Biology subjects

Ma, J.

Publications and source records attributed to Ma, J..

At least 19 recordsLinked to original sources

bioRxiv2026

The Multi-scale Copula Index (MCI): a new information-theoretic measure of association and its applications in functional cancer genomics

Cancer genomic analyses increasingly involve large, complex datasets representing diverse omics variables, such as gene expression, mutations, copy number alterations, genetic perturbations (e.g. CRISPR or iRNA), drug sensitivity, and clinical phenotypes, making it crucial to accurately measure associations among these variables. Traditional correlation-based methods, like the Pearson correlation coefficient, often assume linearity, Gaussian distributions, and independence among variables, leading to oversimplified assumptions, less sensitive readouts and less accurate significance estimation. Information-theoretic measures overcome these limitations by being one step removed from the data and assessing dependencies at the level of probability distributions, thus providing a more data-agnostic, robust measure for identifying associations in common analysis tasks such as feature selection, pattern recognition, and predictive modeling. Building on these foundations, we introduce the Multi-scale Copula Index (MCI), a novel information-theoretic measure of association. The MCI offers significant advantages over existing methods by eliminating the need for density estimation and parameter tuning, thereby ensuring consistent estimation with reduced computational complexity. Furthermore, it enhances statistical power at lower sample sizes, exhibits strong robustness to outliers, and successfully captures both directionality and important symmetries under input-data transformations, such as reflection or complementation. Due to these strengths, the MCI is particularly useful for functional cancer genomic applications involving, e.g., transcriptional and perturbational data, with different statistical properties across a wide range of dataset sizes and complexity. Contextual associations often arise in functional genomics datasets: two genomic variables show little or no correlation in most samples, yet display a strong linkage within the subset that reflects the active biological context. These situations are ideal for quantifying associations with the MCI. We illustrate the performance of the MCI in a variety of benchmarks and cancer genomic examples and applications. We also introduce the Cumulative Entropy Diagram (CED), a graphical display that allows the visualization of the MCI between a reference vector, such as a phenotype, pathway activation or drug response, and a complete set of genomic features.

bioinformatics↗

bioRxiv2026

Cortex-wide single-cell activity mapping in freely moving mice

How the cortex supports complex, naturalistic behavior can be revealed only in freely moving animals. Although head-mounted microscopes promise access to the neural dynamics underlying such behavior, fundamental trade-offs among field of view, spatial resolution, device weight, and background contamination have prevented cortex-wide single-neuron recording, leaving distributed cortical coordination largely inaccessible. To meet these challenges, we introduce COMET (Cortex-wide Observational Miniature Epifluorescence Technique), a 3.75-g head-mounted mesoscope that integrates an aberration-controlled wide-field optical design, uniform high-efficiency excitation and single-coaxial power-and-data transmission with an end-to-end denoising and signal-extraction pipeline. This enables cortex-wide calcium imaging at single-cell resolution in freely moving mice. COMET captures activity from >15,000 layer 2/3 neurons per 5-min recording over fields of view up to 10 mm in diameter while preserving natural behavior. Benchmarking against benchtop two-photon microscopy demonstrates high spatial concordance of detected neurons and matched event-level calcium dynamics. We apply COMET to social interaction to quantify region-specific engagement and to an auditory trace fear-conditioning task that requires natural movement and behavioral expression, revealing time-ordered changes in regional firing-rate structure and functional connectivity preceding a global conditioned response. COMET provides an open, lightweight hardware-software framework for linking single-neuron activity to cortex-scale network dynamics during freely expressed behaviors under changing internal or external conditions.

