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Liu, Y.

Publications and source records attributed to Liu, Y..

At least 343 records · Page 19Linked to original sources

Cryo-EM structures and structure-guided design of Atlas virus capsids

Endogenous viruses and retroelements occupy a large fraction of genomes, but the properties of proteins they encode remain largely uncharted. Here, we define Atlas viruses, a new clade of endogenous viruses in nematodes with a retrovirus-like genome organization, phlebovirus-like envelope glycoproteins, and highly divergent Gag proteins. Cryo-EM structures of particles from three Atlas viruses reveal thin-shelled icosahedral assemblies containing 60, 240, 420 or 720 capsid proteins and ranging from 20 to 60 nm in diameter. The capsid fold and assembly interactions are distinct from those of orthoretroviruses but reminiscent of spumaretrovirus and dArc capsids. Atlas capsids package nucleic acids, enter cell by endocytosis, and disassemble at endolysosomal pH. Through structure-guided engineering, we generated recombinant Atlas particles with increased pH resilience and particles displaying a CTLA-4 receptor-targeting tag. This work identifies Atlas capsids as attractive candidates for development as engineerable scaffolds for tissue-specific nucleic acid delivery.

biochemistry↗

Neurogenin-2 Reprograms Human Microglial Lineage Cells into Neurons In Vitro and in Chimeric Brains

Progressive neuronal loss is a hallmark of many neurological disorders, yet the adult human brain has a limited capacity for endogenous neuronal replacement. Direct neuronal reprogramming represents an alternative strategy for generating new neurons. Microglia, the brains resident immune cells, are uniquely positioned as candidate cellular substrates due to their abundance, self-renewal capacity, high motility, and rapid recruitment to sites of injury. Here, using live-cell imaging and electrophysiological recordings, we show that human pluripotent stem cell (hPSC)-derived primitive macrophage progenitors (PMPs) and their microglial derivatives exhibit neuronal reprogramming competence. Inducible expression of NEUROG2 in hPSC-derived PMPs drives acquisition of neuronal morphology, sequential expression of early and mature neuronal markers, organization of synaptic proteins, and functional excitability characterized by action potential firing. Single-nucleus RNA sequencing reveals a continuous, directionally ordered reprogramming trajectory marked by suppression of myeloid transcriptional programs, progression through intermediate remodeling states, and progressive activation of neuronal gene regulatory networks, consistent with a regulated lineage conversion rather than partial identity switching. Using a xenotransplantation-based human microglia chimeric brain model, we further demonstrate that inducible NEUROG2 expression reprograms donor-derived human microglia toward a neuronal identity in vivo. Together, these findings establish human microglial lineage cells as a previously unexplored substrate for neuronal reprogramming, providing a conceptual framework for microglia-based strategies aimed at neuronal replacement and neural repair.

neuroscience↗

ProAR: Probabilistic Autoregressive Modeling for Molecular Dynamics

Understanding the structural dynamics of biomolecules is crucial for uncovering biological functions. As molecular dynamics (MD) simulation data becomes more available, deep generative models have been developed to synthesize realistic MD trajectories. However, existing methods produce fixed-length trajectories by jointly denoising high-dimensional spatiotemporal representations, which conflicts with MDs frame-by-frame integration process and fails to capture time-dependent conformational diversity. Inspired by MDs sequential nature, we introduce a new probabilistic autoregressive (ProAR) framework for trajectory generation. ProAR uses a dual-network system that models each frame as a multivariate Gaussian distribution and employs an anti-drifting sampling strategy to reduce cumulative errors. This approach captures conformational uncertainty and time-coupled structural changes while allowing flexible generation of trajectories of arbitrary length. Experiments on ATLAS, a large-scale protein MD dataset, demonstrate that for long trajectory generation, our model achieves a 7.5% reduction in reconstruction RMSE and an average 25.8% improvement in conformation change accuracy compared to previous state-of-the-art methods. For conformation sampling task, it performs comparably to specialized time-independent models, providing a flexible and dependable alternative to standard MD simulations.

molecular biology↗

Metabolic adaptation to maternal hyperglycemia via ACLY-dependent acetyl-CoA production drives epigenetic remodeling and dysregulated placental development

