Biology subjects

Yang, Y.

Publications and source records attributed to Yang, Y..

At least 451 records · Page 25Linked to original sources

bioRxiv2025

Midkine Attenuates Aβ Fibril Assembly and Amyloid Plaque Formation

Proteomic profiling of Alzheimers disease (AD) brains has identified numerous understudied proteins, including midkine (MDK), that are highly upregulated and correlated with A{beta} since the early disease stage, but their roles in disease progression are not fully understood. Here we present that MDK attenuates A{beta} assembly and influences amyloid formation in the 5xFAD amyloidosis mouse model. MDK protein mitigates fibril formation of both A{beta}40 and A{beta}42 peptides in Thioflavin T fluorescence assay, circular dichroism, negative stain electron microscopy, and NMR analysis. Knockout of Mdk gene in 5xFAD increases amyloid formation and microglial activation. Further comprehensive mass spectrometry-based profiling of whole proteome and detergent-insoluble proteome in these mouse models indicates significant accumulation of A{beta} and A{beta}-correlated proteins, along with microglial components. Thus, our structural and mouse model studies reveal a protective role of MDK in counteracting amyloid pathology in Alzheimers disease.

biochemistry↗

bioRxiv2025

Restoration of tumor suppressor protein with enhanced activity using engineered tRNAs to induce tumor regression

Cancer develops through a gradual accumulation of mutations including nonsense mutations in tumor suppressor genes (TSGs), which drive tumor proliferation and progression due to the impairment or complete loss of tumor suppressor protein function. The ability to restore functional tumor suppressor protein from mutant driver TSGs is a longstanding aspiration in cancer therapy, however, current strategies face formidable challenges in recovering proteins harboring heterogeneous mutations and circumventing dominant-negative effects exerted by endogenous mutant proteins. Therefore, the development of therapeutic interventions that are effective and generalizable across diverse nonsense mutations in cancer, to rescue endogenous mutant tumor suppressor proteins remains an urgent yet unmet need. Here we find that engineered suppressor transfer RNA (sup-tRNA) could overcome nonsense mutations in key driver tumor suppressor genes, such as TP53, thereby avoiding the dominant-negative effects through the restoration of endogenous mutant p53 with its original functions. Optimized sup-tRNA that we named super tRNA, enabling high-fidelity incorporation of desired amino acids, can further enhanced the transcriptional activity of p53 to suppress tumor cell proliferation. Moreover, we also establish a computational model to guide super tRNAs design, and demonstrate that super tRNA could effectively inhibit tumor growth by targeted readthrough of nonsense mutations in different tumor suppressor genes. In two xenograft models harboring nonsense mutant TP53, we observed up to a 70% reduction in tumor volume after lipid nanoparticle (LNP)-based sup-tRNA treatment, along with robust recovery of p53 expression and function, and no hematological or histological abnormalities detected. Our findings demonstrate the potential of sup-tRNA as a feasible and effective strategy to rescue and enhance tumor suppressor protein function, thereby preventing cancer development. As a novel therapeutic RNA, sup-tRNA provides a flexible strategy for targeting driver mutations in cancer, thereby expanding the potential of tRNA-based therapy in precision oncology.

bioengineering↗

bioRxiv2025

Hi-C for genome-wide detection of enhancer-hijacking rearrangements in routine lymphoid cancer biopsies

