Biology subjects

Yu, S.

Publications and source records attributed to Yu, S..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

FGF21 signals through KLB-expressing glutamatergic neurons in the hindbrain to mediate the effects of dietary protein restriction

Animals adaptively respond to protein restriction by altering both behavior and metabolism. Previous work demonstrated that the metabolic hormone FGF21 acted in the brain to coordinate these adaptive responses, but the exact site of action remains unclear. Here, we identify a discrete population of glutamatergic, Klb-expressing neurons in the nucleus of the solitary tract (NTS), demonstrating that these neurons are key to mediating FGF21 action during protein restriction. Using a novel Klb-Flp mouse line combined with intersectional genetics, we demonstrate that these neurons are directly activated by FGF21. While previous work implicated the SCN, PVN, and VMH in FGF21 action, we find that these areas do not impact the response to protein restriction. Instead, selective ablation of NTS-KLB neurons prevents metabolic adaptations to protein restriction (food intake, food choice, and energy expenditure), while their chemogenetic activation is sufficient to drive these responses. These findings establish NTS-KLB neurons as a critical node for detecting protein status and coordinating whole-body metabolic responses, providing new insight into how the brain monitors and maintains protein homeostasis.

neuroscience↗

bioRxiv2025

Advanced coarse-grained model for fast simulation of nascent polypeptide chain dynamics within the ribosome

The nascent polypeptide exit tunnel (NPET) is a sub-compartment of the ribosome that constrains the dynamics of nascent polypeptide chains during protein translation. Simulating these dynamics has been limited due by the spatial scale of the ribosome and the temporal scale of elongation. Here, we present an automated pipeline to extract the geometry of the NPET and the ribosome surface at high resolution from any ribosome structure. We further convert this into a coarse-grained (CG) bead model that can be used in molecular simulations. This CG model more accurately captures NPET geometry than previous representations and allows for the simulation of co- and post-translational processes that are computationally prohibitive with all-atom approaches. In particular, we illustrate how the CG model may be used to simulate the elongation dynamics of the nascent polypeptide and its escape post-translation, as well as evaluate free energy landscapes and examine the influence of electrostatics on the nascent polypeptide escape. SIGNIFICANCEThe translation of nascent polypeptide chains is mediated by the ribosome, with interactions between the protein and the nascent polypeptide exit tunnel (NPET) impacting the process. However, modeling and simulating protein elongation and its escape from the NPET remain challenging due to computational limitations in spatial and temporal resolution. Here, we develop a computational pipeline for generating coarse-grained (CG) models of the NPET and ribosome surface from any ribosome structure that allow for both effective and accurate computer simulations. We demonstrate how the model can be implemented for various simulations, including the elongation dynamics of the nascent polypeptide and escape of the chain post-translation, as well as in estimating free energy landscapes and examining the impact of the charged environment on the escape time.

biophysics↗

bioRxiv2025

Multiple evolutionary events in host plant adaptation in Lepidoptera

The evolution of insect host adaptation is a key component of insect-plant coevolution, a complex process often shaped by multiple evolutionary events. In this study, we identified two UDP-glycosyltransferase (UGT) genes, SfruUGT33T10 and SfruUGT33F32, in the fall armyworm Spodoptera frugiperda, which play critical roles in the tolerance of benzoxazinoids (BXs), secondary metabolites in maize. These two detoxification enzymes exhibited distinct glycosylation patterns for BXs and varying detoxification efficiencies, reflecting independent evolutionary trajectories. Phylogenetic analyses revealed that SfruUGT33T10 originated independently within Noctuidae, while SfruUGT33F32 resulted from tandem duplication within the UGT33F gene family and may have undergone neofunctionalization within the Spodoptera genus. Our findings provide evidence that the evolution of these two UGT paralogs contributed to the variation in the tolerance to maize BXs among different Lepidopteran species. This research underscores the significance of multiple independent evolutionary routes in host plant adaptation and offer new insights into the complex evolutionary processes underlying insect-plant interactions.

evolutionary biology↗

bioRxiv2025

Detection of archaeal- and prokaryotic-like ribosome exit tunnels within eukaryotic kingdoms