AbstractsGestational diabetes mellitus (GDM) is a common metabolic complication of pregnancy that is paradoxically associated with both fetal overgrowth and fetal growth restriction (FGR). While maternal hyperglycemia is widely presumed to drive macrosomia through excessive nutrient supply, the mechanisms underlying FGR remain poorly understood. Here, using a mouse model that recapitulates the small-for-gestational-age (SGA) phenotype observed in human GDM pregnancies, we identify placental underdevelopment as a principal driver of FGR. Despite systemic nutrient abundance, hyperglycemic placentas exhibit reduced mass and an increased fetal-to-placental weight ratio, indicative of placental insufficiency. Mechanistically, maternal hyperglycemia induces anabolic metabolic rewiring while suppressing oxidative phosphorylation (OXPHOS), accompanied by upregulation and nuclear redistribution of ATP-citrate lyase (ACLY). ACLY converts glucose-derived carbon into acetyl-CoA in the cytosol and nucleus, thereby coupling glycolytic flux to lipid and hexosamine biosynthesis as well as to global histone hyperacetylation. This hyperacetylation-associated epigenetic reprogramming activates metabolic, innate immune, and inflammatory gene programs while repressing pro-proliferative and anti-apoptotic pathways. Consequently, placental growth is compromised despite nutrient excess. Importantly, activation of the ACLY-acetyl-CoA axis and global histone hyperacetylation is consistently observed in human GDM placentas across diverse birth outcomes, suggesting a conserved metabolic-epigenetic adaptation to maternal hyperglycemia. Together, these findings identify ACLY-dependent acetyl-CoA production as a central metabolic node linking maternal hyperglycemia to chromatin remodeling and placental development control, thereby reshaping fetal growth trajectories.

developmental biology↗

A feed-forward loop between niche adenosine and Gzmk⁺ CD8 T cells propagates systemic inflammaging

The causal link between the aging microenvironment and T cell aging remains elusive. Here, we demonstrate that adenosine within aging tissues actively reprograms CD8+ T cells into a pro-aging Granzyme K+ (Gzmk+) population. Mechanistically, senescent cells create an adenosine-rich niche via p16-dependent CD39 upregulation, triggering A2aR signaling to induce Gzmk+ T cell differentiation. Once released, Gzmk promotes systemic inflammaging through PAR1 and complement activation. Crucially, targeting this axis--either via genetic Gzmk ablation or pharmacological A2aR blockade--reverses multi-organ aging phenotypes and significantly extends healthy lifespan in mice. Human analysis reveals age-dependent Gzmk+ T cell accumulation in multi organs, while coffee intake (an A2aR antagonist) inversely correlates with plasma Gzmk levels. Our findings uncover how metabolic niche changes drive T cell aging and establish the adenosine-Gzmk axis as a pivotal therapeutic target for combating age-related diseases.

immunology↗

Spatio-temporal mapping of immune cell dynamics during human sequential lymph node metastasis

Regional lymph node (LN) metastasis critically influences distant metastatic progression, anti-tumour immunity, and patient prognosis. While tumour-induced immune modulation in tumour-draining LNs (TDLNs) has been extensively studied using murine models, the systematic reconstruction of the immune system from primary tumours through TDLNs and subsequent lymph nodes in human cancer progression remains understudied. Here, we utilised integrated multi-omics approaches, including imaging mass cytometry, single-cell RNA sequencing, Visium and Xenium spatial transcriptomics, and multi-colour immunofluorescence to systematically characterise immune cell dynamics across 147 paired primary tumours, sentinel TDLNs (S-TDLNs), and secondary axillary LNs (ALNs) obtained from 50 treatment-naive triple-negative breast cancer patients with different progression statuses. Our comprehensive profiling revealed critical immune alterations, such as decreased type-2 conventional dendritic cells (cDC2), naive T cells, and B cells, along with an increase in immunosuppressive macrophages. Developing a novel single-cell transformer model, we identified substantial alterations in various immune cell populations, notably MARCO+ macrophages, which strongly correlated with breast cancer patient survival outcomes. Spatial analysis combined with our newly integrated cell-cell interaction platform revealed diminished immune cell communication and impaired priming interactions among dendritic cells, B cells, and T cells within metastatic lymph nodes and primary tumour sites. In an independent neoadjuvant immunotherapy cohort of 36 TNBC patients with 52 lymph node samples, we found preservation of CD1c cDC2 in lymph nodes predicted pathological complete response and longer event-free survival, highlighting cDC2 as a potential biomarker and therapeutic target. Collectively, this systematic mapping of immune landscape alterations during human sequential LN metastasis provides essential insights for understanding cancer metastasis mechanisms and paves the way for innovative immunotherapeutic strategies.