neuroscience↗

bioRxiv2026

Programmable design of functional RNAs through multimodal generative learning

RNA engineering is bottlenecked by the tight coupling among sequence, structure, and function, leaving the field reliant on heuristics or screening. We introduce RNAverse, a multimodal generative model that learns a conditionable design grammar from RNA sequences, experimental structural probing profiles, and functional annotations. Beyond setting a new state of the art across 16 predictive modeling tasks, RNAverse inverts into generative design across four distinct RNA classes through three regimes, requiring experimental testing of no more than 20 candidates per-task. Zero-shot in-painting generates snoRNAs that promote premature termination codon (PTC) readthrough, and chimeric aptazymes for ligand-controlled gene regulation, exceeding rational design or large-scale screens. In both settings, RNAverse outperforms family-adapted sequence-only baselines. Fine-tuned in-painting extends to an unseen functional class, yielding IGFBP3-binding aptamers with picomolar affinity that outperform SELEX winners. Iterative optimization engineers 5' UTRs that outperform clinical benchmarks, enhancing protein production in cell-based assays for both the Zolgensma gene therapy and the BNT162b2 COVID-19 vaccine, and boosting antibody responses to BNT162b2 in mice. Together, these results establish multimodal generative learning as a route from predictive RNA modeling to programmable specification of functional RNAs.

bioinformatics↗

bioRxiv2026

Intracellular complement Factor B couples inflammatory sensing to metabolism, chromatin regulation and maladaptive tissue repair

Inflammatory signals are broadly conserved, yet how tissue context converts them into programs of recovery or maladaptive repair remains unclear. Using kidney injury as a model of inflammation-to-repair transitions, we identify an injury-induced proximal-tubule complement program in which cell-intrinsic complement proteins are repurposed across subcellular compartments to couple inflammation to metabolic and chromatin regulation and promote maladaptive fibrotic remodeling. Mechanistically, myeloid-derived IL-1b; signals through IL-1R1 on injured tubular cells to recruit NF-kB and AP-1 to C3 and Cfb, coordinately inducing complement component 3 (C3) and Factor B (FB). Cytoplasmic FB drives cleavage-activation of cell-intrinsic C3, which supports tubular cell mitochondrial metabolic adaptation to stress and accumulation of C3aR-expressing macrophages around injured tubules. Nuclear FB, on the other hand, binds chromatin through a previously unrecognized DNA-binding interface and mediates histone H3 proteolysis and the preferential remodeling of chromatin promotors enriched in transcriptional programs relevant to maladaptive repair. Key features of this injury-associated C3-FB response, including intranuclear FB, are conserved in human kidney disease, associate with kidney dysfunction, and distinguish diseased from healthy kidneys. Together, these findings suggest that extracellular complement-targeting therapies may miss disease-relevant intracellular functions and suggest nuclear FB as a distinct target whose chromatin interaction and processing capacity could selectively limit maladaptive tissue responses beyond conventional inhibition.

immunology↗

bioRxiv2026

Structural variants from donor-specific assemblies affect recurrent chromatin contact divergence in humans

Structural variants (SVs) are a major source of human genetic diversity, yet their contribution to three-dimensional (3D) genome organization remains difficult to resolve using a standard reference genome. Here, we integrate haplotype-resolved chromatin interaction maps across 354 human and 12 nonhuman ape haplotypes with matched genome assemblies and long-read transcriptomes to determine how inherited SVs influence chromatin organization. We observe significant improvements in contact mapping, with 13.2% of cis Hi-C contacts showing >25 kbp changes in inferred genomic separation and an additional 2.8% of valid contact pairs recovered when using donor-specific assemblies instead of standard references. We show that haplotype-specific chromatin differences are highly selective rather than pervasive, concentrating within 1,790 recurrent contact difference hotspots associated with a restricted subset of SVs. We identified 2,495 chromatin-structure-associated SVs that are enriched in regulatory genomic contexts and are linked to expression variation. Notably, more than 90% of these SVs are derived in the human lineage, consistent with recent remodeling of regulatory architecture at the population level. These findings highlight the importance of incorporating haplotype diversity from pangenomes into studies of chromatin organization and provide a framework for understanding how inherited genomic differences are linked to functional consequences across populations and evolution.

genomics↗

bioRxiv2026

Reversion to the Meta Body Form of Life after Complete Cell Death in Pure Liquid Water

