Biology subjects

Zhao, Q.

Publications and source records attributed to Zhao, Q..

At least 19 recordsLinked to original sources

bioRxiv2026

NexuST: A Hierarchical Foundation Model for Spatial Transcriptomics

Spatial transcriptomics captures molecular states within cells and their organisation in tissue. However, integrating fine-grained gene information with spatial context at scale remains challenging for existing foundation models. Here we present NexuST, a hierarchical foundation model that repeatedly interleaves gene-level molecular modelling with cell-level spatial modelling, allowing the two levels to refine one another during end-to-end pretraining. For pretraining, we curated HumanST-46M, comprising 45.7 million human cells from 72 datasets across 11 organs and three imaging-based platforms. Across four held-out datasets totalling approximately 2.6 million cells, NexuST achieved state-of-the-art or competitive performance in cell-type annotation, region prediction, gene recovery and neighbourhood-composition prediction. We find that cell-intrinsic expression remains informative even for spatial tasks, as shown by an expression-only PCA baseline, while NexuST shows particularly strong gains where spatial context is essential. Overall, NexuST establishes a hierarchical framework that can serve as a general backbone for future spatial transcriptomics foundation models.

bioinformatics↗

bioRxiv2026

Dynamic Changes in Endometrial Folding and Secretory Activity Across the Menstrual Cycle

Embryo implantation remains a major limitation of assisted reproductive technology, with failure occurring in approximately 30% of euploid embryo transfers. Implantation requires a synchronized dialogue between the blastocyst and receptive endometrium during the window of implantation (WOI), yet minimally invasive approaches to characterize the structural and molecular features of receptivity remain limited. We analyzed paired sonohysterogram images and uterine lavage samples collected during the proliferative and mid-secretory phases from subjects with regular ovulatory cycles and proven fertility. Endometrial folds were quantified, and lavage samples were analyzed by Luminex multiplex immunoassay. Folds were present in both phases but were significantly more abundant during the mid-secretory WOI, independent of imaging view and endometrial thickness. Folding correlated strongly with circulating estradiol level during the proliferative phase but not the mid-secretory phase, and folding patterns between phases were not correlated, suggesting distinct regulatory mechanisms. Consistent with these structural patterns, uterine lavage demonstrated phase-specific differences in expression of factors associated with endometrial receptivity and implantation, with glandular epithelium, and myeloid-lineage cells emerging as major contributors. Together, these findings identify coordinated structural and secretory processes during the WOI and support further evaluation of endometrial folding and uterine lavage as complementary, minimally invasive markers of endometrial receptivity.

developmental biology↗

bioRxiv2026

fastACCORD enables ultrahigh-dimensional partial correlation modeling for multi-omic data integration

Gene co-expression networks reflect transcription factor-associated regulation together with epigenetic influences such as DNA methylation, chromatin states, and histone modifications. To distinguish gene-gene dependencies that persist after accounting for methylation covariation, large-scale statistical inference conditioning on hundreds of thousands of molecular features is necessary, but the task remains computationally intractable for conventional Gaussian graphical modelling approaches. Here we present fastACCORD, a scalable computational framework for ultrahigh-dimensional partial correlation modeling. fastACCORD combines row-separable optimization, {ell}2 stabilization, and a semismooth Newton solver in a PyTorch implementation for CPU and CUDA-enabled GPU hardware. We applied it to matched transcriptomic and methylomic profiles from 16 TCGA cancer types and obtained joint networks containing >300,000 molecular features per cancer. The resulting multi-omic networks revealed cancer-specific methylation-expression dependencies, including recurrent methylation-associated expression repression of metabolic genes. Methylation-adjusted gene co-expression networks were sparser than networks estimated from mRNA data alone, but more enriched for ChIP-seq-supported TF-target relationships and curated co-regulon annotations. TF-target subnetworks further revealed cancer-specific architectures consistent with lineage identity, oncofetal reactivation, and tumor microenvironment-associated programs. Together, these analyses establish fastACCORD as a practical framework for ultrahigh-dimensional multi-omic partial correlation modeling and demonstrate how joint modeling of transcriptomic and epigenomic measurements can refine the interpretation of gene co-expression networks.

