Biology subjects

Hu, J.

Publications and source records attributed to Hu, J..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Lamins promote trophoblast lineage-associated transcription and trophoblast giant cell development in placental organogenesis

Lamins are the major structural components of the nuclear lamina with a variety of roles in development and organogenesis. However, the function of lamins during trophoblast development, the first lineage to differentiate during mouse embryogenesis, remains unexplored. By utilizing an in vitro trophoblast stem cell differentiation model in a lamin null setting, we uncover that lamins maintain expression of genes related to trophoblast differentiation, while repressing genes involved in maintaining trophoblast stem cell stemness and off-lineage development. By deleting different combinations of lamins in mice, we show that both lamin triple-knockout and lamin-A and -B1 (lamin-A/B1) double-knockout result in placental defects, including reduced placenta size and disrupted placental organogenesis at embryonic day (E)9.5. At this stage, lamin-A/B1 are expressed in trophoblast giant cells of the placenta, and lamin-A/B1 loss leads to their impaired maturation in vivo. Lamin-A/B1 double knockout trophoblast giant cells exhibit reduced nuclear size along with a reduction of DNA damage signaling foci, suggesting a role for lamins in supporting trophoblast giant cell polyploidization. Similar to the transcriptional dysregulation observed during differentiation of lamin triple knockout trophoblast stem cells in vitro, lamin-A/B1 knockout in vivo results in downregulation of genes related to trophoblast giant cell function and upregulation of off-lineage genes. Our results suggest lamins are required for placental organogenesis by maintaining polyploidization and lineage-associated transcriptional programs in trophoblast giant cells.

developmental biology↗

bioRxiv2026

The HES1-SOD1 Antagonism Shapes Senescence Heterogeneity and Impacts Metastatic Relapse of Circulating Tumor Cells

Circulating tumor cells (CTCs) encounter multiple challenges within the blood microenvironment, including oxidative stress, flow shear forces, and immune surveillance, often leading to anoikis. Recently, a transitional state of CTC senescence has been identified, contributing to metastatic inefficiency. However, the molecular mechanisms linking senescent CTCs to disease relapse remain to be defined. By integrating a genetic model of cortactin knockdown-induced CTC senescence with single-cell multi-omic analyses, we revealed two distinct senescent CTC subpopulations marked by HES1 expression levels. These HES1low and HES1high subpopulations exhibited differential evolutionary trajectory dynamics and unique molecular and metabolic signatures, which were significantly correlated with adverse clinical outcome across several patient cohorts. HES1low senescent CTCs displayed enhanced mitochondrial fitness, oxidative phosphorylation, and ROS-detoxifying capabilities, resulting in more efficient tumor regrowth with a pro-inflammatory and thrombotic phenotype when compared to the HES1high group. Mechanistically, HES1 directly bound to the Sod1 promoter and repressed its expression, leading to redox imbalance and mitochondrial dysfunction that were linked to weakened tumor regrowth capacity. Both senescent CTC subpopulations were broadly resistant to cytotoxic and targeted therapies, yet they showed elevated dependency on anti-apoptosis programs that make them susceptible to dual blockade by SOD1 inhibitor and the anti-senolytic drug ABT737 in vivo. Finally, in a prospective cohort of on-treatment melanoma patients, HES1 senescent CTCs were highly enriched in patients with progressive disease. Thus, the HES1-SOD1 antagonism shapes CTC senescence heterogeneity and contributes to differential tumor relapse, which can be therapeutically explored for eliminating residual metastatic disease.

cancer biology↗

bioRxiv2026

Life finds a way: Integrative phylogenomics resolves an overlooked bivalve order with chromosome fusion and mitochondrial translational-code evolution

