Biology subjects

Li, B.

Publications and source records attributed to Li, B..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

A newly identified Duck orbivirus as the etiological agent of egg-production decline in Chinese breeder ducks

The genus Orbivirus comprises double-stranded RNA viruses, many of which are transmitted by arthropods and cause febrile, hemorrhagic, or reproductive diseases in animals. In recent years, unexplained outbreaks characterized by marked egg-production decline have occurred in breeder duck flocks in China. To identify the causative agent, samples were collected from affected farms in multiple regions across China between 2022 and 2025. Representative samples were analyzed by high-throughput sequencing, followed by phylogenetic analysis, transmission electron microscopy, host cell infection assays, and animal challenge experiments. A previously unreported Orbivirus, designated Duck orbivirus (DORV), was identified. Epidemiological investigation indicated that outbreaks mainly affected breeder ducks during the peak laying period (21-55 weeks of age), with higher incidence in summer and autumn. The DORV genome contains ten double-stranded RNA segments encoding seven structural and five nonstructural proteins. Phylogenetic analysis showed that DORV is closely related to Parrys Lagoon virus (PLV) and Corriparta virus (CORV). Electron microscopy revealed icosahedral particles 30-40 nm in diameter. DORV replicated efficiently in DEF, DEL and C6/36 cells but not in MDCK and LMH cells, suggesting a restricted host range with potential arthropod-borne features. Infection of breeder ducks with DORV-SD01 reduced egg production by 30-40% and caused lesions in the ovary, liver, and spleen. This study describes a novel duck-origin Orbivirus linked to egg-production decline, offering new etiological insights and extending the host spectrum of Orbivirus. The results provide a foundation for future surveillance and prevention of emerging waterfowl diseases.

microbiology↗

bioRxiv2025

Macrocyclic Peptides Containing an Imidazopyridinium (IP+) Unit Display Enhanced Passive Cell Permeability

Macrocyclic peptides (MPs) have emerged as interesting therapeutic candidates due to their ability to engage difficult protein targets with high affinity and selectivity. However, their application to intracellular targets is limited by the poor passive membrane permeability of most MPs. We previously showed that incorporation of an imidazopyridinium (IP+) moiety into an MP significantly boosted passive membrane permeability, as measured by the parallel artificial membrane permeability assay (PAMPA)(Li, et al. (2024) J. Amer. Chem. Soc. 146, 14633-14644). In this study we report a detailed analysis of the entry of IP+-containing MPs into living cells. Chloroalkane penetration assay (CAPA) data show that IP+ MPs access the cytoplasm rapidly, often at rates approaching those of drug-like small molecules. Mechanistic studies, including live-cell imaging, ATP-depletion experiments, and organelle colocalization analyses, indicate that IP+ MPs traverse the plasma membrane primarily via passive diffusion, avoiding endosomal entrapment. IP+ MPs do not localize to mitochondria, as is the case for many positively charged molecules. We show that incorporation of an IP+ unit transforms a previously described membrane impermeable macrocyclic antagonist of the p53-MDM2 interaction into a bioactive inhibitor of MCF-7 proliferation. Collectively, these results establish that IP+ incorporation is an effective strategy for the development of bioactive MPs targeting intracellular proteins.

biochemistry↗

bioRxiv2025

PTH-Induced Behavioral and Metabolic Alterations in Mouse Models of Hyperparathyroidism

