Biology subjects

Cui, X.

Publications and source records attributed to Cui, X..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

The emerging contaminant Cl-PFESA/F-53B is toxic to meiotic cell division and reproduction in Arabidopsis thaliana

The emerging contaminant Cl-PFESA/F-53B damages vegetative development in plants and has been evidenced to be toxic to both mitotic and meiotic cells in animals. We have recently reported that F-53B induces nuclei unviability in meristematic cells leading to disrupted root development in Arabidopsis (Arabidopsis thaliana). However, the toxicity of F-53B to reproductive system in plants remains unelucidated. In this study, by using cytogenetic and microscopic approaches, we analyzed embryo and anther development and multiple meiosis processes in Arabidopsis exposed to 50 or 100 M F-53B. We showed that F-53B disrupts embryo development which results in reduced seed setting in Arabidopsis. Histochemical staining of anthers and a live-imaging assay using a reporter line that expresses GFP-tagged Aborted Microspores (AMS), a key regulator of the tapetum, demonstrated that F-53B impairs anther development. Moreover, we showed that F-53B interferes with chromosome segregation and/or distribution and alters microtubule organization during male meiosis. Quantification of the chiasmata and immunolocalization of the Human Enhancer of Invasion 10 (HEI10) protein on diakinesis chromosomes suggested that F-53B reduces crossover rate. Furthermore, F-53B reduced the number of DNA Meiotic Recombinase 1 (DMC1) protein foci on zygotene chromosomes in Arabidopsis wild-type Columbia-0 (Col-0), and it partially promoted meiotic chromosome integrity in Arabidopsis depleted with Ataxia Telangiectasia Mutated (ATM), a central regulator of DNA double-strand break (DSB) repair, which suggested that F-53B reduces meiotic DSB formation. Taken together, our study reveals the toxicity of F-53B to meiotic cells and reproduction in Arabidopsis, which highlights its potential threats to agricultural safety and ecological diversity. HighlightO_LIF-53B impairs embryo and anther development in Arabidopsis. C_LIO_LIF-53B interferes with chromosome segregation and distribution during male meiosis. C_LIO_LIF-53B interferes with meiotic microtubule organization. C_LIO_LIF-53B reduces meiotic crossover formation. C_LIO_LIF-53B reduces DNA double-strand breaks in meiocytes. C_LI

plant biology↗

bioRxiv2025

High-accuracy structure modeling for antibody-antigen complexes

Accurate modeling of antibody-antigen complexes is crucial for advancing therapeutics and diagnostics, yet predicting their binding interface remains a formidable challenge. To address this, we introduce DeepAAAssembly, a protocol that enhances static structural information from AlphaFold3 by integrating dynamic interaction patterns to guide complex assembly. Our approach leverages predicted inter-chain residue distances to construct a flexibility-aware energy function, which drives a two-stage conformational sampling process for global exploration and local exploitation. On a benchmark set of 67 representative antibody-antigen complexes, by incorporating a built-in confidence selection mechanism, DeepAAAssembly outperforms AlphaFold3, achieving not only a 12.9% higher average DockQ score and more medium- and high-quality models, but also reliably elevating the most challenging cases from incorrect to acceptable accuracy. These results demonstrate that DeepAAAssembly effectively captures conserved interaction motifs and conformational flexibility, offering a robust framework for high-accuracy antibody-antigen modeling.

bioinformatics↗

bioRxiv2025

M-DeepAssembly2: A Web Server for Predicting Multiple Conformations of Multi-domain Proteins Using Deep Learning

The biological functions of proteins often depend on dynamic transitions between multiple conformational states, and for multi-domain proteins, inter-domain dynamics play a critical role in their biological functions. Despite significant advances in static structure prediction, accurately modeling these multiple conformations remains a major challenge. Here, we present M-DeepAssembly2, a web server designed for modeling multiple conformations of multi-domain proteins using deep learning-predicted inter-domain and intra-domain constraints. The server operates in three stages. Firstly, evolutionary, physicochemical, and geometric features are extracted from the input and fed into AlphaFlex, a flexible residue prediction network. This process generates multiple distance maps that effectively capture both inter-domain and intra-domain interactions. Secondly, supplementary distance maps that characterize inter-domain interactions are generated using the DeepAssembly method. Finally, all distance maps are integrated as constraints in a multi-objective protein optimization to generate multiple conformational states of the protein. Compared to its predecessor, M-DeepAssembly2 leverages a flexible residue prediction network that directionally decouples coevolutionary information to generate heterogeneous distance maps. Benchmark results demonstrate that this strategy enables accurate prediction of protein multiple conformations and significantly improves the precision of static multi-domain protein structure prediction.