Resolving deep phylogenetic relationships requires integrating multiple lines of evidence, as distinct evolutionary forces shape signals from different genomic markers. Here, we investigate the systematics of the controversial APPD lineage (Anomiidae, Placunidae, Plicatulidae, and, by inference, Dimyidae) within Pectinida sensu lato using phylogenomic, comparative genomic, transcriptomic, proteomic, and morphological approaches. Our analyses consistently recover APPD as a monophyletic lineage sister to Limida and Pectinoidea, divergent at [~]428 Mya. With three novel high-quality genomes, extensive progressive chromosomal fusions demonstrate a reduction in chromosome number of the APPD lineage (6-13), compared with an ancestral 20 molluscan linkage groups (MLGs). Accompanied by extensive intrachromosomal gene-order scrambling, we identify one functional centromere in Placuna vitream flanked by two vestigial centromeric remnants on a single chromosome, providing a potential resource for investigating centromere inactivation and neocentromere formation. Mitochondrial genomes of APPD lineage exhibit unprecedented plasticity in translational decoding: Pododesmus employs the invertebrate mitochondrial code; Heteranomia employs +1 translational frameshifting to bypass in-frame TAG codons, whereas in Anomia, Enigmonia, Placuna, and Plicatulidae, TAA is reassigned to tyrosine and confirmed by proteomic evidence, which supports mitochondrial frameshifting in APPD lineage and defines a novel translation table for bivalves. Integrating phylogenetic distinctiveness, deep divergence, extreme karyotypic restructuring, unique mitochondrial features, and morphological diagnosability, we elevate the APPD lineage into Anomiida ord. nov. This revision resolves long-standing uncertainties for Pectinida sensu stricto and Limida, and establishes the APPD lineage as a valuable system for investigating chromosome fusion, centromere evolution, codon reassignment, and translational recoding. ClassificationBiological Sciences; Evolution SIGNIFICANCE STATEMENTWe have re-examined a controversial group of marine bivalves (Anomiidae, Placunidae, Plicatulidae, and Dimyidae). Our integrative approach shows that these animals split from scallops and their relatives more than 428 million years ago and have undergone drastic chromosomal fusions that reduced their chromosome number from 20 to as few as 6. Additionally, some species evolved unusual ways of reading their mitochondrial genetic code, either reassigning the stop codon to tyrosine or using +1 translational frameshifting to skip stop signals. The combination of deep evolutionary time and genomic divergence warrants recognizing them as a new order, Anomiida ord. nov. This work, as a case study, demonstrates how chromosome fusion and genetic code variation contribute to invertebrate diversity.

evolutionary biology↗

bioRxiv2026

SpatialMOC: Accurate reconstruction of spatial multi-omics landscapes through cross-modality prediction

Spatial multi-omics technologies provide unprecedented opportunities to characterize tissue organization by measuring complementary molecular layers within their native spatial context. However, simultaneous profiling of multiple molecular modalities remains technically challenging, limiting the widespread application of spatial multi-omics and leaving most studies reliant on single-modality measurements. Here, we present Spatial Multi-Omics Cross-prediction (Spatial-MOC), a computational framework that reconstructs missing spatial molecular modalities by integrating spatial context with cross-modality representation learning. Across multiple tissues, molecular modalities, developmental stages, sequencing platforms, and degraded datasets, SpatialMOC consistently outper-formed existing computational approaches in bidirectional molecular prediction. Beyond accurate prediction, SpatialMOC faithfully reconstructed tissue architecture, preserved dynamic molecular and regulatory heterogeneity, and recovered biologically meaningful spatial landscapes from technically compromised measurements. Together, these results establish SpatialMOC as a general framework for spatial multi-omics reconstruction, extending the analytical value of existing spatial omics datasets and facilitating comprehensive investigations of tissue organization, development, and disease.

bioinformatics↗

bioRxiv2026

Monkeys learn to report their own sensory cortical population activity

How sensory cortical activity is read out by downstream circuits to guide behavior is a fundamental unsolved problem. Substantial work has examined correlations between sensory neural responses and animals perceptual judgments, but their interpretations remained controversial due to many intervening variables, such as responses of unrecorded neurons. Furthermore, stimulus and choice encoding in sensory populations are often not well aligned, and it remains contested whether this misalignment indicates a limitation in sensory readout. Here, we introduce a closed-loop, neurofeedback paradigm that directly interrogates the capacity of sensory readout: the key idea is to train subjects to report specific patterns of population activity in a sensory area recorded online, rather than the actual stimuli presented. To test this, we trained macaque monkeys on a visual change-detection task using shape stimuli, implanted an electrode array in visual area V4, and tested whether they could be further trained to rely on their own V4 activity along specific axes in neural state space. Strikingly, monkeys successfully increased the neuron-choice correlation along trained axes in neural population state space. No detectable changes in stimulus selectivity or noise correlations were found within the recorded population, and further model simulations confirmed that adjustment of sensory readouts best accounted for the results. A control experiment that merely disrupted the stimulus-reward contingency without a closed loop failed to enhance neuron-choice correlation. Together, these results demonstrate that closed-loop neural feedback achieves neuron-choice alignment beyond the ceiling of natural perceptual training, suggesting that the misalignment in perceptual tasks reflects constraints on learning within naturally available training regimes.

