Biology subjects

Wang, K.

Publications and source records attributed to Wang, K..

At least 145 records · Page 8Linked to original sources

bioRxiv2025

Aptamer-Enabled Discovery and Clinical Analysis of Exosomal Surface Biomarkers in Hepatocellular Carcinoma

Exosomal membrane proteins hold promise as cancer biomarkers but face detection challenges due to low abundance and conformational sensitivity. We developed AptEx-ID, a microbead-displayed aptamer platform enabling high- throughput screening of hepatocellular carcinoma (HCC)-specific exosomal surface proteins. Aptamers, selected via competitive binding to tumor-derived versus healthy exosomes, demonstrated high affinity and specificity. Clinical validation using 50 HCC and 30 control plasma samples identified a 7-aptamer panel via machine learning, achieving 93.75% accuracy and 0.95 ROC-AUC. These aptamers further revealed HCC-associated biomarkers (e.g., IMPDH1, ASCC3, GTSE1), validated by siRNA knockdown and biophysical assays. Post-treatment monitoring showed aptamer signal reduction in responsive patients, highlighting their prognostic utility. This platform integrates biomarker discovery, diagnostics, and therapeutic monitoring, offering a robust approach for HCC management through exosomal surface proteome profiling.

molecular biology↗

bioRxiv2025

Source tracking of larval bacterial community of Pacific white shrimp across the developmental cycle: ecological insights for microbial management and pathogen prevention in larviculture

Health of postlarvae (as products of larviculture) of Pacific white shrimp (Penaeus vannamei) is critical to subsequent culture. Larval microbiota establishment has potential long-term impact on host health, but bacterial sources of larval shrimps remain largely unexplored. We investigated the larviculture cycles of two shrimp strains by utilizing 16S rRNA gene sequencing alongside mainstream microbial source-tracking tools. Our goal was to evaluate the contributions of environmental elements, feeds, and internal succession to larval bacterial community. Regardless of shrimp strains or tools, the mouth opening marked a pivotal shift in bacterial source composition of larvae, with a notable contribution from the rearing water at the beginning of mouth opening, followed by enhanced internal succession, emphasizing the critical role of early microbiota establishment. Notably, the dominance of external sources at zoea II highlights the necessity for ensuring microbial safety due to the prevalence of zoea-II syndrome at this vital stage. Source tracking of specific bacterial groups suggests regulatory timing and routes of Roseobacteraceae (with potential probiotics) and frozen Artemia as a major source of vibrios (with opportunistic pathogens). The determinism-dominated assembly of bacteria, sourced either internally or externally, highlights strong host selection. This process exhibits overall similarities in taxonomic preferences for internal succession, while differences in taxonomic preferences from external sources reflect the influence of the genetic backgrounds of shrimp strains. Our work presents the first systematic assessment on bacterial sources of P. vannamei larvae across the complete developmental cycle, providing new insights that facilitate microbial management and pathogen prevention in larviculture.

microbiology↗

bioRxiv2025

The interplay between stiffness and hyperglycemia on diabetic foot ulcer wound closure

IntroductionDiabetic foot ulcers are open wounds with impaired wound closure at the bottom of the foot. Although diabetic plantar skin is stiffer, which should enhance fibroblast mechanotransduction, fibroblasts still fail to migrate effectively. This suggests impaired wound closure is driven by another factor; hyperglycemia ([≥]11.1 mM glucose), which alters fibroblast mechanotransduction. PurposeTo mimic diabetic foot ulcers by developing a 2D circular in vitro wound closure model system to investigate fibroblast mechanoresponse under diabetic plantar skin stiffness and hyperglycemia. MethodsPolydimethylsiloxane was used as substrate, fabricated at 57 kPa and 90 kPa for normal and diabetic plantar skin stiffnesses, respectively. Cell culture media contained a 5.5 mM glucose concentration simulating normal blood glucose or an altered 11.1 mM glucose concentration simulating hyperglycemia. ResultsTime-lapse fluorescent imaging of wound assays reveals a restrictive effect of higher stiffness on migrating fibroblasts under normal glucose conditions, and a biphasic response to hyperglycemic conditions. Fibroblasts migrating on softer substrates mimicking normal plantar skin stiffness and under hyperglycemia have decreased velocity as predicted. Whereas cells migrating on stiffer substrates mimicking diabetic plantar skin stiffness and under hyperglycemia demonstrate increased cell velocity, overcoming the higher stiffnesss restrictive effect. Despite faster cell velocities on higher stiffness, wounds under normal glucose conditions still close faster than those under hyperglycemic conditions. ConclusionThis research establishes a wound closure model demonstrating significantly slower wound closure in diabetic plantar skin with higher stiffness and hyperglycemic glucose levels compared to normal plantar skin with softer stiffness and normal glucose levels.

