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Ye, F.

Publications and source records attributed to Ye, F..

At least 37 records · Page 2Linked to original sources

MimicNeoAI: An integrated pipeline for identifying microbial mimicry antigens and tumor neoantigen partners

Tumor-associated microbial antigens represent promising immunotherapy targets, yet systematic identification methods remain underdeveloped. We developed MimicNeoAI, a computational pipeline integrating BiLSTM networks to identify microbial epitopes, mutation-derived neoepitopes, and their microbial mimics from sequencing data. Training on validated epitope datasets yielded 0.90 AUC with 91% accuracy on experimental validation sets. Application to colorectal cancer revealed that microbial epitopes, despite originating from a nine-fold smaller peptide pool, generated twice the immunogenic candidates (153 vs 75) compared to mutation-derived neoepitopes. These microbial epitopes exhibited exclusive tumor-specificity with no overlap in normal tissues. Single-cell TCR sequencing confirmed clonal expansion against 75% of predicted highly immunogenic epitopes, with molecular dynamics simulations demonstrating positive correlation between predicted immunogenicity and HLA-epitope-TCR binding stability. Collectively, our pipeline systematically unveils abundant, tumor-specific, and highly immunogenic microbial epitopes, providing a computational framework for developing broadly applicable cancer immunotherapies that leverage the tumor microbiome as an untapped source of therapeutic targets.

bioinformatics↗

MAIS: an in-vitro sandbox enables adaptive neuromodulation via scalable neural interfaces

Brain-machine interfaces (BMIs) predominantly rely on static digital architectures to decode biological neuronal networks, a paradigm that is incompatible with natural neural coding in the human brain1-4. Bridging this gap is a critical step in combating neuronal dysfunction, enhancing brain functionality, and refining the precision of neuroprosthetics5. The integration of brain organoids with microelectrode array (MEA), as a class of BMIs, offers a humanized in vitro platform with unique biological compatibility advantages for dynamic neuronal decoding. This study resolves the biological-electronic encoding incompatibility of brain organoid-MEA Integration through three progressive breakthroughs. First, a human-machine hybrid agent is developed as a newly proposed bioengineered platform that couples brain organoids together with high-density MEAs and computational chips, enabling closed-loop perturbation of biological neuronal networks via exogenous signals. Second, through plasticity-driven real-time tracking of neuronal activity, we establish dynamically reconfigurable stimulation nodes that self-align with the electrophysiological states of the organoids. This resolves the exogenous-endogenous encoding mismatch by implementing plasticity-driven adaptation principles that ensure biological compatibility through spatially adaptive coordination. Finally, through shared plasticity rules rather than centralized control, we construct the first scalable multi-agent interactive system (MAIS) and demonstrate its real-world applications. Through designed scenarios of pathological/normal neuronal network interaction, we validate that MAIS achieves stable cross-network coordination. MAIS embodies a self-evolving neural coding sandbox in which plasticity-driven dynamic decoding bridges the compatibility gaps between biological and digital systems, providing a scalable and foundational infrastructure for human-centered neural interfaces.

bioengineering↗

Subunit specialisation in AAA+ proteins and substrate unfolding during transcription complex remodelling

Bacterial RNA polymerase (RNAP) is a multi-subunit enzyme that copies DNA into RNA in a process known as transcription. Bacteria use {sigma} factors to recruit RNAP to promoter regions of genes that need to be transcribed, with 60% bacteria containing at least one specialized {sigma} factor {sigma}54. {sigma}54 recruits RNAP to promoters of genes associated with stress responses and forms a stable closed complex that does not spontaneously isomerize to the open state where promoter DNA is melted out and competent for transcription. The {sigma}54-mediated open complex formation requires specific AAA+ proteins (ATPases Associated with diverse cellular Activities) known as bacterial enhancer-binding proteins (bEBPs). We have now obtained structures of new intermediate states of bEBP-bound complexes during transcription initiation, which elucidate the mechanism of DNA melting driven by ATPase activity of bEBPs and suggest a mechanistic model that couples the ATP hydrolysis cycle within the bEBP hexamer with {sigma}54 unfolding. Our data reveal that bEBP forms a non-planar hexamer with the hydrolysis-ready subunit located at the furthest/highest point of the spiral hexamer relative to the RNAP. ATP hydrolysis induces conformational changes in bEBP that drives a vectoral transiting of the regulatory N-terminus of {sigma}54 into the bEBP hexamer central pore causing the partial unfolding of {sigma}54, while forming specific bEBP contacts with promoter DNA. Furthermore, our data suggest a mechanism of AAA+ protein that is distinct from the hand-over-hand mechanism proposed for many AAA+ proteins, highlighting the versatile mechanisms utilized by the large protein family.