bioinformatics↗

bioRxiv2026

An in vitro System for Studying Osteochondrogenic Differentiation of Smooth Muscle Cells and Modeling Intimal Vascular Calcification

Objective: Smooth muscle cells (SMCs) undergo phenotypic transitions during atherosclerosis, including towards a chondromyocyte (CMC) state associated with intimal calcification. Although standard in vitro calcification assays robustly reproduce mineral deposition, it remains unclear how well they recapitulate these disease-associated SMC states. We sought to define the CMC transcriptional phenotype in atherosclerosis and develop an in vitro system that faithfully reproduces it. Approach and Results: We firstly identified a CMC transcriptional signature in murine and human atherosclerotic plaque through single-cell RNA-sequencing, and spatial transcriptomics. CMCs showed a conserved osteochondrogenic program which localized within plaques and adjacent to calcified regions. We then developed an osteochondrogenic differentiation (OCD) assay by combining well-established calcification components with a high-density SMC micromass culture and TGF-{beta}1 supplementation and benchmarked it against a standard calcification (SC) assay using calcium quantification and bulk RNA-sequencing. Despite comparable calcification, OCD and SC resulted in distinct transcriptional states, with OCD showing preferential upregulation of osteochondrogenic programs, and a higher CMC signature score. Additionally, OCD upregulated genes with a stronger enrichment near coronary artery disease (CAD)-associated loci. These responses were reproducible across several primary human SMC lines. Timecourse analysis also showed that chondrogenic programs preceded calcification and showed directional concordance with the inferred in vivo SMC-to-CMC trajectory. To interrogate regulatory pathways controlling this process, we overexpressed the chondrogenic regulator SOX9, which enhanced cartilage and extracellular matrix programs while repressing inflammatory pathways. Finally, we examined 552 CAD-associated genes nominated across five genome-wide association studies. Of these, 240 were differentially expressed by day 12, and included established SMC regulators as well as a number of candidates not previously characterized in osteochondrogenic SMC transition. Conclusions: The OCD assay results in a strong calcification phenotype together with a disease-associated CMC-like transcriptional state, providing a reliable in vitro model for mechanistic investigation of SMC phenotypic transition and prioritization of candidate regulators.

cell biology↗

bioRxiv2026

Placental microRNA signatures of spontaneous preterm birth

Background: The placenta has a unique transcriptomic profile, including microRNAs that are secreted into maternal circulation throughout pregnancy. MicroRNAs are small, non-coding RNA that post-transcriptionally regulate gene expression. Spontaneous preterm birth (sPTB) is associated with substantial differences in both placental pathophysiology and placental gene expression compared to term birth. We aimed to generate microRNA signatures of sPTB and map them to target genes using a microRNA-mRNA network. Methods: This study was conducted within the Conditions Affecting Neurocognitive Development and Learning in Early childhood (CANDLE) study. Placental samples were collected at delivery, and RNA was isolated for mRNA and microRNA sequencing. To investigate sPTB, this study excluded placental samples of participants with iatrogenic indications for PTB or induced labor. We examined differences in microRNA expression in participants who delivered before 37 weeks (N=35) compared to term participants (N=404) in a series of covariate-adjusted linear regression models. We used paired placental microRNA and mRNA expression data from this cohort to validate associations between computationally predicted microRNA-mRNA pairs and establish a microRNA-mRNA network. Results: Expression of 7 microRNAs were increased in sPTB (FDR<0.05) and were inversely correlated with sPTB-associated genes involved in immune signaling. Expression of 12 microRNAs were decreased in sPTB, including 4 members of the maternally expressed chromosome 14 microRNA cluster (miR-376a-3p, miR-376c-3p, miR-377-3p, and miR-381-3p). These microRNAs were predicted to negatively regulate oxidative phosphorylation genes that were increased in sPTB. The associations between miR-376c-3p and miR-377-3p and oxidative phosphorylation were confirmed in microRNA knockdown experiments. Conclusions: This study highlights potential biological mechanisms by which placental microRNA dysfunction might contribute to sPTB and highlights putative sPTB biomarkers that may be detectable in maternal circulation.