bioengineering↗

bioRxiv2025

Neural organoids protect engineered heart tissues from glucolipotoxicity by transferring versican in a co-culture system

Metabolic disorders could cause dysregulated glucose and lipid at the systemic level, but how inter-tissue/organ communications contribute to glucolipotoxicity is difficult to dissect in animal models. To solve this problem, myocardium and nerve tissues were modeled by 3D engineered heart tissues (EHTs) and neural organoids (NOs), which were co-cultured in a generalized medium with normal or elevated glucose/fatty acid contents. Morphology, gene expression, cell death and functional assessments detected no apparent alterations of EHTs and NOs in co-culture under normal conditions. By contrast, NOs significantly ameliorated glucolipotoxicity in EHTs. Transcriptomic and protein secretion assays identified the extracellular matrix protein versican as a key molecule that was transferred from NOs into EHTs in the high-glucose/fatty acid condition. Recombinant versican protein treatment was sufficient to reduce glucolipotoxicity in EHTs. Adeno-associated virus-delivered versican overexpression was sufficient to ameliorate cardiac dysfunction in a murine model of diabetic cardiomyopathy. These data provide the proof-of-concept evidence that inter-tissue/organ communications exist in the co-culture of engineered tissues and organoids, which could be systemically studied to explore potential pathological mechanisms and therapeutic strategies for multi-organ diseases in vitro.

cell biology↗

bioRxiv2025

Triple-N Dataset: Non-human Primate Neural Responses to Natural Scenes

Understanding the neural mechanisms of visual perception requires data that encompass both large-scale cortical activity and the fine-grained dynamics of individual neurons. While the Natural Scenes Dataset (NSD) has provided substantial insights into visual processing in humans (Allen et al., 2022), its reliance on functional magnetic resonance imaging (fMRI) limits the exploration of individual neuron contributions. To bridge this gap, we present a new dataset: the Triple-N (Non-human Primate Neural Responses to Natural Scenes) dataset, which extends the NSD framework to non-human primates, incorporating single-neuron activity and fMRI recorded from the inferotemporal (IT) cortex. Using Neuropixels probes, we recorded neural responses from five macaques as they passively viewed 1,000 shared NSD images. The dataset includes 59 sessions across 27 sub-regions, capturing over 30,000 visual responsive units. Many recordings were obtained from fMRI-defined category-selective regions, such as face-, body-, scene-, and color-selective areas. Our dataset enables in-depth exploration of neural responses at multiple levels - from population dynamics to single-neuron activity, providing new insights into various aspects of visual processing, including the heterogeneity of object selectivity within functional regions and the temporal dynamics of responses to natural images. Furthermore, the dataset enables joint cross-species analyses, by integrating the macaque neural recordings with human fMRI data, offering a framework for comparing and aligning visual representations across primate species. Overall, our dataset provides a valuable resource for advancing our understanding of visual perception, bridging the gap between large-scale neuroimaging and fine-grained electrophysiological signals, while also facilitating the development of computational models of the high-level visual system.

