Biology subjects

Hu, S.

Publications and source records attributed to Hu, S..

At least 19 recordsLinked to original sources

bioRxiv2026

Alignment-Free k-mer Analysis Reveals Age-Associated k-mer Signals in Canine Buccal DNA and Cell-Free DNA

Aging is associated with progressive molecular and cellular changes that alter chromatin organization, epigenetic regulation, and microbial community structure. While DNA methylation-based biomarkers have demonstrated age-prediction performance, the potential of alignment-free sequence analysis for detecting age-associated signals remains unexplored. We performed a k-mer-based analysis of whole-genome sequencing datasets from two canine cohorts: 1,187 buccal DNA samples and 100 cell-free DNA (cfDNA) samples. Age-associated k-mers were identified through correlation analysis, and sequence motifs and nucleotide composition patterns were characterized across both sample types. Ridge regression models were used to predict age from k-mer frequency profiles, and synthetic datasets were generated under biological compositional assumptions to evaluate potential drivers of the observed signals. Age-associated k-mer signals were identified in both buccal DNA and cfDNA, with substantially stronger patterns observed in buccal samples. Buccal-derived k-mers exhibited more pronounced motif patterns, stronger GC and AT enrichment trends, and improved age-prediction performance relative to cfDNA. Nucleotide enrichment trends differed between sample types, suggesting that distinct biological processes may contribute to age-associated sequence composition changes in buccal DNA and cfDNA. Simulation analyses successfully reproduced major enrichment trends observed empirically, and age-associated signals were largely preserved following restriction to read-start sequence composition. These findings demonstrate that alignment-free k-mer analysis can detect age-associated sequence composition signals in canine DNA and highlight its potential as a computationally efficient complementary approach for aging biomarker discovery.

bioinformatics↗

bioRxiv2026

Characterization of artificial riboswitches for Coxsackievirus B3 detection using machine learning

With the increase of recycled water to offset water demand, the potential possibility to spread contagious RNA viruses, such as Coxsackievirus B3, increases. However, detection of viral particles remains challenging because of low viral concentrations in wastewater and high mutation rates of the RNA virus. Robust monitoring is needed with low cost and low infrastructure technologies to increase accessibility of monitoring technologies worldwide. Novel viral detection methods have been developed, based on synthetic riboswitches that bind to the target virus and trigger a reporter gene, thus amplifying the detection signals. Such monitoring technologies can leverage machine learning to optimize the candidate nucleic acid sequences used for detection. To support the design of effective riboswitches, we present a machine learning model for classifying riboswitch performance, integrating RNA sequence data with secondary structural features based on free energy calculations and parameters that represent single strandedness. This model uses a sparsely gated Mixture of Experts (MoE) architecture to route sequence and thermodynamic features to specialized experts, achieving strong generalization performance across cross-validation and held-out testing. When evaluated against baseline Decision Tree, Random Forest, Gaussian Naive Bayes, and Dense Neural Network classifiers, the MoE model demonstrated near-zero classification errors. Furthermore, post-hoc feature importance and k-mer analyzes reveal that near-perfect predictive performance in silico is strongly driven by sequence constructs in addition to generalizable folding mechanics. An ablation study of numerical feature and sequence inputs showed that while the Dense Neural Network also achieved high accuracy across all ablation conditions, the MoE architecture was retained as the primary model because its specialized subnetworks do not require all model parameters to be activated offering a potential computational advantage.

bioinformatics↗

bioRxiv2026

Median Preoptic Brs3-Expressing Neurons Regulate Heat-Evoked Defensive Escalation

Animals confronted with increasing heat must switch from exploratory behavior to vigorous actions that limit further exposure, but the forebrain circuits controlling this transition are poorly understood. We exposed male mice to progressively stronger floor heating while providing continuous access to a climbing mesh separated from the heating plate. Higher plate settings shifted behavior from rearing toward wall-directed digging and climbing, with jumping at the highest setting, and increased c-Fos labeling in the median preoptic nucleus. Neurons expressing bombesin receptor subtype 3 showed greater c-Fos recruitment under strong heating, and their population calcium signals increased when mice entered the plate-controlled zone and decreased when they left. Optogenetic activation without heating produced place avoidance, vigorous actions, and increased locomotion. Inhibition reduced locomotion and, during strong heating, shifted behavior from climbing and jumping toward rearing and weakened avoidance of a localized heat source. These findings identify median preoptic Brs3-expressing neurons as regulators of behavioral escalation and heat avoidance.