biochemistry↗

Multiomics analysis revealed anti-freezing mechanism of Staphylococcus aureus in its anti-freezing strain

Frozen food is currently a common food type. However, the presence of Staphylococcus aureus contamination caused serious challenge to frozen food safety. In this study, we explored the differences between sensitive strains and anti-freeze strains through multiomics analysis such as proteomics, phosphorylated proteomics, and metabolomics studies to understand the anti-freezing mechanism of S. aureus. This study compared the proteomics, phosphorylated proteomics and metabolomic differences between anti-freeze strains and sensitive strains before and after freezing. pre- and post-freezing, antifreeze strains mainly responded to low temperatures by enhancing antioxidant capacity, energy metabolism and antibiotic synthesis before freezing, while after freezing, bacteria depended more on biofilm formation, nitrogen metabolism and amino acid metabolism to improve frost resistance and adaptability. The ket gene such as sucD and coaD in the energy metabolism and metabolic pathways, gapA1 and tpiA in glucose metabolism and energy balance, asd and gnd in the metabolic pathways of amino acid synthesis and protein synthesis, crtN in the context of protective mechanisms and stress response should be explored furthermore. In metabolomic research, the arginine synthesis pathway, biofilm formation pathway, Adenosine triphosphate-binding cassette transporters and other metabolic pathways deserve special attention and research. IMPORTANCEThis study highlights the importance of understanding the anti-freezing mechanisms of *Staphylococcus aureus* in frozen food safety. By analyzing proteomics, phosphorylated proteomics, and metabolomics, it identifies key pathways like energy metabolism, biofilm formation, and amino acid synthesis that enhance bacterial frost resistance, offering insights for improving food preservation and safety.

microbiology↗

An integrated single-cell and spatial transcriptomic atlas of thyroid cancer progression identifies prognostic fibroblast subpopulations

Thyroid cancer progression from curable well-differentiated thyroid carcinoma to highly lethal anaplastic thyroid carcinoma is distinguished by tumor cell de-differentiation and recruitment of a robust stromal infiltrate. Combining an integrated thyroid cancer single-cell sequencing atlas with spatial transcriptomics and bulk RNA-sequencing, we define stromal cell subpopulations and tumor-stromal cross-talk occurring across the histologic and mutational spectrum of thyroid cancer. We identify distinct inflammatory and myofibroblastic cancer-associated fibroblast (iCAF and myCAF) populations and perivascular-like populations. The myCAF population is only found in malignant samples and is associated with tumor cell invasion, BRAFV600E mutation, lymph node metastasis, and disease progression. Tumor-adjacent myCAFs abut invasive tumor cells with a partial epithelial-to-mesenchymal phenotype. Tumor-distant iCAFs infiltrate inflammatory autoimmune thyroid lesions and anaplastic tumors. In summary, our study provides an integrated atlas of thyroid cancer fibroblast subtypes and spatial characterization at sites of tumor invasion and de-differentiation, defining the stromal reorganization central to disease progression.

cancer biology↗

Development of a novel peripherally acting alpha2A-adrenergic receptor antagonist for anti-diabetic