The ribosome exit tunnel is a critical sub-compartment that actively regulates the folding and dynamics of nascent polypeptide chains during protein translation. In this study, we systematically examined tunnel structures of 725 ribosome models obtained through cryo-EM and X-ray crystallography, to quantify structural variations across different species and biological domains. Hierarchical clustering revealed significant geometric differences between prokaryotic and eukaryotic ribosomes, with a surprising discovery: six eukaryotic protist species display tunnel structures remarkably similar to those of archaea and bacteria. By analyzing the sequences and structures of ribosomal components forming the tunnel walls, we identified four specific sequence modifications in ribosomal proteins and ribosomal RNAs (rRNA) responsible for these unique geometric variations, and detected these modifications in additional protist species lacking existing 3D structural data. Overall, our findings highlights some complex evolutionary mechanisms governing ribosomal protein and large subunit rRNA, providing novel insights into the tunnels regulatory role in protein translation.

molecular biology↗

bioRxiv2025

Beyond Pairwise Connections in Complex Systems: Insights into the Human Multiscale Psychotic Brain

Complex biological systems, like the brain, exhibit intricate multiway and multiscale interactions that drive emergent behaviors. In psychiatry, neural processes extend beyond pairwise connectivity, involving higher-order interactions critical for understanding mental disorders. Conventional brain network studies focus on pairwise links, offering insights into basic connectivity but failing to capture the complexity of neural dysfunction in psychiatric conditions. This study aims to bridge this gap by applying a matrix-based entropy functional to estimate total correlation, a mathematical framework that incorporates multivariate information measures extending beyond pairwise interactions. We apply this framework to fMRI-ICA-derived multiscale brain networks, enabling the investigation of interactions beyond pairwise relationships in the human multiscale brain. Additionally, this approach holds promise for psychiatric studies, providing a new lens through which to explore beyond pairwise brain network interactions. By examining both triple interactions and the latent factors underlying the triadic relationships among intrinsic brain connectivity networks through tensor decomposition, our study presents a novel approach to understanding higher-order brain dynamics. This framework not only enhances our understanding of complex brain functions but also offers new opportunities for investigating pathophysiology, potentially informing more targeted diagnostic and therapeutic strategies. Moreover, the methodology of analyzing multiway interactions beyond pairwise connections can be applied to any signal analysis. In this study, we specifically explore its application to neural signals, demonstrating its power in uncovering complex multiway interaction patterns of brain activity, which provide a window to explore connectivity beyond pairwise interactions in the multiscale functionality of the brain.

neuroscience↗

bioRxiv2025

Production of Fc-fused receptor agonists for glucagon-like peptide-1/glucose-dependent insulinotropic polypeptide (GLP-1/GIP) in the milk of transgenic mice

Incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), play pivotal roles in glucose homeostasis and metabolic regulation. Therapeutic incretin receptor agonists (RAs), such as tirzepatide, are widely used to manage type 2 diabetes and obesity. However, incretin RAs are facing production challenges at present. Therefore, we engineered transgenic (tg) mice to secrete incretin RAs in milk, leveraging mammary gland bioreactors for cost-effective peptide production. The goat beta-casein promoter-driven constructs encoding tirzepatide-derived peptide linked to human IgG4 Fc via a (GGGGS)3 spacer were used to produce tg mice. Founders tg-1 and tg-5 exhibited mammary-specific expression, yielding 0.8-1.42 g/L recombinant protein exclusively in milk. Progeny nursed by founders showed sustained hypoglycemia (10-39% reduction; p < 0.05) and marked weight loss (14-49%; p < 0.01) compared to wild-type controls, validating the bioactivity of milk-derived GLP-1/GIP RAs. Moreover, tg-5-nursed offspring experienced high mortality post-Day 16, likely due to overdosing. This proof-of-concept demonstrates the mammary gland bioreactor as a viable platform for incretin RAs production, circumventing complex synthesis and enabling scalable biologics manufacturing.

bioengineering↗

bioRxiv2025

Molecular Insights into Cell Wall Architecture and Xylan-Bound Cellulose Fibrils in the Wheat Straw