neuroscience↗

bioRxiv2026

APOE4 reduction in vascular-associated fibroblasts decreases cerebral amyloid angiopathy and associated vascular dysfunction

Cerebral amyloid angiopathy (CAA), characterized by cerebrovascular amyloid deposition, is strongly associated with Alzheimers disease, ischemic injury, and lobar hemorrhages. APOE4 is the strongest known genetic risk factor for CAA, yet the cellular sources of APOE4 that drive pathogenic vascular amyloid deposition remain poorly defined. Here, we identify vascular-associated fibroblasts (VAFs) as a key source of APOE4 that mediates CAA and cerebrovascular dysfunction. In post-mortem brain tissue from APOE4/E4 patients with confirmed CAA, APOE colocalizes with COL6 VAFs around A{beta}-laden vessels. Therefore, to study the contribution of APOE4 derived from VAFs in CAA, independently of parenchymal sources, we used 5xFAD mice in which the endogenous mouse Apoe coding exons are replaced with floxed human APOE4 sequences. This enables selective suppression of APOE4 expression in VAFs upon tamoxifen induction of Col1a2-CreERT+. APOE4 reduction in VAFs markedly reduced CAA, with the strongest effects observed in leptomeningeal vessels. Additionally, A{beta}40, which preferentially associates with vascular amyloid, was significantly reduced in the vascular fraction. VAF APOE4 depletion resulted in fewer small microbleeds and an approximately 50% reduction in parenchymal border macrophages within the leptomeningeal compartment, whereas astrocytic reactivity remained unchanged. Functional assessment using in vivo multi-parametric photoacoustic microscopy revealed improved arterial dilation and blood flow in amyloid-laden leptomeningeal arteries. Together, these findings establish VAF-derived APOE4 as a compartment-specific driver of CAA and cerebrovascular dysfunction. One Sentence SummaryVascular-associated fibroblasts are a major source of pathogenic APOE4 that drives vascular dysfunction in cerebral amyloid angiopathy.

neuroscience↗

bioRxiv2026

Cross-Tissue Inflammatory Convergence Supports a Putative Muscle-Brain Axis in Alzheimer's Disease

Background Reduced muscle strength is associated with cognitive decline and Alzheimer's disease (AD), suggesting that skeletal-muscle aging and AD-related neurodegeneration may share biological mechanisms. Vascular dysfunction, immune activation, and extracellular-matrix remodeling have been implicated in both tissues, but the extent of shared cellular and molecular programs remains unclear. We investigated cross-tissue transcriptional programs in aging skeletal muscle and AD-related brain tissue and evaluated whether related signals are detectable in peripheral blood. Methods We analyzed independent, unpaired human transcriptomic datasets from skeletal muscle (23 donors), the SEA-AD middle temporal gyrus atlas (84 donors), and peripheral blood. Donor-aware models identified age-associated changes in muscle and transcriptomic changes across continuous pseudoprogression score (CPS) in brain. Cross-tissue comparisons focused on 30 brain donors within an early CPS window. Shared tissue-derived programs were assessed in peripheral blood mononuclear cells and independently tested in frailty bulk-blood and Alzheimer's Disease Neuroimaging Initiative (ADNI) whole-blood datasets. CellOracle simulations were used to prioritize candidate transcriptional regulators. Results Aging muscle showed increased inflammatory, extracellular-matrix, and stromal communication programs. During early AD-related brain progression, vascular and immune populations showed increasing inflammatory and matrix-associated activity together with shifts in intercellular communication. Cross-tissue analysis identified six concordantly enriched pathways comprising 109 leading-edge genes in endothelial populations and four pathways comprising 51 genes in myeloid populations. Related peripheral-blood signatures varied across cohorts and cell types. However, in independent frailty and ADNI mild cognitive impairment and AD datasets, 23 of 30 predefined tissue-derived pathway-subset tests showed significant positive enrichment after false-discovery-rate correction, whereas individual gene-level bulk-blood associations did not survive correction. CellOracle analyses prioritized ETS2 and BHLHE40 as exploratory endothelial regulators whose simulated perturbation consistently reduced selected shared program scores across tissues. Conclusions Aging skeletal muscle and AD-related brain tissue exhibit convergent endothelial and myeloid inflammatory programs, with related pathway-level signals detectable in peripheral blood. These cross-tissue programs and candidate endothelial regulators provide testable hypotheses for mechanisms linking systemic aging, muscle dysfunction, and AD-related neurodegeneration.

