Biology subjects

Liang, Y.

Publications and source records attributed to Liang, Y..

At least 73 records · Page 4Linked to original sources

bioRxiv2025

Cell type diversification and phenotype convergence underlying white fin-ornamentation of cyprinid fishes

Neural crest derived cells offer valuable opportunities to dissect mechanisms of cell fate specification and differentiation within individual ontogenies and the underpinnings of cell type diversification over evolutionary time. Particularly useful for such analyses are pigment cells of ectothermic vertebrates that arise from neural crest cells, or via latent neural crest derived stem cells, and comprise several classes with cell-type specific pigmentary phenotypes. Among these are white cells, "leucophores," present in a variety of species that contribute to patterns on the body or ornamentation on the fins. To better understand developmental and evolutionary origins of these cells we have examined leucophores harboring deposits of yellow/orange carotenoids, "xantholeucophores," of zebrafish and leucophores of white cloud minnow, within the same family Cyprinidae. We show that white phenotypes of both cell types require sepiapterin reductase that promotes accumulation of pale and colorless pteridines. We further demonstrate that xantholeucophores develop directly from yellow sepiapterin rich xanthophore-like cells and that this transition requires both gap junctional activity and permeability of the aquaglyceroporin / peroxiporin channel Aquaporin 3. These findings identify these white cells as distinct developmentally, genetically, and biochemically from another type of white cell in zebrafish and other white cells present across phylogenetic lineages. Our results highlight remarkable convergences and parallelisms in the acquisition of white cell phenotypes within and between species and identify this as a rich system for enquiries into the evolutionary individuation of novel cell types. SignificanceUnderstanding how cell types arise is fundamental to explaining animal complexity. Pigment cells offer opportunities to address this question because they display striking variation. We show that white pigment cells comprise multiple classes with independent origins. In zebrafish, white cells on one fin develop from melanophores whereas white cells on another fin develop from yellow precursors that convert their pigments to colorless ones. White cells of a related minnow require the same colorless pigments yet differ in other ways. These findings illuminate remarkable convergence: white cells have arisen repeatedly from different progenitor cell lineages by different mechanisms. This diversity--even within and between closely related species--identifies a powerful model for understanding the evolution of cell types with distinct identities and functions.

developmental biology↗

bioRxiv2025

Cortical microglia promote noradrenergic signaling to maintain wakefulness

Microglia are essential for maintaining brain homeostasis, including the sleep-wake cycle, but the underlying mechanisms remain unclear. Here, using in vivo two-photon imaging in both head-fixed and freely moving mice with simultaneous electroencephalogram-electromyogram (EEG-EMG) recording, we investigated microglial process dynamics and their interactions with locus coeruleus (LC) noradrenergic (NE) axons in the frontal cortex across sleep-wake states. During sleep or chemogenetic suppression of LC neurons, microglia enhanced their surveillance and increased interactions with NE axons. Correlative electron microscopy at nanometer resolution identified structural contacts between microglial process endings and NE boutons. Mechanistically, microglia-bouton interaction is primed by NE-{beta}2-adrenergic receptor ({beta}2AR) signaling, leading to enhanced Ca{superscript 2} activity in NE axons. These findings suggest that microglial interactions with NE axons promote cortical norepinephrine transmission and maintain stable wakefulness.

neuroscience↗

bioRxiv2025

Cross-species etiologically informed stratification enables T cell receptor-based diagnosis of Parkinson's Disease

BackgroundDeveloping peripheral blood-based diagnostic models for idiopathic Parkinsons disease (iPD), particularly those leveraging the T-cell receptor (TCR) repertoire, has long been considered infeasible because patient-derived TCRs appear to lack convergent sequence motifs. We reasoned that this apparent absence of shared TCR features likely reflects both insufficient sample sizes and unaccounted immune heterogeneity within the iPD population. MethodsWe reconstructed TCR repertoires from the two largest iPD cohorts currently available, anchoring them with three mechanistically distinct mouse models to stratify patients into model-anchored informed subtypes. Within these data-driven subtypes, we trained subtype-specific, multimodal multi-instance classifiers. ResultsWe demonstrated that iPD patients can be successfully stratified into model-anchored informed subtypes. Furthermore, the trained subtype-specific, multimodal multi-instance classifiers achieved an Area Under Curve (AUC) exceeding 0.8 for both subtypes. ConclusionsOur findings underscore the critical role of disease stratification in enabling TCR repertoire-based modeling in neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Plasma plasmalogen levels and risk of lymph node positive breast cancer

