Biology subjects

Tao, J.

Publications and source records attributed to Tao, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Deep-learning predictions of biomolecular structures : persistent limitations and new horizons extended by explicit ion addition

The advent of deep learning-driven tools such as AlphaFold has revolutionized the prediction of biomolecular structures, offering unprecedented accuracy and accessibility for proteins, RNA, and their complexes. While these tools have demonstrated remarkable success in benchmarking competitions and enabled experimentalists to generate models with ease, their widespread use has also highlighted persistent challenges. These include difficulties in assessing model confidence, limitations in predicting transmembrane domains, nucleic acids, conformational diversity, and interactions with ions or ligands, as well as the tendency to misfold intrinsically disordered regions (IDRs). In this perspective, we critically evaluate the strengths and limitations of current AI-based structure prediction tools through illustrative examples with a particular emphasis on the impact of explicit ion modelling. We notably report how the explicit addition of a few potassium cations to the prediction of IDRs or G-quadruplexes can trigger massive conformational switches compared to "dry" predictions. On this basis, we suggest modelling sequences both "dry" and in the presence of explicit potassium cations as a simple, practical way to sample alternative conformations and to expose disordered regions that current predictors tend to over-fold. We discuss the importance of reporting confidence metrics in publications to avoid overinterpretation. Furthermore, we address the unique challenges of RNA structure prediction, where data scarcity and structural complexity limit the performance of both classical and deep learning methods. Our analysis underscores the need for continued methodological advancements, integration of complementary computational tools, and expansion of high-quality experimental datasets. TOC Graphic O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=111 SRC="FIGDIR/small/740587v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@e950e9org.highwire.dtl.DTLVardef@1bf22b3org.highwire.dtl.DTLVardef@17f5229org.highwire.dtl.DTLVardef@1eb2e9f_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2026

M6A-modified circEZH2 Protects Endothelial Cells from Senescence and Suppresses Atherosclerosis by Stabilizing ZNF326

BACKGROUNDEndothelial cell senescence induces endothelial dysfunction, thereby contributing to atherosclerosis progression. Circular RNAs (circRNAs) play diverse roles in multiple physiological and pathological processes. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotic RNAs and dynamically regulates RNA fate and function. However, the functions and therapeutic potential of m6A-modified circRNAs in endothelial cell senescence remain unknown. METHODSm6A-modified circRNAs associated with endothelial cell senescence were screened by circRNA expression and m6A-circRNA microarray profiling of endothelial cells and mouse aortic intima. circEZH2 expression was validated in endothelial cells, vascular tissues, and human atherosclerotic plaques by RT-qPCR, and RNA fluorescence in situ hybridization. The role of circEZH2 in endothelial senescence and atherosclerosis was assessed in vitro and in vivo. RNA pull-down, mass spectrometry, RNA immunoprecipitation, co-immunoprecipitation, ubiquitination assays, and rescue experiments were used to define the underlying mechanism. RESULTSWe identified A novel m6A-modified circRNA, circEZH2, that was downregulated in the aged aortic intima and advanced plaques. CircEZH2 was stabilized by m6A reader IGF2BP2. Endothelial cell-specific overexpression of circEZH2 delayed senescence and suppressed atherosclerosis progression. At the cellular level, circEZH2 overexpression delayed senescence, decreased p53/p21 levels and increased angiogenic activity of endothelial cells, while circEZH2 knockdown exhibited the opposite effect. Mechanistically, circEZH2 functions as a scaffold to promote USP37-mediated deubiquitination, thereby stabilizing ZNF326. Moreover, endothelial cell-specific knockdown of ZNF326 counteracts the anti-senescent and anti-atherosclerotic effects mediated by circEZH2 overexpression. CONCLUSIONSIn summary, the present study identifies circEZH2 as a novel suppressor of endothelial cell senescence, highlighting its potential as a therapeutic target for age-related atherosclerosis. GRAPHIC ABSTRACTA graphic abstract is available for this article. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/730538v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@d3a586org.highwire.dtl.DTLVardef@1180c1forg.highwire.dtl.DTLVardef@1c3d832org.highwire.dtl.DTLVardef@a6d424_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic abstract.C_FLOATNO Schematic model of m6A-modified circEZH2 regulation in endothelial cell senescence and atherosclerosis. In young endothelial cells, IGF2BP2 is highly expressed and recognizes m6A-modified circEZH2, thereby maintaining its RNA stability. CircEZH2 stabilizes ZNF326 protein through USP37-mediated deubiquitination, which leads to suppression of p21 and p53, delays endothelial cell senescence, ameliorates endothelial dysfunction, and ultimately suppresses the progression of atherosclerosis. C_FIG What Are the Clinical Implications?This study identifies circEZH2 as a novel m6A-modified circular RNA that is reduced in the aged aortic intima and in endothelial cells within advanced atherosclerotic plaques. Endothelial circEZH2 overexpression delays endothelial cell senescence, preserves endothelial function, and suppresses atherosclerotic lesion formation, supporting an important role for circEZH2 in vascular aging-associated atherosclerosis. Mechanistically, circEZH2 acts as a scaffold to enhance USP37-mediated deubiquitination and stabilization of ZNF326, while endothelial ZNF326 knockdown counteracts the anti-senescent and anti-atherosclerotic effects of circEZH2. These findings reveal the circEZH2-ZNF326 axis as a previously unrecognized mechanism regulating endothelial senescence and atherosclerosis progression. Our work supports the potential of circEZH2-based gene therapy as a novel therapeutic approach for atherosclerosis.