Standard techniques for detecting genomic rearrangements in formalin-fixed paraffin-embedded (FFPE) biopsies have important limitations. We performed FFPE-compatible Hi-C on 44 clinical biopsies comprising large B-cell lymphomas (n=18), plasma cell neoplasms (n=14), and other diverse lymphoid cancers, identifying consistent topological differences between malignant B cell and plasma cell states. Hi-C detected expected oncogene rearrangements at high concordance with fluorescence in-situ hybridization (FISH) and supported enhancer-hijacking in recurrent rearrangements of BCL2, CCND1, and MYC, plus unanticipated variants involving homologous loci. Hi-C identified unanticipated non-coding rearrangements involving PD-1 ligand genes and other loci of potential therapeutic relevance, distinguished between functionally divergent classes of BCL6 rearrangements, and provided topological information supporting the interpretation of atypical MYC rearrangements. In biopsies lacking MYC-activating rearrangements, Hi-C revealed differential interactions with functionally-validated disease-specific native MYC locus enhancers. FFPE-compatible Hi-C detects oncogene rearrangements and their topological consequences at genome-wide scale, finding clinically-relevant drivers that are missed by standard approaches.

genomics↗

bioRxiv2025

Regulation of alternative polyadenylation events by PABPC1 affects erythroid progenitor cell expansion

Erythropoiesis is precisely regulated by multilayer networks and is crucial for maintaining steady-state hemoglobin levels and ensuring effective oxygen transport. Alternative polyadenylation (APA) is a post-transcriptional regulatory mechanism that generates multiple mRNA isoforms from a single gene, based on specific 3-untranslated region sequences. While APA plays a vital role in various cellular processes, its mechanism in erythropoiesis remains unexplored. Here, we employed an integrative approach combining bioinformatics and experimental validation to systematically analyze APAs role in erythropoiesis. We mapped the APA landscape during erythroid differentiation, discovering notable APA shifts crucial for the maturation from burst-forming unit erythroid to colony-forming unit erythroid. Notably, our findings highlighted PABPC1 as the primary APA regulator of these stages. Functional investigations revealed that knocking down PABPC1 disrupts erythroid progenitor cell proliferation and differentiation, implicating the proteins essential role in modulating cell fate through APA regulation. We further identified that decreased PABPC1 levels led to the increased usage of the proximal polyA site of TSC22D1 and gene overexpression, revealing a novel mechanism through which APA affects erythroid progenitor expansion and differentiation. These insights uncover a novel dimension of APA regulation in early erythropoiesis, providing new strategies for the treatment of diseases associated with erythropoiesis disorders.

developmental biology↗

bioRxiv2025

Leveraging mRNA platform for the development of vaccines against egg allergy

Food allergy has posed a major global health burden due to the rising prevalence and lack of effective prophylactic strategies. During the past decades, allergen-specific immunotherapy (AIT) has been used as a disease-modifying therapy for food allergic conditions, but due to the long-term treatment duration, poor patient compliance and unexpected adverse reactions, only a minority of patients benefit from AIT therapy. In this proof-of-concept study, using well-established mRNA platform, we developed mRNA vaccine candidates encoding for the major egg white allergen Gal d2 (also known as ovalbumin) and comprehensively evaluated the prophylactic efficacy against anaphylaxis in a Gal d2-induced allergic mouse model. Two vaccine formulations, Gal d2 mRNA vaccine and Gal d2-IL-10 mRNA vaccine, both demonstrated effective ability in preventing the onset of allergic disease, which is largely attributed to the versatilities of mRNA vaccine in eliciting allergen-blocking antibody, shifting Th2 towards Th1 immunity, as well as in generating peripheral tolerance.

immunology↗

bioRxiv2025

STIM1 and Endoplasmic Reticulum-Plasma Membrane Contact Sites Oscillate Independently of Calcium-Induced Calcium Release

