Biology subjects

Yuan, Y.

Publications and source records attributed to Yuan, Y..

At least 91 records · Page 5Linked to original sources

bioRxiv2025

Multimodal brain cell atlas across the adult macaque lifespan

High-throughput single-cell omics of non-human primate tissues present a remarkable opportunity to study primate brain aging. Here, we introduce a transcriptomic and chromatin accessibility landscape of 1,985,317 cells from eight brain regions of 13 cynomolgus female monkeys spanning adult lifespan including exceptionally old individuals up to 29-years old. This dataset uncovers dynamic molecular changes in critical brain functions such as synaptic communication and axon myelination, exhibiting a high degree of cell type and brain region specificity. We identify the multicellular networks of the pons and medulla as a previously unrecognized hotspot for aging. Furthermore, comparative analyses with human neurodegeneration datasets highlight both shared and distinct mechanisms contributing to aging and disease. In addition, we uncover transcription factors implicated in monkey brain aging and pinpoint aging-regulated loci linked to longevity and neurodegeneration. This spatiotemporal atlas will advance our understanding of primate brain aging and its broader implications for health and disease.

neuroscience↗

bioRxiv2025

TXA11114: Discovery of an in vivo efficacious efflux pump inhibitor in Pseudomonas aeruginosa

Multi-drug resistance in Pseudomonas aeruginosa is often associated with overexpression of drug efflux pumps which limit antibiotics exposure. So far, successful development of efflux pump inhibitors (EPIs) has been plagued by undesirable toxicities and inconsequential in vivo efficacy. TAXIS Pharmaceuticals Inc. has discovered an effective anti-pseudomonal therapy involving a novel indole carboxamide class of EPI, TXA11114, with a fluorine substituted diamine sidechain, as an adjunctive to levofloxacin. TXA11114 has demonstrated excellent potentiation of levofloxacin MIC by [≥] 8-fold in 90% of Walter-Reed and CDC multi-drug resistant (MDR) isolates. Biophysical and genetic studies with TXA11114 support efflux inhibition while ruling out membrane disruption as a mechanism of action. TXA11114 enhanced the levofloxacin killing and diminished the frequency of resistance emergence to levofloxacin to undetectable levels. Moreover, in murine thigh and lung P. aeruginosa infection models, the TXA11114-levofloxacin combination showed pronounced killing compared to levofloxacin alone, achieving a validated in vivo efficacy milestone that previous EPIs could not. Most importantly, TXA11114 exhibits a safe toxicology profile when screened for cytotoxicity, hERG channel inhibition, in vitro nephrotoxicity, and acute toxicity. Further, pharmacokinetic (PK) parameters of TXA11114 have a complementary profile with that of levofloxacin in plasma and bronchoalveolar lavage fluid (BALF) samples of infected mice, maximizing pharmacodynamic (PD) benefits. Overall, studies on the TXA11114-levofloxacin combination highlight its potential as an anti-pseudomonal agent for combating multidrug-resistant infections.

microbiology↗

bioRxiv2025

Transcriptome-wide Identification of GlycoRNAs by Clier-seq Pipeline

RNA molecules can undergo modification by N-glycans and be displayed on the cell surface. However, recent studies have focused primarily on N-glycan modifications on small RNAs less than 200 nt in length; the transcriptome-wide subtypes of glycosylated RNAs (glycoRNAs) remain poorly characterized. A validation system, which represents only a fraction of the total transcripts, has yet to be established to analyze glycoRNAs accurately. In this study, we aimed to comprehensively characterize transcriptome-wide global glycoRNAs and novel glycoRNA subtypes in both epithelial cells and B cells. Using metabolic labeling and density gradient centrifugation methods, we identified glycoRNAs predominantly below 2000 nt in both epithelial cells and B cells. We then developed the Clier-seq (Click chemistry-based enrichment of glycoRNAs sequencing) method to maximize the coverage of glycoRNAs (ranging from 50 to 2000 nt) and utilized the HISAT-StringTie-Ballgown pipeline to predict novel glycoRNA subtypes. We also established Clier-qPCR assays (click chemistry-based enrichment of glycoRNAs RT-qPCR) to validate the specificity of the candidate glycoRNAs. We demonstrated that transfer RNAs (tRNAs), particularly tRNAs (Ser), tRNAs (Thr), tRNAs (Val), and tRNAs (lys), are the primary targets of glycosylation. Additionally, we found that vault RNAs (vtRNAs), specifically vtRNA2-1, are glycosylated. Furthermore, we discovered several novel glycosylated long noncoding RNAs ranging from 200-400 nt in length. Herein, we propose a standardized bioinformatics pipeline for glycoRNA research, enabling accurate and comprehensive identification of glycoRNAs throughout the transcriptome.

