Biology subjects

Luo, J.

Publications and source records attributed to Luo, J..

At least 55 records · Page 3Linked to original sources

bioRxiv2026

β-Barrel domain swapping in α-hemolysin enables enhanced single-molecule biomolecule sensing

Biological nanopores are powerful platforms for single-molecule analysis, yet rational strategies to tune their transport and sensing properties remain limited. Here we present a modular engineering approach based on {beta}-barrel domain swapping to reprogram the function of the prototypical nanopore -hemolysin. By replacing its native {beta}-barrel with {beta}-barrel domains from diverse pore-forming toxins, we generate a series of chimera nanopores that retain oligomerization capability while exhibiting reduced membrane-permeabilizing activity. Electrophysiological measurements show that selected chimera pores form stable, conductive channels with distinct ion transport properties. Notably, the HL_NetB chimera displays stable conductance, enhanced electroosmotic flow, and improved performance in nucleic acid and protein sensing. Single-molecule experiments demonstrate that this chimera markedly slows the translocation of single-stranded DNA, enabling discrimination by length and sequence, improves the resolution of intrinsically disordered proteins such as -synuclein, and enhances sensitivity to RNA conformational changes. Together, these results establish {beta}-barrel domain swapping as a general and effective strategy for engineering biological nanopores with tailored single-molecule sensing capabilities.

biochemistry↗

bioRxiv2026

Transfer of symbolic numeral adaptation across eyes and hemifields

Visual perception of symbolic numerals is essential for everyday tasks; however, the neural and perceptual mechanisms underlying this ability remain unclear. Partially occluded digital numerals can elicit bistable perception, and adaptation to symbolic numerals alters the perception of these ambiguous stimuli. We aimed to examine how symbolic numeral adaptation is related to hierarchical visual processing by testing its interocular and interhemifield transfer. Experiment 1 tested interocular transfer by presenting the test stimulus to either the same or opposite eye as the adaptation stimulus. Experiment 2 assessed interhemifield transfer by presenting the test stimulus to either the same or opposite hemifield as the adaptation stimulus. Experiment 3 examined the interhemifield transfer of adaptation confined to the upper parts of digital numerals. Our results showed that adaptation to digital numerals induced shifted perceptual interpretations that transferred across eyes. In addition, we found that adaptation to digital numerals induced a relatively small but statistically significant interhemifield transfer. In contrast, adaptation restricted to the upper parts of digital numerals showed no significant interhemifield transfer. These findings suggest that the perceptual interpretation of symbolic numerals involves visual processing stages that integrate information across the eyes and hemifields.

neuroscience↗

bioRxiv2026

Evolutionary profile enhancement improves protein function annotation for remote homologs

Accurate annotation of protein function is essential for understanding biological processes, yet this remains challenging for proteins lacking characterized homologs or belonging to underrepresented functional classes. Although machine learning approaches have become the gold standard for automated function prediction, they often perform poorly on out-of-distribution samples with low sequence identity to training proteins with known annotations. We propose EPERep, an evolutionary input enhancement strategy that leverages the vast space of unannotated protein sequences to improve the prediction of the functions of underrepresented proteins. Our key insight is that, even if a query protein has insufficient similarity to annotated proteins for direct annotation transfer, a wider range of similar unannotated sequences can be identified to facilitate better representation learning. Inspired by profile-based sequence search methods, EPERep incorporates homologous sequences as contextual input to refine the representations of individual proteins from pre-trained protein language models, effectively constructing a pLM-based profile for each query protein. Across four major annotation benchmarks on EC numbers, structural domains, Pfam families, and Gene Ontology predictions, EPERep consistently outperforms strong ML and sequence-alignment baselines. Gains are most pronounced for proteins from rare functional classes, with few or no labeled homologs, and for sequences exhibiting remote homology to the training distribution. These results demonstrate that evolutionary input enhancement provides a principled and scalable strategy for improving protein function prediction, particularly in long-tail and low-identity regimes.

