Biology subjects

Tao, Y.

Publications and source records attributed to Tao, Y..

At least 55 records · Page 3Linked to original sources

bioRxiv2025

Single-Cell Transcriptomics Reveals Dynamic Microglial States and Neural-Immune Networks in Human Diabetic Retinopathy

Diabetic retinopathy (DR) is a major cause of vision loss worldwide. Here, we conduct single-cell RNA sequencing of twenty human retina samples (from living and post-mortem donors) across non-diabetic, diabetic, and DR states to create a comprehensive transcriptomic atlas. We identify two stable microglial populations--homeostatic and inflammatory--that exist along a functional continuum, plus a neutrophil cluster within C1QA+ myeloid cells with dynamic transitions occurring throughout disease progression. Module-level analysis reveals divergent transcriptional trajectories: homeostatic microglia maintain energetic programs while selectively upregulating stress elements, whereas inflammatory microglia layer additional pro-inflammatory programs onto preserved biosynthetic foundations. Eleven co-expression modules organize into two major axes: an inflammatory-stress axis, and a regulatory/metabolic-motility axis, with a stable translation module persisting across disease stages. Cell communication analysis further highlights sophisticated neural-immune interactions, particularly between photoreceptors and microglia. Our findings provide insights into the complex cellular dynamics of DR progression and suggest potential therapeutic targets for early intervention.

bioinformatics↗

bioRxiv2025

The structure of mitochondrial genomes is associated with geography in Arabidopsis thaliana

Chloroplasts and mitochondria are the primary sites for photosynthesis and respiration, each harboring its own unique genome. Although the organellar genomes are considerably smaller compared to the nuclear genome, they are nonetheless essential for survival of the organism. A common feature of many chloroplast and mitochondrial genomes is the presence of large repeated sequences longer than 1 kb. These can be either in inverted or direct orientation, and recombination between them leads to structural heteroplasmy. To understand the intraspecific evolution of organellar genomes, we assembled chloroplast and mitochondrial genomes of 143 A. thaliana accessions from PacBio HiFi sequencing data. We find large repeats to be associated with heteroplasmy and structural variation. Our extensive genome annotation identifies novel open reading frames (ORFs) in those accessions that lost large repeats, potentially introduced via horizontal gene transfer, illuminating additional paths for diversification of plant organelles. The loss of large repeats correlates with geography and phenotypes, pointing to their adaptive importance. The assembled and annotated organellar genomes constitute a rich source for future functional studies of the interaction between the three genomes of a plant.

evolutionary biology↗

bioRxiv2025

Decoding the Molecular Language of Proteins with Evola

Proteins, natures intricate molecular machines, are the products of billions of years of evolution and play fundamental roles in sustaining life. Yet, deciphering their molecular language--understanding how sequences and structures encode biological functions--remains a cornerstone challenge. Here, we introduce Evolla, an interactive protein-language model designed to transcend static classification by interpreting protein function through natural language queries. Trained on 546 million protein-text pairs and refined via Direct Preference Optimization, Evolla couples high-dimensional molecular representations with generative semantic decoding. Benchmarking establishes Evollas superiority over general large language models in functional inference, demonstrates zero-shot performance parity with the state-of-the-art supervised model, and exposes remote functional relationships invisible to conventional alignment. We validate Evolla through two distinct applications: identifying candidate eukaryotic signature proteins in Asgard archaea, with functional Vps4 homologs validated via yeast complementation; and interactively discovering a novel deep-sea polyethylene terephthalate (PET) hydrolase, PsPETase, confirmed to degrade plastic films. These results position Evolla not merely as a predictor, but as a generative engine capable of complex hypothesis formulation, shifting the paradigm from static annotation to interactive, actionable discovery. The Evolla online service is available at http://www.chat-protein.com/.

bioinformatics↗

bioRxiv2025

Ether Rhodamines with Enhanced Hydrophilicity, Fluorogenicity, and Brightness for Super-Resolution Imaging