Lymph node involvement is a key predictor of poor breast cancer prognosis. Systemic lipid alterations can contribute to cancer cell survival in lymph nodes, but their relevance in humans remains unclear. Here, we combine human epidemiologic analyses from the Nurses Health Study 2 and complementary mechanistic studies in mouse models to investigate how systemic lipid profiles relate to lymph node positive breast cancer. We show that in pre-diagnostic human plasma (n=511), lower levels of phosphatidylethanolamine (PE) and phosphatidylcholine (PC)-enriched plasmalogens are associated with increased risk of lymph node positivity, with stronger associations in samples collected closer to diagnosis. Consistent with the human data, lower levels of PE and PC-enriched plasma plasmalogens are found in mice with nodal involvement. Furthermore, in mice, dietary PUFA depletion reduces lipid oxidation in breast cancer cells in lymph nodes and promotes their survival and metastatic spread. These findings suggest that reduced levels of PE and PC-plasmalogens and decreased PUFA availability creates a lipid environment that enables breast cancer lymph node involvement.

cancer biology↗

bioRxiv2025

Satellite microglia gate neuronal excitability by shielding inhibitory synapses in adult brain

Microglia, the primary immune cells of the central nervous system, are known for sculpting excitatory neural circuits via dynamic processes. However, their role in modulating inhibitory synaptic connections in adulthood remains largely unexplored. In this study, we identified an underappreciated microglia subpopulation, satellite microglia with physical soma-soma contact with neurons, that reshape inhibitory circuit connectivity and gate neuronal activity by shielding inhibitory synapses in the adult mouse brain. Using chronic in vivo two-photon imaging in adult mice, we observed in real time that satellite microglia associations displaced perisomatic inhibitory synapses whereas their dissociation permitted inhibitory synaptogenesis. Redistribution of satellite microglia reorganized inhibitory connectivity, altered local neural networks and changed behaviors. These findings establish satellite microglia as key architects of inhibitory circuitry and suggest their broader role in neural plasticity in health and disease.

neuroscience↗

bioRxiv2025

Ecology of hydrocarbon degradation in widespread viruses

Hydrocarbons are vital for energy production and lead to serious environmental issues due to pollution. Microorganisms largely drive the production and degradation of hydrocarbons, yet little is known about viral contributions to hydrocarbon degradation. Here we identified 786 viral contigs from IMG/VR(v4), encoding five aerobic (alkB, ladA, almA, ndoB and dszC) and three anaerobic (bssA, ebdA and abcA) hydrocarbon-degrading genes (HDGs). vOTUs encoding HDGs span 26 distinct viral families, including 249 are mainly associated with host-associated environment and 463 are derived from aquatic habitat, respectively, implying that these viruses are broadly engaged in hydrocarbon-degradation processes across the entire biosphere. alkB (35%) and almA (28%) was tended to be encoded by Schizomimiviridae, bssA was tended to be encoded by T5-like bacteriophages (29%) and SPO1-like bacteriophages (22%), suggesting that the carriage of HDGs by viruses exhibits taxonomic specificity. With respect to host associations, Pseudomonadota and Bacillota constitute the two main potential host lineages, associated with 268 and 71 vOTUs, respectively. The profiling of ecological footprint reveals that viruses contribute a total of up to 30% gene abundance and 32% transcribing activity to hydrocarbon degradation in the global ocean. This study systematically revealed the distribution, diversity, virus-host correlation and activity of virus-encoded HDGs, underscoring the significant role of viruses in hydrocarbon metabolism on a global scale.

ecology↗

bioRxiv2025

Graded BMP signals modulate yellow and red color in fishes impacting adult pigment pattern and behavior