bioinformatics↗

bioRxiv2026

Exploring the mechanism of Panax Notoginseng in the treatment of skin wound based on network pharmacology and experimental verification

BackgroundWhen the skin wound defect is too large, it is difficult for the body to heal itself, and medical treatment is often needed. How to shorten the healing cycle and reduce the incidence of infection is a difficult problem faced by clinicians. Panax notoginseng(PN), a traditional Chinese medicine, can promote the absorption of inflammatory exudates, granulation tissue formation and epidermal proliferation, effectively inhibit the inflammatory reaction of wounds and promote the healing of skin wounds, but its molecular mechanism has not been fully clarified so far. Based on network pharmacology and animal experiments, this study explored the target and molecular mechanism of PN in the treatment of skin wound. MethodsThe active components and potential targets of PN were obtained from the Traditional Chinese Medicine System Pharmacology Database and Analysis Platform (TCMSP) and UniProt database, and the skin wound-related targets were obtained from the GeneCards database. The intersecting targets were filtered using Venny 2.1.0. The intersecting targets were imported into the STRING database to construct a protein-protein interaction (PPI) network. Cluster analysis was performed using the MCODE and CytoHubba plugins in Cytoscape 3.8.2 to obtain core functional network modules and the top 10 key target genes. The intersecting targets were subjected to KEGG and GO enrichment analysis using the DAVID 6.8 database (https://david.ncifcrf.gov/). The component-target-pathway network of PN in the treatment of skin wounds was constructed using Cytoscape 3.8.2 software. In the experimental verification phase, 48 Sprague-Dawley (SD) rats were randomly divided into a control group and a PN group, with 24 rats in each group. A full-thickness skin excision was performed to establish a wound model. The PN group received intraperitoneal injections of the drug, while the control group received an equivalent amount of saline. Wound area measurements were taken on days 1, 4, and 7 after model establishment. Histopathological changes in the injured area and the expression and localization of TNF-, IL-6, and IL-10 were observed through hematoxylin and eosin (HE) staining and immunohistochemical staining. Relative expression levels of the three factors were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). ResultsThis study identified 8 major active components, 156 targets, and 115 signaling pathways involved in the treatment of skin wounds in rats using PN. The top 10 core target genes included TNF, IL-6, and IL-10, primarily enriched in signaling pathways such as NF-{kappa}B, MAPK, and JAK-STAT. Animal experiments revealed that at 4 and 7 days post-injury, the wound area in the PN group was significantly smaller than that in the control group (P<0.05). HE staining showed reduced infiltration of neutrophils and inflammatory cells in the injury area at 7 days in the PN group, accompanied by more pronounced fibroblast proliferation and collagen secretion. Molecular detection indicated that TNF-, IL-6, and IL-10 positive reactants were mainly distributed in the cytoplasm and matrix of epidermal cells, inflammatory cells, and fibroblasts in the skin. qRT-PCR and ELISA results showed that TNF- expression in the PN group was significantly lower than that in the control group at 4 and 7 days (P<0.01). IL-6 expression was lower than that in the control group at all time points, peaking at 4 days and then decreasing (P<0.01). IL-10 expression was significantly lower than that in the control group at 1 and 7 days (P<0.01). ConclusionPN exhibits characteristics such as multi-component, multi-target, multi-pathway synergy, and multiple regulatory pathways in the treatment of skin wounds. It can reshape the dynamic balance of cytokine networks, including TNF-, IL-6, and IL-10, optimize the temporal progression of "inflammation initiation - repair transition - tissue remodeling", and provide a therapeutic effect of "efficient debridement - orderly repair - low scar risk" for skin wounds. It is one of the ideal natural drugs for regulating skin wound healing.