The plant cell wall, a highly abundant renewable resource, remains insufficiently understood in terms of its structure, particularly the architecture of cellulose microfibrils and their interactions with hemicellulose and lignin, which impede the development of efficient downstream conversion. Here we present an alternative model of xylan-bound cellulose microfibril architecture in the cell wall of intact wheat straw, using solid-state nuclear magnetic resonance (ssNMR) coupled with X-ray scattering techniques. We show that the spectroscopic and scattering data can be fit to a simple elementary microfibril consisting of 18 glucan chains, with additional contributions from 0 to 4 tightly bound flat-ribbon xylan chains across the cellulose fibril axis. These xylan-bound cellulose microfibrils are found to serve as the secondary interaction site with lignin, following the non-flat xylan domains. The loose packing of these xylan-bound cellulose fibrils results in a heterogenous hydration landscape within the cell wall, allowing water penetration while maintaining structural integrity through numerous physical contacts between the polymers. This study provides a potential framework to reconcile the mounting biochemical evidence supporting the 18-chain elementary cellulose microfibril model and cellulose synthase complex with the oversized observations from characterization techniques, which report averaged structures influenced by microfibril coalescence and hemicellulose binding. The structural insights also offer valuable information regarding recalcitrance and the potential applications of biomass in biorefinery operations.

biochemistry↗

bioRxiv2025

PRAME Epitopes are T-Cell Immunovulnerabilities in BRD4::NUTM1 Initiated NUT Carcinoma

BackgroundNUT carcinoma is a rare but highly lethal solid tumor without an effective standard of care. NUT carcinoma is caused by bromodomain-containing NUTM1 fusion oncogenes, most commonly BRD4::NUTM1. BRD4::NUTM1 recruits p300 to acetylate H3K27 forming expansive stretches of hyperacetylated chromatin called "megadomains" with the overexpression of corresponding oncogenes, including MYC. We hypothesized that transcriptional dysregulation caused by BRD4::NUTM1 would lead to the generation of cancer-specific antigens that could be therapeutically actionable. MethodsWe integrated genomics, computational antigen prediction software, targeted immunopeptidomics using single- and double-labeled peptide standards, and gain/loss-of-function genetic experiments on a panel of cell lines (N=5), a patient derived xenograft, a tissue microarray (N=77), and patient samples from the Tempus AI Sequencing Database harboring evidence of NUTM1 fusions (N=165). We created an PRAME425 T-cell receptor x SP34 CD3 bispecific molecule modeled after brenetafusp, an PRAME425 T-cell receptor bispecific T-cell engager, as well as PRAME425 TCR T-cells based on anzutresgene autoleucel and we applied these products to NUT carcinoma cells in vitro. ResultsWe identified PRAME as the most commonly expressed cancer/testis antigen in patient samples harboring the three canonical NUT carcinoma fusions (BRD4::NUTM1, BRD3::NUTM1, and NSD3::NUTM1). Additionally, 56% (43/77) of NUT carcinoma tissue microarray samples stained positive for PRAME. BRD4::NUTM1 expression in HEK 293T cells enhanced PRAME levels and BRD4::NUTM1 knockout in NUT carcinoma cells reduced PRAME levels. Immunopeptidomics detected more PRAME-derived HLA ligands (N=9) than all other cancer/testis antigens combined (N=5). Targeted mass spectrometry detected the HLA-A*02:01/SLLQHLIGL (PRAME425) epitope in 100% (4/4) of HLA-A*02+, PRAME+ NUT carcinoma samples at higher levels (>0.01 fM) than HLA-A*02:01/RLDQLLRHV (PRAME312) or HLA-A*02:01/YLHARLREL (PRAME462). The PRAME425 T-cell receptor x SP34 CD3 bispecific molecule and PRAME425 TCR T-cells each exhibited potent, T-cell mediated cytotoxicity against PRAME+ NUT carcinoma cells. ConclusionsPRAME is highly and frequently expressed in NUT carcinoma and the most common oncoprotein causing NUT carcinoma, BRD4::NUTM1, contributes to these high PRAME levels. PRAME epitopes presented by HLA Class I are a previously unrecognized therapeutic vulnerability for NUT carcinoma that warrant clinical trials testing PRAME targeted immunotherapies in this neglected patient population. What is already known on this topicNUT carcinoma is a devastating malignancy that is recalcitrant to cytotoxic chemotherapy, T-cell checkpoint blockade, and targeted therapies in the form of bromodomain inhibitors. What this study addsNUT carcinoma tumors are high in the cancer/testis gene PRAME. The oncogene most commonly causing NUT carcinoma, BRD4::NUTM1, contributes to these high levels. NUT carcinoma cells present PRAME epitopes on HLA Class I molecules and are susceptible to PRAME-directed, T-cell mediated cytotoxicity. How this study might affect research, practice or policyOur results argue for phase I/II clinical trials testing PRAME immunotherapies like brenetafusp or anzutresgene autoleucel in PRAME+ NUT carcinoma patients. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=149 SRC="FIGDIR/small/642090v3_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@495654org.highwire.dtl.DTLVardef@c2b975org.highwire.dtl.DTLVardef@1de507org.highwire.dtl.DTLVardef@a76d33_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Diammonium glycyrrhizinate injection promotes zebrafish angiogenesis through the mTOR/HIF-1 signaling pathway