Yohimbine, a potent alpha2A-adrenergic receptor (2AAR) antagonist, was found therapeutic potential for type 2 diabetes through improving insulin release. However, the adverse side effects mediated by its actions in the brain hampered its use. Here, based on molecular docking analysis and structural modification, we have developed a novel peripherally acting yohimbine derivative (CDS479-2). CryoEM data found that yohimbine and CDS479-2 have similar interactions with the structure of 2AAR. Importantly, CDS479-2 shows similar 2AAR antagonist activity as yohimbine, but with very limited access to the brain, and thus avoiding the unwanted central effects such as hypertension and anxiety. Acute administration of CDS479-2 by injection or gavage lowered blood glucose levels and improved glucose tolerance in the high-fat diet-induced obesity (DIO) mice, an animal model for human type 2 diabetes. Remarkably, DIO mice received 2 weeks of daily administration of CDS479-2, but not yohimbine, exhibited sustained normoglycaemia, and increased density of the insulin-producing beta cells, in which important proliferation genes were found upregulated. Moreover, the overall protein expression levels of their pancreas were more similar to that of the healthy chow-fed mice. Thus, CDS479-2 may indicate a new direction for type 2 diabetes treatment. Importantly, the strategy we employed in this study will inspire the optimization for drugs that with both peripheral and central targets. Graphic abstract O_FIG O_LINKSMALLFIG WIDTH=166 HEIGHT=200 SRC="FIGDIR/small/628818v1_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1d3d7corg.highwire.dtl.DTLVardef@1afbad3org.highwire.dtl.DTLVardef@12a1aborg.highwire.dtl.DTLVardef@1341a02_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

Inferring gene-pathway associations from consolidated transcriptome datasets: an interactive gene network explorer for Tetrahymena thermophila

Although an established model organism, Tetrahymena thermophila remains comparatively inaccessible to high throughput screens, and alternative bioinformatic approaches still rely on unconnected datasets and outdated algorithms. Here, we report a new approach to consolidating RNA-seq and microarray data based on a systematic exploration of parameters and computational controls, enabling us to infer functional gene associations from their co-expression patterns. To illustrate the power of this approach, we took advantage of new data regarding a previously studied pathway, the biogenesis of a secretory organelle called the mucocyst. Our untargeted clustering approach recovered over 80% of the genes that were previously verified to play a role in mucocyst biogenesis. Furthermore, we tested four new genes that we predicted to be mucocyst-associated based on their co-expression and found that knocking out each of them results in mucocyst secretion defects. We also found that our approach succeeds in clustering genes associated with several other cellular pathways that we evaluated based on prior literature. We present the Tetrahymena Gene Network Explorer (TGNE) as an interactive tool for genetic hypothesis generation and functional annotation in this organism and as a framework for building similar tools for other systems. Key PointsO_LIur approach integrates nearly 20-year-old microarray and contemporary RNA-seq datasets. C_LIO_LIrigorously compare co-expression clustering parametrization by way of computational controls. C_LIO_LICo-expression clustering identifies known and novel functionally associated genes in Tetrahymena. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=119 SRC="FIGDIR/small/627356v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1dbe655org.highwire.dtl.DTLVardef@1ef09aaorg.highwire.dtl.DTLVardef@63b670org.highwire.dtl.DTLVardef@5e9209_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioinformatics↗

In situ Membrane Protein Expression by Efficient Recruitment of mRNA to the Membranes of Synthetic Cells

The synthesis of artificial cells is crucial for understanding the origins of life. In synthetic cells, however, the absence of membrane-bound organelles and auxiliary proteins severely limits the efficient expression and precise localization of membrane proteins using cell-free expression systems. Here we introduce a robust method that significantly enhances membrane protein synthesis by recruiting mRNA to phospholipid membranes. This is achieved through the use of cholesterol-modified, single-stranded DNA that anchors to the membrane and pairs with the mRNAs untranslated region. This strategic placement facilitates the assembly of protein expression machinery, promoting direct co-translational folding at the membrane. Our approach not only ensures correct protein topology and functionality but also demonstrates broad applicability for the in situ expression of various membrane proteins. It effectively addresses the challenges of membrane protein localization and assembly in synthetic cells, showcasing its versatility for synthesizing a wide array of membrane proteins.