bioinformatics↗

bioRxiv2026

Type 2 diabetes amplifies environmental Pb toxicity and intergenerational risk

Type 2 diabetes (T2D) and environmental lead (Pb) exposure intersect as prevalent global health challenges. Prior studies report elevated blood Pb in T2D, but the underlying mechanism and directionality remain unresolved. Here we show that T2D fundamentally alters Pb toxicokinetics, converting otherwise modest exposure into progressive organ injury and heritable risk. In a human cohort, elevated blood Pb in T2D specifically associated with impaired renal function rather than glycaemic control or adiposity. In db/db mice, diabetes increased oral Pb absorption through delayed gastrointestinal transit and epithelial barrier dysfunction, leading to enhanced systemic retention. With sustained exposure, renal Pb accumulation induced tubular stress that reduced effective clearance, creating a feed-forward loop in which diabetes promotes Pb retention and retained Pb accelerates kidney injury. Chronic Pb exposure exacerbated diabetic kidney injury without inducing hyperglycaemia, and short-course chelation attenuated renal stress markers. Beyond somatic toxicity, combined paternal T2D and Pb exposure programmed renal and neurobehavioral phenotypes across generations via sperm RNA. These findings redefine Pb from a passive environmental exposure to a context-dependent driver of disease, identify T2D as a vulnerability state that reshapes toxicant handling, and establish a mechanistic link between metabolic disease, environmental exposure and intergenerational risk. This work highlights the need for vulnerability-informed clinical management and environmental regulation in populations burdened by T2D.

genetics↗

bioRxiv2026

A Multimodal Single-Cell Epigenomic and 3D Genome Atlas of the Human Basal Ganglia

The basal ganglia (BG) underlie motor control, reward processing, and many neurological and psychiatric disorders, but a comprehensive epigenomic and 3D-genome atlas of the human BG is lacking. Here we present a multimodal single-cell atlas profiling DNA methylation and 3D chromatin conformation in 261,331 nuclei (snm3C-seq) across eight subregions, resolving 12 classes, 31 subclasses, and 59 groups. Harmonized under the HMBA basal-ganglia consensus taxonomy, this atlas integrates with matched RNA, ATAC-seq, and histone-modification data across five regulatory layers. We identify millions of cell-type- and region-specific differentially methylated regions enriched for distinct transcription factor motifs and link them to disease-associated heritability. Neuron-specific loops dominate cell-type-specific 3D contact remodeling, while most non-neuron-specific loops are constitutive. Among spiny projection neurons (SPNs), chromatin loops, rather than TAD boundaries, distinguish D1, D2, and eccentric SPN subclasses, with eccentric SPNs showing the most loop-level reorganization among the three. We characterize STR D2 SMYD2-HTR7 SPN, a newly recognized POU6F2 D2-SPN subtype, and reveal region-specific methylation and contact gradients of disease-associated genes, including CADM1 and PDE8B. Integrative gene-regulatory networks reconstruct cell-type-resolved enhancer-promoter links to interpret Parkinsons disease risk variants at SNCA. Finally, MERFISH spatial profiling combined with cross-species Patch-seq identifies non-SPN neuronal subtypes, including a MOXD1 striosomal STR FS PTHLH-PVALB GABA subtype with distinct electrophysiology, partitioning across the striatal matrix-striosome boundary. HighlightsO_LIA multimodal single-cell atlas maps DNA methylation and 3D genome architecture across human basal ganglia cell types and subregions. C_LIO_LINeuron-specific loops dominate cell-type-specific 3D contact remodeling in the human BG, whereas most non-neuron-specific loops are constitutive. C_LIO_LISpiny Projection Neuron (SPN) subtypes exhibit regionally organized epigenomic and 3D genome signatures that align with dorsal-ventral identities. C_LIO_LIChromatin loops are the primary distinguishing feature among D1, D2, and eccentric SPN subclasses, with eccentric SPNs being the most 3D-reorganized. C_LIO_LIIntegrated regulatory maps link cell-type-specific enhancers to disease-associated genetic risk in the human basal ganglia. C_LIO_LINon-SPN interneurons differ in distribution and in transcriptional and epigenetic identity across the matrix-striosome boundary. C_LI

neuroscience↗

bioRxiv2026

Deconvolving mutation effects on protein stability and function with disentangled protein language models