neuroscience↗

bioRxiv2026

Chemically modified CRISPR enzymes for multi-organ genome editing in vivo

Delivery remains the main obstacle to the development of in vivo genome editing therapies. CRISPR ribonucleoproteins confer high editing activity with transient exposure but lack intrinsic cell entry and targeting. Here we introduce PERCEPT, a delivery platform featuring reversible, covalent modification of CRISPR enzymes. PERCEPT enables modular installation of shielding polymers, amphiphilic delivery peptides and targeting ligands, allowing traceless cytosolic release of the native editor. A formulation incorporating an amphiphilic delivery peptide and the neuron-targeting ligand TET1 edited approximately 56% of striatal volume and 78% of neurons within edited regions after local striatal administration. In the R6/2 Huntington's disease model, PERCEPT mediated targeted editing of the mutant human HTT transgene, reducing mutant huntingtin aggregate burden and shifting local transcriptional programs away from inflammatory and injury-associated states. Tissue-adapted formulations edited 53% of Muller glia following intravitreal delivery, increased skeletal muscle reporter fluorescence tenfold versus unconjugated control following intramuscular injection, and enabled lung airway epithelial cell that persisted for three months following intranasal delivery. Rapid screening revealed that local anatomical and cellular barriers require distinct surface display for optimal editing. These results establish reversible chemical modification as a general strategy for adapting CRISPR enzyme delivery across multiple target tissues in vivo.

bioengineering↗

bioRxiv2026

Orthoflaviviruses use diverse binding modes to engage LDLR family receptors

Orthoflaviviruses are major human pathogens that cause substantial morbidity and mortality worldwide. The viral envelope (E) mediates entry of orthoflaviviruses into host cells by interacting with cellular receptors, including members of the low-density lipoprotein receptor (LDLR) family. Here, we determined cryo-electron microscopy (cryo-EM) structures of yellow fever virus (YFV) E bound to low-density lipoprotein receptor-related protein 4 (LRP4) and LRP8, and of tick-borne encephalitis virus (TBEV) E bound to LRP8. Structural and functional studies reveal that YFV engages two low-density lipoprotein receptor class A (LA) repeats of LRP4 and LRP8 primarily through domain III (DIII) and the DI-DIII linker of its E protein, with each LA repeat making distinct contacts. In contrast, TBEV relies on a distinct surface on domain II (DII) of its E protein to interact with LRP8. Despite these differences, both viruses require engagement of two sequential receptor LA repeats for binding. Our findings identify key determinants of receptor specificity for these two orthoflaviviruses, with implications for vaccine development and therapeutic antibody targeting.

microbiology↗

bioRxiv2026

Early Emergence of Cultural Differences in Audiovisual Speech Perception

Integrating auditory and visual cues is a hallmark of human speech perception, yet adults from East Asian backgrounds show less reliance on visual speech than their Western counterparts. The origins of this cultural difference, however, remain unknown. To investigate whether this divergence is established early in infancy, we examined audiovisual integration in 6- to 12- month-old White Canadian (n=111) and Chinese (n=115) infants using a novel paradigm measuring their perception of the McGurk effect. Across four experiments, we found a clear developmental divergence: Canadian infants showed a stable McGurk effect from 6 months onward, whereas Chinese infants showed a more protracted developmental trajectory, a cultural pattern that was further highlighted when their integration was challenged by other-race faces. These findings provide the first direct evidence that cultural differences in multisensory speech perception are established within the first year of life, suggesting that the brains strategy for binding sight and sound is shaped by early experience, with broad implications for theories of language acquisition and developmental science.

