echinocandin monotherapy can evolve through a single point mutation and parallels our recent case study of acquired multidrug resistance. IMPORTANCEMultidrug resistance in Candida species severely limits treatment options and increases mortality, particularly in immunocompromised patients. Despite increasing reports of multidrug resistance, the molecular mechanisms driving multidrug resistance remain poorly understood. We find that in vitro MCF exposure alone can drive multidrug resistance in C. lusitaniae via acquisition of de novo point mutations in ERG3, an observation that parallels our recent patient case study. By identifying causative mutations and associated physiological changes, we provide mechanistic insight into the emergence of multidrug resistance and highlight the need for surveillance strategies that account for resistance evolution under echinocandin monotherapy.

microbiology↗

bioRxiv2026

RNA post hoc loading into empty lipid nanoparticles occurs on millisecond timescales during turbulent mixing

Lipid nanoparticles (LNPs) are conventionally produced through mixing of lipids dissolved in ethanol against a buffer containing RNA. An alternative strategy offering improved cold-chain stability involves formulating empty LNPs (eLNPs), removing ethanol, and post hoc loading (PHL) RNA into the aqueous eLNPs. The kinetics of this approach remain unknown. Here, we employ a flowthrough small-angle X-ray scattering (SAXS) setup based on a confined impinging jets (CIJ) mixer to probe PHL kinetics. We show that RNA PHL in a scalable CIJ mixer is efficient and reproducible, and that SAXS data confirms that this process concludes within [~]12 ms under favorable conditions in rapid turbulent micromixing, suggesting a diffusion-limited aggregation mechanism. Favorable conditions were identified as an acidic pH 5.5 buffer combined with turbulent CIJ mixing. In contrast, PHL performed with a neutral pH 7.4 buffer using a CIJ mixer or under laminar flow with a pH 5.5 buffer resulted in inefficient PHL.

bioengineering↗

bioRxiv2026

Computational reconstruction of hierarchical cis-regulatory networks reveals synergistic transcription control and disease-associated rewiring

Gene regulation emerges from coordinated interactions among dispersed cis-regulatory elements, yet how these elements integrate into functional regulatory networks and collectively regulate gene transcription remains poorly understood. Here, we present ORIGAMI, a multi-omics, gene-centric deep learning framework that reconstructs functional cis-regulatory networks constrained by transcriptional output. ORIGAMI formulates cis-regulatory modeling as a latent graph inference task, which integrates DNA sequence, epigenomic signals, and three-dimensional chromatin priors to infer denoised regulatory graphs that capture functional interactions rather than structural proximity alone. The inferred regulatory graphs exhibit distinct topological regimes, where hierarchical and modular organization encodes cell-state-specific functional demands and enables synergistic transcriptional control. Furthermore, we show that these regulatory architectures undergo measurable state-dependent rewiring across disease contexts. Finally, ORIGAMI accurately predicts the transcriptional consequences of both cis- and trans-regulatory perturbations and links the rearrangement of regulatory architecture to perturbation response. Together, ORIGAMI advances a network-based view of gene regulation and establishes a foundation for virtual cell modeling of regulatory dynamics.

bioinformatics↗

bioRxiv2026

Deciphering shared and divergent tissue architectures from cross-species spatial transcriptomics

The integration of spatial transcriptomics (ST) data across species is essential for cross-species and translational studies, but remains challenging due to molecular divergence and anatomical differences between organisms. We present STACAME, a graph attention autoencoder-based framework to decipher shared and divergent tissue architectures from cross-species ST data by explicitly modeling both orthologous and species-specific genes. STACAME aligns ST slices in a spatially aware manner, identifies homologous and species-specific domains, and enables a suite of downstream comparative analyses. We demonstrate its utility by integrating ST datasets from diverse tissues, including hippocampus, isocortex, embryo, breast, liver, and cerebellum, across multiple species such as human, macaque, marmoset, mouse, and zebrafish. STACAME supports cross-species spatial domain alignment, the detection of shared and divergent spatially variable genes, development alignment and comparison, and the 3D integration of tissue architecture. This flexible approach facilitates the translation of findings from model organisms to humans, providing a unified computational platform for cross-species spatial transcriptomics.

bioinformatics↗

bioRxiv2026

Ancient admixture catalyzes homoploid hybrid speciation and intense genomic erosion in Asian langurs