neuroscience↗

bioRxiv2026

Potato Agent: AI-Driven Data and Knowledge Exploration on an Agent-Ready Potato Multi-Omics Platform

Potato is an important non-cereal food crop worldwide. However, the limited number of functionally validated genes remains a major bottleneck to favorable allele stacking and genome design breeding in potato. Rapid advances in AI agents offer a promising means to support crop breeding by translating natural-language questions into coordinated data analysis and knowledge retrieval. Their reliable use for potato breeding, however, is constrained by fragmented multi-omics resources that lack consistent curation and machine-accessible interfaces. Here, we constructed an agent-ready potato multi-omics database integrating genomic resources from 150 potato accessions, 259 bulk RNA-seq samples, and 14 spatial transcriptomic datasets into a pangenome, a tissue expression atlas, co-expression networks, and spatial expression maps accessible through open APIs. We developed 39 potato-specific Agent Skills for reproducible bioinformatics analysis and comprehensive data and knowledge exploration, enabling natural-language questions to be translated into standardized data-retrieval and analysis tasks. By integrating direct evidence from potato studies, functions of homologous genes in Arabidopsis, rice, and maize, and tissue expression patterns, we generated genome-wide functional predictions for 37,658 genes in the DM reference genome. We further developed Potato Agent as a multi-user, browser-based platform with isolated workspaces and online result preview, reducing the technical burden of agent deployment and providing direct access to integrated data, knowledge, and workflows. Case studies demonstrated its capabilities in reproducible bioinformatics analysis, agent-assisted identification of a tuber development regulator, scientific data visualization, and haplotype-aware promoter analysis and sgRNA design. Together, the agent-ready database and Potato Agent provide an integrated infrastructure for functional gene discovery and hybrid breeding in potato.

plant biology↗

bioRxiv2026

Reprogramming VHL with molecular glues enables selective degradation of caspase-2

Molecular glue degraders (MGDs) reprogram E3 ligases to eliminate neosubstrates, yet their application has largely been confined to CRBN. Here, we identify caspase-2 as a new neosubstrate for von Hippel-Lindau (VHL), expanding the scope of VHL-based MGDs. Guided by a focused VHL ligand library design, we employed TurboID-based proximity labeling to discover stereoisomeric compounds (dCASP2-1 and dCASP2-2) that selectively recruit caspase-2 to VHL and promote its ubiquitin-proteasome system-dependent degradation. Further structure-activity relationship (SAR) studies yielded dCASP2-3 and dCASP2-4, which enhanced degradation potency (by 622-fold relative to dCASP2-1) and abolished enantioselectivity. Mechanistic mapping localized the degrader-induced interface to a two-helix region of the caspase-2 CARD domain, with residues H33, P34, and D100 essential for VHL engagement. Degron-guided computational modeling of the VHL/MGD/caspase-2 ternary complex provided structural insight into neosubstrate recognition. Together, we report the development of VHL molecular glues that selectively and potently degrade caspase-2, offering chemical probes to interrogate its functions in apoptosis and stress responses, while broadening the substrate landscape of VHL-based MGDs.

biochemistry↗

bioRxiv2026

Remodeling oligodendrocyte lipid metabolism via liver X receptors overcomes inflammatory blockade of remyelination