immunology↗

Isoform-resolved spatial transcriptomics on a lab-made high-density array via a single-chip NGS-TGS workflow

High-resolution spatial transcriptomics is still cost-prohibitive and dominated by short-read sequencing, limiting in situ detection of transcript structures. Here we present a low-cost, lab-made, high-density bead-in-microwell chip assembled by routine centrifuge and decoded by a tri-part combinatorial long-barcode strategy. The design provides 5.6x107 barcode combinations across 4.1x10{square} capture sites, reducing collisions while remaining tolerant to third-generation sequencing raw errors. Using a single-chip, dual-platform workflow, we split full-length cDNA for next-generation and third-generation sequencing within the same spatial coordinates. In an incompatible tomato-pepper graft, we identified interface-associated splicing reprogramming, including thousands of unannotated isoforms, enriched novel CaGRP1 isoforms, and SlPIP2 intron retention, supported by individual long-read sequences. In mouse embryos, we further demonstrate cross-species applicability by resolving unannotated Col1a2 isoforms in oligodendrocyte progenitors and spatially restricted Dalrd3 intron retention. This cost-efficient system broadens access to spatial full-length transcriptomics and may support diverse biological studies.

plant biology↗

Unpaired TCRα + TCRβ sequencing is sufficient for training machine learning TCR-epitope recognition predictors

T-cell recognition of infected and malignant cells is elicited by the binding of heterodimeric T-Cell Receptors (TCRs) to epitopes and both the TCR and the TCR{beta} chains play a key role in these interactions. Machine learning tools trained on databases of TCRs recognizing diverse epitopes are useful for identifying epitope-specific TCRs in large TCR repertoire datasets. However, collecting paired TCR{beta} sequences to train such tools is associated with significant sequencing costs. Here we demonstrate that unpaired TCR + TCR{beta} sequencing of epitope-specific T cells can be used for training TCR-epitope recognition predictors at a much reduced cost compared to standard single-cell TCR sequencing protocols and with no impact on prediction accuracy. Applying this approach to some unseen epitopes used in the IMMREP community benchmark demonstrates improved accuracy compared to both existing machine learning models and AlphaFold3-based predictions.

immunology↗

Exploration of Orally Disintegrating Tablet for Sublingual Vaccination against Mucosal Bacterial Infection

Oral mucosal bacterial infections impose a substantial global disease burden, yet current clinical management typically reduces microbial load only transiently and rarely establishes durable protection at the oral surface. Analysis of 200 patients with periodontitis revealed that elevated levels of pathogen-specific salivary secretory Immunoglobulin A (sIgA) were strongly associated with reduced bacterial burden and improved clinical periodontal outcomes, identifying sIgA as a key determinant of effective oral protection. Guided by this observation, we developed a sublingual, orally disintegrating tablet vaccine (Capot) that incorporates bacterial extracellular vesicles providing a comprehensive repertoire of native antigens and multiple pathogen-associated molecular patterns, encapsulated within a calcium phosphate nanoshell to enable safe transmucosal delivery to submandibular lymph nodes. The rapidly disintegrating tablet format minimizes inadvertent swallowing and enhances local mucosal bioavailability. In mice and non-human primates, Capot induced robust and long-lasting salivary sIgA responses without overt oral mucosal or gastrointestinal inflammation and conferred strong protection against primary, recurrent, and antibiotic-resistant periodontitis. Together, these findings establish sublingual tablet vaccination as a practical strategy for selectively engaging oral mucosal immunity and preventing chronic bacterial diseases at oral mucosal surfaces.