Rhodamine dyes are widely used fluorophores in super-resolution fluorescence imaging due to their exceptional optical properties and "aggregation-disaggregation" induced fluorogenic activation. However, their excessive lipophilicity often reduces brightness in aqueous environments and causes off-target staining, limiting their effectiveness in high-resolution imaging. To address these challenges, we introduce an ether-decorated N-terminal modification strategy for rhodamine and silicon-rhodamine (Si-rhodamine), replacing conventional N-alkyl groups. The ether chains enhance water solubility, decrease aggregate size, and improve fluorogenicity across a wide concentration range. Their flexible, hydrophilic structure forms a protective shield around the xanthene core, minimizing dye-water interactions and reducing fluorescence quenching. Additionally, the inductive effect of the ether chains decreases the electron-donating strength of the amino groups, suppressing quenching caused by twisted intramolecular charge transfer (TICT). These modifications collectively increase the quantum yields of ER and ESiR in water from 0.35 and 0.19 (for tetraethyl-substituted analogs) to 0.70 and 0.41, respectively. Probes derived from ER and ESiR exhibit outstanding fluorogenicity, enhanced signal-to-noise ratios, and improved resolution in complex aqueous environments, demonstrating superior performance in advanced super-resolution imaging techniques such as structured illumination microscopy (SIM), stimulated emission depletion (STED) microscopy, and single-molecule localization microscopy (SMLM). This work introduces an innovative strategy for fluorophore design, offering significant advancements for super-resolution imaging applications.

biochemistry↗

bioRxiv2024

The 1001G+ project: A curated collection of Arabidopsis thaliana long-read genome assemblies to advance plant research

Arabidopsis thaliana was the first plant for which a high-quality genome sequence became available. The publication of the first reference genome sequence almost 25 years ago was already accompanied by genome-wide data on sequence polymorphisms in another accession, or naturally occurring strain. Since then, inventories of genome-wide diversity have been generated at increasingly precise levels. High-density genotype data for A. thaliana, including those from the 1001 Genomes Project, were key to demonstrating the enormous power of GWAS in inbred populations of wild plants, and the comparison of intraspecific polymorphism with interspecific divergence has illuminated many aspects of plant genome evolution. Over the past decade, an increasing number of nearly complete genome sequences have been published for many more accessions. Here, we highlight the diversity of a curated collection of previously published and so far unpublished genome sequences assembled using different types of long reads, including PacBio Continuous Long Reads (CLR), PacBio High Fidelity (HiFi) reads, and Oxford Nanopore Technologies (ONT) reads. This 1001 Genomes Plus (1001G+) resource is being made available at http://1001genomes.org. We invite colleagues with yet unpublished genome assemblies from A. thaliana accessions to contribute to this effort.

genomics↗

bioRxiv2024

Expanding GABAergic Neuronal Diversity in iPSC-Derived Disease Models

GABAergic interneurons comprise diverse molecular and functional subtypes that contribute to neural circuit assembly and are implicated in a range of neurodevelopmental and neuropsychiatric disorders. Traditional approaches for differentiating human pluripotent stem cells (PSCs) into neurons often face challenges such as incomplete neural differentiation, prolonged culture periods, and variability across PSC lines, which can constrain their application in disease modeling. To address these limitations, we developed a strategy that combines inducible expression of the transcription factors (TFs) ASCL1 and DLX2 with dual-SMAD and WNT inhibition to efficiently drive differentiation of human PSCs into diverse, region-specific GABAergic neuronal types. Using single-cell sequencing, we characterized the cellular heterogeneity of GABAergic induced neurons (iNs) generated with the patterning factors (patterned iNs) and those derived solely with TFs (PSC-derived iNs), revealing distinct interneuron subtype compositions and the regulatory programs that govern their fate specification. Patterned iNs exhibited gene expression features corresponding to multiple brain regions, particularly the ganglionic eminence (GE) and neocortex, whereas GABAergic PSC-derived iNs predominantly resembled hypothalamic and thalamic neurons. Both iN types were enriched for genes relevant to neurodevelopmental and psychiatric disorders, with patterned iNs more specifically linked to neural lineage genes, highlighting their utility for disease modeling. We further applied this protocol to investigate the impact of a recurrent ADNP syndrome-associated mutation (p.Tyr719*) on GABAergic neuron differentiation, revealing that this mutation disrupts GABAergic fate specification and synaptic transmission. Overall, this study expands the toolkit for disease modeling by demonstrating the complementary advantages of GABAergic PSC-derived iNs and patterned iNs in representing distinct GABAergic neuron subtypes, brain regions, and disease contexts. Together, these approaches provide a flexible platform for investigating molecular and cellular mechanisms relevant to neurodevelopmental and neuropsychiatric disorders.