developmental biology↗

bioRxiv2026

A fast 2C-induction method reveals a barrier role of SP2 for totipotency

The acquisition of totipotency in vitro remains a major challenge, limiting our understanding of early embryogenesis and its clinical and translational applications. Here, we reported a robust and rapid chemical reprogramming system that converts mouse embryonic stem cells (mESCs) into totipotent-like cells (TLCs) within 36 hours, with efficiencies exceeding 70%. The induced cells exhibit transcriptomic, epigenomic, and functional features closely resembling 2-cell (2C) stage embryos, as confirmed by scRNA-seq, ATAC-seq, and chimeric embryo analyses. Single-cell trajectory construction revealed a branching reprogramming process that yields both successful totipotent-like and alternative, non-reprogrammed fates. Mechanistically, we identified the transcription factor SP2 as a barrier to totipotency acquisition, promoting lineage-specific gene expression while repressing totipotency networks. Collectively, our study has established a highly efficient in vitro model for totipotency induction and highlighted molecular barriers shaping cell fate decisions, providing a platform to dissect the mechanisms governing the pluripotency-to-totipotency transition.

developmental biology↗

bioRxiv2026

PFOS aggravates atherosclerosis via Bacteroides caecimuris expansion-driven bile acid remodeling and subsequent intestinal FXR-TLR3 signaling cascade

BACKGROUNDPerfluorooctane sulfonate (PFOS) is a widely distributed persistent organic pollutant in the environment and has been associated with an increased risk of atherosclerosis. However, the underlying pathogenic mechanisms remain largely unclear. This study aimed to investigate the effects of PFOS on atherosclerosis and its associated gut-vascular axis. METHODSPseudo-germ-free mouse models and fecal microbiota transplantation (FMT) were used to determine the role of the gut microbiota in PFOS-induced atherosclerosis. Metagenomic sequencing was performed to characterize alterations in gut microbial composition following PFOS exposure, and targeted metabolomics was used to assess bile acid profiles in the ileum and plasma. Transcriptomic analysis of Bacteroides caecimuris (B.caecimuris) was conducted to explore the reasons for the increased abundance of B.caecimuris after PFOS exposure. In addition, intestinal transcriptomics and ChIP-qPCR were performed to validate transcriptional regulation within the FXR-TLR3 signaling axis. RESULTSAmong 127 participants with paired serum and fecal samples, including 82 patients undergoing coronary angiography with Gensini scores (GS score), fecal PFOS levels were significantly associated with lipid profiles and GS score, whereas serum PFOS showed no such association.Mechanistically, PFOS exposure promotes intestinal enrichment of B.caecimuris by upregulating its tolC gene, thereby enhancing efflux capacity.This microbial shift was accompanied by reduced levels of tauro-ursodeoxycholic acid (TUDCA) and aberrant activation of intestinal FXR signaling.Further analyses demonstrated that FXR activation upregulated TLR3 expression and promoted inflammatory responses and atherosclerosis progression via the TLR3-NF-{kappa}B signaling axis. Both intestinal epithelial-specific FXR deficiency (Fxr{Delta}IE) and TUDCA supplementation significantly suppressed pathway activation and alleviated disease phenotypes.Functional experiments identified TLR3 as a key downstream effector of FXR. Overexpression of TLR3 abolished the protective effects observed in Fxr{Delta}IE mice. Moreover, pharmacological inhibition of TLR3 using CU CPT-4a significantly improved established atherosclerotic lesions in vivo. CONCLUSIONSThis study identifies a gut microbiota-driven FXR-TLR3 signaling axis that mediates PFOS-induced atherosclerosis. These findings provide new mechanistic insights into environmentally induced cardiovascular disease and suggest potential targets for risk assessment and therapeutic intervention.