The prevailing view holds that simpler animate beings predating the dawn of cellular life once existed, yet they have long since vanished from the present-day Earth. Our hypothesis posits that these animate beings persist to this day. To this end, we devised a long-term experiment spanning over a decade, keeping Staphylococcus aureus (S. aureus) within a sealed aqueous system of pure water. The findings illustrated that, upon the complete cell death (CCD) of the S. aureus, as cellular remnants progressively succumbed to dissolution, the aqueous solution underwent self-purification, bringing forth a class of lipid bilayer membrane microspheres containing RNA and proteins. These structures maintained long-term sustainable stability within the thermodynamic storm of water molecules and underwent dynamic size fluctuations over time - collectively exhibited phenomena indicative of being "alive". This study reveals that the cell, upon complete cell death, undergoes reversion to a living entity simpler than the cell itself - the Meta Body (MB). The discovery of MB opens an entire re-conceptualization of what death ultimately brings.

biophysics↗

bioRxiv2026

The cleaved C-terminal domain of GmERS1-1 modulates cell cycle via GmACR1

Ethylene signaling orchestrates plant development and stress adaptation, yet how post-translational modifications of its receptors coordinate growth regulation remains unresolved. Here, we uncover a proteolytic processing mechanism of the soybean ethylene receptor GmERS1-1 that directly gates cell cycle progression. The GmERS1-1 mutants exhibit elevated yield under field conditions, whereas overexpression suppresses growth and hypersensitizes plants to ethylene. Ethylene triggers nuclear translocation of C-terminal domain (GmERS1-1-CEND), which is indispensable for receptor function. Mechanistically, GmERS1-1-CEND scaffolds a trimeric complex with GmACR1 and GmCDK7, enforcing G2/M phase arrest, thereby decoupling cell division from canonical ethylene transcriptional responses. Strikingly, ethylene-induced cell cycle blockade during apple fruit maturation mirrors this pathway, suggesting deep conservation across angiosperms. Our work defines a receptor processing-dependent signaling axis that directly interlinks phytohormone perception with cell cycle control, proposing tunable targets (e.g., GmERS1-1 cleavage efficiency) for engineering crop architecture and productivity.

plant biology↗

bioRxiv2026

Mediation Analysis with Compositional Exposures

Understanding the causal pathways linking the gut microbiome to downstream biomarkers and clinical outcomes is central to microbiome research. When the microbiome acts as the exposure, the high dimensionality and compositional structure of the data introduce unique methodological challenges for mediation analysis. To address these challenges, we propose a latent variable mediation framework that captures variation in microbial composition through a microbial balance, defined as the log-ratio between two unknown subsets of taxa. This balance serves as a latent scalar exposure and simplifies the estimation of the overall indirect effect at the community level, while simultaneously identifying specific taxa that contribute to the overall direct and indirect effects. We describe the model's estimation and inference, and illustrate the method using data from the Multiethnic Cohort--Adiposity Phenotype Study, where we examine the mediation pathway from the gut microbiome through lipopolysaccharide-binding protein, a marker of metabolic endotoxemia, to percent liver fat.

bioinformatics↗

bioRxiv2026

A meta-interaction basis for cell-cell communication in tissues

Tissue function depends on signals exchanged between cells and the responses they elicit. Yet whether diverse cell-cell interactions in situ form recurrent sender-receiver programs remains unclear. We present SpiderNet, an interpretable representation-learning framework that discovers such directed programs as a compact basis of cell-cell meta-interactions (MIs) from spatial transcriptomics. SpiderNet jointly learns which sender regulators, ligand-receptor pairs, and receiver targets define each MI and where each program is active across neighboring cell pairs. The resulting representation traces multicellular relays and links communication to cell states, perturbation responses, and phenotypes. SpiderNet recovers ground-truth MIs and their molecular components in simulations and, in real tissues, shows stronger direction-specific agreement with independently curated regulatory programs in senders and receivers than alternative methods. Across more than 5.8 million spatially profiled cells, SpiderNet resolves an SPP1-THBS relay linking monocytes, fibroblasts, and tumor cells within an immune-suppressive ovarian cancer niche, predicts T-cell responses to held-out melanoma-cell perturbations, and identifies a T-cell-associated brain-aging program and age-predictive signals that transfer across regions and platforms. It reveals a recurrent pan-cancer COLLAGEN-linked fibroblast-tumor program whose projected abundance in independent cohorts is associated with poorer survival and non-response to immunotherapy. SpiderNet thus establishes MIs as a reusable organizational layer between molecular interactions and tissue phenotypes, providing a framework to resolve, compare, trace, and perturb multicellular regulation in situ.