developmental biology↗

bioRxiv2024

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↗

bioRxiv2024

Privacy-Preserving Visualization of Brain Functional Connectivity

Data visualizations are an integral part of neuroimging research, supporting activities ranging from exploratory data analysis to the interpretation and communication of findings. While essential, visualizations can also reveal private information about individual participants. In this paper, we discuss how visualizations may inadvertently lead to privacy leakage and explore methods to mitigate such risks. Our work investigates ways to securely share visualizations that faithfully preserve the patterns supporting the derived insights from data analysis, rather than deriving conclusions from the visualizations themselves. We address the problem of privacy-preserving visualization under the framework of differential privacy, focusing on commonly used visualization methods for functional network connectivity. Several perturbation-based strategies are investigated for protecting correlationrelated measures, with analyses of their privacy costs and the effects of pre- and post-processing. To achieve a better balance between privacy and visual utility, we propose workflows for connectogram and seed-based connectivity visualizations that preserve the qualitative structure of non-private results. Overall, this work illustrates how differential privacy can be effectively applied to neuroimaging visualization, highlighting its potential as a principled approach for safeguarding sensitive information.

neuroscience↗

bioRxiv2024

Inter-Kingdom Interactions and Environmental Influences on the Oral Microbiome in Severe Early Childhood Caries

Dental caries arise from intricate interactions among oral microorganisms, impacting ecological stability and disease progression. This study delves into the bacterial-fungal dynamics in severe early childhood caries (S-ECC) among 61 children aged 3-4 years with complete deciduous dentition. We evaluated environmental factors such as saliva pH, buffering capacity, and trace elements (iron, fluoride). We examined the performance of 16S rRNA V1-V9 regions gene and internal transcribed spacer (ITS) primers for bacteria and fungi from plaque and saliva to characterize community compositions and diversity. Saliva pH and buffering capacity were also measured. Findings revealed significant shifts in bacterial diversity in S-ECC saliva samples, marked by decreased diversity and elevated abundance of cariogenic species, particularly Streptococcus mutans. Candida albicans was notably more prevalent in the S-ECC group, implicating its potential role in pathogenesis. Iron and fluoride concentrations showed no significant correlation with microbial community structure. Network analyses uncovered complex intra- and inter-kingdom interactions, underscoring cooperative and competitive dynamics. S-ECC children exhibited higher abundances of bacteria (Streptococcus mutans, Granulicatella, Actinomyces) and fungi (Candida albicans), with specific microbial taxa associated with reduced saliva pH. ImportanceThis study illuminates the intricate relationship between bacteria and fungi within the oral microbial community of children, specifically highlighting differences between those with severe early childhood caries (S-ECC) and those without caries. Through an extensive analysis of the microbial composition in both saliva and dental plaque, we identified a significant increase in the abundance of specific bacterial taxa (e.g., S. mutans, Granulicatella, Actinomyces) and fungal species (e.g., C. albicans) in the oral cavities of children with S-ECC. This finding underscores the potential role of these microorganisms in the development of caries. Contrary to previous studies that emphasize the importance of iron and fluoride in oral health, our research found no significant correlation between the concentrations of these elements and the composition of oral microbial communities. This result challenges conventional understanding and opens new avenues for future research. Additionally, we discovered an association between certain microbial species and reduced salivary pH, offering fresh insights into the relationship between the oral microenvironment and caries development. The implications of our findings are substantial for the development of prevention and intervention strategies targeting childhood caries. They also underscore the critical need for a deeper exploration of oral microbial interactions and their environmental influences.