Multiple sclerosis is characterized by immune-mediated demyelination and inefficient remyelination, owing to impaired differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes (OLs). Inflammatory cytokines within multiple sclerosis lesions inhibit OPC maturation and induce an immune-like phenotype with antigen-presenting properties, but the underlying mechanisms remain poorly defined. Here, we show that inflammation reprograms OPC lipid metabolism, linking altered metabolism to remyelination failure. In cultured rodent OPCs, interferon-{gamma} (IFN-{gamma}) induced a switch from lipid synthesis to utilization, leading to reduced intracellular fatty acid levels and increased dependence on fatty acid oxidation. Transcriptional analyses confirmed similar lipid metabolic changes in OL-lineage cells cultured from human surgical specimens or isolated from mouse models of inflammatory demyelination and human multiple sclerosis lesions. Enhancing lipid availability in OPCs through oleic acid supplementation or inhibition of fatty acid oxidation attenuated immune-like functions and increased differentiation. Pharmacologic activation of liver X receptor (LXR) transcription factors rebalanced lipid metabolism, suppressed immune-like functions, and overcame IFN-{gamma}-induced differentiation blockade in both mouse and human-derived OPCs. In an adoptive transfer-cuprizone mouse model in which inflammation directly impairs remyelination, LXR activation increased mature OL generation and augmented myelin repair. Together, these findings identify lipid metabolic remodeling as a key mechanism by which inflammation impairs OPC differentiation and highlight LXR activation as a therapeutic approach to enhance remyelination in multiple sclerosis.

neuroscience↗

bioRxiv2026

Cellular senescence is associated with age-related loss of liver zonation and hepatocyte function

The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by "expansion" of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A "no-zone" hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

cell biology↗

bioRxiv2026

Repurposing the Antiviral Agent Pibrentasvir: In Vitro Synergistic Effects in Combination with Different Azole Antifungal Agents

ObjectiveTo investigate the combined effects of multiple drugs and provide more therapeutic options for invasive fungal infections, this study evaluated the in vitro susceptibility of Aspergillus spp., Candida auris, Cryptococcus neoformans, and Exophiala dermatitidis to pibrentasvir (PIB) in combination with itraconazole (ITR), voriconazole (VOR), posaconazole (POS), or fluconazole (FLU). MethodsAccording to the M27-A3 and M38-A2 guidelines established by the Clinical and Laboratory Standards Institute (CLSI), the in vitro antifungal activities of PIB combined with ITR, VOR, POS, or FLU against 78 clinical isolates, including Aspergillus spp., E. dermatitidis, C. auris, and C. neoformans, were determined. The minimum inhibitory concentrations (MICs) and fractional inhibitory concentration indices (FICIs) were calculated to evaluate the synergistic effects. ResultsPIB alone exhibited no antifungal activity. Significant synergistic effects were observed when PIB was combined with azole antifungal agents. The PIB-POS combination showed synergistic effects against Aspergillus spp. (27/41, 65.90%), C. auris (9/10, 90.00%), C. neoformans (2/9, 22.20%), and E. dermatitidis (11/18, 61.11%). The PIB-ITR combination also showed synergistic effects against Aspergillus spp. (18/41, 43.9%), C. auris (9/10, 90.0%), C. neoformans (2/9, 22.2%), and E. dermatitidis (10/18, 55.5%). Synergistic effects were less frequently observed with the PIB-VOR or PIB-FLU combinations, and no antagonistic effects were observed. ConclusionThis study demonstrates that PIB acts as an azole sensitizer, with the strongest synergistic effects observed when combined with POS or ITR, providing a new research direction for combination therapy against invasive fungal infections.

microbiology↗

bioRxiv2026

A Neuroendocrine Circuit That Suppresses Excretion and Pelvic Pain During Activity

Mate-seeking during peak sexual receptivity is tightly coupled with exploratory movement, a process made more efficient by transient suppression of excretion. Here, we define a functional hypothalamic-hindbrain circuit in mice that promotes locomotion while eliminating urination and defecation for hours. Chemogenetic stimulation of excitatory estrogen-melanocortin-responsive MC4R+ neurons in the ventrolateral ventromedial hypothalamus (VMHvl) effectively silences bladder and colonic visceral reflexes, even at noxious distension pressures, underscoring the potency of this anti-excretion circuit. Pelvic sensations and excretion are restored only after ablating inhibitory GABAergic neurons in the Barringtons nucleus/locus coeruleus (BAR/LC) hindbrain region or after antagonizing endogenous endorphin signaling. Our study illustrates how a hormone-responsive brain node prioritizes movement over excretion and blunts pelvic discomfort, thereby optimizing an essential voluntary behavior for evolutionary fitness.