Parathyroid hormone (PTH) is a critical endocrine regulator of calcium homeostasis and bone remodeling and is widely employed in clinical settings through synthetic analogs for the treatment of osteoporosis. Although traditionally considered a peripheral regulator, emerging evidence indicates that PTH also exerts effects through the central nervous system (CNS). This study investigated the neuropsychiatric impact of elevated PTH and explored potential CNS involvement using multiple murine models of hyperparathyroidism (HPT). Distinct behavioral phenotypes were observed across models, indicating that psychiatric symptoms vary depending on disease etiology and progression. The effects of hPTH(1-34), a clinically approved PTH analog, were further assessed in male and female mice. Under pharmacological concentrations, hPTH(1-34) enhanced locomotor activity in males but induced mild anxiety-like behavior in females. These behavioral changes in females were independent of the estrus cycle and were amplified by ovariectomy. Metabolic analysis indicates PTH affects the basic metabolism by inhibiting the respiratory exchange ratio, promotes the energy expenditure and locomotion without affecting the food consumption in a 48hr range. To further investigate the molecular effect of PTH in the brain, a PTH1R-Cre mouse line was generated to map PTH receptor-1 (PTH1R) expression. Widespread expression of PTH1R was detected across the brain, including in both neuronal and non-neuronal cell populations. These findings suggest that PTH may influence behavior through interactions with PTH1R-expressing cells in brain vasculature and circumventricular regions. However, further studies are warranted to define the specific brain nuclei and cell types involved in PTH-driven modulation of neurobehavioral function.

neuroscience↗

bioRxiv2025

Enhancing Volatile Fatty Acid Accumulation in Seaweed-Arrested Anaerobic Digestion via a Two-Tier Framework of Engineering Diagnostics and Microbial Surveillance

This study presents a two-tier framework for brown seaweed-arrested anaerobic digestion (SW-AAD) by coupling engineering diagnostics (tier-1) with microbial surveillance (tier-2) to transform conventional digesters into volatile fatty acid (VFAs) biorefineries. In 70-day lab-scale batch tests (volume: 2 L), engineering diagnostics revealed that sequential additions of brown seaweed elevated salinity to 3.3% ash content, stabilized pH at 5.8-6.1, collapsed the CH/CO2 ratio from 2.98 to <0.04, suppressed biogas by 96%, and boosted carbon-conversion efficiency from 10% to 52%. More than half of the influent carbon was redirected from methane to a liquid-phase VFAs pool, dominated by butyrate, hexanoate, and acetate, peaking at 14.5 g L-{superscript 1}. Microbial surveillance using 16S rRNA sequencing presented a 10-fold decline in methanogens, alongside an increase in salt- and acid-tolerant acidogenic microbial families, including Lachnospiraceae, Ruminococcaceae, and Clostridiaceae, as well as seaweed-derived microbial families, including Psychromonadaceae, and Marinomonadaceae. Temporal synchrony and asynchrony-resolved analysis confirmed a strong correlation between two tiers, revealing an operational window featured with two patterns: a rapid engineering parameter response (where changes in engineering parameters were followed by a decline in methanogens within 0-3 days) and a slower microbial restructuring (where the surge in VFA concentration lagged the enrichment of seaweed-derived acidogens by 1-5 days). Based on this operation window, feedback control strategies were simulated for SW-AAD, indicating that cumulative VFAs (cVFAs) yield could be bolstered from 11.38 to 16.13 g COD L-{superscript 1} (+41.8%). A techno-economic assessment (TEA) revealed that this VFA-targeted SW-AAD can reduce capital expenditure by [~]20% compared to conventional AD. This study underscores the promise of asynchrony-resolved analysis of SW-AAD systems for robust and economically viable VFAs production from organic waste. Graphics O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/680780v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1dc596dorg.highwire.dtl.DTLVardef@1731cadorg.highwire.dtl.DTLVardef@5fe025org.highwire.dtl.DTLVardef@74d8d3_HPS_FORMAT_FIGEXP M_FIG C_FIG Environmental synopsisBrown seaweed-arrested anaerobic digestion (SW-AAD) leverages seaweed-driven salinity, and acidification to suppress methanogenesis, diverting >50% of carbon to VFAs (14.5 g COD L-{superscript 1}) while cutting methane by 99%. A two-tier framework couples engineering diagnostics with microbial surveillance and asynchrony-resolved analysis, enabling feedback control and low-emission waste valorization in digesters.