cell biology↗

bioRxiv2026

The free-living wellspring of symbiotic nitrogen fixation in Bradyrhizobium

The evolutionary origin of nitrogen-fixing symbiosis has been a long-standing question. To address this, we focused on Bradyrhizobium, a globally abundant bacterial genus that includes classic symbiotic lineages, which rely on the common Nod factor signaling pathway to form nodules, and close relatives capable of fixing nitrogen in a free-living state. We isolated 88 strains carrying the key genes for nitrogen fixation (nif) from non-legume environments and analyzed them alongside 586 public Bradyrhizobium genomes harboring these genes to reconstruct a robust phylogeny of nif genes. Analysis reveals that the earliest-diverging nif lineages are members capable of free-living nitrogen fixation, establishing this as the ancestral state. The Nod factor-dependent symbiotic lineages are polyphyletic, demonstrating at least three independent origins via horizontal acquisition of symbiosis islands. This evolutionary history is reflected in a genomic dichotomy: lineages capable of free-living nitrogen fixation possess a conserved nif island architecture that consistently includes the oxygen-protective gene glbO, whereas the symbiotic nif-associated regions are highly variable and universally lack glbO. Using both loss-of-function and gain-of-function genetic approaches, we show that glbO contributes significantly to nitrogenase activity under free-living conditions, whereas it is dispensable within the protected nodule environment. This work establishes a new framework for the evolution of symbiosis, identifying free-living ancestors as the source from which nitrogen-fixing symbiosis repeatedly and independently evolved in Bradyrhizobium. SignificanceFor over a century, nitrogen-fixing bacteria called rhizobia have been celebrated for their symbiotic partnership with legumes like soybeans and peas. This study overturns the view that this symbiotic lifestyle was the original, advanced state. By discovering and analyzing diverse Bradyrhizobium bacteria from ordinary soils and non-legume plants, we show that the ancestor was capable of free-living nitrogen fixation. Root nodule nitrogen fixation evolved multiple independent times from free-living ancestors. We identify glbO, an oxygen-protective gene located immediately next to the nitrogen fixing genes, as critical for nitrogen fixation in variable soil conditions but dispensable and lost in Bradyrhizobium specialized inside nodules. This repositions free-living Bradyrhizobium as a major potential nitrogen source beyond legumes, with promise for sustainable agriculture.

microbiology↗

bioRxiv2026

A Computational Pipeline for Quantifying Kinetochore Morphological Changes in Live Cells