Ancient admixture catalyzes evolutionary innovation, yet its long-term genomic consequences for newly formed lineages remain poorly understood. Here, based on 53 genomes covering 19 species of the Asian langur genus Trachypithecus, we explore admixtures role in shaping a reticulated radiation. Genome-wide analyses of phylogenomic triplet topologies demonstrate that phylogenetic discordance across this radiation is primarily driven by widespread introgression rather than incomplete lineage sorting. To mitigate historical noise and resolve the ancestral species tree, we anchored our phylogenetic analysis on the X-linked recombination desert (XLRD), which exhibits an 84.5% introgression reduction compared to autosomes. We identify Delacours langur as a clear case of homoploid hybrid speciation, arising from ancient admixture with [~]70:30 genomic contributions from ancestral northern and southern limestone langur lineages. This hybrid species fixed key reproductive isolation loci; notably, alternate inheritance of pigmentation genes (SLC45A4, HPS5, ADCY10) systematically coupled with a fixed RNF175 chimeric allele to drive its diagnostic pelage phenotype. This illustrates how introgressed multi-gene networks rapidly establish prezygotic visual barriers and profound phenotypic divergence. However, subsequent spatial isolation within fragmented karst landscapes forced a major conversion of genetic burden into realized load. Genome-wide, over 82% of loss-of-function variants occur in a homozygous state, reflecting the expression of lethal recessive mutations within long runs of homozygosity. Together, our findings demonstrate that ancient admixture can trigger homoploid hybrid speciation, yet subsequent ecological restriction locks derived lineages into severe, long-term genomic erosion, revealing a fundamental trade-off in reticulate evolutionary radiations.

evolutionary biology↗

bioRxiv2026

Experiment-free learning of exoskeleton assistance is not an unsolved problem

We present three quantitative methods: 1) estimation of exoskeleton mechanical power and energy ratio from published data, 2) a systematic review of the exoskeleton literature on reported energy ratios, and 3) timing correction analysis of the replication experiment, to address concerns raised by Collins et al. (2026) about Luo et al. (2024). Together, these analyses support the reported metabolic reductions and the validity of exoskeleton control via learning in simulation. The critique rests on an unsupported premise: that exoskeleton energy ratios above 4 are physiologically implausible. This premise of Collins et al. (2026) is not supported by the cited evidence, and the error originates in their own cited source. Sawicki and Ferris (2009), the paper they invoke as authority for the limit of 4, state explicitly that "reported values of the muscular efficiency range from 0.10 to 0.34, with many sources assuming an average of [~]0.25." The value of 4 corresponds to this average, it is not a physiological ceiling. Treating an average as a physiological upper limit is a fundamental error. The published exoskeleton literature further contradicts the claim, including work by the authors of the critique themselves (Collins et al., 2015: 4.3; Young et al., 2017: 5.0) and independent work (Malcolm et al., 2013: 4.8; Seo et al., 2017: 6.7). In contrast, our walking energy ratio is 2.4, calculated directly from Fig. 4 of our paper. Our device delivers higher peak torque (14.1 Nm vs. 10.9 Nm, Lim et al., 2019) and achieves a slightly larger metabolic reduction (24.3% vs. 21%). Independent groups have since demonstrated meaningful metabolic reductions using learning-in-simulation frameworks, including Barati et al. (2026, 15.2% mean and 22.5% maximum) and Zhou et al. (2025, [~]20% during running). The claim of Collins et al. (2026) that this problem "remains unsolved" is directly contradicted by these independent results. The experiment in the critique is not a valid replication of our method. Our controller is a neural network with [~]10,000 parameters learned through deep reinforcement learning in musculoskeletal simulation; the critique instead applies a pre-programmed fixed torque curve with no learnable parameters. Beyond this, the replication contains three methodological errors: 1) a heel-strike timing assumption producing offsets up to 30% of the gait cycle; 2) an averaged torque profile that discards subject-specific control; and 3) a device [~]50% heavier than ours (4.8 kg vs. 3.2 kg) without measuring the metabolic penalty of the added weight. The critique also misreports Samsung data, with reported values approximately double those in the original publication, errors that directly underpin their physiological limit argument.

bioengineering↗

bioRxiv2026

Single-nucleus multiomic analysis reveals modulation of the gene regulatory circuit landscape in pituitary cell types during mouse estrous cycle.