microbiology↗

bioRxiv2024

Fresh Human Retinal scRNA-seq Atlas Reveals a Novel Cone Subtype and Cellular Diversity

BackgroundCurrent human retina studies predominantly utilize post-mortem tissue, and the sample accessibility constraints make the characterization of the living human retina at single-cell resolution a challenge. Although single-nucleus RNA-seq expands the utility of frozen samples, it provides a nuclear-centric view, potentially missing key cytoplasmic information and transient biological processes. Thus, it is important to generate resources directly from living human retinal tissue to complement existing datasets. MethodsWe profiled 106,829 single cells from nine unfrozen human retina samples. Living samples were collected withinLJ10LJmin of therapeutic enucleation and four postmortem samples were collected within 6LJh. After standardized dissociation, single-cell transcriptomes were generated using 10x Genomics 3 RNA-seq and applied scVI to generate batch-corrected integrated atlas. Major cell types and subtypes were annotated through iterative Leiden clustering, canonical markers. Subsequent analyses included differential expression comparisons between cell states and regulon activity profiling to further characterize cellular identities and regulatory networks. Transcriptional dynamics were assessed using RNA velocity, and cell-cell signaling pathways were inferred with CellChat. Key findings were validated in independent samples from two additional donors (four samples) using the identical workflow. ResultsWe contribute to establishing a reference for retinal cell type proportions and cellular states. Our analysis revealed ELF1-mlCone, a distinct cluster of mlCone photoreceptors identified by distinct transcriptional features. The presence and transcriptional features of this cluster were validated in independent samples. Additionally, by comparing living and post-mortem samples, our study highlights differences in transcriptional dynamics: living tissue preserved coherent RNA velocity streams, enabling clear dynamic state transitions, while post-mortem tissue exhibited disorganized patterns. These findings suggest that using living tissue can improve the capture of active cellular states and transitions. ConclusionsOur atlas provides a single-cell reference contrasting living versus early post-mortem human retina, integrating cell type composition, transcriptional diversity, and functional insights. It may serve as a useful resource for retinal research and for understanding aspects of human retinal biology, particularly given its inclusion of living tissue and diverse pathological states.

bioinformatics↗

bioRxiv2024

A Self-Assembling Immune-Featured Osteosarcoma Patient/PDX Derived Organoid Model and Biobank for Personalized Immune Therapy

Osteosarcoma (OS) exhibit intra- and inter-heterogeneity, complicating the exploration of effective therapeutic strategies. Traditional in vitro and in vivo models are limited in inheriting biological and genomic heterogeneities of OS patients, even in inheriting the features on tumor microenvironment. The prolonged generation time of current models makes the drug development of OS slow and is not suitable to clinically rapid timing. Here, we introduce methods for generating and biobanking patient/PDX-derived osteosarcoma organoids (OS PD(X)Os) that recapitulate the histological, biological and genomic features of their paired OS patients. OS PD(X)Os can be generated quickly with high reliability in vitro or transplanted to immunodeficient mice. We further demonstrate an immune-featured OS PD(X)O (named iOS) model and its method for testing personalized chemotherapy response, personalized immune therapeutic strategy and target drug development, such as a novel PRMT5MTA inhibitor ARPN2169 on MTAP-deleted OS. Our studies show that iOS models maintain many typical features of OS and could be rapidly employed to investigate patient-specific therapeutic strategies. Additionally, our biobank establishes a rich resource for basic, translational and even clinical OS researches.

cancer biology↗

bioRxiv2024

Perceived and observed biases within scientific communities: a case study in movement ecology