physiology↗

bioRxiv2026

High-resolution transcriptomic profiling of Arabidopsis thaliana across a 37°C-40°C thermal gradient

Thermal adaptation is critical for organismal viability, with acquired thermotolerance (AT) in Arabidopsis thaliana typically conferred by acclimation temperatures between 34{degrees}C and 37{degrees}C, while acclimation at 40{degrees}C fails to protect against lethal heat stress. To elucidate the transcriptional mechanisms underlying the loss of AT at higher temperatures we performed RNA-seq profiling of Arabidopsis seedlings across a single-degree thermal gradient from 37{degrees}C to 40{degrees}C. Our analysis reveals that all of these temperatures result in a robust heat shock response, characterized by the upregulation of genes involved in protein folding and stress responses. However, each temperature elicits a distinct transcriptional signature. These findings demonstrate that temperature-specific fine-tuning of the heat shock response occurs within this narrow range and that these differences may dictate the successful acquisition of thermotolerance. This dataset provides a valuable resource for understanding the molecular architecture of heat-stress adaptation and the distinct transcriptional states associated with different thermal regimes.

plant biology↗

bioRxiv2026

An IL-34-IGF-1 inflammatory axis fuels KRAS-mutant lung cancer progression

Macrophages are innate immune cells of embryonic or adult origin with tissue specific roles in homeostasis, disease surveillance, and wound repair that can be co-opted to promote tumor growth and spread1-11. An understanding of the specific roles of macrophage subsets in lung tumor initiation and progression could promote new therapeutic approaches for this deadly disease. Here, we show that KRASG12D mutations in lung epithelium drive proliferation of resident, embryonically-derived alveolar macrophages, which then promote tumor cell proliferation and protection from ferroptosis, leading to tumor progression. Using genetically engineered mouse models of mutant KRASG12D non-small cell lung cancer12,13, we found that alveolar macrophages accumulate by proliferation in response to tumor cell-secreted IL-34, recapitulating events observed in late embryonic lung development. Tumor alveolar macrophages in turn drive IGF-1-dependent tumor cell proliferation. Neutralization or deletion of IL-34 suppresses IGF-1 expression, reduces macrophage and tumor cell proliferation and inhibits tumor progression. High IL34 and IGF1 correlate with poor survival in KRASG12D/V lung adenocarcinomas and in other solid tumors, indicating that bi-directional proliferative signaling between resident macrophages and tumor cells can drive human lung tumor progression. These studies identify resident macrophage-tumor cell interactions as key interception points for lung cancer therapy.

cancer biology↗

bioRxiv2026

Peptide additives reprogram the lipid nanoparticle corona and enhance gene delivery in a serum-free environment for lung epithelium

Lipid nanoparticles (LNPs) have become a clinical standard for systemically-administered nucleic acid drugs and vaccines, but the LNP pipeline for locally-delivered LNP therapies remains much less mature. Local delivery in lung represents a particularly compelling application space for DNA-LNP therapeutics, as local gene therapies could support sustained epithelial recovery and functional restoration in various lung diseases. However, locally-delivered DNA-LNPs face multiple barriers, including the limited availability of serum components that often support conventional LNP activity, and the additional delivery barriers posed by the nucleus. We generated hybrid peptide-lipid nanoparticles (hpLNPs) for pulmonary DNA delivery by using a core-shell assembly strategy to incorporate short histone-derived peptides, selected for their DNA-transport capacity, into a clinically inspired LNP formulation. In parallel, we evaluated serum pre-coating of LNPs as a strategy to boost hpLNP activity in the serum-poor airway environment. A peptide:DNA amine/phosphate (N/P) ratio of 0.9 was identified as the highest feasible ratio to permit peptide incorporation into hpLNPs while preserving DNA encapsulation efficiency at >90%, retaining hpLNP colloidal stability, and preserving the overall pKa for LNPs. At N/P = 0.9, hpLNPs showed markedly enhanced DNA delivery in alveolar lung cells, achieving up to a 17-fold increase in transgene expression compared to peptide-free LNPs. Transgene expression levels varied depending on serum concentration, with expression peaking in the presence of 6% serum. Furthermore, serum pre-coating was necessary to enable in vivo hpLNP activity following intratracheal administration in mice, yielding robust local GFP expression. Mechanistic studies in exosome-free serum revealed that peptide incorporation in the hpLNPs enhanced transgene delivery by increasing nanoparticle interactions with serum exosome components, resulting in significant enhancements to hpLNP uptake. Together, these findings identify nanoparticle- serum interactions as a critical determinant of LNP-mediated pulmonary DNA delivery and establish peptide incorporation and serum pre-coating as promising strategies to enable robust, localized gene transfer in serum-free environments.