Summary/AbstractThe estrous cycle transcriptional and chromatin dynamics in pituitary cell types have not been investigated. We report single-nucleus multiomics assays in 18 adult mouse pituitaries (102,069 post quality-control nuclei) across 6 cycle time points. Differential analysis revealed cycle stage-dependent epigenetic and transcriptional remodeling across the major pituitary cell populations. In gonadotropes and lactotropes, we identified temporal patterns of differential gene expression linked to various biological processes, notably neuronal and synaptic-related ontologies. Pseudotime trajectory analysis was consistent with a rapid transition of individual gonadotropes through different cellular states. In gonadotropes and lactotropes, we uncovered gene regulatory circuits whose activity varies between consecutive cycle time points. We experimentally validated a gonadotrope ETS2-driven circuit that differentially regulates Fshb gene expression between 2 and 9 am on estrus. Our data and analyses, available at https://rstudio-connect.hpc.mssm.edu/snpit_estrous_browser/, provide a window into gene regulatory mechanisms underlying estrous cycle stage transitions. HighlightsO_LIPituitary cells show chromatin and transcriptome plasticity across the estrous cycle C_LIO_LIWe identify stage-modulated gene regulatory circuits across pituitary cell types C_LIO_LIGonadotrope DEGs form distinct pathway-annotated temporal trajectory clusters C_LIO_LIWe validate a gonadotrope ETS2-driven circuit regulating the Fshb gene C_LI eTOC blurbZhang et al. conduct a single-nucleus multiomics analysis of mouse pituitaries in vivo across the estrous cycle. They reveal an epigenetic and transcriptomic plasticity in pituitary cell populations. In gonadotropes and lactotropes, they demonstrate that DEGs clustered by temporal trajectories are enriched for distinct biological processes and identify stage-modulated gene regulatory circuits. They experimentally validate a gonadotrope ETS2-driven circuit regulating Fshb expression. Their dynamic molecular atlas of the cycling pituitary captures key cis-regulatory mechanisms underlying estrous cycle stage transitions.

genomics↗

bioRxiv2026

KCNQ2/3 Regulates the Synaptic Remodeling Associated with Drug Seeking in Addiction

Drug-seeking behavior during withdrawal represents a critical obstacle to addiction treatment. In the nucleus accumbens, hyperactive dopamine D1 receptor-expressing medium spiny neurons (D1R-MSNs) promote cocaine-seeking through aberrant synaptic remodeling, including synapse formation and calcium-permeable AMPA receptor (CP-AMPAR) insertion. However, the intermediate molecular control mechanism remains unclear. We identified KCNQ2/3 potassium channels as key regulators of synaptic pathology during withdrawal. Cocaine-conditioned mice showed increased spine density, enhanced surface CP-AMPAR, and elevated neuronal activity 14 days after withdrawal. These phenotypes were reversed by repeated administration of KCNQ2/3 openers or D1R-MSN-specific expression of constitutively active KCNQ2. Functional restoration of KCNQ2/3 suppressed cocaine-seeking behavior and normalized D1R-MSN excitability. These findings suggest that sustained KCNQ2/3 deactivation drives synaptic remodeling during withdrawal, while channel activation offers a potential therapeutic strategy. Furthermore, the results position KCNQ2/3 as a master regulator of drug-seeking behavior and channel activation in D1R-MSNs as a logical target for relapse prevention in addiction.

neuroscience↗

bioRxiv2026

Deciphering cross-omics complexity of tissues via diagonal integration of unpaired spatial multi-omics data

Recent spatial multi-omics technologies enable the simultaneous in situ profiling of multiple omics modalities on the same tissue section; however, they face challenges in experimental complexity and high costs. This technical limitation can be circumvented by diagonal integration methods, which integrate omics data from different modalities. However, existing single-cell diagonal integration approaches overlook spatial information, causing unreliable anchoring across omics layers. Here, we introduce STAMO, a graph attention neural network model for spatially aware integration of unpaired spatial slices from different omics. Systematic benchmarking on spatial epigenome-transcriptome slices proves that STAMO outperforms the state-of-the-art methods in generating aligned embeddings and identifying consensus spatial domains across omics. We apply STAMO to integrate unpaired data from diverse spatial omics types (transcripts, epigenetics, DNA, and proteins), including slices from spatial RNA and four different epigenomic modalities, spatial ATAC and RNA slices across embryonic stages, spatial protein and RNA slices, and spatial DNA and RNA slices. In addition, the integration capability of STAMO can be further used to achieve cross-omics generation, offering a solution for exploring spatial region-specific gene regulatory mechanisms.

bioinformatics↗

bioRxiv2026

Profound CD4+ T-Cell Reprogramming by Melphalan-Driven Oxidative Stress in High-Risk Multiple Myeloma