bioinformatics↗

bioRxiv2025

ProSiteHunter: A unified framework for sequence-based prediction of protein-nucleic acid and protein-protein binding sites

Accurate prediction of protein binding sites is essential for elucidating protein function, understanding molecular interaction mechanisms, and facilitating drug design. However, existing sequence-based approaches are often designed for specific binding-site types and therefore lack generality, whereas structure-based methods typically rely on high-quality structural models, limiting their applicability. Here, we introduce ProSiteHunter, a unified sequence-based framework for protein binding-site prediction, which integrates a fine-tuned protein language model (SiteT5) with a multi-source feature-fusion network that incorporates evolutionary, geometric, and statistical features, while employing bidirectional semantics, local associations, and global dependencies for comprehensive binding-site characterization. The method was systematically evaluated on diverse binding sites prediction tasks, where ProSiteHunter achieved a 39.1% average improvement in PRAUC for protein-DNA/RNA/protein tasks and a 7.4% PRAUC enhancement on the particularly challenging antibody-antigen task over state-of-the-art methods. Moreover, ProSiteHunter is capable of identifying local flexible sites that complement AlphaFold3 predictions and improving the accuracy of antibody-antigen interaction prediction. These results highlight ProSiteHunter as an efficient and unified approach for accurate and robust prediction of diverse protein binding sites.

bioinformatics↗

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

Adipose Tissue Overexpression of Nicotinamide Phosphoribosyltransferase Prevents Metabolic Dysfunction in Obese Mice

Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme and a central factor in energy metabolism. Nicotinamide phosphoribosyltransferase (NAMPT) maintains the cellular NAD+ pool by synthesizing the NAD+ precursor, nicotinamide mononucleotide (NMN), and diminished adipocyte NAMPT activity has been implicated in aging- and obesity-related metabolic dysfunction. Herein, we examined the effects of overexpressing or knocking out NAMPT in adipocytes on metabolic dysfunction and interorgan communication in mice. We generated new adipocyte-specific NAMPT overexpressing(ANOV) mice model. Male ANOV mice are protected from diet-induced metabolic dysfunction including adipose tissue inflammation, glucose intolerance, and insulin resistance. In contrast female ANOV mice were less protected from metabolic dysfunction, possibly due to higher endogenous expression of NAMPT in WT female mice. Livers of ANOV mice showed improved insulin signaling, increased NAD content, and reduced steatosis, suggesting that NAMPT regulates interorgan communication between adipocytes and hepatocytes. Extracellular vesicles (EV) isolated from ANOV mice enhanced insulin signaling in HepG2 cells and improved glucose tolerance in WT obese mice. In contrast, EV from ANKO mice suppressed HepG2 insulin signaling and inhibition of EV release improved glucose tolerance in ANKO female mice. Collectively, these data highlight a novel mechanism by which adipocyte NAD+ metabolism regulates systemic metabolic dysfunction via EVs.

physiology↗

bioRxiv2025

Lzp Ablation Ameliorates Dyslipidemia and Suppresses Atherosclerosis by Reducing Circulating Apolipoprotein B-Containing Lipoproteins

As the principal regulator of systemic lipid homeostasis, the liver uniquely orchestrates dietary lipid assimilation, de novo lipogenesis, very-low-density lipoprotein (VLDL) assembly and secretion, and clearance of atherogenic lipoprotein remnants. This central role positions liver-specific molecular targets as critical therapeutic nodes for mitigating hyperlipidemia and halting atherosclerosis progression. The liver-specific protein Lzp (also named as OIT3), previously shown to stabilize apolipoprotein B (ApoB), the core structural component of triglyceride-rich lipoproteins, has an undefined role in vascular disease pathogenesis. Here, utilizing ApoE-/-mice, a well-established model that closely mimics human atherosclerosis, we demonstrate that Lzp deletion reduces plasma cholesterol, triglycerides, and ApoB levels under both chow and Western diets, concomitant with a marked attenuation of aortic plaque burden. Additionally, Lzp deficiency reduces hepatic and circulating ApoB levels in hyperlipidemic ApoE-/- mice, without exacerbating hepatic steatosis or injury. Mechanistically, Lzp ablation is anticipated to impair hepatic VLDL-ApoB secretion based on our previous findings, resulting in reduced circulating VLDL, intermediate density lipoprotein (IDL) and low-density lipoprotein (LDL) particles, attenuated lipid deposition, and suppressed macrophage-driven plaque inflammation. These results underscore the role of Lzp as a key regulator of systemic lipid metabolism and identify it as a potential candidate for further investigation toward therapeutic intervention of atherosclerotic cardiovascular disease. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/678175v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@118ead8org.highwire.dtl.DTLVardef@e215baorg.highwire.dtl.DTLVardef@1007212org.highwire.dtl.DTLVardef@412757_HPS_FORMAT_FIGEXP M_FIG C_FIG HightlightsO_LILzp deficiency attenuates atherosclerosis and improves plasma lipid profiles in ApoE-/- mice fed chow or Western diets. C_LIO_LILzp deficiency reduces hepatic and circulating apolipoprotein B levels in hyperlipidemic ApoE-/- mice without exacerbating hepatic steatosis or injury. C_LIO_LILzp represents a candidate therapeutic target, warranting further mechanistic and translational studies for atherosclerosis. C_LI