(1) BackgroundGlycyrrhizic acid (GA) is the main component of the traditional Chinese medicine Glycyrrhiza glabra. Many GA preparations in the pharmaceutical market have good efficacy in hepatoprotection and the treatment of liver diseases. However, the pro-angiogenic effects for GA-based agents have not been researched specifically. The aim of this study was to investigate the pro-angiogenic activity of GA preparations commonly used in clinical practice and screen the representative angiogenesis promotor to further elucidate the mechanism of action (2) MethodsA zebrafish vascular injury model induced by PTK787 was used to assess the pro-angiogenic effect of GA preparations. The pro-angiogenic activity of diammonium glycyrrhizinate injection (DGI) was further systematically evaluated by detecting the growth of the intersegmental vessels (ISVs) and subintestinal vein vessels (SIVs) in zebrafish. The underlying mechanism of action for DGI was explored by transcriptomics analysis and RT-qPCR validation; (3) ResultsThe results showed that magnesium isoglycyrrhizinate injection (MII), DGI, compound glycyrrhizinate tablets (CGT), and diammonium glycyrrhizinate enteric-coated capsules (DGEC) could demonstrate significantly pro-angiogenic effects. Among them, DGI exhibited the strongest activity. Transcriptomic analysis showed that the pro-angiogenic activity of DGI was closely associated with the mTOR signaling pathway. RT-qPCR results indicated that the expression levels of key genes of the mTOR/HIF- pathway were significantly upregulated in DGI-treated zebrafish relative to the PTK787 group; (4) ConclusionsGA preparations have an obvious pro-angiogenic effect, in which DGI can exert particularly strong activity by activating the mTOR/HIF-1 signaling pathway. This study broadens the clinical application of GA agents and provides new insights into the pharmacodynamics and potential mechanisms of DGI as a candidate agent for treating ischemic diseases

pharmacology and toxicology↗

bioRxiv2025

cxcl18b-defined transitional state-specific nitric oxide drives injury-induced Müller glia cell-cycle re-entry in the zebrafish retina

In lower vertebrates, retinal Muller glia (MG) exhibit a life-long capacity of cell-cycle re-entry to regenerate neurons following the retinal injury. However, the mechanism driving such injury-induced MG cell-cycle re-entry remains incompletely understood. Combining single-cell transcriptomic analysis and in-vivo clonal analysis, we identified previously undescribed cxcl18b-defined MG transitional states as essential routes towards MG proliferation following green/red cone (G/R cone) ablation. Inflammation blockage abolished the triggering of these transitional states, which expressed the gene modules shared by cells of the ciliary marginal zone (CMZ), where life-long adult neurogenesis takes place. Functional studies of the redox properties of these transitional states further demonstrated the regulatory role of nitric oxide (NO) produced by Nos2b in injury-induced MG proliferation. Finally, we developed a viral-based strategy to specifically disrupt nos2b in cxcl18b-defined MG transitional states and revealed the effect of transitional state-specific NO signaling. Our findings elucidate the precision redox mechanism underlying injury-induced MG cell-cycle re-entry, providing insights into species-specific mechanisms for vertebrate retina regeneration.