T cell-based immunotherapies have become central to the treatment of multiple myeloma (MM), yet their efficacy depends on the functionality of endogenous T cells. How cumulative treatment exposure, particularly high-dose melphalan, together with disease-intrinsic high-risk features shapes T-cell composition and immune competence remains incompletely understood. Here, we analyzed T cell composition and function in bone marrow (BM) and peripheral blood (PB) samples from MM patients across different stages of their treatment journey using flow cytometry (BM, n=162; PB, n=1,733), single-cell RNA sequencing (n=19), and cytotoxicity assays (n=20). We reveal reduced overall T cell frequencies and CD4+/CD8+ T cell ratio, associated with lines of therapy and driven in part by depletion of naive CD4+ T cells in gene-expression defined high risk (HR) disease. Among therapeutic agents, melphalan exerted the strongest effects on T cell populations and induced pronounced redox stress in both T cells and myeloma cell lines. This oxidative stress signature was enriched in HR patients and was reversible with N-acetyl-L-cysteine treatment. Together, these findings identify immune dysregulation as a defining feature of HR MM that extends beyond tumor-intrinsic genomic alterations and is further shaped by treatment-induced remodeling of the BM microenvironment. Given the association between higher CD4+ T cell numbers and improved CAR-T cell outcomes, our data highlight the translational importance of treatment sequencing, particularly in HR MM. One Sentence SummaryMelphalan-induced redox stress depletes CD4+ naive T cells, particularly in patients with high-risk multiple myeloma.

Cancer Biology↗

bioRxiv2026

Engineering tumor-homing bacteria as membrane-anchored immune checkpoint-blockade interfaces

Bacterial cancer therapies can exploit tumor tropism to localize immunomodulatory payloads, but most approaches rely on secretion or lysis-dependent release of soluble biologics that may diffuse beyond the tumor niche. Here, we engineer non-pathogenic, tumor-homing Escherichia coli strains as membrane-anchored immunotherapeutic interfaces, with individual strains displaying immune checkpoint-blocking nanobodies targeting CTLA-4 or PD-L1, either alone or in combination with a separate strain displaying murine decoy-resistant IL-18 (mDR18). By screening multiple bacterial outer-membrane proteins as scaffolds, we identified scaffold-dependent differences in display levels and target engagement, and YiaT as a functional platform for checkpoint nanobody presentation. Delivery of YiaT-displayed nanobodies in combination with OmpA-displayed mDR18 suppressed tumor growth in syngeneic mouse colon cancer and melanoma models in either local or systemic delivery. Upon systemic administration, the combined bacterial therapy preferentially accumulated in tumors, outperformed benchmark checkpoint antibody regimens combining CTLA-4 and PD-L1 under the tested conditions, and promoted tumor rejection and rechallenge resistance, without inducing broad systemic cytokine release. Further immune profiling showed that the combined treatment was associated with increased CD8 and effector-memory T-cell responses in tumors and spleens. This work establishes bacterial surface display as a modular strategy for localized cancer immunotherapy.

Synthetic Biology↗

bioRxiv2026

Genotypic and multi-environment phenotypic evaluation of the lima bean USDA National Plant Germplasm System collection

Lima bean (Phaseolus lunatus L.) is an economically and agronomically important grain legume. Lima beans (or limas) show a range of climatic adaptations with independent domestications in the Andes (large-seeded) and Mesoamerica (small- or medium-seeded). We generated and integrated genotypic and comprehensive field- and laboratory-based phenotypic information for the available accessions in the USDA National Plant Germplasm System collection across multiple environments to inform germplasm utilization in breeding. A total of 810 accessions were genotyped using short-read, low-coverage sequencing. Accession geographic origin and domestication explained population structure. A partially overlapping subset of the panel (n=141-308) was field-evaluated across two years in each of Davis, CA, Central Ferry, WA, and Coachella Valley, CA (the latter was fall-planted for evaluation of photoperiod-sensitive accessions) to assess trait performance in contrasting environments. Agronomic traits such as determinacy and flowering time, and seed traits such as seed coat color and hundred-seed weight, were scored. Macronutrient traits (protein, starch, fat, and ash content) were measured on dry (mature) harvested grain via near-infrared spectroscopy. Genome-wide association analyses identified loci significantly associated with descriptive, agronomic, and seed traits, including orthologs of known genes in common bean and novel candidate regions. Genomic predictive abilities were moderate to high for key traits. Finally, we established a conditional core collection that was constrained to include 211 extensively phenotyped accessions and for which 91 supplemental accessions were selected to maximize genetic diversity from among the genotyped accessions. Overall, these resources provide a foundation to support genomics-assisted breeding of limas.

plant biology↗

bioRxiv2026

A horizontally transferred fungal deubiquitinase facilitates insecticides resistance in whitefly