Among the most interesting adult traits are those with roles in animal communication. Yet developmental mechanisms by which genes drive cell behaviors in building the final forms of such traits are rarely known. In this context, pigmentation is useful because colors and patterns often provide signals in mate choice, predation avoidance and other behaviors and pigmentation is unusually accessible to observation and manipulation. Here we focus on some of the most prominent signaling colors--red, orange and yellow--and show how BMP signaling at the cellular level allows for a very different kind of signal at the organismal level. Using pearl danio, Danio albolineatus, we find that spatially and temporally graded BMP signals promote development of yellow/orange xanthophores over red erythrophores in the fin of this species and a distantly related minnow, Tanichthys albonubes, and that conserved mechanisms, involving BMP co-receptor Rgmb, regulate differentiation of other pigment cell types in corresponding locations of zebrafish, D. rerio. We further use mutants of D. albolineatus with more red or more yellow cells than wild-type to demonstrate female responsiveness to carotenoid-based color differences between males in shoaling preference assays, and we show the existence of polygenic standing variation for this pigmentary trait. Our findings illustrate a chain of function spanning hierarchical levels and provide a deeper understanding of pigmentary form and function and its evolution. HIGHLIGHTSO_LIFate specification of alternative red or yellow pigment cell types in the fin of a minnow, pearl danio, depends on thresholds and gradients in BMP signaling during fin outgrowth. C_LIO_LIGenetic loss of BMP signaling leads to production of red over yellow carotenoids with resulting "super-red" fish preferred by females in shoaling assays. C_LIO_LIBMP-dependence of pigmentary traits is conserved across species with standing, polygenic variation for fin pattern and color in pearl danio. C_LI

developmental biology↗

bioRxiv2025

The m6A reader protein YTHDF2 facilitates HTLV-1 infectious and mitotic propagation by stabilizing Tax RNA

N6-methyladenosine (m6A) is one of the important RNA modifications that affect RNA abundance and function and has also been implicated in viral infection. In this study, we identify a number of m6A modification sites within human T-cell leukemia virus type 1 (HTLV-1) RNAs, particularly in the RNA of the Tax oncogene. We demonstrate that YTH domain family, member 2 (YTHDF2), a key m6A reader protein that binds m6A-modified RNAs and influences RNA metabolism, is required for HTLV-1 replication in both de novo and persistently infected cells. Mechanistically, YTHDF2 interacts with and stabilizes Tax RNA in an m6A-dependent manner, thereby promoting Tax-driven HTLV-1 replication. Importantly, YTHDF2 activates oncogenic cellular pathways and promotes proliferation in HTLV-1 infected cells, aligning with the functions of Tax. Overall, our findings characterize YTHDF2 as a host factor critical to HTLV-1 RNA metabolism and viral propagation, offering novel insights into the understanding of HTLV-1 life cycle and the development of targeted interventions. Importancem6A is an RNA modification that plays crucial roles in physiological and pathological conditions; however, its roles in HTLV-1 infection are poorly understood. In this study, we identify that m6A modification is widely present in HTLV-1 RNAs including Tax. We demonstrate that YTHDF2, a prominent m6A reader protein, enhances the stability of Tax RNA, thereby promoting both de novo and persistent HTLV-1 replication. Our findings position YTHDF2 as an essential factor for HTLV-1 persistence and suggest it as a potential therapeutic target for viral clearance.

microbiology↗

bioRxiv2025

Binary vector origin predictably determines Agrobacterium-mediated transformation outcome across eukaryotic kingdom