Understanding how evolutionary constraints shape protein sequences is fundamental to deciphering the molecular mechanisms underlying protein stability and function, which has broad implications in protein engineering and therapeutics development. Recent advances in protein language models (pLMs) have enabled accurate prediction of mutation effects through evolutionary information, effectively capturing the selective pressure that governs protein sequence variation. A critical challenge, however, remains in disentangling the intertwined mutation effects on protein stability and function, as evolutionary signals conflate both stability-driven and function-driven pressures, obscuring the mechanistic basis of mutation effects and limiting their utility for rational protein engineering. In this work, we introduce DETANGO, a novel deep learning framework that explicitly deconvolves the mutation effects on protein functions by removing components attributable to stability perturbations from the pLM-predicted mutation effects. Guided by computational or experimental stability measurements, DETANGO estimates a functional plausibility score for each single-point mutation that is the component of the mutation effect not accounted for by changes in stability. Single-point mutations with low functional plausibility are predicted to be stable-but-inactive (SBI) variants, whose compromised activities are caused by direct perturbations on functional mechanisms rather than structural stability. Residues enriched for such variants are inferred to be functionally critical, as indicated by the strong evolutionary pressures to maintain protein function. Through extensive benchmarking experiments, we show that DETANGO accurately identifies SBI variants and pinpoints functionally important residues across contexts, including ligand binding, catalysis, and allostery. Moreover, extending DETANGO from individual proteins to homologous protein families reveals shared and distinctive functional patterns across protein families. Collectively, these results establish DETANGO as a biologically grounded framework for disentangling evolutionary constraints on protein stability and function, advancing mechanistic understanding of protein function, and informing rational protein engineering.

bioinformatics↗

bioRxiv2026

StrIPETrack: a real-time, ROI-flexible tracking platform for high-throughput zebrafish behavior

Quantitative phenotyping is essential to studies of animal behavior, enabling systematic analysis of variation arising from natural diversity or experimental manipulation. High-throughput behavioral assays that can simultaneously test multiple animals support sufficiently powered studies of behavioral variation, but accurate tracking of each animal is critical. Furthermore, behavioral tasks and experimental arenas span a wide range of complexity, from the reaction of a single larval zebrafish to an acoustic stimulus to associative conditioning in cue-rich environments. Here, we developed and validated StrIPETrack (Structural similarity-based Image Processing for Estimation and Tracking), a Python-based, modular animal tracking software designed for flexible region-of-interest (ROI) definitions and extensibility across assays. We show that StrIPETrack measures activity comparably to our previous LabVIEW-based zebrafish tracking software and detects similar behavioral differences between wild-type clutches. In addition, StrIPETrack accurately captures behavior in a complex arena: the Y-maze. Our approach for analyzing Y-maze navigation yields an expanded set of metrics beyond turn count and direction, revealing more subtle behavioral variation. Overall, this versatile software can be applied to monitor the activity of multiple animals in parallel in both simple high-throughput and more complex assays, and can be readily adapted to new paradigms. SummaryOur open-source tracking software provides rich behavioral phenotyping of animals in many behavioral tasks. The flexible ROI design and live tracking makes the software adaptable to diverse paradigms.

animal behavior and cognition↗

bioRxiv2026

Proteomic composition and mutual assembly of the C2a projection in vertebrate motile cilia