bioengineering↗

bioRxiv2026

Epithelial QKI Protects Against Emphysema by Maintaining Mitochondrial Integrity

Single-cell transcriptomic profiling of chronic obstructive pulmonary disease (COPD) lungs identified QKI, an RNA-binding protein, as a candidate emphysema-associated gene, but its epithelial role in COPD pathobiology remains unclear. We show that QKI expression is reduced in human COPD lungs and that alveolar type 2 epithelial (AT2) cell QKI protein levels correlate strongly with spirometric indices and diffusing capacity (DLCO). Lung epithelium-specific QKI knockout mice (QKI{Delta}/{Delta}) developed spontaneous airspace enlargement with emphysema-like mechanics, and QKI-deficient AT2 cells showed impaired spheroid colony formation and increased apoptosis. Integrated transcriptomic and proteomic analyses of primary AT2 cells revealed a selective reduction in functional mitochondrial (respiratory-chain and metabolic) protein abundance despite relatively preserved transcript levels, consistent with mitochondrial transcriptome-proteome discordance. QKI loss increased mtDNA abundance and TOMM20 staining but decreased ATP5A, indicating accumulation of structurally increased but functionally dysfunctional mitochondria. In human epithelial cells, CRISPR-mediated QKI deficiency reduced oxidative respiration, increased glycolytic reliance, elevated mitochondrial ROS and membrane potential, and increased apoptosis; these phenotypes were partially rescued by QKI re-expression. These findings identify epithelial QKI as a regulator of mitochondrial integrity and stress tolerance in COPD.

cell biology↗

bioRxiv2026

Synthesizing Mechanistic Hypotheses from Single-Cell Omics via Discretized Feature Attribution and Empirical Language Model Grounding

Single-cell multimodal omics offer unprecedented resolution of cellular networks, yet translating continuous computational attributions into structured, testable biological mechanisms remains a persistent bottleneck. To address this limitation, we introduce an analytical pipeline employing decision trees to discretize continuous neural network attributions into explicit regulatory thresholds. These boundaries then structurally constrain large language models, enabling them to integrate established literature with empirical data to synthesize context-specific hypotheses. Applying this continuous-to-discrete framework across sparse datasets yielded novel biological mechanisms. Specifically, the framework articulated a cytoskeletal gating hierarchy governing EGF-stimulated pathways, identified transcriptomic drivers of input resistance in cortical interneurons, and delineated translational logic predicting Ki-67 abundance within spatial transcriptomics. Retrospective benchmarking validated the frameworks capacity to autonomously reconstruct published regulatory logic. Supported by a locally deployable open-weight language model and a code-free interface, this approach establishes an auditable methodology to extract robust experimental hypotheses from high-dimensional single-cell data.