To segregate chromosomes kinetochores must resist yet deform under spindle forces. Measuring changes in kinetochore morphology can provide insight into kinetochore structure and function. This remains challenging in live cells because kinetochores are diffraction-limited with irregular, changing shapes. Here, we present a computational pipeline for quantifying kinetochore morphology in live cells, using mammalian cells with fluorescently tagged kinetochore proteins. First, the pipeline tracks, pairs and rotates kinetochores to align with their load-bearing axis. Second, it segments kinetochore signal from background, removing frames with overlapping neighboring kinetochore signals. Third, it provides metrics to define complex, non-Gaussian shape changes: (i) a non-parametric size metric that is more robust than the commonly used full-width-at-half-maximum (FWHM); (ii) analysis to classify common morphological patterns such as asymmetry, low intensity "tails" and multimodality; (iii) a 2D protein1-to-protein2 kinetochore vector as a reporter of structural rearrangements, if two kinetochore proteins were imaged. Finally, we validate the method using simulations, convolving ground-truth objects with the measured point spread function. Although kinetochore shape diversity makes assigning kinetochore size challenging, we show that our metrics better capture kinetochore size and shape changes than FWHM. Together, this pipeline provides a framework for analyzing complex kinetochore shape changes, with potential applications to other small and dynamic cellular structures.

cell biology↗

bioRxiv2026

REBEL, Reproducible Environment Builder for Explicit Library resolution

BackgroundAchieving FAIR-compliant computational research in bioinformatics is systematically undermined by two compounding challenges that existing tools leave unresolved: long-term reproducibility and accessibility. Standard package managers re-download dependencies from live repositories at every build, making environments vulnerable to library disappearance and version drift, and pinning a package version does not pin the versions of its transitive dependencies, causing divergences between builds performed at different points in time. Compounding this, packages from repositories such as CRAN, Bioconductor, and PyPI frequently omit critical system-level dependencies from their installation metadata, leaving users to manually discover which underlying library is missing or which version is required. Beyond these technical failures, constructing a truly reproducible environment demands expertise in containerization making reproducibility in practice a privilege and not a standard. FindingsWe present REBEL (Reproducible Environment Builder for Explicit Library Resolution), a framework that addresses both challenges through three dependency inference heuristics: (i) Deep Inspection of source code, (ii) Fuzzy Matching against a manually curated knowledge base, and (iii) Conservative Dependency Locking. The resolved dependency stack is then archived into a self-contained local store, enabling offline and deterministic rebuilds at any future time. We compared the installation of 1,000 randomly sampled CRAN packages in isolated Docker containers versus the standard package manager and REBEL resolved 149 of 328 standard installation failures (45.4%). Moreover through its DockerBuilder component, REBEL further generates fully reproducible Docker images from a plain text requirements file, making deterministic environment construction accessible without expertise in containerization. ConclusionsREBEL provides a practical foundation for FAIR-compliant, long-term reproducible bioinformatics analyses, making deterministic environment construction accessible to researchers regardless of their technical background. REBEL is freely available at https://github.com/Rebel-Project-Core

bioinformatics↗

bioRxiv2025

Mammalian metaphase kinetochores are elastic and require condensin for robust structure and function

SummaryTran et al. show that mammalian metaphase kinetochores undergo large-scale, complex, and elastic deformations under forces of different timescales, magnitudes and directions. They demonstrate that condensin is required for kinetochore local structural organization and microtubule attachment under force. AbstractThe mammalian kinetochore connects chromosomes to dynamic spindle microtubules. To remain attached, it must maintain its structural integrity under force, but to what extent and how it does so remain unclear. Under spindle forces, we find using super resolution microscopy that inner (CENP-A) and outer (Hec1) metaphase kinetochores undergo correlated, large-scale (1 {micro}m) deformations along the force axis, suggesting dynamic, relative sliding of parallel protein linkages. Kinetochore shape changes can be asymmetric, with centromere-facing "tails" correlating with erroneous attachment geometries. Applying microneedle pulling forces, we demonstrate that kinetochores are elastic, stretching under force and relaxing in seconds afterwards. Finally, we show that SMC2 depletion results in more variable kinetochore deformations, despite maintained elasticity, and in reduced microtubule attachment stability. Thus, the kinetochore is structurally highly dynamic and requires a stable centromere base to maintain its structure and function under force. We propose a model whereby individual protein linkages are stiff yet global kinetochore structure flexible to accommodate different attachment geometries and forces while maintaining function.