pathology↗

bioRxiv2025

Unpredictable circadian rhythm disruption in Wistar rats: biological and behavioural changes reflecting bipolar disorder pathophysiology

Circadian disturbances are implicated in dysregulation of arousal and general neurobiological function, contributing to conditions such as bipolar disorder (BD). However, the behavioural and biological consequences of circadian disruption on arousal dysfunction remain poorly quantified. Here, we developed a novel unpredictable circadian disruption (UCD) protocol - consisting of unpredictable exposure to light and sound - to investigate its impact on locomotor activity and its association with metabolic, inflammatory, stress, and circadian markers in the nucleus accumbens (NAc). Forty-eight Wistar rats were exposed to UCD or control conditions, with or without corticosterone administration, for five weeks. Body weight was tracked throughout the study. Locomotor activity was assessed over the final two weeks (nine sessions) in an open-field arena. Real-time PCR was used to quantify NAc gene expression of inflammatory, metabolic, stress, and circadian markers, while liquid chromatography-mass spectrometry (LC-MS) measured neurotransmitter and central carbon metabolite concentrations. UCD animals exhibited initial hyperactivity at three weeks, followed by hypoactivity at four weeks. UCD was associated with increased NAc expression of inflammatory, stress, and circadian markers. Male UCD animals showed significant weight gain, an effect reversed in females. UCD also induced increases in NAc insulin resistance markers and reductions in central carbon metabolites, indicating disrupted striatal glucose metabolism. These findings highlight the central effects of circadian disruption on locomotor behaviour, stress, and immunometabolic signalling, offering mechanistic insights into arousal dysfunction in BD. HighlightsO_LIUnpredictable circadian disruption (UCD) triggers a biphasic shift in locomotor behaviour C_LIO_LIUCD alters levels of striatal inflammatory, circadian, stress, and metabolic markers C_LIO_LIUCD has sex-specific effects on behaviour, weight, and molecular biomarkers C_LIO_LICorticosterone administration mitigates key molecular disruptions induced by UCD C_LI

neuroscience↗

bioRxiv2025

Human-scATAC-Corpus: a comprehensive database of scATAC-seq data

Single-cell Assay for Transposase-Accessible Chromatin using sequencing (scATAC-seq) profiles chromatin accessibility at cellular resolution, making it possible to reveal epigenomic landscapes that govern gene regulation in a variety of cells. Nevertheless, heterogeneous feature spaces and complex processing pipelines have impeded the construction of an ensemble resource capable of supporting diverse downstream analytical scenarios. To address this gap, we present Human-scATAC-Corpus (https://health.tsinghua.edu.cn/human-scatac-corpus/), a comprehensive database of human scATAC-seq comprising 5,407,621 cells from 35 datasets across 37 tissues or cell lines. To support complementary use cases, each dataset is distributed in three aligned formats: cell-by-candidate cis-regulatory element matrices for cross-dataset integration, raw fragment files for flexible processing, and cell-by-peak matrices for within-dataset analyses. This resource spans diverse biological contexts and includes rich metadata, enabling method benchmarking and development, as well as pretraining of foundation models. The website offers searchable browsing, detailed dataset pages, on-demand downloads, and tutorials. EpiAgent, a foundation model pretrained on Human-scATAC-Corpus, is further integrated to provide online analyses, including reference mapping, embedding extraction, and cell type annotation. Human-scATAC-Corpus establishes a unified and scalable substrate for single-cell epigenomics and is intended to accelerate discovery while standardizing evaluation across tasks. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=79 SRC="FIGDIR/small/674505v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@e2c4c3org.highwire.dtl.DTLVardef@1e3eaf8org.highwire.dtl.DTLVardef@5768c1org.highwire.dtl.DTLVardef@9e96ad_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

bioRxiv2025

Melatonin mitigates oxidative stress and metabolic dysfunction induced by interleukin-6 and dopamine in SH-SY5Y cells