neuroscience↗

bioRxiv2025

Exploring the Dynamics of Follicle Development and Hormone Synthesis: The Role of Oxygen Tension in Rhesus Macaque Follicle Culture

In vitro culture of cryopreserved ovarian follicles has the potential to extend fertility options for young women seeking to preserve ovarian tissue prior to undergoing cancer treatments. Successful implementation of this strategy has been elusive and likely requires a more complete understanding of the microenvironment of the developing ovarian follicles, including ovarian oxygen concentrations. The oxygen tension within the reproductive tract plays a crucial role in follicular development and oocyte maturation. While in vitro culture systems often use atmospheric oxygen (21%), the native environment in vivo is significantly lower, ranging from 1.5% to 8.7%. This study aimed to investigate the effects of reduced oxygen tensions (3% and 5%) on follicle survival, growth, antrum formation, and hormone production in cultured secondary follicles from rhesus macaques (macaca mulata). A total of 300 follicles were isolated from 7 animals and cultured under three oxygen conditions: 3%, 5%, and 21% O2. Follicle survival and antrum formation were assessed weekly by microscopy and Kaplan-Meier survival analysis, while growth dynamics and hormone levels (estradiol, progesterone, AMH, and inhibin B) were monitored throughout the culture period. Results demonstrated that follicles cultured at 3% and 5% oxygen exhibited significantly higher survival rates and antrum formation compared to those cultured at 21% O2. No significant differences in survival were observed between the 3% and 5% oxygen groups. Growth dynamics revealed distinct patterns, with both low oxygen groups promoting more robust and sustained follicle growth, while atmospheric oxygen led to rapid degeneration. Hormonal analysis showed that follicles in 21% O2 had elevated early hormone production but exhibited reduced long-term viability. In contrast, 3% and 5% oxygen delayed hormone production, reflecting a more stable and sustained follicular environment. These findings underscore the importance of low oxygen tensions in mimicking the physiological conditions of the reproductive tract, improving follicular development, and supporting optimal hormonal function in vitro. This study suggests that further reducing oxygen levels to 3% may offer additional advantages for long-term follicle viability and function in reproductive technologies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=71 SRC="FIGDIR/small/652505v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@11fcb62org.highwire.dtl.DTLVardef@61c0beorg.highwire.dtl.DTLVardef@1b5328forg.highwire.dtl.DTLVardef@10a7538_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2025

Deep learning inference of cell type-specific gene expression from breast tumor histopathology

Cell type-specific gene expression from single-cell RNA sequencing (RNA-seq) is valuable for breast cancer precision oncology but available cohorts are still limited due to its high cost. Deconvolution methods infer cell type-specific expression from bulk RNA-seq at a lower cost, yet expenses and processing time of bulk RNA-seq are also non-negligible and limit their application too. To address these limitations, we developed SLIDE-EX (SLide-based Inference of DEconvolved gene EXpression), a deep-learning tool that predicts cell type-specific gene expression and abundances directly from routine breast cancer histopathology whole slide images (WSIs), using deconvolved bulk RNA-seq data as training labels. Trained on the TCGA-breast cohort and tested in cross validation and on an independent cohort of 160 cases, SLIDE-EX robustly infers the expression of thousands of genes across 9 distinct cell types, performing best for cancer associated fibroblasts and cancer cells. The abundance of these two cell types could also be robustly predicted, together with that of myeloid cells. The robustly predicted genes reflect key biological functions of their respective cell types. From a translational perspective, the inferred cell type specific expression profiles predict chemotherapy response more accurately than models based on direct prediction from the slides or from the inferred bulk expression in two independent cohorts. Going forward, SLIDE-EX is a generic approach that opens up possibilities for rapid, cost-effective cell type-specific gene expression inference in potentially any cancer type, further democratizing the characterization of the tumor microenvironment.

cancer biology↗

bioRxiv2025

BRAFV600E-Driven Lung Tumorigenesis Requires Ligand-Mediated Activation of ERBB Receptor Signaling