synthetic biology↗

Tenascin-C potentiates Wnt signaling in thyroid cancer

Tenascin-C (TNC) is a secreted extracellular matrix protein that is highly expressed during embryonic development and re-expressed during wound healing, inflammation, and neoplasia. Studies in developmental models suggest that TNC may regulate the Wnt signaling pathway. Our lab has shown high levels of Wnt signaling and TNC expression in anaplastic thyroid cancer (ATC), a highly lethal cancer with an abysmal [~]3-5 month median survival. Here, we investigated the role of TNC in facilitating ligand-dependent Wnt signaling in thyroid cancer. We utilized bulk RNA-sequencing from three independent multi-institutional thyroid cancer patient cohorts. TNC expression was spatially localized in patient tumors with RNA in situ hybridization. The role of TNC was investigated in vitro using Wnt reporter assays and in vivo with a NOD.PrkdcscidIl2rg-/- mouse ATC xenograft tumor model. TNC expression was associated with aggressive thyroid cancer behavior, including anaplastic histology, extrathyroidal extension, and metastasis. Spatial localization of TNC in patient tissue demonstrated a dramatic increase in expression within cancer cells along the invasive edge, adjacent to Wnt ligand-producing fibroblasts. TNC expression was also increased in areas of intravascular invasion. In vitro, TNC bound Wnt ligands and potentiated Wnt signaling. Finally, in an ATC mouse model, TNC increased Wnt signaling, tumor burden, invasion, and metastasis. Altogether, TNC potentiated ligand driven Wnt signaling and promotes cancer cell invasion and metastasis in a mouse model of thyroid cancer. Understanding the role of TNC and its interaction with Wnt ligands could lead to the development of novel biomarkers and targeted therapeutics for thyroid cancer.

cancer biology↗

Tunable Elliptical Cylinders for Rotational Mechanical Studies of Single DNA Molecules

The angular optical trap (AOT) is a powerful technique for measuring the DNA topology and rotational mechanics of fundamental biological processes. Realizing the full potential of the AOT requires rapid torsional control of these processes. However, existing AOT quartz cylinders are limited in their ability to meet the high rotation rate requirement while minimizing laser-induced photodamage. In this work, we present a novel trapping particle design to meet this challenge by creating small metamaterial elliptical cylinders with tunable trapping force and torque properties. The optical torque of these cylinders arises from their shape anisotropy, with their optical properties tuned via multilayered SiO2 and Si3N4 deposition. We demonstrate that these cylinders can be rotated at about 3 times the rate of quartz cylinders without slippage while enhancing the torque measurement resolution during DNA torsional elasticity studies. This approach opens new opportunities for previously inaccessible rotational studies of DNA processing.

biophysics↗

ElixirSeeker: A Machine Learning Framework Utilizing Attention-Driven Fusion of Molecular Fingerprints for the Discovery of Anti-Aging Compounds

Despite the growing interest in anti-aging drug development, high cost and low success rate pose a significant challenge. We present ElixirSeeker, a new machine-learning framework designed to help speed up the discovery of potential anti-aging compounds by utilizing the attention-driven fusion of molecular fingerprints. Our approach integrates molecular fingerprints generated by different algorithms and utilizes XGBoost to select optimal fingerprint lengths. Subsequently, we assign weights to the molecular fingerprints and employ Kernel Principal Component Analysis (KPCA) to reduce dimensionality, integrating different attention-driven methods. We trained the algorithm using DrugAge database. Our comprehensive analyses demonstrate that 64-bit Attention-ElixirFP maintains high predictive accuracy and F1 score while minimizing computational cost. Using ElixirSeeker to screen external compound databases, we identified a number of promising candidate anti-aging drugs. We tested top 6 hits and found that 4 of these compounds extend the lifespan of Caenorhabditis elegans, including Polyphyllin , Medrysone, Thymoquinone and Medrysone. This study illustrates that attention-driven fusion of fingerprints maximizes the learning of molecular activity features, providing a novel approach for high-throughput machine learning discovery of anti-aging molecules.

systems biology↗

Dual modes of DNA N6-methyladenine maintenance by distinct methyltransferase complexes