Melatonin has emerged as a promising pharmacological candidate for bipolar disorder (BD), though its mechanisms of action remain incompletely understood. Its antioxidant, anti-inflammatory, and anti-dopaminergic properties suggest potential relevance to BD pathophysiology. This study investigated melatonins effects on dopamine signalling, metabolism, and oxidative stress under inflammatory and hyperdopaminergic conditions in differentiated SH-SY5Y neuronal cells. Cells were pretreated with 100nM melatonin or vehicle for 2 hours, then exposed to vehicle, IL-6 (20ng/mL), dopamine (5{micro}M or 500{micro}M), or dopamine (500{micro}M) with ascorbic acid (1mM) for 12 or 24 hours. Dopaminergic markers were assessed via real-time PCR and HPLC; metabolic outcomes were measured using Seahorse assay, central carbon metabolomics, in-cell Western assay, and glucose uptake assay; and oxidative stress was evaluated via reactive oxygen species (ROS), superoxide (SOX), and total antioxidant capacity (TAC) assays. IL-6 increased dopamine levels, p-Erk1/2/Erk1/2, p-AMPK/AMPK, nucleotide pools, and TAC, while reducing dopamine turnover, SV2C expression, and spare respiratory capacity. Melatonin alone increased nucleotides and NADH, while reducing dopamine turnover, ROS, and glucose-1-phosphate. In IL-6 conditions, melatonin pretreatment enhanced spare respiratory capacity, glucose uptake, and NADH, while reducing dopamine, TAC, p-AMPK/AMPK, p-GSK3{beta}/GSK3{beta}, and non-mitochondrial oxygen consumption. High-dose dopamine (500{micro}M) elevated SOX, p-Erk1/2/Erk1/2, insulin receptor-, GLUT1, glycolytic ATP (glycoATP), and non-mitochondrial oxygen consumption. Melatonin pretreatment attenuated p-Erk1/2/Erk1/2 and GLUT1 elevations. Combined dopamine and ascorbic acid further increased glycolytic intermediates, ROS, p-AMPK/AMPK, and TAC, while reducing p-Erk1/2/Erk1/2, p-mTOR, GLUT1, glucose uptake, and glycoATP. Overall, melatonin mitigated IL-6-induced dopaminergic, oxidative, and metabolic alterations, and partially protected against dopamine-induced metabolic shifts. These findings suggest melatonin may alleviate manic symptoms in BD via both direct dopaminergic modulation and indirect antioxidant and metabolic regulatory effects.

molecular biology↗

bioRxiv2025

RNA helicase Ddx21 safeguards fetal HSPC expansion by recruiting Kdm5a to epigenetically sustain ribosomal and hematopoietic gene transcription

Fetal hematopoietic stem and progenitor cells (HSPCs) require active ribosome biogenesis to sustain their rapid proliferation, yet how non-structural ribosomal factors regulate this process remains unclear. Here, we identify the RNA helicase Ddx21 as a critical determinant of fetal hematopoiesis through its epigenetic role in maintaining active ribosomal transcription. Conditional knockout of Ddx21 in murine fetal hematopoietic cells resulted in severe anemia, fetal liver hypoplasia, and depletion of HSPCs, accompanied by erythroid maturation arrest. Mechanistically, Ddx21 deficiency disrupted ribosomal and hematopoietic gene expressions, impaired translational capacity, and activated p53 pathway, triggering cell cycle arrest and apoptosis. While p53 inhibition partially rescued proliferation defects, it failed to restore rRNA transcription, pointing to p53-independent mechanisms. Multi-omics profiling revealed that Ddx21 interacts with the histone demethylase Kdm5a, co-occupying active promoters marked by H3K4me3. Loss of Ddx21 diminished H3K4me3 levels at ribosomal DNA (rDNA) and hematopoietic genes such as cKit and Gata1, downregulating their transcription. Strikingly, Kdm5a inhibition restored rRNA expression and protein translation in Ddx21-deficient cells, and combined inhibition of Kdm5a and p53 cooperatively rescued HSPC function. These findings demonstrate a paradigm wherein Ddx21 couples ribosome biogenesis to epigenetic regulation by sequestering Kdm5a at active chromatin, thereby preserving transcriptional output essential for fetal hematopoietic expansion.