bioengineering↗

bioRxiv2025

The Critical and Unexpected Role of a Methyl Group in Interleukin-17A Inhibitors

Interleukin-17 (IL-17) is a pro-inflammatory cytokine primarily secreted by Th17 cells. It plays a crucial role in the bodys immune defense against fungal and bacterial pathogens. However, an imbalance in IL-17 production can contribute to the development of autoimmune and inflammatory disorders. Therapeutic strategies targeting IL-17, such as blocking antibodies like secukinumab (Cosentyx), have been successfully developed. These antibodies are currently employed in the treatment of various conditions, including psoriasis, psoriatic arthritis, and ankylosing spondylitis. More recently, a small molecule inhibitor of IL-17, LY3509754, progressed to clinical trials but was halted during Phase 1 due to unfavorable hepatotoxicity. Two derivatives, compounds 7 and 8, did not advance to clinical trials due to safety concerns. These three compounds (7, 8, and the original lead compound, presumably implied) share a common difluoro substituent, which was hypothesized to be the cause of the observed safety issues. In subsequent structure-activity relationship (SAR) studies, replacing the difluoro substituent with a single methyl group (resulting in compound 9) unexpectedly led to a significant improvement in cellular activity. Furthermore, compound 9 exhibited a very low unbound fraction and reduced liver distribution, ultimately translating to high in vivo efficacy with a sufficient safety margin. This seemingly minor methyl substitution transformed the compound into a highly promising preclinical candidate (compound 9), now slated for further development. Co-development inquiries are welcome. Please contact us at enan1@dcpc.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/680113v2_ufig1.gif" ALT="Figure 1"> View larger version (13K): org.highwire.dtl.DTLVardef@3f31adorg.highwire.dtl.DTLVardef@d6873forg.highwire.dtl.DTLVardef@494af7org.highwire.dtl.DTLVardef@1d8b7eb_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

A Dual Assay to Compare Protein Levels and Toxicity of Alpha-Synuclein Variants: Acute Expression of Wild-Type versus S129A

Parkinsons disease (PD) affects over 12 million people worldwide and has the fastest-growing global impact. The pathological hallmark is the presence of Lewy bodies and Lewy neurites, which are intraneuronal lesions enriched in aggregated alpha-synuclein (S) that is typically hyper-phosphorylated at serine 129. Therefore, lowering phosphoserine 129 (pS129) may be a viable therapeutic strategy to treat PD. However, pS129 has also been proposed to regulate synaptic transmission and S degradation. In both cases, inhibiting pS129 could be detrimental. Here, we developed a sensitive assay in a human neuroblastoma model and utilized it to assess the relative expression levels and cytotoxicity of pS129 by comparing S wild-type (WT) vs. S129A (pS129-deficient). We show that the S129A mutant does not affect the acute expression levels or toxicity of S in a transient transfection paradigm. This provides new insight into the intricate interplay between S, phosphorylation, toxicity, and degradation. Our assay provides a versatile platform for understanding disease-relevant mechanisms and opens novel avenues for the design of future therapeutic interventions in PD and other -synucleinopathies.

cell biology↗

bioRxiv2025

Charting the Normal Development of Structural Brain Connectivity in Utero using Diffusion MRI

Understanding the structural connectivity of the human brain during fetal life is critical for uncovering the early foundations of neural function and vulnerability to developmental disorders. Diffusion-weighted MRI (dMRI) enables non-invasive mapping of white matter pathways and construction of the brains structural connectome, but its application to the fetal brain has been limited by data scarcity and technical difficulties in analyzing fetal dMRI data. Here, we present the largest study to date of in utero brain connectivity, analyzing high-quality dMRI data from 198 fetuses between 22 and 37 gestational weeks from the Developing Human Connectome Project. We employed advanced fetal-specific tools for brain segmentation and parcellation, and used ensemble tractography to encourage more complete reconstruction of various white matter tracts. For connection weighting, we relied on the notion of fiber bundle capacity. We reconstructed individual structural connectomes and characterized the developmental trajectories. Graph-theoretical analysis revealed consistent increases in integration and segregation metrics over gestation, while bootstrapping confirmed the robustness of nodal and edgewise developmental patterns. Furthermore, we proposed a novel method for constructing age-specific connectome templates based on aggregation of individual subject connectomes. The new method follows an optimization-based approach to ensure that the connectome templates closely represent individual subject connectomes, are temporally consistent, and proportionally preserve short and long connections. Our analysis shows that this approach is superior to spatial alignment and averaging of the data in image space, with the resulting connectome templates supporting accurate prediction of the gestational age of individual fetuses (mean error= 0.90 {+/-} 0.81 weeks). In summary, this study provides robust normative benchmarks for fetal brain structural connectivity and demonstrates that connectome-based measures capture meaningful developmental signatures, offering a framework for future studies of early brain development.