bioengineering↗

Automated Cyclic Super-Resolution Microscopy for Nanoscale Protein Mapping

Nanoscale mapping of multiple molecular targets is essential for decoding cellular architecture, but current approaches are limited by low throughput, intensive manual intervention, and signal variability across imaging cycles. Here, we introduce CycSTORM, an integrated super-resolution imaging platform for automated cyclic (d)STORM that enables multiplexed nanoscale protein mapping in single cells. To overcome the instability inherent in multi-day imaging, CycSTORM combines automated fluidic exchange, active 3D drift correction, and an oxygen-excluded imaging environment to stabilize fluorophore blinking and enables sub-5 nm registration across day-long experiments. Furthermore, CycSTORM incorporates a rapid chemical inactivation step using meta-chloroperoxybenzoic acid (mCPBA), eliminating >99.9% residual fluorescence within 10 minutes and minimizing inter-cycle crosstalk while preserving sample integrity. By standardizing labeling to Alexa Fluor 647, a fluorophore with stable and well-characterized blinking behavior, CycSTORM minimizes fluorophore-dependent variation and provides a robust platform for consistent localization precision across cycles, enabling reliable mapping of protein organization in single cells. Using CycSTORM, we simultaneously map multiple protein targets within the same cells with nanometer precision. Together, these advances transform cyclic super-resolution imaging into a scalable approach for quantitative nanoscale mapping of molecular organization in single cells.

cell biology↗

Zhi-Shi-Huang-Wu slows Parkinson's disease progression in transgenic C. elegans models

Parkinsons disease (PD) is the second most progressive degenerative disorder of the brain due to dopaminergic (DA) neuron degenerations and alpha-synuclein (-Syn) accumulations. At present, the disease has no effective treatment. Therefore, the current study objective is to identify a novel anti-PD formula (Zhi-Shi-Huang-Wu Formula, F-2) computed at 8:4:2:1 ratio from HSP 70 promoter activators Valeriana jatamansi (V), Acori talarinowii (A), Scutellaria baicalensis (S), Fructus Schisandrae (F). Traditionally, V is used to cure memory impairments, A treats mental disorders, and chronic mild stress, S for neuroprotection, and F showed multiple therapeutic actions to treat insomnia. This study investigated the neuroprotective potential of the V, A, S, F, formula F-2 and its underlying molecular mechanisms in transgenic Caenorhabditis elegans models. A, S, F, and F-2 successfully restored 6-hydroxydopamine intoxicated DA neuron degenerations, reduced food-sensing behavior disabilities, and attenuated -Syn aggregations. Moreover, activates the lipid deposition and proteasome expressions to confirm -Syn degradations at the cellular level. Reactive oxygen species (ROS) cause oxidative stress, and A, S, F, and F-2 repressed ROS and raised SOD-3 expressions. Overall, these data indicate that V, A, S, F combined into F-2 (22.3%) are more effective against PD progression-like symptom than individual drugs V (0.7%), A (11.4%), S (9.6%), and F (12.6%). These improved neuroprotective actions of F-2 possibly due to following the antioxidative pathway. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=144 SRC="FIGDIR/small/709540v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1a6f1f7org.highwire.dtl.DTLVardef@157a270org.highwire.dtl.DTLVardef@69a238org.highwire.dtl.DTLVardef@1194b5e_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

UniST: A Unified Computational Framework for 3D Spatial Transcriptomics Reconstruction

Spatial transcriptomics (ST) enables the measurement of gene expression in its native spatial context, yet most ST datasets are acquired as two-dimensional (2D) sections. Consequently, the underlying three-dimensional (3D) organization of tissues is only partially observed, and 3D ST data generated from serial sections are typically sparse and heterogeneous, with substantial tissue loss and missing measurements. These limitations pose major analytical challenges for reconstructing coherent 3D tissue architecture, rather than issues of experimental scalability alone. Here, we present UniST, a unified generative artificial intelligence (AI) framework designed to computationally reconstruct dense and continuous 3D ST landscapes from sparse serial sections, without altering the underlying experimental ST technologies. UniST integrates three complementary modules: kernel point convolution with cross-attention layers for point cloud upsampling, optical flow-based interpolation for continuous slice reconstruction, and a graph autoencoder with implicit neural representations for gene expression imputation. Together, these components densify sparse slices, resolve discontinuities, and map spatial coordinates to high-dimensional transcriptomics. Across multiple ST platforms and tissue contexts, UniST accurately restored structural continuity and biologically meaningful expression patterns. In a mouse embryo dataset, UniST reconstructed a dense 3D heart architecture from sparsely sampled slices. In two 3D human cancer tissues, UniST recovered critical spatial features, including tumor-immune boundaries and tertiary lymphoid structures, that were fragmented in the original data. By providing a generalizable computational solution that complements existing ST acquisition protocols, UniST facilitates cost-efficient and scalable reconstruction of 3D ST landscapes, enabling more faithful investigation of tissue organization and disease biology.