neuroscience↗

bioRxiv2025

Deep-learning-based interpolation of longitudinal microbiome data powers biologically informative discovery

The human microbiome is a foundational and dynamic foundation for several health-related functions and disease processes. Advances in microbiome sequencing have enabled the characterization of microbial communities in several niches. Longitudinal microbiome studies further strive to discover clinically informative microbial community trajectories. However, these data are fraught with dropout events, high noise, and irregular sampling that limit and prevent the use of many available longitudinal analysis tools. To address these challenges, we introduce Bidirectional GRU-ODE-Bayes (BGOB), a deep learning framework developed for longitudinal microbiome interpolation. BGOB combines bidirectional information flow and ODE-based continuous modeling to jointly interpolate and smoothen trends across individual participants, providing uniform, denoised time intervals across patients. BGOB enables vastly improved performance in differential abundance testing and time-to-event analysis, and makes possible longitudinal analyses requiring uniformity, such as lead-lag detection and temporal clustering. After interpolation, previously low-powered datasets are able to broadly recapitulate known microbiology and elucidate interacting microbial communities. We highlight several associations between microbial taxa and disease, including novel species associated with Early Childhood Caries and disruption of key healthy gut microbiota in Inflammatory Bowel Disease. The BGOB package is publicly available at https://github.com/Rachel-Lyu/BGOB_n_test.

microbiology↗

bioRxiv2025

The Protective Role of Intestinal Alkaline Phosphatase in Inflammatory Bowel Disease-Associated Non-Alcoholic Fatty Liver Disease

BackgroundInflammatory bowel disease (IBD) is a chronic and progressive inflammatory condition characterized by weight loss as a prominent feature. Non-alcoholic fatty liver disease (NAFLD), typically linked to obesity and metabolic dysregulation, is increasingly recognized as being influenced by the gut-liver axis. Notably, IBD patients exhibit a heightened susceptibility to NAFLD, although the underlying mechanisms remain poorly understood. Intestinal alkaline phosphatase (IAP), an endogenous enzyme, plays a critical role in preventing intestinal bacterial translocation. We hypothesized that IAP may serve as a potential therapeutic agent for mitigating IBD-associated NAFLD. MethodsAn IBD model was established using three cycles of 2% dextran sulfate sodium (DSS) administration. Mice were subsequently treated with L-phenylalanine or IAP. The activity of stool IAP, gut microbiota composition, hepatic lipid accumulation, inflammatory markers, and gut microbiome diversity were assessed. ResultsDSS treatment markedly reduced IAP levels. Suppression of IAP significantly increased gut permeability and exacerbated hepatic inflammation and lipid deposition. Conversely, IAP supplementation restored these parameters, improved gut microbial diversity, and normalized microbiota composition. However, IAP failed to ameliorate hepatic inflammation and lipid accumulation in Toll-like receptor 4 (TLR4) knockout mice. ConclusionDeficiency in endogenous IAP contributes to the onset of NAFLD in the context of IBD. Oral IAP supplementation enhances gut barrier integrity, stabilizes gut microbiota, and prevents NAFLD development in IBD through a TLR4-dependent mechanism.

microbiology↗

bioRxiv2025

Construction of a low-temperature degrading synthetic bacterial community of corn straw