neuroscience↗

bioRxiv2025

Selective spread of mobile antibiotic resistance genes in wastewater microbiomes driven by the non-antibiotic pharmaceutical carbamazepine

Carbamazepine (CBZ), a widely used anticonvulsant, is a persistent aquatic micropollutant that withstands biodegradation and accumulates in wastewater-impacted environments. While non-antibiotic pharmaceuticals, including CBZ, have been shown to stimulate horizontal gene transfer (HGT) under laboratory conditions, their effects in complex microbial communities remain poorly understood. Here, we applied an experimental evolution framework to wastewater microbiomes exposed to a gradient of environmentally relevant CBZ concentrations (0-50 {micro}g/mL) for three days. CBZ reduced growth of the community in a concentration-dependent manner. Still, community composition was largely unaffected by CBZ exposure. However, antibiotic resistance gene (ARG)- and mobile genetic element (MGE)-specific responses emerged. Among the tested 26 ARGs, four clinically relevant ones (blaCMY, blaOXA-48, blaCTX-M, dfrA1) increased in relative abundance in a dose-dependent manner, correlating with proliferation of IncP and IncW plasmids and the transposon IS26, pointing to enhanced HGT as the underlying mechanism. In contrast, only ermF abundance rose independently of MGEs, suggesting direct selection. Other ARGs and MGEs, including integron integrase intI1 and IncQ plasmids, showed no consistent CBZ response. Effects were strongest at subinhibitory concentrations (0.05-5 {micro}g/mL), matching upper levels detected in surface waters. These findings demonstrate that CBZ can selectively promote AMR dissemination through both HGT and direct selection, but in a targeted rather than community-wide manner. Our results highlight the need to consider non-antibiotic pharmaceuticals in AMR surveillance and environmental risk assessment frameworks, as they may shape the environmental resistome beyond antibiotic exposure.

microbiology↗

bioRxiv2025

Multiscale modeling of cell-substrate adhesion dynamics: effects of integrin activation, clustering and internalization

Cell adhesion is a fundamental biological process that governs cell proliferation, differentiation, migration, and tissue development. Cells adhere to the extracellular matrix through specialized transmembrane proteins, whose structures and functions are well studied. However, how mechanical, chemical, and biological factors interact to regulate these proteins and hence to shape cross-scale adhesion dynamics from molecular clustering to cellular migration remains unclear. Here, we propose a multiscale mechano-biochemical coupling framework to investigate the dynamics of cell-substrate adhesions, incorporating comprehensive molecular steps in the integrin life cycle, including activation, clustering, signal transduction and internalization. Our model elucidates the roles of caveolin transport and actin flow in modulating integrin dynamics and FA morphology. We identify the antagonistic interplay between integrin internalization and clustering that governs cross-scale adhesion dynamics. Furthermore, our model quantitatively demonstrates how the substrate stiffness regulates the integrin clustering size and internalization rate. These findings provide mechanistic insights into the regulation of cell migration, particularly the transition between durotaxis and negative durotaxis, driven by intracellular and extracellular microenvironmental factors. Our model offers an effective framework for understanding the cross-scale regulation process of cell adhesion involved in physiological and pathological activities, such as stem cell differentiation and cancer metastasis.

biophysics↗

bioRxiv2025

Genome-wide SNVs revealed reticulate evolutionary history of an Eurasia-African songbird radiation