Agrobacterium-mediated transformation (AMT) is the primary means of genetic engineering in plants and many fungi, but the factors that control transformation outcomes--efficiency, transgene insertion number, and transgene integrity--remain poorly characterized. Although transformation outcomes dictate an events potential utility in both industrial and academic contexts, AMT remains largely unoptimized for these metrics. Here, we systematically analyze the impact of the transgene-harboring binary vector on transformation outcomes across plant and fungal species. Through a comparison of different plasmid origin of replication (ORI) families and engineered copy number variants, our results reveal that the ORI family--not plasmid copy number--dictates T-DNA insertion number, backbone inclusion, and transformation efficiency, while plasmid copy number tuning alters efficiency without changing ORI family-specific signatures. Independent of plasmid copy number across kingdoms, the most widely used pVS1 ORI-based vectors (e.g. pCambia) result in significantly more insertions per transformant and high levels of transgene silencing compared to the less-utilized pSa ORI family, which enriches for more uniform single insertion events. Furthermore, we demonstrate that ORI-dependent transformation outcomes in yeast predictably reflect those in Arabidopsis. Together, these results lay the foundation for future binary vector design aimed at achieving more predictable, controllable, and optimized transformation outcomes across diverse eukaryotic hosts.

plant biology↗

bioRxiv2025

Systems analysis reveals alternate metabolic states adopted by Mycobacterium tuberculosis across species

Mycobacterium tuberculosis (Mtb) persists within macrophages, yet how different host species shape bacterial state remains poorly understood. Here, we directly compared the intracellular transcriptome of Mtb during infection of human and mouse macrophages, revealing distinct host-imposed microenvironments that drive the pathogen into separable metabolic states. Lipid metabolism and regulatory circuits were prominently remodeled, with mouse macrophages inducing iron- and oxidative-stress responses while human macrophages promoted fatty acid import programs. Using fluorescent fatty acid tracing, we uncovered a striking species-specific phenotype: Mtb forms intracellular lipid inclusions (ILIs) in murine macrophages but not in human macrophages. This phenotype was independent of culture media, macrophage ontogeny, or host antimicrobial factors such as nitric oxide and itaconate. Access of Mtb to host-derived lipids required the ESX-1 secretion system and was inversely correlated with host triacylglycerol (TAG) synthesis. Inhibition of TAG formation in human macrophages partially restored Mtb ILI formation, revealing a metabolic gate that governs lipid flow between host lipid droplets and intracellular Mtb. Together, these findings establish a cross-species framework for decoding host-driven bacterial metabolic states and identify a key barrier limiting Mtbs access to host lipid stores in human macrophages.

microbiology↗

bioRxiv2025

MetaboliteChat: A Unified Multimodal Large Language Model for Interactive Metabolite Analysis and Functional Insights

Accurately characterizing the mechanisms and properties of metabolite molecules is essential for advancing metabolomics and systems biology. Yet most existing approaches are narrow, task-specific models that do not transfer across tasks and cannot express the richer, multimodal biological context of a metabolite in natural language. To address these challenges, we introduce MetaboliteChat, a multimodal ChatGPT-like large language model (LLM) that provides a unified and interactive framework for metabolite analysis. MetaboliteChat integrates molecular-graph and image reasoning with natural language understanding to generate comprehensive, free-form predictions about metabolite mechanisms and properties. The MetaboliteChat architecture consists of a graph neural network (GNN), a convolutional neural network (CNN), a large language model (LLM), and adapters, all trained end to end. This unified, multimodal design enables interactive reasoning over unseen metabolites, allowing the model to integrate structural and contextual cues and support discovery and translational insights across diverse biological systems.

bioinformatics↗

bioRxiv2025

Retinal ganglion cell input to superior colliculus encodes salient information

The superior colliculus (SC) is critical in detecting and responding to salient stimuli. However, it is unknown whether salience signals are inherited from external sources such as retina and cortex, or arise from the intrinsic circuitry within SC. We used in vivo 2-photon calcium imaging with adaptive optics to examine the activity of retinal ganglion cell (RGC) axon terminals in superficial SC (sSC). We found that RGC boutons exhibit similar saliency-related activity as sSC neurons. A majority of boutons respond more strongly to salient discontinuities of visual features, and change their orientation preference depending on stimulus properties such as the orientations of edges of drifting gratings. We furthermore demonstrate that these effects arise from the center-surround receptive field structure of RGCs. Our results show that the orientation tuning of RGCs is highly flexible, and that saliency encoding originates in retina rather than sSC.