Calcium (Ca{superscript 2}) release from intracellular stores, Ca{superscript 2} entry across the plasma membrane, and their coordination via store-operated Ca{superscript 2} entry (SOCE) are critical for receptor-activated Ca{superscript 2} oscillations. However, the precise mechanism of Ca{superscript 2} oscillations and whether their control loop resides at the plasma membrane or intracellularly remain unresolved. By examining the dynamics of stromal interaction molecule 1 (STIM1)--an endoplasmic reticulum (ER)-localized Ca{superscript 2} sensor that activates the Orai1 channel on the plasma membrane for SOCE--and in mast cells, we found that a significant proportion of cells exhibited STIM1 oscillations with the same periodicity as Ca{superscript 2} oscillations. These cortical oscillations, occurring in the cells cortical region and shared with ER-plasma membrane (ER-PM) contact sites proteins, were only detectable using total internal reflection fluorescence microscopy (TIRFM). Notably, STIM1 oscillations could occur independently of Ca{superscript 2} oscillations. Simultaneous imaging of cytoplasmic Ca{superscript 2} and ER Ca{superscript 2} with SEPIA-ER revealed that receptor activation does not deplete ER Ca{superscript 2}, whereas receptor activation without extracellular Ca{superscript 2} influx induces cyclic ER Ca{superscript 2} depletion. However, under such nonphysiological conditions, cyclic ER Ca{superscript 2} oscillations lead to sustained STIM1 recruitment, indicating that oscillatory Ca{superscript 2} release is neither necessary nor sufficient for STIM1 oscillations. Using optogenetic tools to manipulate ER-PM contact site dynamics, we found that persistent ER-PM contact sites reduced the amplitude of Ca{superscript 2} oscillations without alteration of oscillation frequency. Together, these findings suggest an active cortical mechanism governs the rapid dissociation of ER-PM contact sites, thereby control amplitude of oscillatory Ca{superscript 2} dynamics during receptor-induced Ca{superscript 2} oscillations.

cell biology↗

bioRxiv2025

A parsimonious model for learning order relations provides a principled explanation of diverse experimental data

Brains are able to extract diverse relations between objects or concepts, and to integrate relational information into cognitive maps that form a basis for decision making. But is has remained a mystery how relational information is learnt and represented by neural networks of the brain. We show that a simple synaptic plasticity rule enables neurons to absorb and represent relational information, and to use it for abstract inference. This inherent capability of neurons and synaptic plasticity is supported by a rigorous mathematical theory. It explains experimental data from the human brain on the emergence of cognitive maps after learning several linear orders, it explains the terminal item effect that enhances transitive inference if a terminal item of an order is involved, and it provides a simple model for fast configuration of internal order representations in the face of new evidence. We also present a rigorous theoretical explanation for the surprising fact that 2D projections of neural representations of linear orders are curved, rather than linear. Since our model does not require stochastic gradient descent in deep neural networks for learning order relations, it is suited for porting the capability to learn multiple relations and using them for fast inference into edge devices with a low energy budget.

neuroscience↗

bioRxiv2025

Galectin-3 deletion modulates microglial phenotype and Aβ response via TREM2 activation while attenuating neuroinflammation