cell biology↗

bioRxiv2025

Long-read sequencing of single cell-derived melanoma subclones reveals divergent and parallel genomic and epigenomic evolutionary trajectories

Tumor evolution is driven by various mutational processes, ranging from single-nucleotide vari- ants (SNVs) to large structural variants (SVs) to dynamic shifts in DNA methylation. Current short-read sequencing methods struggle to accurately capture the full spectrum of these genomic and epigenomic alter- ations due to inherent technical limitations. To overcome that, here we introduce an approach for long-read sequencing of single-cell derived subclones, and use it to profile 23 subclones of a mouse melanoma cell line, characterized with distinct growth phenotypes and treatment responses. We develop a computational frame- work for harmonization and joint analysis of different variant types in the evolutionary context. Uniquely, our framework enables detection of recurrent amplifications of putative driver genes, generated by indepen- dent SVs across different lineages, suggesting parallel evolution. In addition, our approach revealed gradual and lineage-specific methylation changes associated with aggressive clonal phenotypes. We also show our set of phylogeny-constrained variant calls along with openly released sequencing data can be a valuable resource for the development of new computational methods.

genomics↗

bioRxiv2025

An activated wheat CCG10-NLR immune receptor forms an octameric resistosome

Nucleotide-binding and leucine-rich repeat (LRR) receptors (NLRs) are widespread intracellular immune sensors across kingdoms. In plants, the G10-type coiled-coil (CCG10)-NLRs form a distinct phylogenetic clade that remains poorly characterized. Here, we identified a gain-of-function (GOF) mutant of Wheat Autoimmunity 3 (WAI3), designated WAI3GOF, which encodes a constitutively activated CCG10-NLR protein due to an amino acid substitution. Cryo-EM structural analysis revealed that activated WAI3 assembles into a distinctive octameric resistosome. Arabidopsis RPS2, another CCG10-NLR, also forms an octamer, indicating a conserved structural property across monocot and dicot plants. The WAI3 resistosome mediates a prolonged and sustained increase in cytosolic calcium influx, facilitated by a unique channel architecture arising from its divergent CC domain configuration. Notably, this domain arrangement may be shared by many plant NLRs that lack the conserved EDVID motif in their CC domains. Our findings uncover a previously uncharacterized resistosome structure and provide insights into plant immune receptor plasticity.

plant biology↗

bioRxiv2025

Production of unreduced microspores in Arabidopsis flowers cultivated in culture medium suggests a role of sucrose in facilitating meiotic cytokinesis

Live-imaging microscopy technology has been increasingly applied for meiosis study in plants, which largely relies on the set up of a healthy ex vivo culture system for inflorescences ensuring that the captured chromosomes dynamics approaches the natural features of meiosis. Here, we report that Arabidopsis thaliana flowers cultivated in a culture medium (CCM) composed of the half-strength Murashige and Skoog basal salt, MES, Myo-inositol, sucrose and agar produce diploid microspores due to occurrence of meiotic restitution. Cytological studies revealed adjacent nuclei distribution and incomplete cytokinesis at late meiosis II in meiocytes within the CCM flowers. Immunolocalization of -tubulin and the microtubule-associated protein MAP65-3 showed that the orientation of spindles at metaphase II and the organization of radial microtubule arrays at the tetrad stage are interfered, which explains the production of meiotically-restituted microspores. Moreover, the CCM flowers showed a gradually impaired expression of Aborted Microspores (AMS), a key transcription factor regulating tapetum development and meiotic cytokinesis. Interestingly, an increased supply of sucrose in culture medium promoted the expression of AMS and partially rescued haploid microspore formation in the CCM flowers. Taken together, this study suggests a role of sucrose in facilitating meiotic cytokinesis and gametophytic ploidy stability in plants. One-sentence summaryArabidopsis flowers cultivated in culture medium produce unreduced microspores due to interfered meiotic cytokinesis, which is partially rescued by increased sucrose supply.

plant biology↗

bioRxiv2025

Dorsal Attention Network as a Convergent Hub of Diverse Non-pharmacological Interventions Preserving Functional Gradients and Cognition in Aging