pathology↗

bioRxiv2026

SRPK3 regulates back-splicing of pre-MYOCD through Phosphorylating SRSF10 to modulate cardiac hypertrophy

Cardiac hypertrophy represents a hallmark of pathological remodeling in heart failure, involving complex molecular networks that remain incompletely defined. While post-transcriptional regulation is increasingly recognized as a key control layer, the role of splicing kinases in this process requires further elucidation. This study identifies serine/arginine-rich protein kinase 3 (SRPK3) as a central regulator of myocardial hypertrophy through its control of circular RNA (circRNA) biogenesis. We observed marked SRPK3 upregulation in phenylephrine/angiotensin II-treated cardiomyocytes, transverse aortic constriction (TAC) rats, and human heart failure datasets. Gain- and loss-of-function studies demonstrated that SRPK3 overexpression exacerbates hypertrophic phenotypes, including increased cell surface area and upregulation of markers (ANP, BNP, Myh7). Conversely, siRNA knockdown or pharmacological inhibition with the pan-SRPK inhibitor MSC-1186 effectively attenuated these pathological features. Mechanistically, SRPK3 interacts with and phosphorylates the splicing factor SRSF10 at specific serine residues (S129, S131, and S133). This phosphorylation event inhibits the back-splicing of pre-MYOCD, resulting in reduced cardioprotective circ-MYOCD levels and a concomitant increase in linear MYOCD expression. The depletion of circ-MYOCD relieves its competitive inhibition on linear splicing, driving the transcriptional activation of pro-hypertrophic signaling pathways. Crucially, restoring circ-MYOCD expression reversed SRPK3-driven pathology, confirming its protective role. These findings establish the SRPK3-SRSF10-circ-MYOCD axis as a critical regulatory circuit in cardiac remodeling. By bridging kinase activity with splicing dynamics, this study highlights RNA processing as a vital therapeutic target. Targeting this axis via SRPK3 inhibition or circ-MYOCD delivery represents a promising dual-modality strategy for treating heart failure.

Molecular Biology↗

bioRxiv2026

Proteome wide serology reveals immune defined subtypes of gastrointestinal disease in systemic sclerosis

BackgroundGastrointestinal (GI) involvement in systemic sclerosis (SSc) affects up to 90% of patients and is a major driver of morbidity and mortality. Despite its clinical importance, GI disease in SSc is highly heterogeneous, with upper and lower GI manifestations representing distinct phenotypic extremes whose underlying immunologic basis remains poorly defined. MethodsWe performed unbiased, proteome-wide autoantibody profiling using a human protein microarray comprising >21,000 full-length proteins (>80% of the human proteome). Sera from patients with SSc and isolated upper GI dysmotility (n=23), isolated lower GI dysmotility (n=17), and non-SSc controls (n=20) were analyzed. Enriched autoantibodies were identified using Fishers exact test, and unsupervised clustering was applied to define serology-based patient subsets and relate immune signatures to clinical phenotypes. ResultsDistinct autoantibody profiles differentiated patients with upper versus lower GI disease. Upper GI-predominant SSc was characterized by enrichment of previously unreported autoantibodies, including those targeting TiSSc1/2 (newly identified proteins encoded within the MIRLET7BHG locus), FAM9C, SPATA20, FAM110D, EMILIN1, CARD14, SMN1, KCTD7, and PHYHD1, whereas lower GI disease was associated with antibodies against HAO2, KLHL7, SUFU, APPL1, BNIP2, UCHL3, ZNF385A, LIMD1, MAGEA9, and PPP2R3C. Serology-driven clustering identified four reproducible subgroups with distinct patterns of GI, pulmonary, vascular, and autonomic involvement, defining clinically meaningful disease phenotypes that extend beyond traditional anatomic classification. ConclusionsProteome-scale serological profiling reveals previously unrecognized autoimmune signatures underlying GI heterogeneity in SSc. These findings support a shift from anatomy-based to serology-defined classification of SSc GI disease and provide a foundation for biomarker development, patient stratification, and precision medicine approaches in this population.