Neuroinflammation is a hallmark of Alzheimers disease (AD), yet the molecular mediators driving microglial dysfunction and neurotoxicity remain poorly understood. Here, we identify Galectin-3 (Gal3) as a central regulator of plaque-associated microglial responses, linking amyloid-beta (A{beta}) aggregation, lysosomal function and plaque-associated neuritic damage. Using postmortem brain tissue from AD patients, we demonstrated that Gal3 microglia are selectively enriched around highly immunogenic dense-core plaques, and correlate with increased LAMP1+ dystrophic neurites. Notably, Gal3 was also detected in extra-microglial dystrophic structures and in close association with extracellular amyloid fibrils, suggesting a role in both intracellular and extracellular A{beta} dynamics. In APP mice, Gal3 deficiency resulted in more compact plaques, reduced neuronal dystrophies and increased TREM2 expression around amyloid plaques, suggesting altered plaque-associated microglial responses. Mechanistically, in vitro studies revealed that Gal3 modulates A{beta} uptake and its intracellular processing while lysosomal stress conditions showed increased A{beta} fibrillation from monomeric species in Gal3-deficient microglia. In parallel, cell-free assays demonstrated that Gal3 directly interacts with A{beta} and selectively inhibits secondary nucleation, thereby stabilizing intermediate assemblies associated with increased neurotoxic potential. Finally, in silico and transcriptomic analysis revealed that Gal3 interacts with key immune receptor patterns, having leucine-rich repeats as well as immunoglobulin-like domains. Moreover, Gal3 favors pro-inflammatory microglial programs, while its deletion suppresses type I interferon and microglial neurodegenerative (MGnD) signatures. Together, these findings position Gal3 as a central regulator of amyloid aggregation, lysosomal dysfunction, and microglial activation, driving a neurotoxic phase of AD and highlighting a potential therapeutic window for intervention. Significance StatementNeuroinflammation and amyloid-beta (A{beta}) plaques drive Alzheimers disease progression, but the molecular bridges between plaque formation, microglial dysfunction, and neurodegeneration remain unclear. This study identifies Galectin-3 (Gal3) as a pivotal regulator at this interface. We demonstrate that Gal3 is enriched around amyloid dense-core plaques in human brains and directly shapes A{beta} aggregation into highly neurotoxic intermediate structures. Genetic deletion of Gal3 in Alzheimers mouse models reduces nerve cell damage and change microglial cells toward a protective, less inflammatory state. By linking extracellular protein aggregation with intracellular lysosomal stress and inflammatory gene expression, these findings establish Gal3 as a major driver of Alzheimers neurotoxicity and highlight it as a promising therapeutic target

neuroscience↗

bioRxiv2025

Programmable macromolecule delivery via engineered trogocytosis

Trogocytosis, the transfer of plasma membrane fragments during cell-cell contact, offers potential for macromolecular delivery but is limited by uncertain fate of trogocytosed molecules, constraints to membrane cargo, and unclear generalizability. Here, we demonstrate that donor cells engineered with designed receptors specific to intrinsic ligands can transfer proteins to recipient cells through direct contact. We identified key principles for enhancing contact-mediated transfer and subsequent functionalization of transferred macromolecules, including receptor design, pH-responsive membrane fusion, inducible cargo localization, release, and subcellular translocation. Exploiting these findings, we developed TRANSFER, a versatile delivery system that integrates logic gate-based control to sense multiple ligand inputs and deliver diverse functional cargos for genome editing and targeted cell ablation across cell types. The study establishes trogocytosis as a novel, programmable framework for cell-based macromolecular delivery.

bioengineering↗

bioRxiv2025

AGP-Net: A Universal Network for Gene Expression Prediction of Spatial Transcriptomics

In the era of high-throughput biology, molecular phenotypes have proven effective in predicting disease states and future trajectories. Transcriptomics, in particular, has enabled the dissection of complex diseases with heterogeneous genetic and environmental aetiology, both aiding diagnosis and augmenting treatment. As improving technology has led to measurements of gene expression at increasing granularity, it has become progressively feasible to resolve disease traits that present locally or with spatial heterogeneity. Principal among these are cancers in which tumour gene expression, while itself heterogenous, exhibits a distinct signature from that of the surrounding tissue. Identifying this signature through molecular phenotyping facilitates specific cancer diagnosis and treatment. Here, we introduce AGP-Net, a multi-modal foundation framework capable of predicting gene expression from histopathology images. Rather than produce an aggregated estimate of expression for each gene, AGP-Net disaggregates images into spots and attempts to resolve the variation in gene expression across them, thereby providing coarse spatial transcriptomic predictions across the tumour slice and surrounding region. The challenge in doing so is due to data sparsity relative to the dimensionality of the problem: the number of genes and their contextual heterogeneity within and between tissue and cancer types makes it difficult to train a model on the limited data available. The innovation of AGP-Net lies in borrowing strength across similar genes as defined by their textual language descriptions. Our AGP-Net supports datasets with varying gene coverage and facilitates the prediction of gene expression for previously unseen genes based on their textual descriptions. Trained on millions of spots from diverse dataset sources, AGP-Net establishes state-of-the-art performance in zero-shot spatial gene expression prediction, demonstrating its adaptability to generalize across novel scenarios.