Who conducts biological research, where, and how the results are disseminated varies among geographies and identities. Identifying and documenting these forms of bias by research communities is a critical first step towards addressing them. We documented perceived and observed biases in movement ecology. Movement ecology is a rapidly expanding sub-discipline of biology, which is strongly underpinned by fieldwork and technology use. First, we surveyed attendees of an international conference, and discussed the results at the conference (comparing uninformed vs informed perceived bias). Although most researchers identified as bias-aware, only a subset of biases were discussed in conversation. Next, by considering author affiliations from publications in the journal Movement Ecology, we found among-country discrepancies between the country of the authors affiliation and study site location related to national economics. At the within-country scale, we found that race-gender identities of postgraduate biology researchers in the USA differed from national demographics. We discuss the role of potential specific causes for the emergence of bias in the sub-discipline, e.g. parachute-science or accessibility to fieldwork. Undertaking data-driven analysis of bias within research sub-disciplines can help identify specific barriers and first steps towards the inclusion of a greater diversity of participants in the scientific process.

ecology↗

bioRxiv2024

Coordinated regulation of chemotaxis and resistance to copper by CsoR in Pseudomonas putida

Copper is an essential enzyme cofactor in bacteria, but excess copper is highly toxic. Bacteria can cope with copper stress by increasing copper resistance and initiating chemorepellent response. However, it remains unclear how bacteria coordinate chemotaxis and resistance to copper. By screening proteins that interacted with the chemotaxis kinase CheA, we identified a copper-binding repressor CsoR that interacted with CheA in Pseudomonas putida. CsoR interacted with the HPT (P1), Dimer (P3), and HATPase_c (P4) domains of CheA and inhibited CheA autophosphorylation, resulting in decreased chemotaxis. The copper-binding of CsoR weakened its interaction with CheA, which relieved the inhibition of chemotaxis by CsoR. In addition, CsoR bound to the promoter of copper-resistance genes to inhibit gene expression, and copper-binding released CsoR from the promoter, leading to increased gene expression and copper resistance. P. putida cells exhibited a chemorepellent response to copper in a CheA-dependent manner, and CsoR inhibited the chemorepellent response to copper. Besides, the CheA-CsoR interaction also existed in proteins from several other bacterial species. Our results revealed a mechanism by which bacteria coordinately regulated chemotaxis and resistance to copper by CsoR.

microbiology↗

bioRxiv2024

Chromogranin A Deficiency Attenuates Tauopathy by Altering Epinephrine Alpha-Adrenergic Receptor Signaling

Our previous studies have indicated that insulin resistance, hyperglycemia, and hypertension in aged wild-type (WT) mice can be reversed in mice lacking chromogranin-A (CgA-KO mice). These health conditions are associated with a higher risk of Alzheimers disease (AD). CgA, a neuroendocrine secretory protein has been detected in protein aggregates in the brains of AD patients. Here, we determined the role of CgA in tauopathies, including AD (secondary tauopathy) and corticobasal degeneration (CBD, primary tauopathy). We found elevated levels of CgA in both AD and CBD brains, which were positively correlated with increased phosphorylated tau in the frontal cortex. Furthermore, CgA ablation in a human P301S tau (hTau) transgenic mice (CgA-KO/hTau) exhibited reduced tau aggregation, resistance to tau spreading, and an extended lifespan, coupled with improved cognitive function. Transcriptomic analysis of mice cortices highlighted altered levels of alpha-adrenergic receptors (Adra) in hTau mice compared to WT mice, akin to AD patients. Since CgA regulates the release of the Adra ligands epinephrine (EPI) and norepinephrine (NE), we determined their levels and found elevated EPI levels in the cortices of hTau mice, AD and CBD patients. CgA-KO/hTau mice exhibited reversal of EPI levels in the cortex and the expression of several affected genes, including Adra1 and 2, nearly returning them to WT levels. Treatment of hippocampal slice cultures with EPI or an Adra1 agonist intensified, while an Adra1 antagonist inhibited, tau hyperphosphorylation and aggregation. These findings reveal a critical role of CgA in regulation of tau pathogenesis via the EPI-Adra signaling axis.