The central apparatus of motile cilia, consisting of central microtubules and various protein projections, is essential for dictating the ciliary movement. Although three proteins (FAP65, FAP147, and FAP70) have been localized to the C2a projection in Chlamydomonas reinhardtii, the full protein composition and functional roles of the vertebrate C2a remain inadequately defined. Here, we use three knockout mouse models corresponding to their respective homologs (Ccdc108, Mycbpap, and Cfap70) to systematically investigate their functions in vertebrates. Notably, all three knockout strains exhibit distinct phenotypes related to primary ciliary dyskinesia (PCD), including hydrocephalus and sinusitis. The ciliary incorporation of CCDC108, MYCBPAP, and CFAP70 is essential for one anothers stability, with the loss of any single component triggering C2a collapse, which destabilizes the central pair microtubules and ultimately alters the ciliary movement pattern. Furthermore, we significantly expand the vertebrate C2a proteome by identifying ARMC3 and MYCBP as additional C2a components. Collectively, our findings illuminate the proteomic composition and strict physiological requirements of the vertebrate C2a projection, providing new insights into the molecular pathogenesis of PCD. Impact StatementDeficiency in any of the interdependent C2a proteins (CCDC108, MYCBPAP, and CFAP70) collapses this central pair microtubule-associated projection, disrupting vertebrate ciliary movement and causing primary ciliary dyskinesia phenotypes in mice.

cell biology↗

bioRxiv2026

Control of grain dimensions via ALLENE OXIDE CYCLASE

Cereal grain is a global food staple. Grain formation starts with fertilization of the embryo sac which generates filial tissues, such as the embryo and endosperm, that grow embedded in the maternal ovule and surrounding ovary wall. Maternal tissues provide nutrition and protection but are progressively reduced and degraded, such that filial tissues dominate the mature grain. While we know some enzymatic players, regulation of this process in temperate cereals like wheat and barley, remains less understood. However, previous work suggested a role for the phytohormone Jasmonate (JA). To learn more, we edited the barley ALLENE OXIDASE CYCLASE (HvAOC) gene encoding a JA biosynthetic enzyme. Defective HvAOC alleles caused enhanced vegetative growth, faster flowering and larger, heavier grain - phenotypes rescued by MeJA treatment. HvAOC control of final grain parameters is parentally-derived, consistent with enriched HvAOC expression in maternal compared to filial tissues. Defective HvAOC function enlarged maternal tissues involved in nutrient transfer, correlating with larger endosperm and higher expression of genes linked to sucrose transport. This work provides the first genetic dissection of JA in barley and highlights a key role for HvAOC in the coordination between growth and death of maternal tissues with grain size and weight.

plant biology↗

bioRxiv2026

An Aggregation Prone Region (APR) in talin controls talin self-interactions to regulate integrin adhesion complex dynamics

The tight regulation of the integrin family of extracellular matrix (ECM) receptors is essential for the coordination of most cellular processes. Talin regulates integrin function by binding to the cytoplasmic tail of the integrin beta subunit. Two integrin-binding sites (IBS) in talin have been reported, one in the talin head domain (IBS1), and a second in the C-terminal rod region of talin (IBS2), mapped to the R11-R12 domains. Whilst the structural details of integrin binding to IBS1 are well understood, IBS2s mode of binding integrin is less clear, and the biochemical details of this site have been elusive. Here we report that talin R11 contains a cryptic high affinity talin-binding site. We show that mechanical unfolding of R11 exposes an Aggregation Prone Region (APR) in Helix50 that oligomerizes with other talin R11s. Our data support a model whereby the process of mechanically unfolding one R11, exposes and maintains the APR in a high affinity conformation that drives unfolding of other R11 domains and oligomerisation. Atomic Force Microscopy confirms that the APR region alone forms micron long amyloid-like fibres, via a beta-sheet amyloid arrangement which can be abolished using a canonical "gatekeeper" point mutation, V2078K, that prevents APR interactions. Introducing this gatekeeper mutant in talin eliminates recruitment of talin IBS2 to integrin adhesion sites. The APR region in talin overlaps with a vinculin-binding site in Helix50, and we show a novel role for vinculin as a mechano-chaperone for talin, able to resolve the talin large species by binding to the VBS in Helix50. In light of this new information, we propose that the ability of R11-R12 to target to integrin adhesion complexes and enhance integrin activation can be better explained by a model where functional aggregation of talin serves to recruit and activate more talin molecules at the adhesion site leading to enhanced integrin activation. Whilst further work is required to fully exclude integrin binding to R11 we suggest that the name IBS2 might be a misnomer and propose the name Aggregation Prone Region 1 (APR1) for this talin oligomerisation motif.