Non-pharmacological interventions (NPIs) in aging neuroscience have largely focused on intervention-specific regional effects, with limited understanding of generalizable network-level mechanisms. Here, adopting a previously unexplored gradient-based perspective of functional brain organization, we analyzed an NPI dataset involving four interventions in older adults (training/control group: n = 112/59). NPIs led to strengthened intra-network functional integration and maintained macroscale gradient architecture. Virtual lesion analyses identified the dorsal attention network (DAN) as a key contributor to gradient maintenance. Critically, enhanced post-intervention DAN connectivity was associated with maintained gradient structure and improved global cognition. These findings establish a unifying framework in which the DAN acts as a convergent hub through which diverse NPIs preserve functional brain organization and attenuate cognitive aging.

neuroscience↗

bioRxiv2025

Overcoming breeding constraints in polyploid oat from evolutionary insights

Polyploidy provides adaptive advantages in plants by buffering deleterious mutations1,2. While polyploidization can enhance agronomic traits such as increased biomass, known as the gigas effect1-4, increasing genetic gain in polyploid crops remains a critical but difficult goal due to the difficulty in dissecting complex trait inheritance5,6. Here we present chromosome-scale genome assemblies for 26 Avena taxa, spanning diploid, tetraploid, and hexaploid lineages. We traced four independent polyploidization events across the genus, including the formation of A. agadiriana as an allotetraploid (AgAgAg'Ag'), and revealed a reticulate evolutionary history shaped by gene flow involving four subgenomes (A, B, C, D), for example, the hybrid speciation of A. hirtula. Transcriptomic analysis of 286 samples across 11 tissues, combined with deleterious mutation analysis from a cultivated population of 112 accessions, showed that polyploidization led to widespread functional redundancy among homoeologs, supporting a genome-wide buffering effect. However, derived allele frequency analysis revealed that, while disrupting functional genes may yield desirable traits, the buffering effect impedes the fixation of beneficial loss-of-function mutations and thereby limits breeding efficiency. Based on these integrative analyses, we propose breeding strategies to circumvent these limitations by targeting beneficial loss-of-function alleles within the complex polyploid background of oat. Our study highlights broader challenges in the improvement of polyploid crops and provides a foundation for future breeding strategies.

evolutionary biology↗

bioRxiv2025

AlphaFlex: Accuracy modeling of protein multiple conformations via predicted flexible residues

Understanding protein conformational dynamics is critical for elucidating disease mechanisms and facilitating structure-based drug design. While AlphaFold2-based methods have advanced static structure prediction, modeling multiple conformation states with both accuracy and efficiency remains challenging. We present AlphaFlex, an innovative framework that integrates flexible residue prediction with a directed masking strategy for multiple sequence alignments. By selectively relaxing co-evolutionary constraints in dynamic regions, AlphaFlex enables accurate prediction of biologically relevant states while preserving structural fidelity. Benchmarking on 69 apo-holo pairs from the CoDNaS dataset, including enzymes, binding proteins, and chaperones, reveals AlphaFlexs superior performance in both flexible residue identification and multiple conformation prediction. Comparative analysis against AF-Cluster, AF2-conformations, and AlphaFlow demonstrates AlphaFlexs significant advantage, achieving the highest success rate (42%) in accurately predicting apo/holo structures (TM-score >0.95 for both states) while consistently outperforming these methods in reproducing both apo and holo conformations. Notably, AlphaFlex maintains robust performance for membrane proteins, resolving inward- and outward-facing conformations with equal fidelity. Case studies further reveal its unique ability to sample physically plausible intermediate states along transition pathways. These results establish AlphaFlex as a pivotal computational tool for mapping protein conformational landscapes, with promising potential to accelerate structure-based therapeutic development.

bioinformatics↗

bioRxiv2025

Vector semantics of multidomain protein architectures

Multidomain proteins are mosaics of domains, protein modules that are associated with a specific structure or function and are found in diverse combinations. This modular organization facilitates the evolution of novel protein functions, but the principles that govern the relationship between the domain content of a protein and its function is poorly understood. In particular, do domains always contribute the same function, or does the functional contribution of a domain depend on the neighboring domains in the protein? To answer this question, we used vector embeddings, which account for local contextual signals, to model the protein domain content of multidomain proteins. We observe that multidomain architectures that are semantically similar share more functional attributes than multidomain architectures selected based on domain content similarity, alone, suggesting that context is important for understanding the relationship between domain content and protein function. Surprisingly, vector semantics also identified multidomain architecture pairs with significantly high functional similarity, despite having no domains in common at all, suggesting that vector semantics may be discovering domain "synonyms". Taken together, our results underscore the importance of contextual models for understanding the interplay between domain architecture evolution and functional innovation in multidomain proteins.

evolutionary biology↗