systems biology↗

bioRxiv2026

Targeting glucocorticoid signalling in dendritic cells for glioblastoma treatment

Glioblastoma (GBM) remains a devastating disease with few meaningful therapeutic advances over the past three decades. Dendritic cell (DC) vaccination is a promising immunotherapeutic strategy for GBM, but its efficacy is limited by the clinical use of dexamethasone to control cerebral oedema and associated symptoms. Here we show that steroid signalling is a central regulator of DC dysfunction in GBM. Through targeted metabolomics of primary GBM samples, we identified a steroid-rich tumour microenvironment in which dexamethasone is present at high levels. Across bulk and single-cell transcriptomic and epigenomic datasets, NR3C1 emerged as the dominant steroid receptor in GBM immune cells and was negatively associated with activated DC states. In patient-derived DCs, dexamethasone altered NR3C1 chromatin occupancy, induced broad transcriptional and chromatin remodelling, and suppressed co-stimulatory antigen-presentation and cytokine programmes. DC-specific deletion of Nr3c1 restricted syngeneic glioblastoma growth, enhanced DC activation, promoted cytotoxic CD8+ T cell responses and remodelled myeloid states in vivo. In GBM patient-derived DCs, pharmacological or non-viral CRISPR-mediated disruption of NR3C1 restored inflammatory, antigen presentation and T cell-stimulatory programmes, enhanced antigen-specific CD8+ T cell priming, and improved tumour lysate-loaded DC vaccination. Together, these findings identify glucocorticoid signalling as a key barrier to DC immunotherapy in GBM and establish NR3C1-targeted, steroid-resistant DCs as a potential therapeutic strategy.

immunology↗

bioRxiv2026

A durably colonizing engineered native symbiont enables sustained intestinal delivery for metabolic dysfunction and colitis

BackgroundEngineered bacterial therapeutics represent a promising strategy for sustained intestinal delivery of therapeutic molecules, but their efficacy is limited by inefficient colonisation, safety concerns and the need for repeated administration or auxiliary delivery systems. ObjectiveTo develop a safety-optimised native bacterial chassis capable of long-term gut colonisation and sustained therapeutic delivery for intestinal inflammatory and metabolic diseases. DesignNative murine Escherichia coli isolates were screened for antibiotic susceptibility, genetic tractability and long-term intestinal colonisation. The selected strain, MEc30, was further optimised by deleting the putative virulence-associated clb and irp loci. MEc30 was then engineered to deliver murine interleukin-10 (MEc30-mIL-10) or produce nicotinic acid (MEc30-NA), and therapeutic efficacy was evaluated in Il10-/- colitis and high-fat diet-induced metabolic dysfunction models. ResultsMEc30 achieved stable lifelong colonisation of the murine intestine after a single oral administration, without antibiotic preconditioning or auxiliary delivery systems, and did not detectably disturb host physiology or gut microbial ecology. Deletion of clb and irp abolished potential colibactin- and yersiniabactin-associated biosafety risks while preserving bacterial growth and colonisation capacity. MEc30-NA continuously produced nicotinic acid in the gut, activated epithelial GPR109a-associated barrier signalling, improved glucose and lipid metabolism, reduced systemic inflammation and avoided the sharp peak exposure associated with conventional nicotinic acid administration. MEc30-mIL-10 enabled sustained intestinal IL-10 delivery, suppressed inflammatory macrophage activation, improved barrier integrity and alleviated spontaneous colitis in Il10-/- mice. ConclusionThis study identifies MEc30 as a durable and safety-optimised native E. coli chassis for sustained intestinal therapeutic delivery. Engineered native symbionts may provide a long-acting live biotherapeutic strategy for chronic intestinal inflammatory and metabolic diseases.