cell biology↗

bioRxiv2025

Rapid ecosystem collapse and biofilter formation following seabed methane leakage

Globally, vast amounts of methane are trapped within subseafloor gas hydrates. Recent evidence suggests that climate- and human-induced perturbations can destabilize gas hydrates and trigger methane release, yet the response of deep-sea ecosystems to these changes remains poorly understood. Here we show multi-year in situ monitoring of seabed ecosystem following methane leakage induced by hydrate exploration activities. Within just two years, benthic microbial and eukaryotic diversity in the affected areas declined significantly, while microbial and macrofaunal abundance increased. Integrated geochemical and omics analyses reveal the rapid successional shift of seabed ecosystem to a novel chemosynthetic system. Aerobic methanotrophs (Methyloprofundus) co-established with unexpectedly fast growing anaerobic methanotrophic archaea (ANME-3), accompanied by a rapid recruitment of opportunistic polychaetes that bioirrigated the seabed to >50 cm depths. The active animal-microbe interactions sustained exceptionally high rates of methane oxidation that utilized diverse electron acceptors. We demonstrate that methane hydrate destabilization can trigger rapid collapse of native seabed ecosystem while driving the formation of an effective methane biofilter consuming this potent greenhouse gas much faster than previously estimated. Understanding seabed ecosystem response and feedback is critical for predicting benthic methane cycling under ongoing global change and for developing sustainable strategies for methane hydrate resource management.

ecology↗

bioRxiv2025

An Integrated Single-Cell Atlas Reveals Hepatic Stellate Cell Heterogeneity and Spatiotemporal Dynamics after Liver Injury

BackgroundHepatic stellate cells (HSCs) orchestrate fibrosis-free repair after acute liver injury (ALI) and sustain fibrogenesis in chronic liver injury (CLI). However, the heterogeneity and spatiotemporal dynamics of HSCs across these different injury models remain elusive. This study sought to construct a cross-etiological HSC atlas to delineate HSC states and transitions during liver injury. MethodsWe integrated 86,072 single-cell transcriptomes from 84 mouse samples across four etiologies and validated findings using multi-omics data from 277 mouse and 798 human samples. Cellular dynamics were characterized through clustering, trajectory inference, spatial analysis, and multicellular coordination network analysis. Experimental validation included liver injury models and gain-of-functional assays in primary mouse HSCs and LX-2 cells. ResultsWe established a cross-etiological, spatiotemporally resolved HSC atlas comprising 11 subpopulations. Trajectory analysis delineated a continuous quiescence-activation-attenuation (QAA) trajectory, recapitulating the in vivo full spectrum of state transitions and being supported by sequential pathway activation validated in vitro. In ALI, HSCs spatiotemporally completed the QAA trajectory around injury zones, whereas collagen-producing S100a6 HSCs pathologically accumulated in mouse and human CLI due to trajectory dysregulation. Notably, the atlas identified a previously unrecognized apoptosis-prone Mrc2 HSC subtype strongly co-localized with p53 in both mice and humans. Overexpression of transcription factors confirmed that Hbp1, Tbx20, Atoh8, and Plagl1 enriched in Mrc2+ HSCs promoted HSC apoptosis. Finally, we revealed the microenvironment of distinct cellular modules which coordinated HSC progression along the QAA trajectory. A 531-gene signature derived from the inflammatory-fibrotic cellular module significantly correlated with fibrosis stage and hepatocellular carcinoma risk in human cohorts. ConclusionsWe established a comprehensive HSC atlas and delineates HSC heterogeneity and spatiotemporal dynamic across etiologies. Dysregulation of the QAA trajectory underlies fibrotic progression, providing a resource for identifying antifibrotic targets.

cell biology↗

bioRxiv2025

Diel rhythms shape viral community structure and activity across the host domains of life