Secretion of ligands of the human epidermal growth factor (EGFR) family of receptors or erythroblastic leukemia viral oncogene family (ERBB1-4) is a feature common to many cancer cells. However, our understanding of the role of autocrine ligands in the aberrant behavior of cancer remains incomplete. Here we demonstrate that, in numerous preclinical models of lung tumorigenesis, BRAFV600E signaling promotes expression of ligands including HB-EGF, TGF, Epi- and Amphiregulin. Moreover, using both genetic or pharmacological approaches, we demonstrate that ligand-mediated activation of EGFR signaling in the tumor cell is required to sustain both early-stage BRAFV600E-driven lung tumorigenesis and supports late-stage BRAFV600E-driven lung cancer maintenance. Unbiased Reverse Phase Protein Analyses (RPPA) analyses, paired with targeted validation, reveals ERBB signaling serves to sustain signaling through the ERK1/2 MAP kinase pathway, through effects on ARAF and CRAF, and on the parallel JUN kinase (JNK) pathway. Furthermore, EGFR is activated in a cohort of BRAF-mutated lung cancer patients both pre- and post-treatment. Finally, we noted significant improvement in the depth and durability of therapeutic responses in preclinical models of BRAFV600E-driven lung cancer by combined inhibition of both BRAFV600E signaling plus pan-ERBB signaling. Collectively, this work provides evidence for an important role for ERBB family signaling in the genesis and maintenance of BRAFV600E-driven lung cancers, and the potential for future therapeutic improvement by rational combination targeting of these pathways. SIGNIFICANCEBRAFT1799A serves as a predictive biomarker for FDA-approved targeted inhibition of BRAFV600E oncoprotein kinase signaling in non-small cell lung cancer (NSCLC). However the occurrence of primary or acquired drug resistance limit the depth and durability of patient responses. Studies described here provide a mechanistic rationale for clinical testing of first-line BRAFV600E inhibition combined with pan-ERBB inhibition to improve the depth and durability of initial patient responses, and delay the emergence of lethal drug resistant disease.

cancer biology↗

bioRxiv2025

Differential Regulation of Hepatic Macrophage Fate by Chi3l1 in MASLD

Metabolic dysfunction-associated steatotic liver disease (MASLD) progression involves the replacement of protective embryo-derived Kupffer cells (KCs) by inflammatory monocyte-derived macrophages (MoMFs), yet the regulatory mechanisms remain unclear. Here, we identify chitinase 3-like 1 (Chi3l1/YKL-40) as a critical metabolic regulator of hepatic macrophage fate. We observed high expression of Chi3l1 in both KCs and MoMFs during MASLD development. Genetic deletion of Chi3l1 specifically in KCs significantly exacerbated MASLD severity and metabolic dysfunction, whereas MoMF-specific Chi3l1 deletion showed minimal metabolic effects. Mechanistic studies revealed that this cell type-specific regulation arises from differential metabolic requirements: KCs display elevated glucose metabolism compared to MoMFs. Chi3l1 directly interacts with glucose to inhibit its cellular uptake, thereby selectively protecting glucose-dependent KCs from metabolic stress-induced cell death while having negligible effects on less glucose-dependent MoMFs. These findings uncover a novel Chi3l1-mediated metabolic checkpoint that preferentially maintains KCs populations through glucose metabolism modulation, providing important new insights into the pathogenesis of MASLD and potential therapeutic strategies targeting macrophage-specific metabolic pathways.

molecular biology↗

bioRxiv2025

THLANet: A Deep Learning Framework for Predicting TCR-pHLA Binding in Immunotherapy Applications