bioinformatics↗

bioRxiv2026

LoGoPPI enables fast and accurate protein protein interaction mapping at scale

Graph-based protein function analysis is powerful, but protein-protein interaction (PPI) networks exist for only a small fraction of animal and plant genomes. We present LoGoPPI, which infers PPIs from sequence by combining bi-encoder global protein representation with local residue-level late interaction. LoGoPPI matches or exceeds state-of-the-art PLM-based cross-encoders while achieving orders-of-magnitude faster inference, up to ~1,500-fold, and its local branch provides residue-level signals associated with interaction interfaces and structurally flexible regions. This efficiency enables practical proteome-wide PPI reconstruction at scales prohibitive for cross-encoder models, potentially extending interactome mapping to tens of thousands of animal and plant species. LoGoPPI thus provides a scalable framework for comparative and functional analysis of protein networks across diverse taxa.

bioinformatics↗

bioRxiv2026

Genomic splice-donor disruption rescues systemic disease in progeria

RNA splicing determines which protein isoforms a gene produces, and aberrant splice-site activation can cause severe disease. In Hutchinson-Gilford progeria syndrome, a synonymous LMNA mutation strengthens a cryptic 5' splice donor site to produce progerin, a toxic lamin A isoform driving premature cardiovascular death. Within this cryptic donor, the activating mutation lies near the canonical GT dinucleotide required for splice-site recognition. A single guide can therefore preferentially pair with the mutant sequence while positioning Cas9 cleavage at this dinucleotide. Here we show that CRISPR/Cas9-mediated disruption of this splice site suppresses progerin without requiring precise correction of the activating mutation and prolongs lifespan in progeroid mice. In patient-derived fibroblasts and induced pluripotent stem cell-derived mesenchymal stem cells, this intervention reduced progerin by 92.7-96.8% while retaining lamin A and lamin C expression. A single neonatal injection of AAV9 carrying the corresponding mouse guide increased median survival from 115 to 279 days in Cas9-expressing LmnaG609G/G609G mice. Treatment attenuated aortic, skeletal and multiorgan pathology. Treated homozygous pairs produced 52 offspring across seven litters. These findings establish pathogenic splice signals as genomic targets for sustained suppression of toxic isoforms while retaining canonical gene outputs.

cell biology↗

bioRxiv2026

Cardiomyocytes upregulated PD-L1 expression to alleviate cardiac injury induced by irradiation combined with anti-PD-1 antibody: an in vitro and in vivo study

Objective: Preclinical studies suggest that irradiation combined with anti-PD-1 antibody (iRT) exacerbates cardiac injury in mice, partly through CD8 T-cell-mediated mechanisms. We investigated radiation-induced PD-L1 expression in cardiomyocytes and explored its potential role in iRT-associated cardiac injury. Methods: AC16 cells were exposed to different doses of irradiation. PD-L1 expression was assessed at different time points by flow cytometry, qRT-PCR, western blotting, and immunofluorescence. Cell viability, apoptosis, and cytokine levels were evaluated. PD-L1 was knocked down using siRNA to assess its function. PBMCs or CD8 T cells were co-cultured with irradiated or non-irradiated AC16 cells at different E:T ratios, with or without PD-1 blockade. A C57BL/6J mouse model of iRT-induced myocardial injury was established, and myocardial PD-L1 expression and T-cell infiltration were evaluated. Results: Irradiation upregulated PD-L1 expression in AC16 cells, with increased membrane and cytoplasmic signals at 48 h and prominent nuclear-associated fluorescence at 72 h. Irradiation increased IL-6, MCP-1, CCL5, and CXCL10 release, decreased IL-10, reduced cell viability, and increased apoptosis. PD-L1 knockdown further increased inflammatory cytokine and chemokine release but did not significantly alter apoptosis or further reduce viability in irradiated AC16 cells. In the presence of a high density of activated CD8 T cells, disruption of PD-1/PD-L1 signaling was associated with a further reduction in AC16 cell viability. In vivo, myocardial PD-L1 expression was increased, whereas CD8 T-cell infiltration remained limited and focal. Conclusion: PD-L1 upregulation in cardiomyocytes may exert an adaptive protective and immunoregulatory role during iRT-associated injury, potentially by limiting inflammatory mediator release and modulating susceptibility to activated CD8 T-cell mediated injury. CD8 T-cell density and activation are the key issues.