Circadian rhythms, driven by endogenous clocks and synchronized with environmental cues, are fundamental to life on Earth. While extensively studied in diverse organisms, their influence on viral ecology remains largely unexplored. This study takes the temporal dynamics of viruses in Daya Bay as an example to uncover the rhythmic control of viral replication and activity. Using a high-resolution time-series dataset collected every 2 hours over a 3-day period, we identified a total of 22,151 viral operational taxonomic units (vOTUs) and 414 Nucleocytoplasmic Large DNA Virus (NCLDV) genomes. Our analysis revealed significant diel fluctuations, with 14.48% of vOTUs exhibiting diel patterns in metagenomic abundance and 1.97% showing diel transcriptional activity. We found that these abundant diel viruses infect hosts across the domains of life, including cyanobacteria, pelagibacteria, Marine Group II (MGII) archaea and protists, all known for their diel metabolism. The expanded spectrum of host diversity with diel viral interactions significantly broadens our understanding of virus-host rhythmic dynamics in natural environmental settings. A strong positive correlation was detected between the transcriptional activities of these diel viruses and their respective hosts. Contrary to bacteriophages, which mostly peaked during the day, we demonstrated that NCLDVs showed nocturnal diel abundance with a co-fluctuating diel transcriptomic activity pattern tightly hitched to their hosts, peaking at night and declining during the day. Furthermore, we identified a rich compendium of viral genes with significant diel expression patterns, including those related to structural protein production, DNA replication, and stress response. Notably, several essential viral genes involved in stress response and repair were found to be diel transcribed for the first time, including UV-endonuclease (UvdE), peroxidase, chaperones, and early light-induced protein (ELIP). Our findings suggest that viruses across host domains actively synchronize with environmental cues to optimize their replication and transmission, despite their dependence on host metabolism. This study provides novel insights into the rhythmic control of viral communities and their intricate interactions with hosts, with profound implications for microbial community succession and biogeochemical cycles.

ecology↗

bioRxiv2025

A hypothalamic circuit for anticipating future changes in energy balance.

AgRP neurons cause hunger, the drive to seek and consume food. Their activation by fasting is key for survival and is thought to be triggered by feedback when energy stores are low. However, we know that environmental cues can also regulate AgRP neurons, since cues that predict future food intake rapidly inhibit AgRP neurons. But is the converse true: can the prediction of future fasting rapidly activate AgRP neurons? Here we show that such rapid fasting activation of AgRP neurons does occur. This fasting response is driven by excitatory input from paraventricular hypothalamic neurons expressing Sim2, which are bidirectionally sensitive to predictions of future energy state. In this way, cognitively-processed contextual information conveyed by PVHSim2 neurons strongly activates AgRP neurons. Lastly, chronic silencing of PVHSim2 neurons causes persistent hypophagia. This PVHSim2 to AgRP neuron circuit, by anticipating and preventing negative energy balance, provides an important new dimension of hunger regulation.

neuroscience↗

bioRxiv2025

Riemann-GNN: Causal Reasoning on Hyperbolic Riemannian Manifolds for Interpretable Drug-Disease Prediction

The high cost and low success rate of de novo drug development have driven increasing interest in drug repurposing. Computational approaches to drug repurposing leverage large-scale biomedical knowledge graphs (KGs) to identify new indications for existing drugs. However, the structural heterogeneity, relation sparsity, and limited interpretability of current models remain significant challenges. In this study, we propose Riemann-GNN, an end-to-end framework that combines hyperbolic geometry, graph neural networks (GNNs), and causal inference for interpretable drug repurposing. Riemann-GNN embeds multi-relational biomedical KGs into a hyperbolic Riemannian manifold modeled by the Poincare ball, effectively capturing the hierarchical structure of biomedical entities. On top of this geometry, we introduce a causal reasoning module that extracts disease-centric subgraphs and applies intervention-based inference using structural causal models. This module provides mechanistic explanations for predicted drug-disease associations. We evaluate our model on PrimeKG, a comprehensive biomedical KG with over 129,000 nodes and 4 million edges, achieving AUROC = 0.971, AUPRC = 0.963, and Recall@20 = 0.847, significantly outperforming several state-of-the-art baselines. In a case study on amyotrophic lateral sclerosis (ALS), Riemann-GNN identifies 20 novel candidate drugs--such as Bosutinib, Masitinib, and Tamoxifen--and provides interpretable causal paths explaining their therapeutic relevance. Several predictions without existing ALS labels in the KG are supported by literature evidence, while others suggest new hypotheses for future validation. These results demonstrate the utility of integrating hyperbolic representation learning with causal semantics for robust and explainable biomedical AI.