Horizontal gene transfer (HGT) has enabled insects to acquire novel genetic material that can fuel adaptation to environmental change. However, the role of HGT in the evolution of insecticide resistance remains poorly characterised. Here, we identify BtUCH19, a fungal gene that has integrated into the genome of the global pest Bemisia tabaci and functions as a deubiquitinating enzyme (DUB). We show that compared to endogenous DUB, BtUCH19 specifically removes K63-linked ubiquitin chains from a cytochrome P450, CYP4C64, thereby stabilizing this key detoxification enzyme in vivo. Sustained CYP4C64 abundance enhances metabolic detoxification of two commonly used insecticides thiamethoxam (TMX) and clothianidin (CLO) to their low-toxicity products TMX-Urea and CLO-Urea. Consequently, BtUCH19 drives insecticide resistance through a novel "HGT-PTM-Metab" axis. Our work reveals the instrumental role of a HGT in orchestrating ubiquitin-proteasome system (UPS)-mediated protein level regulation of a key detoxification pathway. These findings offer new insights into the intricate mechanisms underlying co-evolutionary biology, and provide a new molecular target for Integrated Pest Management (IPM).

zoology↗

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

ACLY integrates metabolism and chromatin accessibility to enable B Cell activation and humoral immunity

B cell activation and differentiation into antibody-secreting cells require extensive metabolic and epigenetic remodeling, yet the molecular mechanisms that integrate these programs remain incompletely understood. ATP-citrate lyase (ACLY) links glucose metabolism to acetyl-CoA production, supporting lipid biosynthesis and protein acetylation. However, its role in humoral immunity has not been fully defined. Here, using genetic and integrated multi-omics approaches, we show that B cell activation is accompanied by coordinated metabolic, transcriptional, and epigenetic reprograming. Although ACLY is dispensable for B cell development and homeostasis, it is required to establish chromatin accessibility programs in activated B cells, with a more pronounced impact on the epigenetic landscape than on transcriptional output. ACLY-deficient B cells exhibit profound defects in TLR and BCR elicited activation, survival and metabolic fitness ex vivo. In vivo, B cell-intrinsic loss of ACLY results in impaired antigen-specific antibody production, associated with reduced germinal center and plasmablast formation, but normal homeostatic proliferation. Deletion of ACLY after B cell activation reduces plasmablast generation in vivo, indicating a continued requirement for ACLY beyond the initial activation phase. Together, these findings identify ACLY as a central regulator that links metabolism to epigenetic programing that supports B cell activation and humoral immunity.

immunology↗

bioRxiv2026

Context-dependent functional diversity of dorsomedial posterior parietal neurons revealed by single-unit fMRI mapping during naturalistic viewing

The dorsomedial posterior parietal cortex (dmPPC) plays an important role in episodic processing by integrating sensory, cognitive, and motor information across distributed brain systems. However, how individual dmPPC neurons participate in large-scale functional organization during naturalistic experience remains poorly understood. To address this question, we combined single-unit electrophysiology and awake fMRI in separate cohorts of rhesus macaques viewing identical naturalistic video stimuli. Using single-unit fMRI mapping, we generated whole-brain neuron-BOLD functional maps by correlating individual neuronal activity with voxel-wise fMRI signals across the brain. We found that neuron-BOLD functional maps exhibited strong context-dependent organization, with neurons recorded during the same video context showing substantially greater similarity than neurons recorded during different video conditions. Compared with neuronal spiking activity or critical fMRI frames alone, neuron-BOLD functional maps more robustly capture contextual structure. Despite this shared large-scale organization, neighboring neurons recorded simultaneously from the same electrode often displayed markedly distinct whole-brain association patterns, revealing substantial local functional heterogeneity within the dmPPC. In addition, distributed cortical and medial temporal regions exhibited highly context-dependent neuron-BOLD association patterns during naturalistic viewing. Together, these findings demonstrate that dmPPC neurons participate in dynamic and heterogeneous large-scale functional organization during naturalistic episodic processing. More broadly, this study establishes single-unit fMRI mapping as a framework for linking single-neuron activity to distributed whole-brain dynamics across contextual conditions. Significance StatementUsing single-unit fMRI mapping, this study examined how individual dorsomedial posterior parietal cortex (dmPPC) neurons relate to large-scale brain activity during naturalistic video viewing in macaque monkeys. We found that neuron-BOLD functional maps exhibit strong context-dependent organization and capture contextual structure more robustly than neuronal spiking activity or fMRI frames alone. Despite this shared organization, neighboring dmPPC neurons often displayed markedly distinct whole-brain association patterns, revealing substantial local functional heterogeneity. These findings provide insight into how local neuronal populations participate in distributed cortical organization during naturalistic episodic processing.

neuroscience↗

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↗