Phylogenomics has the power to uncover complex evolutionary hypothesis across taxa, thereby allowing important glimpses into the evolutionary history, such as incomplete lineage sorting (ILS) and introgression among closely related species. The Saxicola torquatus complex comprises several widely distributed insectivorous bird species across the Palearctic and Afrotropical realms. Nevertheless, the evolutionary history within this complex remains contentious, and previous findings suggest complication caused by cytonuclear discordance. Here, we conducted a phylogenomic analysis of nearly complete taxa within the complex using genome-wide SNVs to investigate potential causes of phylogenetic discordance across genomic regions and elucidate its evolutionary history. We detected multiple reticulate events during their diversification, leading to extensive phylogenetic discordance across the genome. The mitochondrial genome and W chromosome exhibited a consistent gene tree that conflicted with the species tree, with introgression being the most plausible explanation among several hypotheses. The Z chromosome was less affected by ILS/introgression and exhibited relatively stable local phylogenies compared to autosomes. Furthermore, we found that strongly introgressed regions were predominantly concentrated at the ends of smaller chromosomes, and the strength of introgression among species pairs showed consistently positive correlations, likely attributed to shared recombination hotspots in these regions. These findings stress the heterogeneous genomic landscape influenced by intricate evolutionary processes that endorse a reticulate evolution model for global speciation in the S. torquatus complex.

evolutionary biology↗

bioRxiv2025

T-cell signaling relies on partial CD45-exclusion at sub-micron sized cellular contacts

How cell contact initiates T-cell activation is uncertain. The local exclusion of the receptor-type protein tyrosine phosphatase CD45 at cell contacts is believed to trigger immune receptor signaling but this is yet to be observed for T cells interacting with authentic cellular targets. Here, quantitative imaging of T cells interacting with tumor cells presenting either native or clinically relevant bi-specific TCR ligands, revealed that they form multiple sub-micron sized close contacts with their targets. The contacts were stabilised by the adhesion protein CD2, but efficient ligand detection required both CD2 and integrin ligation. CD45 was excluded from close contacts at the time of ZAP70 recruitment and signaling, but only partially (30- 40%). A single-cell, mass cytometric analysis showed that this change in kinase/phosphatase activity provoked strong T-cell activation and potent cytotoxicity via very small changes in signaling fluxes. Spatial stochastic simulations suggested that the proximal T-cell signaling network is optimised for efficient antigen discrimination in the setting of partial CD45 exclusion. Our work re-frames early T-cell activation as a process initiated by relatively subtle changes in kinase/phosphatase activity acting on small numbers of signaling effectors at minute cellular contacts.

immunology↗

bioRxiv2025

Bidirectional translocation of actomyosin drives epithelial invagination in ascidian siphon tube morphogenesis

How epithelia perform a spatiotemporal heterogeneous force generating program to drive a sequential tissue morphogenesis remains unclear, particularly the underlying precise mechanical mechanisms. This study investigated dynamic actomyosin reorganization between apical and lateral membrane cortex regions during two sequentially invaginated stages during ascidian atrial siphon tube morphogenesis. At the initial invagination stage, the originally lateral-located actomyosin redistributed to the apical domains, while those actomyosin redistributed back to lateral domains at the accelerated invagination stage. Using genetic mutants to modulate myosin activities, the initial invagination was strengthened or abolished, indicating invagination is apical constriction dependent. Optogenetic inhibition of myosin activities in lateral domains after initial invagination stage blocked the further processes, suggesting lateral constriction of actomyosin is required for the accelerated invagination. Vertex model simulations uncovered a coupled mechanism underlying epithelial invagination driven by apicobasal tension imbalance and lateral contraction. We thus propose an actomyosin redistribution mechanical model: lateral actomyosin first redistributes apically to drive apical constriction and shape the initial invagination, then apical actomyosin redistributes laterally to promote lateral contractility and accelerate invagination. Our findings reveal a bidirectional reorganization of actomyosin network as a central mechanism driving epithelial invagination, providing insights on epithelial invagination and the organ morphogenesis during development.