bioinformatics↗

bioRxiv2025

Assessing plant phenological changes based on drivers of spring phenology

Understanding plant phenological responses to climate warming is crucial for predicting changes in plant communities and ecosystems but challenging when relying on sensitivity analysis that is not based on drivers of spring phenology. In this article, we present a new measure phenological lag to quantify the overall effect of phenological constraints including insufficient winter chilling, photoperiod, and environmental stresses, based on observed response and that expected from species-specific changes in spring temperatures, i.e., changes in spring forcing (degree days) from warming and average temperature at budburst with the warmer climate. We applied this new analytical framework to a global dataset with 980 species and 1527 responses to synthesize observed changes in spring budburst (leafing or flowering) and investigate the mechanisms of differential phenological responses reported previously. We found longer phenological lags with experimental studies and native plants in flowering, likely due to more stressful environments associated with warmer and drier climate. Less forcing changes were mainly responsible for the smaller responses in leafing and flowering in boreal region (compared to temperate region) and in grass leafing (compared to trees and shrubs). Higher budburst temperatures also contributed to the smaller responses in flowering for experimental studies and with herbs and grasses. The effects of altitude, latitude, MAT, and average spring temperature change were minor (all combined <2.5% variations), while those of photoperiod and long-term precipitation were not significant in influencing spring phenology. Our method helps to determine mechanisms responsible for changes in spring phenology and differences in plant phenological responses.

ecology↗

bioRxiv2025

A global P-Process map to avoid P-value abuse

P-abuse is serious in difference identification analysis of data. How to avoid P-abuse is a huge challenge. Here, we evolve P-value (a single value) to P-Process (a global landscape of P-values under different sample size) to help researchers correctly recognize and use p-value. We observed -ln(P-Process) after rotation has very similar morphology with Wiener Process (or Brownian motion). Based on this property, for any sample size, we estimated the 95% fluctuation range of P-value and further estimated how many samples (N95()) could make sure 95% of P-values less than the given significant level . Tests proved that the estimation obtains a good performance with only a small number of samples in each group. For broader accessibility, a free web-service, P-Process Map, is available online to show the whole landscape of P-Process. At the end of the article, we explained 10 of the most typical P-abuse problems which can be easily voided by using P-Process. This "rethinking" of P-value from a higher position, which is profoundly different from the way we have seen this for the past century, would yield a new era - 2P era in which hypothesis testing is strongly required to evolve from P-value to P-Process.

bioinformatics↗

bioRxiv2025

Functional and structural characterization of a combination of pan-sarbecovirus antibodies with potent antiviral activity

Sarbecoviruses, a subgenus of coronaviruses, include strains with zoonotic spillover risk as exemplified by recent outbreaks (SARS-CoV-1, SARS-CoV-2). Monoclonal antibodies targeting conserved spike protein regions (RBD class 4, S2 fusion machinery) exhibit broad sarbecovirus neutralization, but their utility has been impacted by immune selection leading to escape and suboptimal neutralization. Using structure-conditioned machine-learning protein design we optimized two broadly neutralizing sarbecovirus antibodies to rescue the activity of a class 4 anti-RBD antibody against Omicron variants and improve the neutralization profile of an anti-S2 stem antibody, resulting in the identification of the lead candidates PRO-37587 and GB-0669. Both antibodies displayed remarkable resilience to SARS-CoV-2 evolution. Structural analyses elucidated the mechanistic basis of their broad neutralization profiles. In combination, these antibodies exhibited improved SARS-CoV-2 neutralization in vitro and in vivo and a higher barrier to resistance. These findings support further evaluation of such antibody combination as countermeasure against current and emerging sarbecoviruses.