microbiology↗

bioRxiv2026

Barcode-integrated reverse transcription for accurate, complete, and low-input RNA sequencing

In conventional total-RNA sequencing, unwanted RNA is removed by ribosomal-RNA depletion or messenger-RNA enrichment, and contaminating genomic DNA is cleared by DNase, both before reverse transcription. A sample index is added only later, during amplification, so each sample is carried through reverse transcription and cleanup on its own. These steps lose material that low-input samples cannot spare, and the per-sample handling limits throughput. Here we describe BIRT (Barcode-Integrated Reverse Transcription), a hairpin primer that carries a sample barcode and begins reverse transcription preferentially at RNA 3' ends, folding both barcoding and 3'-end capture into first-strand synthesis. Barcoding at reverse transcription enables early pooling, so samples are combined before any cleanup. It also authenticates RNA against DNA contamination: the primer barcodes RNA 909-fold more often than genomic DNA, and non-barcoded reads, which report DNA, are discarded. The 3'-end preference recovers terminal sequence that random priming loses: for a typical small nucleolar RNA, 66% of reads begin within two nucleotides of the mature 3' end, against a few percent for random hexamers. We pair BIRT with PERD (Probes for Excess RNA Depletion), a modular set of blocking probes that removes unwanted RNA within the same reaction without distorting expression (Pearson r = 0.98). We have applied BIRT to 8,079 samples across seven species, from cultured cells and primary tissue to FFPE and extracellular-vesicle RNA.

molecular biology↗

bioRxiv2026

Recognition Mechanism of Serotonin by a G-Quadruplex-Duplex Hybrid Aptamer

Serotonin is a key neurotransmitter, and aptamer-based tools using the 44-nt Apt44 have been successfully developed for its in vitro and in vivo detection. Nevertheless, the structural basis of recognition by this aptamer remains unclear. Here we report high-resolution NMR structures of Apt38, a 6-nt truncated variant in the third loop of Apt44, in free and serotonin-bound states. Both structures reveal a two-layered antiparallel chair-type G-quadruplex core with three edgewise loops and a terminal duplex, forming a G-quadruplex-duplex hybrid structure. Serotonin binds at the G-quadruplex-duplex junction, stabilized by stacking, electrostatic attraction, hydrogen bonding, and hydrophobic contacts. Apt38 is preorganized for binding, whereas the longer third loop of Apt44 introduces conformational dynamics into the G-quadruplex scaffold, which enables a pronounced binding-triggered conformational switch in PBS buffer, explaining its sensing mechanism. Our work reveals the recognition and sensing mechanism of the serotonin aptamer and provides a framework for aptamer design in serotonin biosensing.

biophysics↗

bioRxiv2026

CWF19L2 couples pre-mRNA alternative splicing with the maternal-to-zygotic transition to safeguard female fertility

The maternal-to-zygotic transition (MZT) requires precise spatiotemporal execution of pre-mRNA alternative splicing (AS), yet the core splicing machinery driving this developmental reprogramming remains incompletely understood. Here, we identify the CWF19-like protein 2 (CWF19L2) as an indispensable pre-mRNA AS regulator that safeguards against oocyte and early embryo competence defects (OECD). While murine germline-specific depletion of Cwf19l2 spares morphological folliculogenesis, oocyte maturation, or fertilization, it induces complete female sterility characterized by profound developmental arrest at the 2-cell stage. Mechanistically, maternal deficiency of CWF19L2 localized to nuclear speckles disrupts transcription-splicing-translation coupling, collapsing AS homeostasis during maternal reserves and zygotic genome activation. We further demonstrate that CWF19L2 orchestrates the pre-mRNA splicing network through directly binding to target transcripts and indirectly modulating via interacting with the core spliceosomal factor PRPF8. Importantly, exogenous Cwf19l2 mRNA partially rescues the embryonic arrest. Together, our findings establish CWF19L2 as an indispensable AS engine during the MZT, providing a mechanistic foundation for OECD and a novel molecular etiology for female infertility.