pathology↗

bioRxiv2025

Molecular and biological characterization of a distinct species of Lolavirus infecting different accessions of seashore paspalum, a turfgrass, widely grown in the United States

Seashore paspalum (Paspalum sp.), is an economically significant grass used in golf courses, sports fields, and landscaping in the United States. A novel Lolavirus, tentatively named paspalum latent virus (PaLV), was identified for the first time in seashore paspalum plants from the USDA National Plant Germplasm System (NPGS) using high-throughput sequencing. Three complete genome sequences of PaLV from different Paspalum accessions, with a length of 6,995 nucleotides (nt), not including the poly(A) tail, were obtained by Rapid Amplification of cDNA Ends and Sanger sequencing. Phylogenetic analysis based on the replicase protein sequences from the Alphaflexiviridae family revealed that PaLV grouped with the Lolavirus genus, with the closest relative being Lolium latent virus (LoLV). PaLV shares less than 72% nt identity to the replicase and coat protein genes of LoLV, which demarks PaLV as a new species and the second member of the genus. Furthermore, the coat protein region showed intense negative selection pressure and low spatially structured diversity. Host range analysis of PaLV showed that wheat, corn, sorghum, and Lolium are systemic hosts of PaLV. A one-step RT-PCR technique was developed to reliably detect PaLV infection.

pathology↗

bioRxiv2025

Uncovering the Genetic Basis of Heterodichogamy in Pterocarya and Cyclocarya Using a Low-Input Pan-Genomic Approach

The heterodichogamous mating system, characterized by two distinct mating types (protogyny and protandry), is rare among flowering plants, but it is present in nearly all species in Juglandaceae (the walnut family). Recent studies have identified distinct structural variations underlying heterodichogamy in Juglans and Carya. To verify the independent origins of this trait in Juglandaceae and investigate whether structural variations also drive heterodichogamy in Juglans closely related genera, we explored its genetic basis in Pterocarya and Cyclocarya. Using a pan-genome graph approach, we identified a structural variation region associated with mating types across the Pterocarya genus. This region includes 30 kb tandem repeats in the dominant allele and an insertion in the recessive allele, with shared polymorphisms spanning 78 kb from the 3'UTR of S12e, covering a FAF-like gene, to a Gypsy transposable element. Downstream analyses suggest that the specific expression of FAF-like gene and small RNAs uniquely expressed from the tandem repeats of dominant allele regulate heterodichogamy. Further investigation in Cyclocarya identified nine candidate loci associated with heterodichogamy, which are non-homologous regions with those found in Pterocarya, Juglans, and Carya. These findings provide novel evidence for the multiple independent originations of convergent genetic basis in regulating heterodichogamy in Juglandaceae and highlight the utility of pan-genome approaches in deciphering structural variation-associated traits.

evolutionary biology↗

bioRxiv2025

Transcriptomic splicing analysis reveals a gene-independent form of TE reactivation in tumors representing unrecognized source of oncogenes and neoantigens