bioinformatics↗

A Deep Quantitative Proteome Turnover Platform for Human iPSC-derived Neurons

Quantitative evaluation of protein turnover in human neurons is crucial for understanding neuron homeostasis and guiding drug development for neurological diseases. However, measuring protein turnover in postmitotic neurons remains challenging due to the high dynamic range of protein half-lives and limited proteome coverage in SILAC (Stable Isotope Labeling by Amino acids in Cell culture) experiments. Despite broad applications of dynamic SILAC proteomics to measure protein turnover in rodent tissues and primary neurons, few studies have measured protein half-lives in human neurons with limited proteome coverage. Here, we established a comprehensive platform to quantify protein half-lives in human induced pluripotent stem cell (iPSC)-derived neurons. By integrating optimized dynamic SILAC labeling in human neuron cultures, extensive peptide fractionation, optimized data-dependent and data-independent LC-MS/MS acquisition methods, and a streamlined computational pipeline, we achieved deep and accurate measurement of 10,792 protein half-lives from 162,854 unique peptides. We then compared the protein turnover and abundances in iPSC-derived glutamatergic cortical neurons and spinal motor neurons, revealing globally conserved proteome dynamics alongside subtype-specific differences consistent with specialized neuronal functions. To enable broad community access, we created NeuronProfile (www.neuronprofile.com), an interactive web platform for exploring protein turnover, abundance, and subcellular location in human neurons. Together, this work provides a comprehensive analytical platform to assess human neuronal proteostasis and a foundational resource for neurological disease research and therapeutic development.

neuroscience↗

Microencapsulation of a novel Bacteroides thetaiotaomicron strain: a promising strategy to fortify intestinal barrier fortification in weaned pig model

Porcine Bacteroides thetaiotaomicron LYH5 demonstrated in vitro antimicrobial activity, suggesting probiotic potential. Due to poor gastric juice tolerance, LYH5 was encapsulated via extrusion using sodium alginate (SA) and gellan gum. Box-Behnken design optimization yielded optimal parameters: SA 1.5%, gellan gum 0.4%, CaCl2 0.9%, bacteria:glue ratio 1:4, achieving an encapsulation rate of 84.22{+/-}0.17%. Its effect on weaned piglet intestinal health was evaluated using 78 piglets (7.69{+/-}0.52 kg) randomly assigned to 4 groups for 40 days: CON (control), T (basal diet + LYH5 live bacteria, 1x10{superscript 1} CFU/mL), TJ (basal diet + LYH5 microcapsules, 1x10{superscript 1} CFU/mL, J (basal diet + empty capsules). The results of this experiment showed that compared with the control group, LYH5 microcapsule can improve the intestinal barrier function without affecting the growth performance of piglets, and provide ideas and references for the development of human next-generation probiotics (NGP). IMPORTANCEThis study addresses the key bottleneck of poor gastric acid tolerance of probiotics via microencapsulation and provides a practical reference for the development of human next-generation probiotics.