Cell Biology↗

bioRxiv2026

Detecting DNA methylation patterns suggestive of variable escape from X-chromosome inactivation

The X chromosome is often excluded from studies analyzing associations between traits and DNA methylation. In females, one copy of most genes on the X is inactivated (X-chromosome inactivation; XCI) through DNA methylation of the gene promoter on the inactive X. This leads to challenges in analyzing and interpreting DNA methylation data patterns. Particularly for sex-biased diseases and traits, there may be many loci of interest on the X chromosome, which contains about 5% of the genome. To address the need for appropriate analysis of DNA methylation data on the X chromosome, we develop a statistical approach to infer locus-specific escape from XCI sensitive to phenotype or covariate values. Performance of this method is illustrated by analysis of data from two sex-biased traits: rheumatoid arthritis which is 3-fold more common in females, and recurrent venous thromboembolism which occurs 2.5 times more often in males. Analyses of these two datasets identify new trait-associated loci on the X chromosome, demonstrate the capabilities of the new method for both bisulfite sequencing data and Illumina EPIC data, suggest at least one locus where variable escape may explain a sex-specific disease association, and rule out variable escape as a potential explanation at other loci. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=176 HEIGHT=200 SRC="FIGDIR/small/732395v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@108c23aorg.highwire.dtl.DTLVardef@77dc0org.highwire.dtl.DTLVardef@1d105d0org.highwire.dtl.DTLVardef@1d4b543_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender (bioRender.com)

genomics↗

bioRxiv2026

A biointegrated living brain stimulator evokes specific neural signalling

Implanted brain stimulators play a crucial role in treating various neurological disorders, including Parkinsons disease (PD), Alzheimers disease, epilepsy, and depression. However, none of the existing implanted brain stimulators can realize specific neuromodulation due to fundamental disparities in signal transmission between electrical signal-induced neuronal responses and neurotransmitter-evoked neural signalling in natural neural circuits, leading to persistent challenges in biosafety and therapeutic effectiveness. Inspired by the dopaminergic neural circuit, we report a biointegrated living brain stimulator (BBS) that integrates ferroelectric bioelectronics, dopaminergic cells, and a gelatin hydrogel matrix, enabling dopamine neurotransmitter-evoked neural signalling. In contrast to conventional brain stimulators, the BBS are capable of programmed secretion of physiological-level dopamine, specifically activating nigral dopamine pathways and restoring motor function in a rodent PD model. By integrating the advantages of both bioelectronics and medicine, this lifelike BBS offers a great promise for next-generation bioelectronics, medicine, and brain-machine interfaces.

bioengineering↗

bioRxiv2026

dbGIST: An LLM-Assisted Multi-Omics Resource for Target Exploration and Cross-Dataset Validation in Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, yet GIST-specific omics evidence remains scattered across small cohorts and is not represented as a dedicated disease project in major cancer genomics resources, limiting reproducible target exploration. Here, we present dbGIST (https://www.dbgist.com), a dedicated GIST-focused multi-omics resource built to make dispersed GIST evidence searchable, analyzable, and reusable. dbGIST harmonizes data from 37 centers and 1,991 samples, including pathologically verified in-house cohorts, across genomics, bulk transcriptomics, proteomics, phosphoproteomics, and single-cell transcriptomics, and couples these data with curated clinical annotations covering survival, mutation status, risk stratification, metastasis or recurrence, mitotic index, tumor site and size, and imatinib response. The platform supports cohort-level molecular-clinical association, survival, enrichment, immune-infiltration, drug-sensitivity, and single-cell analyses through interactive visualizations, downloadable source data, and public APIs for programmatic access to reusable analysis outputs and visualization-ready data. An optional LLM-assisted interface helps users navigate analyses and interpret outputs. Using MCM7 as a case study, dbGIST linked a resource-derived candidate to survival, risk features, metastatic or recurrent disease, imatinib-response phenotypes, proliferative cell states, and in vitro GIST-cell behavior. dbGIST therefore provides a traceable and interoperable resource for target exploration and precision oncology research in GIST.