molecular biology↗

bioRxiv2025

Dietary cysteine enhances intestinal stemness via CD8+ T cell-derived IL-22

A critical question in physiology is understanding how tissues adapt and alter their cellular composition in response to dietary cues. The mammalian small intestine, a vital digestive organ that absorbs nutrients, is maintained by rapidly renewing Lgr5+ intestinal stem cells (ISCs) at the intestinal crypt base. While Lgr5+ ISCs drive intestinal adaptation by altering self-renewal and differentiation divisions in response to diverse diets such as high-fat diets and fasting regimens, little is known about how micronutrients, particularly amino acids, instruct Lgr5+ ISC fate decisions to control intestinal homeostasis and repair after injury. Here, we demonstrate that cysteine, an essential amino acid, enhances the ability of Lgr5+ ISCs to repair intestinal injury. Mechanistically, the effects of cysteine on ISC-driven repair are mediated by elevated IL-22 from intraepithelial CD8{beta}+ T cells. These findings highlight how coupled cysteine metabolism between ISCs and CD8+ T cells augments intestinal stemness, providing a dietary approach that exploits ISC and immune cell crosstalk for ameliorating intestinal damage.

cell biology↗

bioRxiv2025

Decoding auditory working memory load from EEG alpha oscillations

Working memory (WM) enables temporary retention of task-relevant information for imminent use. Increases in visual WM load are accompanied by elevated contralateral delay activity (CDA), and EEG alpha-band power. While most WM research focuses on the visual domain, it remains unknown whether similar EEG responses also reflect WM load in the auditory domain. Using EEG, we set out to establish such neural markers of auditory WM load. Participants memorized the pitches of 1 to 4 pure tones presented to one ear, with 1 to 4 identical distractor tones presented to the other ear. Behaviorally, auditory WM capacity plateaued between set-sizes two and three. Unlike for visual WM, auditory WM load was not reflected in lateralized EEG responses. This shows that the CDA is a vision-specific rather than domain-general neural marker of WM load. Applying multivariate pattern analyses on the delay activity revealed that auditory WM load is reflected in patterns of alpha-band oscillations. Surprisingly, a temporal generalization analysis revealed that the alpha patterns reflecting specific load conditions changed throughout the maintenance period (despite load being inherently constant), revealing dynamic coding of auditory WM load.

neuroscience↗

bioRxiv2025

Effective in vivo RNA base editing via engineered cytidine deaminase APOBECs fused with PUF proteins

Base editing stands at the forefront of genetic engineering, heralding precise genetic modifications with broad implications. While CRISPR-based DNA and RNA base editing systems capitalize on sgRNA-guided specificity and diverse deaminase functionalities, the pursuit of efficient C-to-U RNA editing has been hampered by the inherent constraints of cytidine deaminases. Here, we report an RNA base editing platform by refining cytidine deaminases, termed professional APOBECs (ProAPOBECs), through systematic enhancements and AI-driven protein engineering. ProAPOBECs demonstrate unprecedented catalytic versatility, particularly fused with RNA-recognizing Pumilio and FBF (PUF) proteins. We present the first effective use of RNA base editing in the brain with ProAPOBECs in Mef2c mutant mice, a model for autism. The AAV-mediated RNA base editing via ProAPOBEC not only corrects genetic mutation in mRNAs but significantly alleviates autistic-like behaviors in the mice. This work introduces a pioneering collection of RNA base editing instruments, emphasizing their therapeutic potential in combatting genetic disorders.