cell biology↗

bioRxiv2026

The anisotropic sensitivities of perceptual speed between expanding and contracting optic flows

Retinal optic flow provides critical visual cues for locomotion and self-navigation. Forward self-motion, such as walking or driving, typically induces an expanding radial flow pattern on the retina. Despite the predominance of expanding optic flow in everyday self-motion, several studies have reported higher perceptual sensitivity for contracting flow that arises under relatively rare conditions, such as walking backward or falling onto ones back. The underlying basis of this perceptual anisotropy remains elusive. In this study, we compared perceptual sensitivity to speed for expanding versus contracting optic flow, given that speed is a fundamental attribute of motion and that perceptual sensitivity to it provides insight into underlying visual mechanisms. We found that sensitivity in speed discrimination was comparable between expansion and contraction at low and high speeds, but was significantly higher for contraction at an intermediate speed corresponding to ecologically relevant self-motion, such as walking. This anisotropic pattern was observed for both 2D planar (Experiment 1) and simulated 3D (Experiment 2) optic flow stimuli. Together, these findings suggest that anisotropic perceptual sensitivity to expanding and contracting optic flow at ecologically typical egomotion speeds may reflect an adaptive visual mechanism that supports postural stability and balance during relatively rare backward self-motion.

animal behavior and cognition↗

bioRxiv2025

Residue-Specific Modulation of Aggregation-Associated Interactions bySpermine in Tau, α-Synuclein, and Aβ40

Preventing neurodegenerative diseases associated with intrinsically disordered proteins (IDPs) remains a major challenge due to the lack of a detailed, sequence-level picture of disease-relevant structures formation and the influence of cellular factors that modulate these transitions. Here, we probe spermine (Spm), a +4 charged polyamine abundant in cells, to determine how it reshapes the conformational ensembles and fibril-associated contact propensities of three disease-linked IDPs: the K18 domain of Tau, -synuclein (S) and amyloid-{beta}40 (A{beta}40). Using long all-atom molecular dynamics simulations across a range of Spm concentrations, we quantify residue-level changes in intra-chain contacts relative to native contacts observed in fibrils, and corroborate computational predictions with ThT fluorescence assays for Tau constructs. Spm acts in a sequence-and region-specific manner, not simply through overall net charge. In K18, Spm binds near the fourth microtubule binding repeat, disrupting intra-chain contacts associated with Alzheimers fibril structures and thereby inhibiting aggregation. In S, Spm binds mainly to acidic residues in the C-terminal half of the sequence and redistributes intramolecular contacts in a way that increases contact propensity in the central aggregation-prone region and therefore aggregation, in line with previous studies showing Spm-enhanced S aggregation. For A{beta}40, Spm neutralizes acidic residues near positions 22-24 and shifts the balance of intra-chain interactions toward its aggregation-prone core, resulting in a net promotion of fibril-like conformations. These divergent effects show that net charge alone cannot predict polyamine influence on IDPs. Instead, residue-specific binding hotspots and local reweighting of aggregation-linked contacts determine whether Spm promotes or suppresses fibril-like conformations. This combined simulation-experimental framework provides a mechanistic basis for how small molecules reprogram IDP conformational ensembles and suggests principles for designing ligands that exploit similar residue-level modulation.

biophysics↗

bioRxiv2025

Molecular insights into Profilin1-dependent regulation of cellular phosphatidylinositol-(4,5)-bisphosphate