neuroscience↗

bioRxiv2024

Nuclear speckle rejuvenation alleviates proteinopathies at the expense of YAP1

Current treatments targeting individual protein quality control pathways have limited efficacy in alleviating proteinopathies, highlighting the prerequisite for a common druggable target capable of global proteostasis modulation. Building upon our prior research establishing nuclear speckles as pivotal membrane-less organelles for transcriptional control of proteostasis, we aim to alleviate proteinopathies through nuclear speckle rehabilitation. We identified pyrvinium pamoate as a nuclear speckle rehabilitator that enhances protein quality control gene expression and suppresses YAP1 transcriptional activity via decreasing the surface/interfacial tension of nuclear speckle condensates through interaction with the intrinsically disordered region of nuclear speckle scaffold protein SON. In pre-clinical models, nanomolar pyrvinium pamoate protected against retinal degeneration and tauopathy mainly by promoting autophagy and ubiquitin-proteasome activity in a SON-dependent manner without causing stress. Aberrant nuclear speckle morphology, reduced protein quality control and increased YAP1 activity were observed in human tauopathies. Our study provides proof-of-principle of targeting nuclear speckles to ameliorate proteinopathies.

cell biology↗

bioRxiv2024

Complete telomere-to-telomere assemblies of two sorghum genomes to guide biological discovery

Sorghum is a C4 crop well-known for its high efficiency of biomass accumulation and adaptation to drought and hot environments. This study reports the assembly of complete genome sequence of two sorghum genomes using a combination of ultra-long reads from Oxford Nanopore Technology, high-fidelity long reads from Pacbio and Hi-C reads. The accuracy and completeness of the T2T assemblies were comprehensively validated using a range of parameters, including coverage depth assessment, BUSCO, LTR assembly index, ect. Our T2T assembly of BTx623 identified 36.25 Mb of new sequence, in addition to dozens of misoritation and mispositioning of large DNA segments in the BTx623-v3. Correcting these assembly errors in the reference genome is critical for exploiting genetic information in these complex regions in sorghum. Comparison of the two T2T genomes shed new insights on variation of centromeres in sorghum. The two high-quality T2T genomes represent an important resource for sorghum improvement and gene discovery. They would serve as the new reference genomes to unlock the full potential of global sequence variation of this valuable crop.

genomics↗

bioRxiv2024

Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1

Melanin-concentrating hormone (MCH) is a 19-amino-acid neuropeptide playing crucial roles in energy homeostasis, sleep, and various physiological processes. It acts through two G protein-coupled receptors, MCHR1 and MCHR2, with MCHR1 being universally present in mammals and a potential target for treating metabolic and mental health conditions. However, drug development efforts have been impeded by the lack of structural information. Here, we present the cryo-EM structures of MCHR1 in its active state complexed with MCH and Gi1, as well as in its inactive state bound to a selective antagonist SNAP-94847. Structural and mutagenesis analyses disclosed the recognition mechanisms for both MCH and SNAP-94847, the activation mechanism and antagonism of MCHR1, and the determinants of ligand specificity. These findings are expected to accelerate the development of better drugs targeting the MCH system.

biophysics↗

bioRxiv2024

3D Bioprinting of Human Neural Tissues with Functional Connectivity

Probing how the human neural networks operate is hindered by the lack of reliable human neural tissues amenable for dynamic functional assessment of neural circuits. We developed a 3D bioprinting platform to assemble tissues with defined human neural cell types in a desired dimension using a commercial bioprinter. The printed neuronal progenitors differentiate to neurons and form functional neural circuits in and between tissue layers with specificity within weeks, evidenced by the cortical-to-striatal projection, spontaneous synaptic currents and synaptic response to neuronal excitation. Printed astrocyte progenitors develop into mature astrocytes with elaborated processes and form functional neuron-astrocyte networks, indicated by calcium flux and glutamate uptake in response to neuronal excitation under physiological and pathological conditions. These designed human neural tissues will likely be useful for understanding the wiring of human neural networks, modeling pathological processes, and serving as platforms for drug testing.

bioengineering↗