molecular biology↗

bioRxiv2025

Single-Cell Genomics Elucidates Molecular Variations and Regulatory Mechanisms in Circulating Immune Cells

The human peripheral blood displays diverse molecular characteristics across populations, understanding the drivers and underlying mechanisms of which remains challenging. Here, we introduce the Chinese Immune Multi-Omics Atlas (CIMA), elucidating sex-, age-, and genetic-related molecular variations by analyzing multi-omics data from 428 adults with over 10 million immune cells. CIMA generated an enhancer-driven gene regulatory network, identifying 237 high-quality regulons and revealing cell type-specific regulatory mechanisms. Additionally, 11,521 lead cis-expression quantitative trait loci (eQTLs) and 46,339 chromatin accessibility QTLs (caQTLs) were identified at cell type level. CIMA also uncovered pleiotropic associations among immune-related disease risk loci, eQTLs, and caQTLs in a cell type-specific manner. Lastly, a novel cell language model, CIMA-CLM, was developed to predict chromatin accessibility and noncoding variant effects using chromatin sequences and gene expressions. This work represents a population-scale multi-omics resource of human immune cells, providing a valuable reference for future investigation of immune-related diseases.

immunology↗

bioRxiv2025

From spots to stripes: Evolution of pigmentation patterns in monkeyflowers via modulation of a reaction-diffusion system and its prepatterns

The reaction-diffusion (RD) system is widely assumed to account for many complex, self- organized pigmentation patterns in natural organisms. However, the specific configurations of such RD networks and how RD systems interact with positional information (i.e., prepatterns) that may specify the initiation conditions for the RD operation remain largely unknown. Here, we introduced a three-substance RD system underlying the formation of repetitive pigment spots and stripes in Mimulus flowers. It consists of an R2R3-MYB activator (NEGAN), an R3-MYB inhibitor (RTO), and a coactivator represented by two paralogous bHLH proteins. Through fine- scale genetic analyses, transgenic experiments, and computer simulations, we identified the causal loci contributing to the evolutionary transition from sparsely dispersed spots to longitudinal stripes. Genetic changes at these loci modulate the prepatterns of the activator and coactivator expression and the promoter activities of the inhibitor and one of the coactivator paralogs. Our findings highlight the importance of prepatterns towards a realistic description of RD systems in natural organisms, and reveal the genetic mechanism generating pattern variation through modulation of the kinetics of the RD system and its prepatterns.

developmental biology↗

bioRxiv2025

Looking for the optimal pathway to stimulate hippocampus in human participants using transcranial ultrasound stimulation (TUS): a simulation study

At present, very limited methods can directly modulate the neural activities in deep brain structures in human participants. Low-intensity transcranial ultrasound stimulation (TUS), as an emerging and advanced modality of non-invasive brain stimulation (NIBS), has great potential for focally stimulating the subcortical structures that are related to sleep, emotion and the functions of motor of cognition. Due to the focality, the integration of various methods, including magnetic resonance imaging and possible pathways, is important to perform TUS intervention for precise targeting and dosing. Based on structural MRI scans, we constructed a simulation model of low-intensity TUS, with a particular focus on the optimal pathways of targeting hippocampus in human participants. Finally, we outlooked the future perspectives of TUS in clinical applications in neurological and psychiatric fields.

neuroscience↗

bioRxiv2024

Single-cell analysis of the epigenome and 3D chromatin architecture in the human retina