Adaptive immunity is a targeted immune response that enables the body to identify and eliminate foreign pathogens, playing a critical role in the anti-tumor immune response. Tumor cell expression of antigens forms the foundation for inducing this adaptive response. However, the human leukocyte antigens (HLA)-restricted recognition of antigens by T-cell receptors (TCR) limits their ability to detect all neoantigens, with only a small subset capable of activating T-cells. Accurately predicting neoantigen binding to TCR is, therefore, crucial for assessing their immunogenic potential in clinical settings. We present THLANet, a deep learning model designed to predict the binding specificity of TCR to neoantigens presented by class I HLAs. THLANet employs evolutionary scale modeling-2 (ESM-2), replacing the traditional embedding methods to enhance sequence feature representation. Using scTCR-seq data, we obtained the TCR immune repertoire and constructed a TCR-pHLA binding database to validate THLANets clinical potential. The models performance was further evaluated using clinical cancer data across various cancer types. Additionally, by analyzing divided complementarity-determining region (CDR3) sequences and simulating alanine scanning of antigen sequences, we unveiled the 3D binding conformations of TCRs and antigens. Predicting TCR-neoantigen pairing remains a significant challenge in immunology, THLANet provides accurate predictions using only the TCR sequence (CDR3{beta}), antigen sequence, and class I HLA, offering novel insights into TCR-antigen interactions. Author summaryT-cell receptor (TCR) recognition of peptide-human leukocyte antigen (pHLA) complexes is fundamental to immune responses. However, predicting their binding poses a significant challenge due to the intricate dynamics of their interactions. We developed THLANet, a novel deep learning model, to address this challenge by integrating the ESM-2 and Transformer-Encoder modules. This approach enhances sequence feature encoding, improving the models generalization capability and enabling accurate predictions of TCR-pHLA binding in clinical datasets. Using data processed from open-source databases, THLANet outperformed existing methods, such as PanPep and pMTnet, in precision-recall metrics across multiple epitopes. Additionally, THLANet demonstrates superior capability in identifying critical binding sites within 3D structures, providing structural insights into TCR-pHLA interactions. THLANet offers a robust framework for advancing immunotherapy research, with potential applications in the development of personalized medicine.

bioinformatics↗

bioRxiv2025

FAK Differentially Mechanoregulates Cell Migration During Wound Closure

Cell migration is an essential step in wound healing. Mechanical input from the local microenvironment controls much of cell velocity and directionality during migration, which is translated into biochemical cues by focal adhesion kinase (FAK) inside the cell. FAK induces both regeneration and fibrosis. The mechanisms by which FAK decide wound fate (regenerative or fibrotic repair) in soft, normal wounds or stiff, fibrotic wounds remains unclear. Here we show that FAK differentially mechanoregulates wound behavior on soft substrates mimicking normal wounds and stiff substrates mimicking fibrotic wounds by converting mechanical substrate stimuli into variable cell velocity, directionality, and angle during wound healing. Cells on soft substrates migrate slower and less persistently; cells on stiff substrates migrate faster and more persistently with the same angle as the cells on normal wound substrates. Inhibition of FAK results in substantially slower, less persistent, and less correctly angled cell migration, which leads to slowed wound closure. Moreover, FAK inhibition impairs fibroblast ability to respond to substrate stiffness when migrating. Here we show FAK is an essential mechanoregulator of wound migration in fibroblast wound closure and is responsible for controlling cell migration dynamics in response to substrate stiffnesses mimicking normal or fibrotic wounds. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=176 SRC="FIGDIR/small/646098v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@b93ab5org.highwire.dtl.DTLVardef@bd4693org.highwire.dtl.DTLVardef@646059org.highwire.dtl.DTLVardef@1f1aec1_HPS_FORMAT_FIGEXP M_FIG TOC Graphic: Cell migration dynamics regulated by substrate stiffness via focal adhesion kinase (FAK). Cells on softer substrates mimicking normal wounds display slower, more random migration that is impaired by FAK inhibition. Cells migrate faster and more persistently on stiffer substrates mimicking fibrotic wounds that is dysregulated by FAK inhibition. C_FIG

bioengineering↗

bioRxiv2025

Lipid metabolism of hepatocyte-like cells supports intestinal tumor growth by promoting tracheogenesis