neuroscience↗

bioRxiv2025

A chromosome-level assembly and functional genomic resources for the model annelid Capitella teleta

BackgroundThe polychaete Capitella teleta is a commonly used annelid for studies in evolutionary developmental biology, comparative genomics, conservation, and ecotoxicology. Over a decade ago, it was the first polychaete to have its genome sequenced and assembled, contributing to pioneering studies that transformed our understanding of animal genomes and their evolution. However, this early resource is now outdated compared to current genome sequencing standards, limiting the use of modern functional genomic tools that could further our understanding of numerous biological processes. ResultsWe combine long-read and short-read sequencing with Hi-C chromatin conformation capture data to assemble the chromosome-level nuclear and mitochondrial genomes of the laboratory strain of C. teleta. This reference assembly more accurately reflects the expected genome size for this polychaete ([~]243.6 Mb) and contains a highly complete, evolutionarily conserved gene repertoire. Notably, the nuclear and mitochondrial genomes are heavily rearranged, indicating a decoupling between gene family repertoire and chromosomal evolution. The analyses of multi-omic datasets available for C. teleta, including developmental time courses of bulk and single-cell RNA-seq, ATAC-seq, and EM-seq, using the new reference assembly, resulted in a significant quality improvement, allowing us to identify new cell-type-specific gene markers and gain additional insights of biological relevance. Finally, we generated a publicly available genome browser that ensures all these resources are easily findable, accessible, interoperable, and reusable. ConclusionsOur study provides state-of-the-art genomic resources for the polychaete model C. teleta, addressing a pressing community need that will open new research opportunities in animal and genome evolution.

genomics↗

bioRxiv2025

Structural basis for substrate specificity and MSMEG_0435-0436 binding by the mycobacterial long-chain acyl-CoA carboxylase complex

The presence of mycolic acid is a defining feature of the mycobacterial cell wall, which provides a highly impermeable barrier to many antibiotics. Biosynthesis of this fatty acid, as well as tuberculostearic acid, requires precursor molecules produced by the essential long-chain acyl-coenzyme A (CoA) carboxylase (LCC) complex. The LCC complex catalyzes carboxylation of the -carbon of long-chain acyl-CoA, but also short-chain acetyl-CoA and propionyl-CoA. The complex includes the subunits AccA3, which contains a biotin carboxylase (BC) domain and a biotin carboxyl carrier protein (BCCP) domain, the long-chain acyl-CoA carboxyltransferase AccD4, the short-chain acyl-CoA carboxyltransferase AccD5, and the incompletely characterized protein AccE. We used electron cryomicroscopy (cryo-EM) to determine structures of the LCC complex from Mycobacterium smegmatis. In the structures, two AccE subunits tether eight AccA3 subunits to an AccD42AccD54 heterohexamer core. Cryo-EM of the enzyme during catalysis reveals how AccD4 and AccD5 achieve substrate specificity, with AccD5 binding tightly to CoA and AccD4 binding long acyl chains. The BCCP domains of AccA3 undergo long-distance translocation to transfer a carboxyl group from the BC domain of AccA3 to the acyl-CoA substrate bound in AccD5. Further, we find that two copies of a protein complex formed from MSMEG_0435 and MSMEG_0436 can bind the LCC complex, sequestering the biotin moiety of BCCP domains near AccD5. Rv0263c, the Mycobacterium tuberculosis ortholog of MSMEG_0435, has a role in bacterial survival during transmission, suggesting that these proteins may regulate production of branched fatty acid precursors for the mycobacterial cell wall.