cancer biology↗

bioRxiv2026

Restoring the Chondron: Pericellular Matrix Reconstitution Enhances Mechano-Inflammatory Resilience and Modulates Chondrocyte-Neuron Crosstalk

Abstract Chondrocytes in native articular cartilage are enclosed within a collagen VI (COL VI)-rich pericellular matrix (PCM), forming functional units known as chondrons. However, enzymatic isolation disrupts the PCM, and the functional consequences of its loss and restoration remain poorly understood. In this study, primary human chondrocytes were cultured in alginate beads to promote PCM reconstitution and subsequently recovered as reconstituted chondrons. Chondrocytes and reconstituted chondrons were encapsulated in gelatin methacryloyl hydrogels and compared under inflammatory and mechanical stimulation. Alginate preconditioning generated chondron-like units with a distinct COL VI-positive PCM that was retained after transfer to three-dimensional culture. Under inflammatory conditions, reconstituted chondrons exhibited reduced inflammatory, catabolic, neuroinflammatory, and angiogenic responses compared with isolated chondrocytes at both gene and protein levels. Under interleukin-1{beta} stimulation, mechanical loading further increased inflammatory gene expression in chondrocytes in a donor-dependent manner, whereas responses remained comparatively limited in reconstituted chondrons. Conditioned medium from reconstituted chondrons was also associated with lower capsaicin- and potassium chloride-evoked calcium responses in human induced pluripotent stem cell-derived sensory neurons than corresponding chondrocyte-conditioned medium. These findings demonstrate that reconstitution of a COL VI-rich PCM restores a chondron-like pericellular microenvironment that attenuates inflammatory activation and buffers load-associated inflammatory amplification, while exploratory sensory neuron experiments suggest downstream modulation of neuronal responsiveness. PCM restoration may therefore provide a promising strategy for cartilage tissue engineering and regenerative applications.

molecular biology↗

bioRxiv2026

Novel Dissymmetric Ionizable Lipid-Assembled Lipid Nanoparticles for Delivery of Ferroptosis-Related siRNA in Diabetic Treatment

Small interfering RNA (siRNA) enables precise post-transcriptional gene silencing for refractory diseases, yet its clinical translation remains limited by the lack of safe and efficient delivery vectors. Inspired by the dissymmetric alkyl chain architecture of natural membrane phospholipids, we designed and synthesized 34 novel ionizable lipids with dissymmetric hydrophobic tails and formulated them into lipid nanoparticles (LNPs). Through systematic physicochemical and biological assessments, we established clear structure-activity relationships and identified two lead LNPs (O14-LNP, H18a-LNP) with superior endosomal escape capacity, enhanced in vivo gene silencing potency, and favorable biosafety relative to the clinical benchmark MC3-LNP. In both streptozotocin-induced and spontaneous db/db type 2 diabetes (T2D) mouse models, lead LNPs delivering ferroptosis-related siRNAs effectively ameliorated glucose and lipid metabolic disorders, restored islet function, and alleviated hepatic steatosis. This study not only lays a theoretical foundation for the rational design of novel ionizable lipids, but also validates the therapeutic potential of siRNA therapy targeting ferroptosis, providing a versatile delivery platform and targeted therapeutic strategy for the treatment of T2D.