Tumors reprogram lipid metabolism in distant tissues to support their growth. In adult Drosophila, gut tumors secrete the PDGF/VEGF-like factor Pvf1, which activates the TORC1-Hnf4 pathway in hepatocyte-like oenocytes. This drives production of very long-chain fatty acids and wax esters essential for tracheal growth around the tumor. Blocking Hnf4 or the elongase mElo in oenocytes strongly suppresses tracheogenesis, tumor progression, and cachexia-like organ wasting, while extending host lifespan. The same pathway also controls tracheal development in healthy flies. Lipoprotein receptor LpR2 depletion in oenocytes rescues the observed tumor induced tracheal tracheal remodeling. This tumor-host interaction is conserved: VEGF-A induces lipid metabolism genes in human hepatocytes, and lung tumor-bearing mice show elevated hepatic Hnf4 and Elovl7. The study reveals a non-autonomous role of the TORC1-Hnf4 axis in lipid-mediated tumor progression and identifies potential therapeutic targets for cancer-associated metabolic dysfunction.

cell biology↗

bioRxiv2025

Developing a zebrafish xenograft model of diffuse midline glioma

Diffuse midline glioma (DMG) is a highly aggressive brain tumor that predominantly affects children. Conventional treatments such as radiation therapy can control progression for a time, but DMG kills nearly 100 percent of patients. Although murine models have provided critical insights into the biology of DMG and in assessing new therapeutic strategies, they are not suitable for high-throughput screening to identify and profile novel therapies due to technical challenges, ethical considerations and high cost. Zebrafish (Danio rerio) is an established vertebrate model for large-scale drug screening, and zebrafish have demonstrated the ability to replicate the key biological and pathlogical aspects of human malignancies. Here, we developed a novel method for transplanting human DMG cells into large numbers of zebrafish embyros to speed the assessment of anti-tumor drug efficacy in vivo and thereby facilitate the development of novel therapeutics for clinical translation. We transplanted red fluorescent protein (RFP)-labeled, patient-derived DMG cell lines into zebrafish blastulas. Remarkably, many DMG cells migrate into the developing brain and are present in the midline of the brain 24 hours after blastula injection. Tumor cell burden was monitored by measuring RFP fluorescence intensity changes over time. Time-course images of transplanted tumor cell volumes were acquired, and the interactions between transplanted DMG cells and microglial cells were further analyzed using Imaris software. We have developed a simple and rapid transplantation protocol to establish a zebrafish xenograft model of DMG. Our method involves transplanting DMG cells into the blastula stage (1000 cell stage) of zebrafish embryos, which does not require complex surgical techniques. This approach allows for the transplantation of hundreds of embryos per hour, significantly increasing the efficiency of creating DMG zebrafish xenografts that are suitable for high-throughput drug and gene discovery screens.

cancer biology↗

bioRxiv2025

Helminth infection favors reprogramming and proliferation of lung neutrophils

Neutrophils are a granulocytic population of myeloid cells that have critical effector functions during infectious disease but are generally thought to be short-lived and nonproliferative with markedly limited activation states. In these studies, we directly compared lung neutrophil activation following infection with different groups of pathogens including bacteria, fungi, and helminths. Our results demonstrate considerable heterogeneity depending on the type of infectious agent. In contrast to bacterial and fungal infection, after helminth infection neutrophils expressed markers associated with characteristic type 2 responses and unexpectedly upregulated genes associated with cell cycling and protein synthesis. Further studies showed reduced neutrophil cell death following helminth infection and increased proliferation, which was dependent on IL-4R signaling. This distinct subset of proliferating neutrophils expanded following helminth infection and was released from the endothelial niche to colocalize with invading parasites in the airways. These studies demonstrate a novel long-lived cycling phenotype for neutrophils following helminth infection.

immunology↗

bioRxiv2025

Ontogeny Dictates Oncogenic Potential, Lineage Hierarchy, and Therapy Response in Pediatric Leukemia