systems biology↗

bioRxiv2026

Molecular and Structural Basis of Cardiac Remodelling in Niemann-Pick Type C

Key Point SummaryNiemann-Pick disease type C (NPC) patients showed a high prevalence of ECG abnormalities, with additional echocardiographic evidence of altered left-ventricular structure and function. Npc1-/- mouse hearts exhibited age-associated glycosphingolipid accumulation accompanied by marked myocardial fibrosis and increased collagen deposition. Ex vivo electrophysiology revealed QT prolongation and atrioventricular conduction defects in Npc1-/- hearts, particularly under {beta}-adrenergic stress. Transcriptomic profiling identified inflammatory and fibrotic pathway activation consistent with the structural and electrophysiological abnormalities observed. Together, these findings demonstrate previously unrecognised cardiac involvement in NPC and support routine cardiac screening to improve clinical management. Niemann-Pick disease type C (NPC) is a rare autosomal recessive neurodegenerative lysosomal storage disease caused by pathogenic variants in NPC1 or NPC2. Sudden death can occur due to seizures, but cardiac involvement has not been well defined. We performed 12-lead electrocardiograms (ECG) in 14 adult NPC patients (8 male, 6 female). Cardiac structure and function were examined in Npc1-/- adult mouse hearts, alongside wild-type controls. Glycosphingolipid accumulation was quantified by high-performance liquid chromatography, fibrosis and collagen deposition were quantified using Massons Trichrome (M&T) and Picrosirius Red (PR) staining. Whole-heart morphology, including chamber size and wall thickness, was assessed. Ex vivo ECG recordings assessed conduction abnormalities and arrhythmias. RNA-seq transcriptomics characterised molecular pathways altered in Npc1-/- hearts. 8/14 patients showed ECG abnormalities including abnormal QRS transitions (N=8), increased QRS amplitude (N=4), fascicular block (N=2), and abnormal T wave inversion (N=1). 13 patients also had transthoracic echocardiograms identifying mildly impaired LV systolic function (N=2) and increased wall thickness/LV mass (N=4). In Npc1-/- mice, age-related glycosphingolipid accumulation was associated with pronounced ventricular fibrotic remodelling. There was a significant increase in stained connective tissue area and connective tissue to cardiac tissue ratio in both M&T and PR staining. ECG from Langendorff-perfused Npc1-/- hearts showed QT prolongation and atrioventricular conduction abnormalities under isoprenaline stress. Transcriptomics revealed major changes in Npc1-/- hearts, consistent with histological fibrosis and linking NPC to inflammation-driven remodelling and arrhythmogenesis. These findings support routine cardiac screening in NPC patients and highlight the need for further studies to improve management and treatment.

physiology↗

bioRxiv2026

An Integrated Knowledge Graph and Network Medicine Pipeline for Drug Repurposing: Benchmarking Across Human Diseases and Application to Amyotrophic Lateral Sclerosis

Drug repurposing offers a practical strategy to identify new therapeutic uses for approved drugs, potentially reducing the time and cost associated with conventional drug development. We present a novel three-stage drug repurposing pipeline that integrates knowledge graph-based gene prediction, network-based drug-disease association analysis, and systematic classification of candidate drugs by therapeutic class. The pipeline integrates DGLinker to predict novel disease-associated genes, SAveRUNNER to identify drug repurposing candidates, and ATC Category Enrichment Analysis (ATCEA) to prioritise candidates by pharmacological class. We benchmarked the pipeline across twelve diseases using DrugBank and MEDI2-HPS as validation resources. Utilising DGLinker-expanded disease-gene sets as input increased the number of predicted repurposed drugs, while overall discriminative performance remained stable across diseases (AUROC 0.71-0.77). Application of ATCEA consistently improved precision, F1-score, and specificity, while reducing recall, reflecting a conservative prioritisation strategy that contracts the candidate space while retaining pharmacologically coherent drug-disease candidates. We further applied the pipeline to amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with limited therapeutic options and performed a deeper literature-based validation of the results. Incorporation of DGLinker-predicted genes substantially increased the number of significant candidate drugs and uncovered enriched ATC categories not identified using known ALS genes alone, including antidepressants and antipsychotics. Moreover, several drugs with supporting evidence available in literature were identified only when DGLinker-predicted genes were used. Overall, 77 candidate drugs were prioritised within significantly enriched ATC categories, several of which are supported by previously published studies. To provide exploratory real-world support for these findings, we further evaluated candidate drugs in a longitudinal electronic health record (EHR) dataset of 2361 patients with ALS from Kings College Hospital. Although the number of evaluable drugs was limited due to sample size, the EHR analysis provided additional clinically relevant context for selected prioritised drugs and pharmacological classes. Our pipeline demonstrates potential to accelerate drug repurposing by integrating complementary computational approaches to each step of the process, providing an end-to-end framework that showed robust performance across benchmarking experiments and use cases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/736387v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@17bf49borg.highwire.dtl.DTLVardef@f80998org.highwire.dtl.DTLVardef@3e1833org.highwire.dtl.DTLVardef@a6efaf_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