Transposable elements (TEs) are reactivated in tumors and serve as significant contributors to tumor transcriptomic complexity and heterogeneity. However, their repetitive nature and diverse transcriptional forms have hindered efforts to characterize TE-derived transcripts independent of host gene contexts. Here, using our self-developed splicing-junction analysis tool ASJA, we systematically interrogated TE transcription across 32 cancer types, identifying transcripts autonomously initiated from and exclusively spliced among TEs with high TE content, termed TEtrans. Our analysis revealed 5,361 TEtrans exhibiting pan-cancer prevalence, tumor-specific expression and features of mature transcripts, including canonical splicing, 5 caps and polyA tails. Mostly unannotated and enriched in intergenic regions, TEtrans are predominantly derived from primate-specific classes with conserved splice pattern. TEtrans burden demonstrates heterogeneous associations with prognosis and immune activity across cancers, while their expression can be epigenetically dual-regulated by stemness- and inflammation-associated transcription factors. Functional studies uncovered that TEtrans could act as oncogenes, exemplified by tsTE1, a HERVH-derived transcript that promotes colorectal cancer proliferation by enhancing TOP1-mediated DNA supercoil relaxation. Remarkably, [~]7.2% of TEtrans are identified to encode tumor neoantigens, including viral proteins and unannotated peptides, which are shared among patients and validated by proteogenomic analysis. These TEtrans-derived neoantigens are immunogenic both in vitro and in vivo, and exceed neoepitopes from genomic alterations in abundance per tumor, particularly in cancers with low mutational burden. Collectively, as a gene-independent form of TE-derived transcripts, TEtrans represents a unique source of oncogenes and tumor neoantigens, expanding the functional repertoire of TEs in cancer biology and offering new avenues for therapeutic targeting. HighlightsO_LITEtrans are tumor-specific transcripts with conserved splicing patterns, predominantly derived from primate TEs in intergenic regions. C_LIO_LITEtrans expression is epigenetically activated and dually regulated by stemness/inflammation transcription factors. C_LIO_LITEtrans function as oncogenes, exemplified by tsTE1 enhancing TOP1-mediated DNA relaxation. C_LIO_LITEtrans encode tumor neoantigens that elicit CD8+ T cell responses, providing targets for immunotherapy, especially in low-mutation tumors. C_LI Abstract figure O_FIG O_LINKSMALLFIG WIDTH=198 HEIGHT=200 SRC="FIGDIR/small/640928v1_ufig1.gif" ALT="Figure 1"> View larger version (78K): org.highwire.dtl.DTLVardef@1d2d4cforg.highwire.dtl.DTLVardef@918f14org.highwire.dtl.DTLVardef@489465org.highwire.dtl.DTLVardef@1069d17_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Restoration of excitation/inhibition balance enhances neuronal signal-to-noise ratio and rescues social deficits in autism-associated Scn2a-deficiency

Social behavior is critical for survival and adaptation, which is profoundly disrupted in autism spectrum disorders (ASD). Social withdrawal due to information overload was often described in ASD, and it was suspected that increased basal noise, i.e., excessive background neuronal activities in the brain could be a disease mechanism. However, experimental test of this hypothesis is limited. Loss-of-function mutations (deficiency) in SCN2A, which encodes the voltage-gated sodium channel NaV1.2, have been revealed as a leading monogenic cause of profound ASD. Here, we revealed that Scn2a deficiency results in robust and multifaceted social impairments in mice. Scn2a-deficient neurons displayed an increased excitation-inhibition (E/I) ratio, contributing to elevated basal neuronal noise and diminished signal-to-noise ratio (SNR) during social interactions. Notably, the restoration of Scn2a expression in adulthood is able to rescue both SNR and social deficits. By balancing the E/I ratio and reducing basal neuronal firing, an FDA-approved GABAA receptor-positive allosteric modulator improves sociability in Scn2a-deficient mice and normalizes neuronal activities in translationally relevant human brain organoids carrying autism-associated SCN2A nonsense mutation. Collectively, our findings revealed a critical role of the NaV1.2 channel in the regulation of social behaviors, and identified molecular, cellular, and circuitry mechanisms underlying SCN2A-associated disorders. HIGHLIGHTSO_LINaV1.2 deficiency leads to pronounced social deficits in mice. C_LIO_LINaV1.2 deficiency results in an overall enhanced E/I ratio, elevated basal neuronal activity, and impaired signal-to-noise ratio. C_LIO_LIBoth the enhanced E/I ratio and impaired sociability are reversible through the restoration of NaV1.2 expression in adulthood. C_LIO_LITargeted restoration of NaV1.2 in striatum-projecting neurons rescues social impairments. C_LIO_LIGABA transmission is reduced in both mouse and human organoid models of SCN2A deficiency, and acute systemic administration of GABAA receptor-positive allosteric modulators restores sociability. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/641498v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@154a323org.highwire.dtl.DTLVardef@1a27fbaorg.highwire.dtl.DTLVardef@16fa3beorg.highwire.dtl.DTLVardef@6712c2_HPS_FORMAT_FIGEXP M_FIG C_FIG Graphical abstract: Severe Scn2a deficiency leads to a predominate decrease in GABA transmission with an overall enhanced E/I ratio, elevated basal neuronal activity, impaired SNR, and social deficits in adult NaV1.2-deficient mice.