Accumulating evidence links pediatric cancers to prenatal transformation events, yet the influence of the developmental stage on oncogenesis remains elusive. We investigated how hematopoietic stem cell developmental stages affect leukemic transformation, disease progression, and therapy response using a novel, humanized model of NUP98::NSD1-driven pediatric acute myeloid leukemia, that is particularly aggressive with WT1 co-mutations. Fetal-derived hematopoietic stem cells readily transform into leukemia, and WT1 mutations further enhance stemness and alter lineage hierarchy. In contrast, stem cells from later developmental stages become progressively resistant to transformation. Single-cell analyses revealed that fetal-origin leukemia stem cells exhibit greater quiescence and reliance on oxidative phosphorylation than their postnatal counterparts. These differences drive distinct therapeutic responses, despite identical oncogenic mutations. In patients, onco-fetal transcriptional programs correlate with worse outcomes. By targeting key vulnerabilities of fetal-origin leukemia cells, we identified combination therapies that significantly reduce aggressiveness, highlighting the critical role of ontogeny in pediatric cancer treatment.

cancer biology↗

bioRxiv2025

Demonstration and structural basis of a therapeutic DNA aptamer for SARS-CoV-2 spike protein detection

At the onset of the COVID-19 pandemic, the absence of a rapid and highly specific diagnostic method for the SARS-CoV-2 virus led to significant delays in detection, adversely affecting clinical outcomes. This shortfall highlights the urgent need for adaptable, scalable, and reusable diagnostic technologies to improve future pandemic responses. To address this challenge, we developed a renewable electrochemical impedance biosensor device employing a synthetic nucleotide-based therapeutic aptamer (termed aptasensor) targeting the SARS-CoV-2 spike (S) protein receptor-binding domain (RBD). We demonstrate that our aptasensor can detect the Omicron BA.2 S protein within one hour and possesses concentration-dependent sensitivity at biologically relevant levels. Notably, the aptasensor is reusable after regeneration by a simple pH 2 buffer treatment. Aptamer binding to the S protein was confirmed by immunogold labeling and visualization by negative-stain electron microscopy. We used cryogenic electron microscopy (cryo-EM) to resolve high-resolution maps of the S protein in both the open and closed conformations and characterized aptamer binding to the up RBD in the open conformation. Taken together, these results establish the versatility and scalability of aptamer-based biosensors, presenting them as a potential transformative diagnostic platform for emerging pathogens. This combination of rapid detection, specificity, and renewable capabilities in a single diagnostic solution marks a significant advance in pandemic preparedness.

bioengineering↗

bioRxiv2025

Structural variants contribute to the gut microbiome, blood metabolic traits and their causal relationships