Most genetic risk variants linked to ocular diseases are non-protein coding and presumably contribute to disease through dysregulation of gene expression, however, deeper understanding of their mechanisms of action has been impeded by an incomplete annotation of the transcriptional regulatory elements across different retinal cell types. To address this knowledge gap, we carried out single-cell multiomics assays to investigate gene expression, chromatin accessibility, DNA methylome and 3D chromatin architecture in human retina, macula, and retinal pigment epithelium (RPE)/choroid. We identified 420,824 unique candidate regulatory elements and characterized their chromatin states in 23 sub-classes of retinal cells. Comparative analysis of chromatin landscapes between human and mouse retina cells further revealed both evolutionarily conserved and divergent retinal gene-regulatory programs. Leveraging the rapid advancements in deep-learning techniques, we developed sequence-based predictors to interpret non-coding risk variants of retina diseases. Our study establishes retina-wide, single-cell transcriptome, epigenome, and 3D genome atlases, and provides a resource for studying the gene regulatory programs of the human retina and relevant diseases.

genomics↗

bioRxiv2024

A Witches' Broom Phytoplasma effector induces stunting by stabilizing a bHLH transcription factor in plants

O_LIPhytoplasmas are specialized phloem-limited bacteria that cause diseases on various crops resulting in significant agricultural losses. This research focuses on the jujube Witches Broom (JWB) phytoplasma and investigates the host-manipulating activity of the effector SJP39. C_LIO_LIWe found that SJP39 directly interacts with the plant transcription factor bHLH87 in the nuclei. SJP39 stabilizes the bHLH87 homologs in A. thaliana and jujube, leading to growth defects in the plants. C_LIO_LITranscriptomic analysis indicates that SJP39 affects the gibberellin (GA) pathway in jujube. We further demonstrate that ZjbHLH87 regulates GA signalling as a negative regulator and SJP39 enhances this regulation. C_LIO_LIThe research offers important insights into the pathogenesis of JWB disease and identified SJP39 as a virulence factor that can contribute to the growth defects caused by JWB phytoplasma infection. These findings open new opportunities to manage JWB and other phytoplasma diseases. C_LI

plant biology↗

bioRxiv2024

TSvelo: Comprehensive RNA velocity inference by jointly modeling Transcription and Splicing

RNA velocity approaches fit gene dynamics and infer cell fate by modeling the splicing process using single-cell RNA sequencing (scRNA-seq) data. However, due to short time scale of splicing, high noise and large complexity of data, existing RNA velocity methods often fail to precisely capture the complex velocity dynamics for individual gene and single cell, which makes its downstream analysis less reliable and less robust. We propose TSvelo, a comprehensive RNA velocity mathematics framework that can model the cascade of gene regulation, Transcription and Splicing using highly interpretable neural Ordinary Differential Equations (ODEs). TSvelo can precisely capture the transcription-unspliced-spliced 3D dynamics of all genes simultaneously, infer unified latent time shared by genes within single cell, and be applied to multi-lineage datasets. Experiments on six scRNA-seq datasets, including two multi-lineage datasets, demonstrate TSvelos superiority.

bioinformatics↗

bioRxiv2024

Vascular endothelial growth factor-D improves lung vascular integrity during acute lung injury

Disorders in pulmonary vascular integrity are a prominent feature in many lung diseases. Paracrine signaling is highly enriched in the lung and plays a crucial role in regulating vascular homeostasis. However, the specific local cell-cell crosstalk signals that maintain pulmonary microvascular stability in adult animals and humans remain largely unexplored. In this study, we employed single-cell RNA-sequencing (scRNAseq)-based computational pipelines to systematically profile ligand-receptor (L/R) interactions within the lung microvascular niche and identified vascular endothelial growth factor-D (VEGF-D) as a key local factor with previously unrecognized barrier-protective properties in models of acute lung injury. Our scRNAseq data revealed that, under physiological conditions, soluble L/R interactions between mesenchymal cells, in particular alveolar fibroblast, and microvascular endothelial cells are predominantly associated with pathways involved in maintaining vascular integrity as compared to all other cells. Upon treatment with top identified ligands, we found that VEGF-D significantly enhanced endothelial barrier function and conferred protection against inflammatory challenges induced by tumor necrosis factor- (TNF-), interleukin-1{beta} (IL-1{beta}), and thrombin. This barrier-protective effect of VEGF-D was significantly attenuated by inhibition of VEGFR2, either through siRNA knockdown or pharmacological blockade using specific VEGFR2 inhibitors. Intravenous administration of recombinant VEGF-D in lipopolysaccharides (LPS)-induced acute lung injury models significantly reduced vascular permeability (7339 {+/-} 2510 (LPS) v.s. 5350 {+/-} 1821 (LPS + VEGF-D), p < 0.05), immune cell infiltration (0.791 {+/-} 0.199 x 106 WBC/mL (LPS) v.s. 0.540 {+/-} 0.190 x 106 WBC/mL (LPS + VEGF-D), p < 0.01), and the expression of pro-inflammatory markers TNF- and IL-6 in the lung tissue. This effect was abolished in VEGFR2iECKO mice, confirming that VEGF-D mediates its effects via VEGFR2-dependent signaling. This study demonstrates an unexpected protective role for VEGF-D in promoting lung endothelial barrier integrity and suggests that paracrine signaling from the alveolar fibroblast niche contributes critically to lung capillary homeostasis.