microbiology↗

bioRxiv2025

IQI: Individualized Quantitative trait loci (QTL) Index

There is currently no standard efficient method to precisely detecting and characterizing the difference of quantitative trait loci (QTL) effect among groups and/or populations at individual level. The main reason is that the traditional global regression based QTL analyses can only derive an overall effect of genetic variants on the quantitative trait in a specific group. It is a big challenge to obtain the individual-level QTL effect, which is necessary for accurate testing and precise characterization. Here, we first proposed an individualized QTL index (IQI) that represents the degree of regulation between genetic variants and the trait for each individual. Based on IQI, Differential QTL (DQ) analysis framework was presented to accurately detect the case-control differences in more detail. In addition, IQI can be a new feature/biomarker applied to various accurate bioinformatics analysis, such as differential analysis, disease prediction, and survival analysis. Overall, IQI affords a new perspective on pathogenic mechanisms and will facilitate the study of genetic regulation more detailedly and precisely.

bioinformatics↗

bioRxiv2025

Anxiety-like behavior during protracted morphine withdrawal is driven by gut microbial dysbiosis and attenuated with probiotic treatment

The development of anxiety during protracted opioid withdrawal heightens the risk of relapse into the cycle of addiction. Understanding the mechanisms driving anxiety during opioid withdrawal could facilitate the development of therapeutics to prevent negative affect and promote continued abstinence. Our lab has previously established the gut microbiome as a driver of various side effects of opioid use, including analgesic tolerance and somatic withdrawal symptoms. We therefore hypothesized that the gut microbiome contributes to the development of anxiety-like behavior during protracted opioid withdrawal. In this study, we first established a mouse model of protracted morphine withdrawal, characterized by anxiety-like behavior and gut microbial dysbiosis. Next, we used fecal microbiota transplantation (FMT) to show that gut dysbiosis alone is sufficient to induce anxiety-like behavior. We further demonstrate that probiotic therapy during morphine withdrawal attenuates the onset of anxiety-like behavior, highlighting its therapeutic potential. Lastly, we examined transcriptional changes in the amygdala of morphine-withdrawn mice treated with probiotics to explore mechanisms by which the gut-brain axis mediates anxiety-like behavior. Our results support the use of probiotics as a promising therapeutic strategy to prevent gut dysbiosis and associated anxiety during opioid withdrawal, with potential implications for improving treatment outcomes in opioid recovery programs.

neuroscience↗

bioRxiv2024

Aging drives a program of DNA methylation decay in plant organs

How organisms age is a question with broad implications for human health. In mammals, DNA methylation is a biomarker for biological age, which may predict age more accurately than date of birth. However, limitations in mammalian models make it difficult to identify mechanisms underpinning age-related DNA methylation changes. Here, we show that the short-lived model plant Arabidopsis thaliana exhibits a loss of epigenetic integrity during aging, causing heterochromatin DNA methylation decay and the expression of transposable elements. We show that the rate of epigenetic aging can be manipulated by extending or curtailing lifespan, and that shoot apical meristems are protected from this aging process. We demonstrate that a program of transcriptional repression suppresses DNA methylation maintenance pathways during aging, and that mutants of this mechanism display a complete absence of epigenetic decay. This presents a new paradigm in which a gene regulatory program sets the rate of epigenomic information loss during aging.

plant biology↗

bioRxiv2024

Spatiotemporal transcriptomic maps of mouse intracerebral hemorrhage at single-cell resolution

Intracerebral hemorrhage (ICH) is a severe and widespread disease that results in high mortality and morbidity. Despite significant advances made in clinical and preclinical research, the prognosis of ICH remains poor due to an incomplete understanding of the complex pathological responses. To address this challenge, we generated single-cell resolution spatiotemporal transcriptomic maps of mouse brain 1, 3, 7, 14, and 28 days after ICH. Our analysis revealed the cellular constituents and their dynamic responses following ICH. We found changes in gene expression that are indicative of active phagocytosis and lipid processing in the lesion core and identified genes associated with brain repair at the lesion border. Persistent lipid accumulation culminated in the phenotypic transition of macrophages into foam cells. Furthermore, our results demonstrate that ICH could stimulate neural stem cells in the subventricular zone, thereby enhancing neurogenesis in this niche. This study provides a spatiotemporal molecular atlas of mouse ICH that advances the understanding of both local and global responses of brain cells to ICH and offers a valuable resource that can aid the development of novel therapies for this devastating condition.

neuroscience↗