Stable inheritance of DNA N6-methyladenine (6mA) is crucial for its biological functions in eukaryotes. Here, we identify two distinct methyltransferase (MTase) complexes, both sharing the catalytic subunit AMT1, but featuring AMT6 and AMT7 as their unique components, respectively. While the two complexes are jointly responsible for 6mA maintenance methylation, they exhibit distinct enzymology, DNA/chromatin affinity, genomic distribution, and knockout phenotypes. AMT7 complex, featuring high MTase activity and processivity, is connected to transcription-associated epigenetic marks, including H2A.Z and H3K4me3, and is required for the bulk of maintenance methylation. In contrast, AMT6 complex, with reduced activity and processivity, is recruited to initiate maintenance methylation immediately after DNA replication. These two complexes coordinate in maintenance methylation. By integrating signals from both replication and transcription, this mechanism ensures the faithful and efficient transmission of 6mA as an epigenetic mark in eukaryotes. Significance statementDNA N6-methyladenine (6mA) has recently been recognized as an epigenetic mark in eukaryotes. The stable inheritance of 6mA is essential for its biological functions. However, the precise mechanisms by which 6mA patterns are faithfully and efficiently transmitted remain largely unknown. Here, we have identified two distinct 6mA methyltransferase (MTase) complexes and elucidated their coordinated role in maintenance methylation. This dual- complex mechanism ensures rapid and accurate methylation at newly replicated loci with proper transcription-associated epigenetic marks.

molecular biology↗

Optical Torque Calculations and Measurements for DNA Torsional Studies

The angular optical trap (AOT) is a powerful instrument for measuring the torsional and rotational properties of a biological molecule. Thus far, AOT studies of DNA torsional mechanics have been carried out using a high numerical aperture oil-immersion objective, which permits strong trapping, but inevitably introduces spherical aberrations due to the glass-aqueous interface. However, the impact of these aberrations on torque measurements is not fully understood experimentally, partly due to a lack of theoretical guidance. Here, we present a numerical platform based on the finite element method to calculate forces and torques on a trapped quartz cylinder. We have also developed a new experimental method to accurately determine the shift in the trapping position due to the spherical aberrations by using a DNA molecule as a distance ruler. We found that the calculated and measured focal shift ratios are in good agreement. We further determined how the angular trap stiffness depends on the trap height and the cylinder displacement from the trap center and found full agreement between predictions and measurements. As further verification of the methodology, we showed that DNA torsional properties, which are intrinsic to DNA, could be determined robustly under different trap heights and cylinder displacements. Thus, this work has laid both a theoretical and experimental framework that can be readily extended to investigate the trapping forces and torques exerted on particles with arbitrary shapes and optical properties. SIGNIFICANCEWe developed a simulation platform based on the finite element method for force and torque calculation for particles in an angular optical trap (AOT), with considerations of tightly focused Gaussian beam, spherical aberrations, and optically anisotropic particles. Experimental measurements of focal shift ratio, force, and torque under multiple conditions were in good agreement with predictions from the simulations. We also demonstrated that intrinsic DNA torsional properties can be robustly measured under different AOT measurement conditions, strongly validating our simulations and calibrations. Our platform can facilitate trapping particle design for single-molecule assays using the AOT.

biophysics↗

Structural insights into sphingosine 1-phosphate receptor 4 activation

S1PR4 is one of five subtypes of sphingosine 1-phosphate receptors (S1PRs) that regulate immune cell functioning, with functional distinctions to other subtypes. S1PR1-targeted modulators caused serious cardiac and vascular adverse effects because S1PR1 was expressed throughout the whole body. Since S1PR4 was only expressed in lung and lymphoid cells, S1PR4-targeted modulators might not trigger these side effects. However, the development of S1PR4-specific agonists is greatly hindered because of the lack of activated S1PR4 structure. Here, we resolved cryo-EM structures of activated S1PR4 and revealed the structural mechanism of ligand recognition, receptor activation, and Gi coupling. Our results offered structural templates for the development of selective S1PR4 agonists with improved safety profiles.

biochemistry↗

Comprehensive genome annotation of the model ciliate Tetrahymena thermophila by in-depth epigenetic and transcriptomic profiling