developmental biology↗

bioRxiv2025

An Objective Detection Method for Tinnitus using Memristors

Approximately 10-20% of the world population experiences tinnitus, which is increased with age and comorbid with frustration, annoyance, anxiety, depression, cognitive dysfunction, insomnia and stress. The underlying mechanisms of tinnitus remain largely unknown and there are no quantifiable biomarkers, making this prevalent disorder a global burden. There are no FDA-approved therapeutics and the current assessment mainly relies on self-reports (e.g., questionnaires), which underscore the need for diagnostic tools for tinnitus. Memristors, nanoscale electronic components mimicking synaptic plasticity, can monitor and control neuronal activity, hold transformative potential for detecting and characterizing tinnitus objectively. Here, we harvested the blood from human and mice with tinnitus, and engineered memristors via magnetron sputtering and made the functional layer with serum. Its core mechanism lies in regulating the reversible formation and rupture of conductive filaments which is formed by utilizing abnormally elevated glutamate concentrations in serum assisted Ag+ ions. This serum-based memristor achieves unprecedented discrimination between tinnitus and non-tinnitus individuals. Furthermore, this platform provides mechanistic insights into tinnitus pathogenesis, with potential implications in other neurological disorders.

pathology↗

bioRxiv2025

Three-dimensional spatial transcriptomics at isotropic resolution enabled by generative deep learning

Mapping the complete three-dimensional (3D), transcriptome-wide spatial architecture of tissues and organs remains a fundamental challenge in biology. Typically, studies approximate 3D structures by profiling serial two-dimensional (2D) tissue sections, resulting in incomplete and anisotropic reconstructions. Here, we demonstrate that organ-wide, isotropic-resolution 3D gene expression landscapes can be effectively inferred from sparse 2D spatial transcriptomics data using artificial intelligence. Our framework, isoST, leverages stochastic differential equations (SDEs) to model the intrinsic biological continuity of gene expression along tissue depth, enabling the integration of discrete 2D measurements into coherent 3D transcriptomic maps. isoST is applied across diverse biological systems, including the brain, kidney, spinal cord, and gastrulating embryos, accurately reconstructing anatomical structures and molecular patterns that are only partially resolved in 2D analyses. isoST enables the comprehensive characterization of tissue niches at full 3D resolution, uncovering radial and spherical gene expression gradients associated with disease progression that are often distorted or missed in 2D approaches. Furthermore, isoST is extended to integrate histological imaging for reducing experimental complexity and to reconstruct high-resolution developmental spatial trajectories over time. Together, isoST provides a practical and scalable solution toward comprehensive high-resolution 3D spatial transcriptomic atlases.

bioinformatics↗

bioRxiv2025

Helicobacter pylori genome aggregation database reveals complex evolutionary forces shaping its genomic landscape and clinical impact in East Asia

We assembled HPgnomAD, a comprehensive global genome aggregation database of Helicobacter pylori (H. pylori) featuring 7,544 high-quality genomes from 278 populations, along with the first species-wide haplotype reference panel for genotype imputation. The panel provides high accuracy across diverse H. pylori populations, including those from low-coverage data, and is openly accessible with integrated analysis tools (https://www.hpgnomad.top/). Variant discovery revealed 1.82 million SNPs and 0.65 million InDels, with African strains exhibiting the most tremendous diversity and East Asian strains showing unexpectedly high novel variation. Fine-scale analysis of the hpEAsia lineage revealed six new sublineages shaped by altitude-, latitude-related divergence and region-specific admixture. Phylogenomic dating revealed two divergence waves in East Asia, paralleling Upper Paleolithic settlement and Neolithic human expansions, with highland-lowland separation at [~]18.8 kya, followed by the formation of complex geography-related population substructures. Genome-wide scans revealed adaptive loci related to metal acquisition, nitrogen metabolism, surface adhesion, and membrane transport, including altitude-associated highly differentiated variants linked to antibiotic resistance and gastric disease. By integrating genomic, evolutionary, environmental, and clinical data, HPgnomAD offers a framework for understanding H. pylori evolution, host-pathogen adaptation, and precision medicine worldwide.

evolutionary biology↗

bioRxiv2025

CLM-access: A Specialized Foundation Model for High-dimensional Single-cell ATAC-seq analysis