Phosphatidylinositol (4,5)-bisphosphate (PIP2), the most abundant cellular poly-phosphoinositide (PPI) class of phospholipid, is a central plasma membrane (PM)-associated signaling hub that controls many cellular processes. In this study, we demonstrate that either deletion of the gene encoding actin-binding protein profilin1 (Pfn1) or disruption of Pfn1-actin interaction leads to downregulation of PM PIP2 content in cells. This is also phenocopied when F-actin is depolymerized implying that Pfn1-dependent PIP2 alteration is related to its actin-regulatory function. Phospholipase C (PLC) activity is critical for Pfn1-deficient cells to exhibit the PIP2-related phenotype. These findings, taken together with biochemical signatures of elevated PIP2 hydrolysis (higher baseline PM diacylglycerol-to PIP2 ratio and protein kinase C activity) exhibited by Pfn1-deficient cells, imply that PLC-mediated PIP2 hydrolysis plays a role in Pfn1-dependent regulation of PM PIP2. Furthermore, we unexpectedly found that Pfn1 loss leads to dramatic alterations in several other important forms of lipids, revealing a previously unrecognized role of Pfn1 as a broad regulator of cellular lipid environment that extends beyond PPI control. In conclusion, our study establishes Pfn1 as an important regulator of cellular lipid homeostasis. SUMMARY STATEMENTThis study uncovers a mechanism of how functional loss of Profilin1, a key regulator of actin cytoskeleton, can trigger downregulation of plasma membrane content of PIP2, an important class of phospholipid, in cells.

cell biology↗

bioRxiv2025

Beyond Inheritance: De novo Fast Motion Computation in Primate Visual Cortex

Objects move through space and time, generating sequential visuotopic activations in all sighted animals leading to motion perception of velocity defined by direction and speed. Humans can effortlessly see motion with speeds ranging from 0.25 to 500{degrees}/s. However, direction-selective neurons in the primary visual cortex (V1)--from which all subsequent processing is presumed to derive-- only encode directionality at low speeds. To resolve this paradox, we recorded neuronal responses to moving dots, gratings, and movies across the LGN, V1, MT and MST of the macaque motion pathway. Regardless of cell type and motion stimuli, V1 neurons lost direction selectivity at [~]29{degrees}/s while MT and MST neurons maintained it up to [~]82{degrees}/s and [~]183{degrees}/s, respectively. A cascaded spatiotemporal integration model reveals that at each cortex direction-selective neurons can generate velocity selectivity de novo, by integrating sequential visuotopic activations from preceding areas, irrespective of speed and directionality. By computing velocity anew, the primate brain effectively uses the cortical hierarchy itself to shift gears to efficiently encode slow and fast motion. Thus, five visual areas from the retina into the brains processing hierarchy, external spatiotemporal information is being computed afresh, offering insights for motion processing in other species, modalities and machine vision.

neuroscience↗

bioRxiv2025

Cancers modulate p53 truncal neoantigen display to evade T cell detection

Summary paragraphTP53 mutations are early truncal events across cancers1,2. These are perceived to encode tumour-specific neoantigens representing prime cytotoxic T lymphocyte (CTL) targets3,4. However, studies systematically examining the physical cell surface display of p53 peptides bound to major histocompatibility complex molecules (pMHC), their relative antigenicity, and resultant immunogenicity have yet to be conducted. Here, we develop an epitope discovery platform using p53-reconstituted lung cancer cells as well as various tumour cells as pMHC sources. Combining data-independent acquisition mass spectrometry (MS), nanoscale chromatography, and peptide detection based on probabilistic measure and three-dimensional ion visualization techniques allows attomole sensitivity identification of pMHCs. This approach excluded [~]97% of algorithm-based virtual p53 immunopeptidomes, highlighting that only a few p53 pMHCs can be presented by common human MHC (human leukocyte antigen, [HLA]) alleles. Strikingly, surface expressed neoantigens are restricted to the corresponding set of such limited self-p53 peptide arrays and unaffected by enhancing p53 proteasomal turnover. Further curtailment of MS-validated, high affinity p53 neoepitopes that are structurally deviant from self-pMHC occurs in established tumours due to immune selection against the antigen presenting MHC allele or by a novel mechanism involving p53 neoepitope destruction by endoplasmic reticulum aminopeptidase 1 (ERAP1). In contrast, given the extremely weak MHC affinity and resultant short-lived cell surface pMHC expression, the common p53 neoepitope R175H/HLA-A*02:01 escapes immune selection despite CTL with high quality T-cell receptors. Rigorous tumour-protective immunoediting makes effective truncal neoepitope targeting a challenge, requiring attentive MS analysis and functional vetting to focus protective cytolytic responses.