immunology↗

bioRxiv2026

Structure-guided reinterpretation of a disease-associated CWH43 residue-533 truncation identifies internal disruption of a conserved C-terminal module in idiopathic normal pressure hydrocephalus

Idiopathic normal pressure hydrocephalus (iNPH) is a chronic neurological disorder characterized by ventricular enlargement together with gait impairment, cognitive decline, and urinary dysfunction. Disease-associated CWH43 variants have emerged as genetic clues in iNPH, but the molecular consequences of truncating variants remain poorly defined. Here, we used structure-guided analysis to reinterpret the disease-associated human CWH43 variant c.1596del, annotated as p.Leu533Ter and referred to here as the residue-533 truncation. AlphaFold-based modeling of the full-length 699-amino-acid protein supported a conserved C-terminal D3 module spanning residues 407-699. Within this framework, the residue-533 truncation is best interpreted as an internal interruption of D3 rather than deletion of a poorly constrained terminal tail. Pocket analysis identified a dominant candidate surface site within D3 containing 18 pocket-lining residues, 55.6% of which (10/18) are removed by truncation. Independent cavity mapping further showed that the affected region is better understood as a broader cavity-bearing architecture rather than a single local pocket. Cross-boundary contact analysis, multi-model reproducibility, and representative local geometry supported structural coupling between retained and deleted D3 segments, indicating that truncation is predicted to cause retained-side decoupling in addition to direct residue loss. Together, these findings support a model in which the disease-associated residue-533 truncation disrupts a structurally integrated C-terminal module and its associated cavity-bearing architecture. This framework refines interpretation of CWH43-associated iNPH variants and provides a mechanistic bridge between human genetic association and architecture-level loss of function.

genetics↗

bioRxiv2026

AM-DMF-SCP-pro: An Ultrafast and Streamlined Nanolitre-Scale Lab-on-a-Chip Platform for Single-Cell Proteomics and Tumor Microenvironment Profiling

Single-cell proteomics (SCP) remains constrained by slow sample preparation and background interference in low-input, multistep workflows, limiting its broader practical use in complex biological samples. Here we report AM-DMF-SCP-pro, a streamlined active-matrix digital microfluidic workflow that enables rapid on-chip lysis and digestion in 6 nL droplets within a closed nanolitre-confined microenvironment. AM-DMF-SCP-pro reduces total sample-preparation time to as little as 30 min, including a 15 min digestion step, while maintaining quantitative reproducibility and digestion performance. Systematic optimization of mass spectrometry acquisition and nanolitre-scale digestion conditions enables deeper, more sensitive and lower-background proteome profiling from ultra-low peptide inputs. In murine tumor samples, AM-DMF-SCP-pro reliably resolves immune and tumor compartments, identifies treatment-associated tumor cell states and enables quantitative analysis of neutrophil-associated proteomic signatures. These results establish AM-DMF-SCP-pro as a practical workflow for rapid, low-background single-cell proteome profiling in complex biological samples.

systems biology↗

bioRxiv2026

Pancreatic cancer-associated organ dysfunction promotes muscle autophagy and contributes to peripheral tissue wasting

Normal pancreas function supports both digestion and the hormonal regulation of whole-body metabolism. We find pancreatic ductal adenocarcinoma (PDAC) disrupts the normal function of the remaining pancreas, leading to altered systemic metabolism and peripheral tissue wasting that begins early in disease progression. Using mouse models of PDAC, we find small pancreas tumors lead to both endocrine and exocrine pancreatic dysfunction that results in systemic nutrient depletion and loss of both muscle and fat tissue. Providing free glucose in the diet that is absorbed despite pancreatic exocrine dysfunction causes hyperglycemia and blunts fat wasting without affecting muscle loss. Muscle mass can be restored by free dietary amino acids or pancreatic enzyme supplementation. Exocrine dysfunction causing reduced dietary protein digestion promotes muscle proteolysis and autophagy. Autophagy is a major driver of muscle wasting in PDAC, as muscle-specific deletion of the core autophagy gene Atg7 also reduces muscle wasting. Disrupting muscle autophagy without restoring systemic nutrition slows tumor growth and improves survival of mice with PDAC. Tracing the fate of amino acids released from muscle of mice with PDAC shows redistribution to both tumor and host tissues. Notably, improving nutrition in mice with disrupted muscle autophagy promotes tumor growth. Together, the data argue that early peripheral tissue wasting associated with early pancreatic cancer is driven by altered normal pancreatic organ function that leads to reduced nutrition and enhanced muscle autophagy, releasing nutrients to support both tumor and host metabolism.