neuroscience↗

bioRxiv2025

DeepSeMS: a large language model reveals hidden biosynthetic potential of the global ocean microbiome

Microbial biosynthetic diversity holds immense potential for discovering natural products with therapeutic applications, yet a substantial quantity of natural products derived from uncultivated microorganisms remains uncharacterized. The intricate nature of biosynthetic enzymes poses a major challenge in accurately predicting the chemical structures of secondary metabolites solely based on genome sequences using current rule-based methods. Here, we present DeepSeMS, a large language model designed to predict the chemical structures of secondary metabolites from various microbial biosynthetic gene clusters. Built on the Transformer architecture, DeepSeMS innovatively identifies sequence features using functional domains of biosynthetic enzymes, and incorporates feature-aligned chemical structure enumeration for training data augmentation. External evaluation results show that DeepSeMS predicts more accurate chemical structures of secondary metabolites with a Tanimoto coefficient up to 0.6 compared with the ground truth, significantly outperforming antiSMASH and PRISM with coefficients of only 0.14 and 0.45 respectively. Moreover, DeepSeMS successfully predicted secondary metabolites for 96.60% of cryptic biosynthetic gene clusters, surpassing existing methods with success rates less than 50%. Leveraging DeepSeMS, we characterized over 65,000 novel secondary metabolites from the global ocean microbiome with previously undocumented structural types, ecological distribution, and biomedical applications especially antibiotics. A login-free and user-friendly web server for DeepSeMS (https://biochemai.cstspace.cn/deepsems/) has been launched, featuring an integrated global ocean microbial secondary metabolites repository to expedite the discovery of novel natural products. Collectively, this study underscores the great capacity of a large language model-driven method in revealing hidden biosynthetic potential of the global ocean microbiome.

synthetic biology↗

bioRxiv2025

Enhancing plant broad-spectrum resistance through engineered pattern recognition receptors

Conventional plant resistance breeding has primarily focused on intracellular immune receptors, while cell-surface pattern recognition receptors (PRRs) have been underexplored due to their comparatively modest contributions to resistance. However, PRRs offer significant untapped potential for crop improvement. In this study, we demonstrate that the Arabidopsis receptor-like protein RLP23, which recognizes molecular patterns from three distinct microbial kingdoms, confers broad-spectrum resistance when introduced into the Solanaceae crop tomato. We also identify the intracellular (IC) domain of RLP23 as crucial for ensuring compatibility and efficacy during heterologous expression. Targeted engineering of the IC domain significantly enhances RLP23 potential utility, enabling transfer of robust resistance against bacterial, fungal, and oomycete pathogens to other plants without compromising yield. We extended this RLP engineering strategy to rice and poplar, highlighting its broad applicability. These findings establish a versatile framework for PRR-based engineering, opening new avenues for sustainable crop protection.

plant biology↗

bioRxiv2025

SCOIGET: Predicting Spatial Tumor Evolution Pattern by Inferring Spatial Copy Number Variation Distributions