Research on genetic variants affecting the gut microbiome and blood metabolites has mainly focused on single nucleotide variants (SNPs), with structural variants (SVs) remaining largely unexamined. In this study, we utilized an advanced structural variant detection pipeline on whole-genome sequencing data from 2,002 individuals with an average sequencing depth of 42 folds, identifying 138,859 high-confidence SVs, 49.57% of which were previously unreported. We performed genome-wide association studies on 22,519 common SVs with 616 gut microbial features and 121 blood metabolic traits, uncovering 30 significant links between SVs and microbial taxa/pathways and 48 connections between SVs and blood metabolites. Notable results include 19 associations reaching study-wide significance, such as an Asian-specific 6.5k deletion at the TENT2 gene, which is strongly associated with the abundance of Coprobacillus sp. 29_1 ({beta}=0.158, p=2.5x10-9), and a deletion covering HBA1/HBA2/HBM/HBQ118 linked to nine blood metabolic traits, most significantly with mean corpuscular volume (MCV; {beta}=-0.570, p=1.22x10-91). Most SVs showed a greater impact than nearby SNPs in their associations with the microbiome/metabolites. Analysis of rare SVs also identified multiple genes associated with the microbiome/metabolites. Additionally, Mendelian randomization using SVs demonstrated causal relationships, including effects from the microbiome to metabolites, such as Clostridium ramosums impact on serum uric acid and hyperuricemia, and from metabolites to the microbiome, like the influence of mean corpuscular hemoglobin concentration on MF0064: triacylglycerol degradation. This study provides a detailed SV catalog for the Chinese population and highlights the significant role of SVs in the gut microbiome, blood metabolites, and their causal relationships. HighlightsO_LIProvides a catalog of 138,859 high-confidence SVs and 49.57% of which were novel C_LIO_LIIdentify 30 genome-wide significant "SVs--microbial taxa/pathways" and 48 "SVs--blood metabolites" associations, respectively C_LIO_LIAn Asian-specific 6.5k deletion at TENT2 gene associated with the species Coprobacillus sp. 29_1 C_LIO_LIA deletion spanning HBA1/HBA2/HBM/HBQ118 associated with 9 blood metabolic traits C_LIO_LIThe majority of SVs demonstrated a more pronounced impact than neighboring SNPs in the associations with microbiome/metabolites C_LIO_LISVs help to reveal the host-microbe causal relationships such as Clostridium ramosums causal effects on serum uric acid and hyperuricemia C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/643427v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@e660d0org.highwire.dtl.DTLVardef@ddfe4dorg.highwire.dtl.DTLVardef@62a704org.highwire.dtl.DTLVardef@c31bb5_HPS_FORMAT_FIGEXP M_FIG Graphic abstract Based on a multi-omics cohort of 2,002 individuals comprising high-depth whole genome and metagenomic sequencing data, blood metabolites, and detailed questionnaires, we identified 138,859 high-confidence SVs, uncovering 36 significant associations between SVs and microbial taxa/pathways, as well as 48 associations between SVs and blood metabolites. Mendelian randomization using SVs demonstrated causal relationships, such as Clostridium ramosums causal effect on serum uric acid and hyperuricemia. This study provides a detailed SV catalog for the Chinese population and highlights the significant role of SVs in the gut microbiome, blood metabolites, and their causal relationships. C_FIG

genomics↗

bioRxiv2025

Sky islands of Southwest China. II: Unraveling hidden species diversity of talpid moles using phylogenomics and skull-based deep learning

The sky islands of Southwest China, characterized by dramatic topographical and climatic variations, are prominent hotspots of biodiversity and endemism. Organisms inhabiting middle-to-high elevation habitats in this region are geographically isolated within distinct mountain chains, which over geological time have been subjected to isolation-by-distance and isolation-by-environment. These processes have led to profound allopatric diversification and strong phylogeographic structuring, resulting in a plethora of genetically distinct cryptic species, as is becoming increasingly evident for many small mammal families. However, morphological conservatism can pose significant challenges in delineating these clades within species complexes. In this study, we leverage artificial intelligence technologies to unravel the hidden species diversity of moles (family Talpidae) in Southwest Chinas sky islands. We first employed ultraconserved elements (UCEs) to investigate the evolutionary history of talpid moles, conducted molecular species delimitation using mitochondrial and multi-locus genes, and utilized both traditional and geometric morphometrics to examine their morphological disparity. To address the challenges of morphology based cryptic species identification, we developed a deep learning Hierarchical Identification of Species NETwork (HIS-NET) to create an image-based model that analyzes four different views of the skull/mandible to distinguish genera and species hierarchically. HIS-NET not only achieved expert-level accuracy in species identification but also effectively distinguished between cryptic and known species, aiding in the identification of key morphological variation intervals. Our results support the recognition of allopatrically distributed taxa in Euroscaptor and Parascaptor as full species, thereby confirming that species diversity in this region remains underestimated. Beyond advancing our understanding of speciation in this unique and fragile ecosystem, our study serves as a proof-of-concept, demonstrating the power of deep learning in unraveling hidden biodiversity within this and other species complexes.

zoology↗