cancer biology↗

bioRxiv2026

GlycoForge generates realistic glycomics data under known ground truth for rigorous method benchmarking

Quantifying all complex carbohydrates in a sample produces glycomics data, which constitutes compositional data and is stymied by biosynthetic dependencies between glycans, requiring dedicated analytic workflows. Properly assessing such methods frequently requires simulated data with known ground truths and injectable effects. However, simulating glycomics data, especially with control over effects and biases, is still unsolved. Here, we present GlycoForge, a feature-complete solution for simulating comparative glycomics data. GlycoForge supports simulating fully synthetic glycomics data and templated simulations based on real-world data, with specified motif-level effects, based on Gaussian copulas and estimated covariances. We further support injection of batch effects, both mean and variance shifts, via center-log ratio transformations to maintain compositional closure, and realistic missing data simulation. We showcase the utility of GlycoForge by evaluating batch effect correction algorithms for glycomics data, with automated guidelines for when to use such methods on real-world data. GlycoForge is available as an open-access Python package at https://github.com/BojarLab/GlycoForge.

bioinformatics↗

bioRxiv2026

Representational invariance of numerosity via divisive normalization in coarse and fine visual channels

Robust evidence now suggests that numerosity perception emerges from the early visual cortex. However, such empirical findings pose a theoretical challenge for explaining how a low-level perceptual system represents discrete values from continuous input independently of other magnitude dimensions. Among proposals for this representational invariance, two computational accounts with ties to neural data have garnered attention: divisive normalization and Fourier decomposition. Here, we test these hypotheses using an integrated neural, behavioral, and computational approach and show that: (1) The visual cortex remains sensitive to numerosity even when the input images are equalized for their Fourier power, inconsistent with the Fourier decomposition account. (2) The divisive normalization model explains this neural phenomenon through the selective disruption of fine but not coarse visual channels when encoding normalized local contrast. (3) Backward masking that disrupts fine processing in a psychophysical experiment degrades the acuity of intact dot arrays to the level of Fourier-power equalized dot arrays, which validates the unique prediction of the divisive normalization model. These findings provide converging evidence for the proposal that normalized local contrast enables representational invariance of numerosity in the visual cortex.

neuroscience↗

bioRxiv2026

Detection of Somatic Point Mutations Directly from Spatial Transcriptomics Enables in vivo Spatiotemporal Lineage Tracing

Spatial transcriptomics reveals tissue organization but lacks in vivo lineage-tracing methods applicable to humans. We introduce SpaceTracer, a computational framework that accurately detects somatic single-nucleotide variants (SNVs) directly from spatial transcriptomics data. By leveraging naturally occurring somatic SNVs, SpaceTracer reconstructs cellular phylogenies within native tissue architecture, enabling the mapping of lineage spread, migration, lineage-coupled expression changes and lineage-aware local interactions. Applied to human cutaneous squamous cell carcinoma, it traced tumor initiation and progressions, uncovered widespread pre-invasive migration of dedifferentiated epithelial cells and characterized mutant B cells migrating from tertiary lymphoid structures (TLS) into the tumor boundary. The framework also reconstructed developmental lineages across multiple tissues and identified tissue-resident mutant immune cells. SpaceTracer thus provides a perturbation-free platform for high-resolution spatiotemporal lineage tracing, offering a transformative tool for elucidating complex biological systems--especially tumor-immune ecosystems--with direct implications for advancing cancer immunotherapy.

bioinformatics↗