The stability of the cellulose structure in straw creates a challenge for short-term degradation in the natural environment, especially in the cold regions of north China. Therefore, to secure strains that can degrade straw at low temperatures, we selected soil samples from straw-returning land and used cellulose as the only carbon source. After conducting preliminary screening and further re-screening, we ultimately selected three strains that exhibited efficient degradation of corn straw at a temperature of 4 . Subsequently, the synthetic bacterial community C was constructed using these strains: Stenotrophomonas maltophilia, Flavobacterium johnsoniae and Pantoea rodasii. We conducted a 45-day solid-state and liquid-state fermentation experiment at low-temperature (12 ). The activity of lignocellulase was determined, and the enzyme production conditions were optimized. The results show that the liquid fermentation degradation rate of straw increased by 40 % compared with the control group in the natural state (without adding C). Similarly, the solid-state fermentation degradation rate of straw increased by 30 %, which was significantly faster than that of the control group. Finally, the enzyme production conditions of strain C were optimized as follows: culture time 96 h, inoculation amount 4 %, temperature 12 , pH 6.0, and Alkaline Carboxymethyl Cellulase (CMCase) activity 24.34 U/mL. The microbial system C efficiently degrades straw at low temperature, which is valuable for improving the comprehensive utilization rate of straw and has a broad application prospect in improving soil fertility.

microbiology↗

bioRxiv2025

Dnmt3b deficiency in adipocyte progenitor cells ameliorates obesity in female mice

Obesity arises from chronic energy imbalance where energy intake exceeds energy expenditure. Emerging evidence supports a key role of DNA methylation in the regulation of adipose tissue development and metabolism. We recently discovered a key role of DNA methylation, catalyzed by DNA methyltransferase 1 or 3a (Dnmt1 or 3a), in the regulation of adipocyte differentiation and metabolism. Here, we aimed to investigate the role of adipocyte progenitor cell Dnmt3b, an enzyme mediating de novo DNA methylation, in energy metabolism and obesity. We generated a genetic model with Dnmt3b knockout in adipocyte progenitor cells (PD3bKO) by crossing Dnmt3b-floxed mice with platelet-derived growth factor receptor alpha (Pdgfr)-Cre mice. Dnmt3b gene deletion in adipocyte progenitors enhanced thermogenic gene expression in brown adipose tissue, increased overall energy expenditure, and mitigated high-fat diet (HFD)-induced obesity in female mice. PD3bKO mice also displayed a lower respiratory exchange ratio (RER), indicative of a metabolic shift favoring fat utilization as an energy source. Furthermore, female PD3bKO mice exhibited improved insulin sensitivity alongside their lean phenotype. In contrast, male PD3bKO mice showed no changes in body weight but demonstrated decreased insulin sensitivity, revealing a sexually dimorphic metabolic response to Dnmt3b deletion in adipocyte progenitor cells. These findings underscore the critical role of Dnmt3b in regulating energy homeostasis, body weight, and metabolic health, with significant implications for understanding sex-specific mechanisms of obesity and metabolism.

systems biology↗

bioRxiv2025

PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted

Abstract/SummaryO_ST_ABSPurposeC_ST_ABSSarcomas are a heterogeneous group of cancers with few shared therapeutic targets. PI3K signaling is activated in various subsets of sarcomas, representing a shared oncogenic signaling pathway. Oncogenic PI3K signaling has been challenging to target therapeutically. An integrated view of PI3K and Hippo pathway signaling is examined to determine if this could be leveraged therapeutically. Experimental designA tissue microarray containing sarcomas of various histological types was evaluated for PTEN loss and correlated with levels of activated TAZ and YAP. PI3K and Hippo pathways were dissected in sarcoma cell lines. The role of TAZ and YAP were evaluated in a PI3K-driven mouse model. The efficacy of mTORC1 inhibition and TEAD inhibition were evaluated in sarcoma cell lines and in vivo. ResultsPI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30-60%), representing a common therapeutic target. TAZ and YAP are transcriptional co-activators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage independent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. Furthermore, this combination therapy showed a synergistic effect in vivo, reducing tumor proliferation and size. ConclusionsTAZ and YAP are transcriptional co-activators downstream of PI3K signaling, a pathway that has lacked a well-defined oncogenic transcription factor. This PI3K-TAZ/YAP axis exists in parallel to the known PI3K-Akt-mTORC1 axis allowing for synergistic combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1 in sarcomas.

cancer biology↗

bioRxiv2025

Contrastive Learning for Omics-guided Whole-slide Visual Embedding Representation