biochemistry↗

bioRxiv2025

Targeting serine dehydratase supports amino acid homeostasis and skin repair

Serine and glycine are altered in patients with metabolic disorders, and this dysregulation can lead to diverse pathologies1-6. Modulation of serine levels via diet can influence relevant phenotypes in mouse models of metabolic syndrome7,8. Here we identify serine dehydratase (Sds), a gluconeogenic hepatic enzyme involved in serine and threonine catabolism, as a key regulator of systemic serine and sphingolipid metabolism. We show that SDS is expressed and active in human liver tissue. Furthermore, Sds abundance strongly correlates with hepatic serine. This enzyme is highly active in BKS-db/db mice, which show amino acid alterations reminiscent of type 2 diabetes. Hepatic Sds overexpression increases serine and threonine degradation and promotes the accumulation of toxic 1-deoxysphingolipids (doxSLs). Conversely, Sds deletion dramatically increases systemic serine, glycine, and threonine while altering canonical and non-canonical sphingolipids. Finally, Sds deletion in BKS-db/db mice reduces skin doxSLs and accelerates wound healing. Our results demonstrate that Sds constrains serine levels in circulation and suggest therapeutic approaches for targeting this enzyme to improve chronic disorders.

physiology↗

bioRxiv2025

RobPicker: A Meta Learning Framework for Robust Identification of Macromolecules in Cryo-Electron Tomograms

Accurate particle picking of macromolecules of all kinds, shapes, and sizes in cryogenic electron tomograms (cryo-ET) is critical for understanding the molecular architecture of biological systems in their native state. Current deep learning methods have shown potential in identifying macromolecules from tomograms, but they are vulnerable to issues of noise in the training dataset obtained through human or automatic labeling and imbalanced distribution of macromolecule species. To address these limitations, we developed RobPicker, a meta-learning framework that effectively mitigates these issues by automatically learning deep neural networks to correct label errors and give greater emphasis to underrepresented macromolecule species. In evaluations across diverse cryo-ET datasets with noisy labels and imbalanced species distributions, RobPicker substantially outperforms state-of-the-art methods, particularly in identifying small and rare macromolecules. The efficiency and robustness of RobPicker can also be used for rapid fine-tuning of the tilt-series alignment, leading to improved tomogram reconstruction and enabling high-resolution cellular structural biology analysis.

bioinformatics↗

bioRxiv2025

Embryonic Atrial Injury Programs an Anti-Fibrotic Atrial Fibrillation Substrate

Atrial myopathy is associated with atrial fibrillation in adults, yet the role of embryonic atrial injury in predisposing individuals to atrial fibrillation remains unclear. Using an inducible, cardiomyocyte-specific diphtheria toxin A-mediated injury mouse model, we found that injured embryonic atria exhibited upregulation of apoptosis and TNF signaling pathways, alongside downregulation of calcium handling and atrial fibrillation-associated genes. Single-cell RNA sequencing revealed two distinct cardiomyocyte populations with differential injury responses. Importantly, although myofibroblasts increased in the fibroblast population, these cells displayed an extracellular matrix gene expression profile distinct from the pro-fibrotic phenotype typically observed in fibrillating adult atria and showed no evidence of fibrosis. Concurrently, monocytes/macrophages were activated and showed upregulated expression of the anti-fibrotic factor GPNMB. These findings suggest that adaptive tissue remodeling is counterintuitively prevented from progressing to fibrosis, potentially through GPNMB-mediated mechanisms. This study elucidates molecular pathways linking developmental atrial injury to myopathy and proposes novel strategies to attenuate atrial fibrillation progression.

pathology↗

bioRxiv2025

Enhanced cellular and transdermal delivery of the modified chromatin using gH625 cell-penetrating peptide

The transdermal drug delivery system has been used as a noninvasive route for drug administration, but often requires specialized equipment or invasive treatment. To examine recombinant synthetic chromatin as a non-invasive transdermal delivery vehicle, a modified histone H2A fused with a cell-penetrating peptide (gH625) was examined for its utility. Both in vitro porcine skin-based test and in vivo mice studies showed significantly enhanced passive skin penetration of gH625-modified chromatin compared to control groups. The gH625-H2A chromatin was examined as a delivery vehicle of EGF by displaying it at the carboxy terminus of histone H2B to enhance stability and skin penetration. The experimental results showed that the biological activities of EGF-displayed chromatin are comparable to those of the isolated EGF peptide in the HaCa-T cell line. The enhanced skin penetration capabilities of the gH625-H2A-modified chromatin offer great potential for developing non-invasive transdermal delivery of therapeutic proteins or peptides.

synthetic biology↗