cancer biology↗

bioRxiv2026

De novo steroidogenesis maintains female-specific Th2 identity and constrains effector function

T helper 2 (Th2) lymphocytes drive type-2 immunity and allergic diseases that disproportionately affect females, yet the mechanisms underlying this sexual dimorphism remain poorly understood. Current models attribute sex-biased immune differences to circulating gonadal hormones and to sex chromosome composition, leaving unresolved whether immune cells possess cell-autonomous mechanisms acting independently of both. Here we show that female and male Th2 cells differentiated under identical, hormone-free conditions are transcriptionally distinct but functionally equivalent: female cells carry a heightened inflammatory and interferon-response programme, yet produce IL-13 and IL-4 at rates indistinguishable from male cells, with only a modest baseline difference in proliferative capacity. Using T cell-specific deletion of Cyp11a1 that encodes the first and rate-limiting enzyme of de novo steroidogenesis, we identify the constraint that maintains this equivalence. Cyp11a1 loss acts almost exclusively in females, where it simultaneously dampens the female-specific inflammatory programme and drives proliferation and IL-13 production above the level seen in either sex. Male Th2 cells are essentially unaffected. The effect requires differentiation, being absent in naive precursors, indicating that the steroidogenic machinery becomes functionally consequential only in the mature effector state. Cross-species analysis of two human atopic dermatitis single-cell datasets identifies a shared directional signature of gene expression. Cell-intrinsic steroidogenesis therefore constitutes a third axis of immunological sexual dimorphism, one that operates by uncoupling transcriptional identity from effector output rather than by specifying identity itself.

immunology↗

bioRxiv2026

Mapping Individualized Developmental Imbalance in Youth and Its Association with Psychopathology

The emergence of psychiatric symptoms during adolescence is increasingly hypothesized as arising from maturational imbalance across brain systems. However, this concept largely lacks quantitative grounding, which requires measuring fine-grained imbalance patterns that accurately capture acceleration or delay relative to normative developmental trajectories of brain regions. To address this gap, we leverage predictive normative modeling to learn models that predict chronological age from regional multivariate functional connectivity patterns. We demonstrate that these region-specific models are highly generalizable across independent cohorts and capture greater developmental effects than traditional functional connectivity metrics. From these models, we then derive a region-wise Relative Maturity (RM) index that quantifies individualized, region-specific deviations from normative development. Rigorous cross-cohort and longitudinal evaluations across four datasets show that RM maps are reproducible, subject-specific fingerprints of neurodevelopmental imbalance. These fingerprints are organized along continuous, low-dimensional axes aligned with intrinsic functional gradients and can predict dimensions of psychopathological vulnerability. Together, our findings establish RM as a robust, sensitive, and generalizable framework for quantifying individual vulnerability to psychopathology through system-level patterns of developmental imbalance.

neuroscience↗

bioRxiv2026

NFIC-mediated CaSR endocytosis defines a hyperactive TOMM20highCHGAhigh oxyphil cell state as a pathological driver of autonomous secondary hyperparathyroidism