molecular biology↗

bioRxiv2024

The oncogene SLC35F2 is a high-specificity transporter for the micronutrients queuine and queuosine

The nucleobase queuine (q) and its nucleoside queuosine (Q) are micronutrients derived from bacteria that are acquired from the gut microbiome and/or diet in humans. Following cellular uptake, Q is incorporated at the wobble base (position 34) of tRNAs with a GUN anticodon, which is important for efficient translation. Early studies suggested that cytosolic uptake of queuine is mediated by a selective transporter that is regulated by mitogenic signals, but the identity of this transporter has remained elusive. Here, through a cross-species bioinformatic search and genetic validation, we have identified the solute carrier family member SLC35F2 as a unique transporter for both queuine and queuosine in Schizosaccharomyces pombe and Trypanosoma brucei. Furthermore, gene disruption in HeLa cells revealed that SLC35F2 is the sole transporter for queuosine in HeLa cells (Km 174 nM) and a high-affinity transporter for the queuine nucleobase (Km 67 nM), with the presence of another low-affinity transporter (Km 259 nM) in these cells. Competition uptake studies show that SLC35F2 is not a general transporter for other canonical ribonucleobases or ribonucleosides, but selectively imports q and Q. The identification of SLC35F2, an oncogene, as the transporter of both q and Q advances our understanding of how intracellular levels of queuine and queuosine are regulated and how their deficiency contributes to a variety of pathophysiological conditions, including neurological disorders and cancer. Significance StatementThe discovery of SLC35F2 as the eukaryotic transporter of queuine and queuosine is key to understanding how these micronutrients are salvaged from the human gut and distributed to different body tissues. Queuosine modification of tRNAs enhances the accuracy and efficiency of codon-anticodon pairing and regulates a range of biological and pathophysiological states, including oxidative stress responses, cancer, learning, memory, and gut homeostasis.

biochemistry↗

bioRxiv2024

The glycosyltransferase POGLUT1 regulates muscle stem cell development and maintenance in mice

Mutations in protein O-glucosyltransferase 1 (POGLUT1) cause a recessive form of limb-girdle muscular dystrophy (LGMD-R21) associated with reduced satellite cell number and NOTCH1 signaling in adult patient muscles and impaired myogenic capacity of patient-derived muscle progenitors. However, the in vivo roles of POGLUT1 in the development, function, and maintenance of satellite cells are not well understood. Here, we show that conditional deletion of mouse Poglut1 in myogenic progenitors leads to early lethality, postnatal muscle growth defects, reduced Pax7 expression, abnormality in muscle extracellular matrix, and impaired muscle repair. Poglut1-deficient muscle progenitors exhibit reduced proliferation, enhanced differentiation, and accelerated fusion into myofibers. Inducible loss of Poglut1 in adult satellite cells leads to their precocious differentiation and impairs muscle repair upon serial injury. Cell-based signaling assays and mass spectrometric analysis indicate that POGLUT1 is required for the activation of NOTCH1, NOTCH2, and NOTCH3 in myoblasts and that NOTCH3 is a target of POGLUT1 like NOTCH1 and NOTCH2. These observations provide insight into the roles of POGLUT1 in muscle development and repair and the pathophysiology of LGMD-R21.