immunology↗

bioRxiv2025

LaCONIC: A Label-Aware and Graph-Guided Contrastive Multi-Omics Collaborative Learning Model for Cancer Risk Prediction

Investigating accurate cancer survival prediction models has important clinical value for optimizing therapeutic strategies and improving clinical outcomes. Although an increasing number of models have shifted from relying solely on clinical variables to integrating multi-omics data, there remains insufficient exploitation and integrative utilization of gene regulatory network (GRN) structures and cancer subtype information, which limits the predictive accuracy and biological interpretability of multi-omics models. Therefore, this study proposes label-aware and graph-guided multi-omics collaborative learning framework, termed LaCONIC, to achieve accurate and interpretable cancer survival prediction. To obtain biologically meaningful regulatory features of different molecular types, we first construct a gene regulatory network comprising multiple molecular entities and their relations, and design a heterogeneous graph self-supervised pre-training module to obtain unified graph-based gene representations. To fully leverage multiomics and multi-modal information, we develop an adaptive cross-omics representation learning module that performs intraomics modality alignment (i.e., graph and expression modals) and inter-omics representation alignment, thereby achieving synergistic integration of multi-source information. Moreover, to comprehensively capture global cross-omics molecular interactions, we present a graph-guided cross-omics interactive learning module that explicitly encodes gene regulatory network priors within a Transformer-based architecture. Finally, we introduce cancer subtype information to construct a label-aware constraint mechanism that improves predictive performance while enhancing inter-class separability and intra-class consistency of the learned representations. Experiments on multiple cancer datasets show that LaCONIC outperforms existing state-of-the-art methods in various metrics. SHAP-based interpretability analysis on breast cancer further identifies survival-associated regulatory modules and high-risk molecules (e.g., hsa-miR-148a-3p, ARMC1, TMEM242), highlighting its potential for biological mechanism elucidation and prognostic assessment. The source code is available at https://github.com/Liangyushi/LaCONIC.

bioinformatics↗

bioRxiv2025

Modular mRNA lipid nanoparticle platform rescues diverse genetic male infertility

Genetic male infertility arises from diverse mutations that disrupt spermatogenesis, yet therapeutic strategies capable of restoring germ-cell function remain limited. Messenger RNA (mRNA) therapeutics offer a programmable and non-integrating approach, but their functional compatibility in structured and immune-privileged tissues remains unclear. Here we identify a temporal mismatch between mRNA delivery kinetics and the progression of spermatogenesis as a key barrier to functional rescue. We show that delivery efficiency does not predict outcome: formulations with high peak expression but short duration fail to support spermiogenesis, whereas sustained expression aligned with developmental timing enables recovery. Guided by this principle, we establish a testis-targeted mRNA delivery platform that restores spermatogenesis across multiple genetic models and generates functional sperm capable of supporting embryo development and multigenerational inheritance. The approach is modular, extends to human seminiferous tubules ex vivo, and is supported by comprehensive safety analyses. Together, these findings define a design constraint for RNA therapeutics in structured tissues: functional rescue requires temporal alignment between delivery kinetics and the therapeutic window defined by tissue-specific biological programs.

bioengineering↗