Secondary hyperparathyroidism (SHPT) is a debilitating complication of chronic kidney disease. Its clinical management is frequently compromised by calcimimetic resistance, a refractory state primarily driven by the progressive downregulation of the membrane calcium-sensing receptor (CaSR). Despite the centrality of CaSR as a therapeutic target, the mechanisms governing its aberrant expression and membrane localization remain incompletely elucidated. Here, we generated a single-cell transcriptomic atlas of human parathyroid tissues from SHPT and primary hyperparathyroidism (PHPT) patients, uncovering a unique stromal-immune niche that is specifically induced by uremic stress in SHPT. Our data also observed a striking dissociation between CaSR mRNA and its abundance as a membrane protein in SHPT tissues. Pseudotime trajectory analysis showed a progressive decline in CaSR pathway activity and a concomitant increase in endo-lysosomal activity along the trajectory, terminating in pathological oxyphil cells as the endpoint of chief cell differentiation in SHPT. Mechanistically, Nuclear Factor I C (NFIC) transcriptionally activated clathrin light chain B (CLTB) and Ras-related protein Rab7a (RAB7A) to trigger clathrin-mediated endocytosis and lysosomal degradation of CaSR, thus reducing its membrane abundance. This degradative program was further validated by multiplex immunofluorescence in TOMM20highCHGAhigh pathological oxyphil cells in human SHPT tissues. To translate these mechanistic findings into a clinically actionable strategy, we repurposed the clinically approved lysosomal inhibitor hydroxychloroquine (HCQ) to block this CaSR degradation pathway. In patient-derived xenograft (PDX) mouse models, co-administration of HCQ and cinacalcet acted synergistically to restore membrane CaSR expression, normalize serum PTH and calcium levels and suppress parathyroid tumor growth more effectively than monotherapies. Collectively, our single-cell-guided study identifies an NFIC-driven endo-lysosomal program as a previously unrecognized mechanism underlying CaSR downregulation and calcimimetic resistance in SHPT, and establishes HCQ repurposing as a clinically tractable therapeutic strategy for patients with refractory SHPT.

cell biology↗

bioRxiv2026

Combinatorial epigenomic patterns define regulatory programs underlying disease heterogeneity

Complex diseases exhibit substantial variation in clinical presentation and outcome despite shared diagnoses. Current genetic models typically represent inherited risk as a single additive liability, obscuring the diverse biological mechanisms through which variants influence disease. Here, we show that disease-associated variants are organized into recurrent regulatory programs that reveal latent disease mechanisms. Using genome-scale epigenomic maps across human tissues and cell states, we identify regulatory programs that partition disease-associated variants without phenotypic or disease-specific priors. Variants assigned to different programs exert distinct biological effects that translate into divergent clinical outcomes. In type 2 diabetes, these programs reveal previously unrecognized disease subtypes with opposing cardiometabolic profiles that stratify future risk of myocardial infarction and non-alcoholic fatty liver disease. Together, our findings establish that inherited disease risk is organized into latent regulatory programs, revealing a fundamental layer of biological heterogeneity underlying complex disease.

genomics↗

bioRxiv2026

Comparative Mapping of Functional and Structural Homologies in the Pig and Human Brain

Comparative mapping of functional and structural homologies across humans, small animals, and nonhuman primates has been extensively pursued due to its strong translational relevance. However, these experimental models possess inherent limitations in fully recapitulating the complexity of human cortical organization. The porcine model has recently emerged as a promising alternative, given its neuroanatomical and physiological similarities to the human brain. Despite these advantages, systematic cross-species characterization of functional and structural homologies between humans and pigs remains largely understudied. In the present study, we acquired resting-state functional MRI and diffusion MRI data from pigs and analyzed them alongside corresponding human datasets to investigate cross-species correspondence in large-scale brain organization. First, to enhance functional network alignment across species, group independent component analysis was performed separately within each species to identify intrinsic large-scale functional networks. Our results demonstrated that multiple canonical human resting-state networks are represented in the porcine brain, including sensorimotor, default mode, cerebellar, frontal, and central executive networks. Moreover, we observed significant cross-species concordance in intrinsic functional architecture across multiple distributed networks, both in spatial distribution and temporal patterns, indicating homologous large-scale brain organization between pigs and humans. Second, we conducted comparative structural analyses using diffusion MRI-based fiber tractography, color-encoded fractional anisotropy maps, and structural connectivity analyses to examine and compare white matter organization in pigs and humans. Cross-species comparison revealed substantial similarities in major white matter pathways and their spatial organization, supporting structural correspondence at the level of tract geometry. Together, these findings underscore the translational value of the porcine model as a robust and neurobiologically relevant platform for investigating human brain function, structural organization, and related neurological disorders.

neuroscience↗