developmental biology↗

bioRxiv2024

CellPatch: a Highly Efficient Foundation Model for Single-Cell Transcriptomics with Heuristic Patching

The rapid advancement of foundation models has significantly enhanced the analysis of single-cell omics data, enabling researchers to gain deeper insights into the complex interactions between cells and genes across diverse tissues. However, existing foundation models often exhibit excessive complexity, hindering their practical utility for downstream tasks. Here, we present CellPatch, a lightweight foundation model that leverages the strengths of the cross-attention mechanism and patch tokenization to reduce model complexity while extracting efficient biological representations. Comprehensive evaluations conducted on single-cell RNA-sequencing datasets across multiple organs and tissue states demonstrate that CellPatch achieves state-of-the-art performance in downstream analytical tasks while maintaining ultra-low computational costs during both pretraining and finetuning phases. Moreover, the flexibility and scalability of CellPatch allow it to serve as a general framework that can be incorporated with other well established single-cell analysis software, thereby enhancing their performance through transfer learning on diverse downstream tasks.

bioinformatics↗

bioRxiv2024

Synergistic effects of tRNA modification defects in Escherichia coli K12.

Transfer RNAs (tRNAs) are essential components of the translation machinery and carry numerous post-transcriptional modifications that contribute to decoding accuracy, efficiency and cellular fitness. In Escherichia coli K-12, all tRNA modification pathways have been identified, yet the functional interactions between these pathways remain largely unexplored. Here, we systematically analyze genetic interactions between 29 non-essential tRNA modification genes using a pairwise synthetic lethal screen based on P1 transduction. Most combinations of tRNA modification gene deletions are tolerated during growth in rich medium; however, we identify five synthetically lethal pairs and fifteen additional combinations that display negative genetic interactions. Deletions of truA, which encodes the pseudouridine synthase responsible for modifications at positions 38-40 of multiple tRNAs, show the highest frequency of negative epistasis. Synthetic lethality associated with truA can be complemented by expression of truA in trans and, in specific cases, partially suppressed by overexpression of its tRNA substrates, indicating substrate-specific functional dependencies. Analysis of tRNA abundance by northern blotting and AQRNA-seq demonstrates that loss of individual tRNA modification enzymes does not generally lead to widespread tRNA destabilization. Instead, further phenotypic characterization of viable double mutants reveals condition-dependent growth defects influenced by carbon source, temperature and metabolic stress, as well as toxicity associated with overexpression of specific tRNAs. Together, these results reveal a limited but distinct set of genetic interactions among bacterial tRNA modification pathways and highlight the importance of physiological context in uncovering their cellular roles.

microbiology↗

bioRxiv2024

Single-nucleus multiple-organ chromatin accessibility mapping in the rat

The chromatin accessibility landscape is the basis of cell-specific gene expression. We generated a multiorgan, single-nucleus chromatin accessibility landscape from the model organism Rattus norvegicus. For this single-cell atlas, we constructed 25 libraries via snATAC-seq from nine organs in the rat, with a total of over 110,000 cells. Cell classification integrating gene activity scores with known marker genes identified 77 cell types, which were strongly correlated with those in published mouse single-cell transcriptome atlases. We further investigated the enrichment of cell type- and organ-specific transcription factors (TFs), the dynamics of T-cell developmental trajectories across organs, and the conservation and specificity of gene expression patterns across species. These findings provide a foundation for further investigations of the cell composition and gene regulatory networks throughout the rat body. HighlightsO_LIGeneration of a single-cell atlas of chromatin accessibility in nine organs of the rat C_LIO_LICharacterization of cell type- and organ-specific transcription factors (TFs) C_LIO_LIDynamics of chromatin accessibility in developing T cells revealed by cross-organ analysis C_LIO_LIConservation and specificity of gene expression patterns among humans, mice, and rats revealed by cross-species analysis C_LI

genomics↗