While computational pathology has transformed cancer diagnosis and prognosis prediction, existing computational methods remain limited in their ability to decipher the complex molecular characteristics within tumors. We present CLOVER (Contrastive Learning for Omics-guided whole-slide Visual Embedding Representation), a novel deep learning framework that leverages self-supervised contrastive learning to integrate multi-omics data (genomics, epigenomics, and transcriptomics) with slide representations, connecting the morphological and molecular features of tumors. Using the breast cancer cohorts comprising diagnostic slides and multi-omics paired data from 610 breast cancer patients, we validated CLOVERs excellence by demonstrating its ability to generate effective slide-level representations that consider molecular states of cancer. CLOVER outperforms existing methods in few-shot learning scenarios, particularly in cancer subtype classification and clinical biomarker prediction tasks (ER, PR, and HER2 status). Through comprehensive interpretability analysis, we identified tumor microenvironment components within slides and revealed molecular features associated with breast cancer. Our results demonstrate that CLOVER enables detailed molecular characterization from single slide analysis, suggesting its potential for effective utilization in future cancer diagnosis and prognosis prediction studies.

pathology↗

bioRxiv2025

Ustilaginoidea virens suppresses floral immunity through promoting GA biosynthesis by the effector SCRE9

Rice false smut caused by Ustilaginoidea virens has become one of the most important rice diseases. U. virens specifically infects rice florets through stamen filaments. However, it is mysterious how U. virens inhibits floral immunity for successful colonization. Here, we show that a small cysteine-rich effector SCRE9 is a key virulence factor in U. virens. Expression of SCRE9 in rice not only suppresses immune responses and false smut resistance, but also significantly increases expression of expansin and gibberellin (GA) biosynthetic genes and GA content in young rice panicles. We further demonstrate that OsSIP1 (SCRE9-interacting protein 1) in rice is targeted by SCRE9 and interacts with the OsMADS63 and OsMADS68 transcription factors that transcriptionally regulate the GA synthesis gene GA3ox1. Interestingly, the chloroplast-localized OsSIP1 recruits OsMADS63/68 into the chloroplast. SCRE9 causes OsSIP1 to be translocated into the nucleus, thereby releasing OsMADS63/68 from the chloroplast into the nucleus to promote GA3ox1 transcription. Therefore, SCRE9 promotes GA biosynthesis and expression of expansins in rice florets, thus loosening cell walls and overcoming the physical barrier during U. virens infection. The finding uncovers an unidentified floret infection strategy that offsets the deficiency in cell wall degrading ability in the unique floret colonizing fungus.

plant biology↗

bioRxiv2024

Synergistic activation of the human phosphate exporter XPR1 by KIDINS220 and inositol pyrophosphate

Inorganic phosphate (Pi) is fundamental to life, and its intracellular concentration must be tightly regulated to prevent toxicity. XPR1, the only known phosphate exporter, plays a crucial role in maintaining this delicate balance. However, the mechanisms underlying the function and regulation of XPR1 remain elusive until now. Here we present cryo-electron microscopy structures of the human XPR1-KIDINS220 complex in both substrate-free closed states and substrate-bound outward-open states, as well as the structure of an XPR1 mutant alone in a substrate-bound inward-facing state. In the presence of inositol hexaphosphate (InsP6) and phosphate, the XPR1-KIDINS220 complex adopts an outward-open conformation. InsP6 binds both the SPX domain and the peripheral juxtamembrane regions of XPR1, indicative of an active phosphate-export state. Conversely, in the absence of either phosphate or InsP6, the complex assumes a closed state, where the extracellular half of transmembrane 9 occupies the outward cavity, and a C-terminal plug-in loop blocks the intracellular cavity. Notably, XPR1 without KIDINS220 adopts a closed state despite the presence of phosphate and InsP6. The functional mutagenesis experiments further demonstrate that InsP6, whose concentrations fluctuate in response to Pi availability, functions synergistically with KIDINS220 to regulate the phosphate export activity of XPR1. These findings not only elucidate the intricate mechanisms of cellular phosphate regulation but also hold promise for the development of targeted therapies for ovarian cancer, where XPR1 plays a significant role.

biophysics↗