The ciliate Tetrahymena thermophila is a well-established unicellular model eukaryote, contributing significantly to foundational biological discoveries. Despite its acknowledged importance, current Tetrahymena biology studies face challenges due to gene annotation inaccuracy, particularly the notable absence of untranslated regions (UTRs). To comprehensively annotate the Tetrahymena macronuclear genome, we collected extensive transcriptomic data spanning various cell stages. To ascertain transcript orientation and transcription start/end sites, we incorporated data of epigenetic marks displaying enrichment towards the 5 end of gene bodies, including H3 lysine 4 tri-methylation (H3K4me3), H2A.Z, nucleosomes, and N6-methyldeoxyadenine (6mA). Additionally, we integrated Nanopore direct sequencing (DRS), strand-specific RNA-seq, and ATAC-seq data. Using a newly-developed bioinformatic pipeline, coupled with manual curation and experimental validation, our work yielded substantial improvements to the current gene models, including the addition of 2,481 new genes, updates to 6,257 existing genes, and the incorporation of 5,917 alternatively spliced isoforms. Furthermore, novel UTR information was annotated for 26,223 high-confidence genes. Intriguingly, 16% of protein-coding genes were identified to have natural antisense transcripts (NATs) characterized by high diversity in alternative splicing, thus offering insights into understanding transcriptional regulation. Our work will enhance the utility of Tetrahymena as a robust genetic toolkit for advancing biological research.

bioinformatics↗

The Natural Products Discovery Center: Release of the First 8490 Sequenced Strains for Exploring Actinobacteria Biosynthetic Diversity

Actinobacteria, the bacterial phylum most renowned for natural product discovery, has been established as a valuable source for drug discovery and biotechnology but is underrepresented within accessible genome and strain collections. Herein, we introduce the Natural Products Discovery Center (NPDC), featuring 122,449 strains assembled over eight decades, the genomes of the first 8490 NPDC strains (7142 Actinobacteria), and the online NPDC Portal making both strains and genomes publicly available. A comparative survey of RefSeq and NPDC Actinobacteria highlights the taxonomic and biosynthetic diversity within the NPDC collection, including three new genera, hundreds of new species, and [~]7000 new gene cluster families. Selected examples demonstrate how the NPDC Portals strain metadata, genomes, and biosynthetic gene clusters can be leveraged using genome mining approaches. Our findings underscore the ongoing significance of Actinobacteria in natural product discovery, and the NPDC serves as an unparalleled resource for both Actinobacteria strains and genomes.

microbiology↗

CryoSTAR: Leveraging Structural Prior and Constraints for Cryo-EM Heterogeneous Reconstruction

Resolving conformational heterogeneity in cryo-electron microscopy (cryo-EM) datasets remains a significant challenge in structural biology. Previous methods have often been restricted to working exclusively on volumetric densities, neglecting the potential of incorporating any pre-existing structural knowledge as prior or constraints. In this paper, we present a novel methodology, cryoSTAR, that harnesses atomic model information as structural regularization to elucidate such heterogeneity. Our method uniquely outputs both coarse-grained models and density maps, showcasing the molecular conformational changes at different levels. Validated against four diverse experimental datasets, spanning large complexes, a membrane protein, and a small single-chain protein, our results consistently demonstrate an efficient and effective solution to conformational heterogeneity with minimal human bias. By integrating atomic model insights with cryo-EM data, cryoSTAR represents a meaningful step forward, paving the way for a deeper understanding of dynamic biological processes.1

biophysics↗

Molecular mechanism of acid stress response of A. acidoterrestris DSM 3922T under sublethal pH environment

Acid-responsive proteome expression profiles of Alicyclobacillus acidoterrestris (A. acidoterrestris) were analysed using label-free quantitative mass spectrometry to investigate its acid resistance mechanism at sublethal pH. Totally, 325 differential expression proteins were identified during acid stress at pH2.5 condition for 15 min, of which the expressions of 83 proteins were up-regulated and the other 242 proteins expressions were down-regulated. Differentially expressed proteins were mainly involved in organic nitrogen compounds metabolism, small molecule metabolism, organic acid metabolism and signal transduction. Overall, they were mapped into 97 metabolic pathways. Combination of KEGG pathway analysis and protein functional analysis suggested that the pH homeostasis system, changes in metabolic pathways, cell membrane permeability and DNA repair are the main acid resistance mechanisms of A. acidoterrestris at sublethal pH conditions. It is speculated that A. acidoterrestris may sense and transmit pH signals from the external environment through the nhaB protein which holds histidine-dependent acid resistance system, initiating a series of acid tolerance reactions. Our study demonstrated global physiological response of A. acidoterrestris to sublethal pH, which provided a better understanding of acid adaption mechanism of A. acidoterrestris.

microbiology↗