Inspired by the success of large language models (LLMs) in natural language processing, cell language models (CLMs) have emerged as a promising paradigm for learning cell representations from high-dimensional single-cell data--particularly transcriptomic profiles from scRNA-seq. These foundation models have shown remarkable potential across a variety of downstream applications. However, there remains a lack of foundation models for scATAC-seq data, which measures chromatin accessibility at single-cell level and is critical for decoding epigenetic regulation. Developing such models is considerably more challenging due to the unique characteristics of scATAC-seq data, including the vast number of chromatin regions, lack of standardized annotations, extreme sparsity, and near-binary distributions. To address these challenges, we systematically explore various strategies and propose CLM-access, a specialized foundation model for scATAC-seq data. CLM-access incorporates three main innovations: (1) an unified data processing pipeline that maps 2.8 million cells onto an unified reference of over 1 million chromatin regions; (2) a specialized patching and embedding strategy to effectively manage high-dimensional inputs; and (3) a tailored masking and loss function design that preserves fine-grained regional information while enhancing training efficiency and representation quality. With comprehensive benchmarks, we show that CLM-access significantly outperforms existing methods in key downstream tasks, including batch effect correction, cell type annotation, RNA expression prediction, and multi-modal integration. This work establishes a scalable and interpretable foundation model for single-cell epigenomic analysis and expands the application of CLMs in single-cell research. Code is available at https://github.com/HIM-AIM/CLM-access

bioinformatics↗

bioRxiv2025

High-Speed AFM Reveals IDR-Mediated Structural Plasticity of EML4-ALK Modulated by ALK Inhibitors

EML4-ALK is a key oncogenic driver in lung cancer, but variant-specific chemoresistance limits the efficacy of current ALK inhibitors. Because the N-terminus contains an intrinsically disordered region (IDR), how ALK inhibitors affect the structure and dynamics of full-length EML4-ALK remains unclear. Here, using high-speed atomic force microscopy (HS-AFM), we visualize the overall structures of three full-length EML4-ALK variants (v1, v3, and v5) at the single-molecule level. We identified a transient globular subdomain (residues 191-217) within the v3 IDR that contributes to distinct oligomerization patterns. Notably, ALK inhibitors compact the IDR subdomain and reduce oligomerization, whereas this effect is abolished by the resistance mutation ALKG1202R, suggesting that ALK inhibitors not only affect kinase activity but also modulate IDR dynamics. Our findings shed new light on the structural regulation of EML4-ALK and provide a foundation for developing next-generation targeted therapies that account for IDR-driven molecular behavior. TeaserHigh-speed AFM revealed the full-length EML4-ALK structures and their IDR-mediated plasticity caused by ALK kinase inhibitors

cancer biology↗

bioRxiv2025

Targeting CyclinD1-CDK6 to Mitigate Senescence-Driven Inflammation and Age-Associated Functional Decline

Cellular senescence contributes to aging and age-related diseases by driving chronic inflammation through the Senescence Associated Secretory Phenotype (SASP) and interferon-stimulated genes (ISGs). Cyclin D1 (CCND1), a key cell cycle regulator, is paradoxically upregulated in these non-proliferating cells. We show that CCND1 and its kinase partner CDK6 drive SASP and ISG expression in senescent cells by promoting DNA damage accumulation. This leads to the formation of cytoplasmic chromatin fragments (CCFs) that activate pro-inflammatory CGAS-STING signaling. The tumor suppressor p53 (TP53) and its target p21 (CDKN2A) antagonize this CCND1-CDK6-dependent DNA damage accumulation pathway to suppress the SASP. In aged mouse livers, senescent hepatocytes show increased Ccnd1 expression. Hepatocyte-specific Ccnd1 knockout or treatment with the Cdk4/6 inhibitor Palbociclib reduces DNA damage and ISGs in aged mouse liver. Notably, Palbociclib also suppresses frailty and improves physical performance of aged mice. These findings reveal a novel role for CCND1/CDK6 in regulating DNA damage and inflammation in senescence and aging, highlighting it as a promising therapeutic target.

cell biology↗