Constructing a comprehensive spatiotemporal map of tumor heterogeneity is essential for understanding tumor evolution, with copy number variation (CNV) as a significant feature. Existing studies often rely on tools originally developed for single-cell data, which fail to utilize spatial information. Our study aims to develop a model that fully leverages spatial omics data to elucidate spatio-temporal changes in tumor evolution. Here, we introduce SCOIGET (Spatial COpy number Inference by Graph on Evolution of Tumor), a novel framework using graph neural networks with graph attention layers to learn spatial neighborhood features of gene expression and infer copy number variations. This approach integrates spatial multi-omics features to create a comprehensive spatial map of tumor heterogeneity. Notably, SCOIGET achieves a substantial reduction in error metrics (e.g., mean squared error, cosine similarity, and distance measures) and produces superior clustering performance as indicated by higher Silhouette Scores compared to existing methods. Our model significantly enhances the efficiency and accuracy of tumor evolution depiction, capturing detailed spatial and temporal changes within the tumor microenvironment. It is versatile and applicable to various downstream tasks, demonstrating strong generalizability across different spatial omics technologies and cancer types. This robust performance improves research efficiency and provides valuable insights into tumor progression. In conclusion, SCOIGET offers an innovative solution by integrating multiple features and advanced algorithms, providing a detailed and accurate representation of tumor heterogeneity and evolution, aiding in the development of personalized cancer treatment strategies. Key PointsO_ST_ABS1. Innovative Framework for Spatially Contextualized CNV InferenceC_ST_ABSIntroduces SCOIGET, a graph-based model that integrates spatial omics data with graph neural networks and attention mechanisms to accurately infer spatial copy number features. 2. Detailed Tumor Heterogeneity MappingConstructs representations of tumor evolution, capturing heterogeneity and clonal dynamics at both cellular and subcellular resolutions. 3. Versatile and Robust PerformanceOutperforms existing methods across multiple datasets, demonstrating reliability and adaptability to diverse spatial omics platforms and cancer types. 4. Broad Downstream ApplicationsEnables tasks such as tumor subclone identification, clustering, and evolutionary trajectory analysis, facilitating precision oncology strategies.

bioinformatics↗

bioRxiv2025

A piece of evidence for pathogenesis of cerebral small vessel disease caused by blood-brain barrier dysfunction

BackgroundBlood-brain barrier (BBB) dysfunction caused by endothelial cell injury is one of the widely accepted pathogenesis of small cerebral vessel disease (CSVD). However, the early microcirculation studies were notably deficient in providing compelling imaging evidence, which has hampered a comprehensive understanding of the pathophysiological processes underlying BBB dysfunction in CSVD. The onset of CSVD is insidious and the clinical manifestations are diverse, diagnosis of CSVD relies primarily on neuroimaging information currently. These MRI imaging features mainly represent the end-stage brain parenchyma injury, rather than the vascular lesion itself. Therefore, clarifying the pathophysiological processes related to cerebral microcirculation in CSVD is of great significance for early treatment intervention of CSVD. MethodsTwenty rats were used to prepare CSVD animal model by ultrasound combined with ultrasonic microbubble contrast agent. MRI, functional ultrasound (fUS) imaging and ultrasound localization microscopy (ULM) were used to evaluate microcirculation changes in acute and chronic models. ResultsCurrently, our research has successfully validated that the imaging characteristics of this model align with the four established criteria outlined in the STRIVE-2 classification. FUS shows increased microflow velocity in the molding area, which can be used for initial evaluation of CSVD models in the acute phase. ULM has revealed a progressive reduction in the density of both the short cortical arteries and the long medullary arteries, along with their respective branches, over time. Concurrently, there has been a noted deviation in blood flow velocity. ConclusionThis model offers compelling evidence at the microvascular level, suggesting that blood-brain barrier (BBB) dysfunction is a central pathophysiological mechanism in the etiology of CSVD. Then it provides a straightforward, efficient, and widely applicable tool and continuous monitoring method for the further investigation of CSVD from the macroscopic to the microscopic circulation level, with significant long-term implications for CSVD diagnosis and treatment.

neuroscience↗