pharmacology and toxicology↗

bioRxiv2026

Spatial profiling of pooled mRNA-LNP delivery in vivo with NanoSTAMP

Existing pooled lipid nanoparticle (LNP) screens lack spatial information on formulation localization, cellular uptake, and associated multicellular tissue responses. Here we introduce NanoSTAMP, a spatially resolved, pooled in vivo screening platform for barcoded LNP libraries that uses fluorescence in situ hybridization (FISH)-based barcode readout and is compatible with spatial omics. NanoSTAMP links LNP formulation to cell-type specific uptake, cargo expression, and nearby multicellular neighborhoods within intact tissue, which enables spatially-informed design of RNA delivery, establishing tissue architecture as a dimension of LNP performance.

bioengineering↗

bioRxiv2026

Bridging Morphology and Genomics: A rapid image-based assessment of genomic admixture in the endangered gayal (Bos frontalis)

Abstract The gayal (Bos frontalis) is an endangered semi-domesticated bovine species renowned for its high-quality beef. However, its semi-feral lifestyle, ongoing habitat fragmentation, and extensive genetic introgression from sympatric local cattle have led to dramatic population decline and severe erosion of purebred genetic integrity, posing substantial challenges to its conservation and utilization. To address the urgent demand for rapid, non-invasive, and field-compatible germplasm identification, we developed an integrated artificial intelligence (AI) framework that predicts genomic admixture composition from external morphological images. We constructed a comprehensive dataset comprising 6,245 morphological images and matched genomic sequences from 52 gayals maintained at the Yunnan Provincial Gayal Conservation Farms. Following a preliminary evaluation of nine deep learning models, five were incorporated into a anatomical segment-based multi-modal pipeline, among which Inception_V3 delivered the optimal overall performance. To enhance simultaneous extraction of local fine-grained features and global structural information, we further designed an innovative HybridInceptionViT model by integrating the multi-scale Inception module with the Vision Transformer (ViT) framework. This hybrid model significantly outperformed the baseline Inception_V3, boosting the accuracy of phenotype-derived prediction against genomic admixture estimate from 69.69% to 87.87% (absolute error <15%). This study establishes a practical, low-cost "phenotype-to-genotype" tool for rapid on-site gayal germplasm screening, offering a scalable strategy for the conservation and breeding management of endangered livestock, and holds broad application prospects for agricultural and livestock production systems.

zoology↗

bioRxiv2026

In situ Discovery of Immune Repertoire Reveals Antitumor Immunity and Therapeutic Antibodies

Spatial transcriptomics offers a glimpse into the immunology of tissues. However, limitations in spatial transcriptomics preclude the detection of highly diverse, low-abundance, and previously unknown sequences, including immune repertoires and microbiota. Here, we introduce Archimap, a spatial transcriptomic platform that simultaneously profiles spatial transcriptomes, immune repertoires, and microbiota from formalin-fixed paraffin-embedded (FFPE) tissues. Using Archimap, we profile the spatial localization of TCRs, BCRs, and the microbiota landscape in archived clinical tissues at single-cell resolution. Through comprehensive benchmarking, we validate Archimaps performance and fidelity. Archimap in situ assembles the immune complex and reconstructs the clonal evolution of antibodies. Together, Archimap shows the power of in situ discovery of functional immune repertoires for their antitumor immunity.

bioinformatics↗

bioRxiv2026

Architectural trade-offs between environmental stability and genomic redundancy reveal divergent pneumoviral entry strategies

Human respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) exhibit distinct seasonal epidemiology, with RSV circulating in early autumn and hMPV peaking in midwinter, yet the structural basis for this niche partitioning remains undefined. Here, we integrate in situ cryo-electron tomography and functional virology to decode the architectural logic governing their entry dynamics. RSV employs a matrix (M)-regulated prefusion F (pre-F) organization, partitioning trimers into stabilizing hexagonal superlattices and fusion-competent pools to maintain superior thermotolerance. By contrast, hMPV compensates for its intrinsically unstable, monomeric pre-F with extreme ribonucleoprotein polyploidy, packaging [~]4-fold more genome equivalents to ensure productive infection. Fusion events localize exclusively to M-depleted, non-arrayed membrane regions, establishing a spatial checkpoint for activation. These findings reveal a conserved trade-off between environmental resilience and genomic redundancy that dictates divergent pneumoviral entry strategies, explaining their distinct seasonal ecological niches.

microbiology↗