microbiology↗

Programming Biomolecular Interactions with All-Atom Generative Model

Biomolecular interactions lie at the core of cellular life, spanning diverse molecular modalities from small molecules to nucleic acids and proteins. Nevertheless, design strategies remain separated despite shared physicochemical principles of molecular recognition. Here we present AnewOmni, a unified generative framework trained on more than 5 million biomolecular complexes, that enables transferable molecular design across molecular scales by assembling chemically meaningful building blocks at atomic resolution. We further introduce programmable graph prompts to support user-defined chemical, topological, and geometric steering during generation, exploring hybrid and unconventional chemistries beyond canonical structures. We demonstrate that transferable learning of interaction patterns and physical constraints across molecular modalities is possible, via an atom-to-block latent space capturing both atomic details and structural priors. The framework successfully designed small molecules, peptides, and nanobodies targeting the challenging KRAS G12D switch II pocket, as well as orthosteric peptides and allosteric small-molecule inhibitors for PCSK9 in the absence of known binding site, achieving 23%-75% success with only low-throughput validation, bypassing modality-specific high-throughput screening. AnewOmni is the first to succeed in functional molecular design across all scales, from small chemical entities to large biologics, and represents a stepstone towards general molecular reasoning engines, advocating a generative foundation model for biomolecular interactions to enter regimes where data and human intuition remain limited.

bioengineering↗

Comprehensive long-read transcriptome analysis uncovers alternative RNA processing feature and isoform diversity in ovarian cancer progression

Post-transcriptional processing has a crucial yet largely unresolved dynamic change and role during the malignant progression of ovarian cancer, especially due to the limited read length of short-read RNA sequencing being insufficient to capture transcript diversity. Here, we performed Iso and RNA sequencing on paired normal, primary tumor, and metastatic samples, generating a comprehensive isoform atlas of over 41,000 full-length transcripts including many unannotated isoforms. Integrative analyses revealed extensive isoform-level remodeling across disease states that often occurred without concordant alterations at the gene level, emphasizing the importance of qualitative transcript regulation. Notably, we identified isoform-level alterations with distinct biological and clinical relevance, including differential expression of the short KRAS isoform, a tumor-specific isoform switch of TMEM201, and an alternative first-exon event in FNDC3B associated with poor survival. Together, these findings provide a high-resolution map of the ovarian cancer transcriptome and illustrate how long-read sequencing exposes multiple layers of post-transcriptional and clinical insight that remain hidden in conventional expression profiling.

bioinformatics↗

Single-cell transcriptomic atlas of mouse oocyte development from growth to ovulation

Oocyte growth and maturation depend on tightly coordinated programs within oocytes and their surrounding granulosa cells, yet defining the transcriptional continuum of growing oocytes has been challenging due to their large size and the limitations of current droplet-based and spatial transcriptomic platforms. Here, we optimized a high-density array-based platform called Stereo-cell for high-throughput dual-modality profiling of large mouse oocytes, allowing for both the preservation of morphology and transcript capture. By integrating unsupervised transcriptomic clustering with cell morphological features, we delineated successive temporal windows from growing oocytes to metaphase II and uncovered stage-linked shifts from early programs toward later programs. We also profiled the ovarian somatic fraction, reconstructed granulosa-cell subtype relationships, and placed ovarian cell states in tissue context using single-cell-resolution spatial data.

developmental biology↗

Baseline cellular state dictates the molecular impact of KRAS mutant variants in pancreatic cancer cells

KRAS is mutated in over 90% of pancreatic ductal adenocarcinomas (PDAC), where hotspot alterations in codons 12, 13, and 61 drive tumor initiation and progression. Although distinct biochemical properties have been described for individual KRAS mutants, whether they generate unique allele-specific signaling programs in PDAC cells remains unresolved. Here, we systematically interrogated the molecular consequences of seven common KRAS mutant variants in reconstituted isogenic, KRAS-deficient PDAC cell lines by integrated transcriptomic, proteomic, and phosphoproteomic profiling. We found that baseline cellular state, rather than allele identity, was the predominant driver of molecular variation. Comparisons with established KRAS reference signatures revealed significant but moderate overlap at the mRNA level and less so at the proteome level. Pathway analyses highlighted interferon response and mitochondrial translation as recurrently altered across alleles, while phosphoproteomic data confirmed robust ERK1/2 activity and suppression of DYRK kinase substrates by mutant KRAS expression. Importantly, no robust allele-specific molecular programs were identified. Together, our study establishes a comprehensive multi-omics resource for KRAS signaling in PDAC and demonstrates that cellular context exerts a stronger influence than allele identity in shaping molecular profiles, with implications for interpreting putative allele-specific signaling dependencies and therapeutic vulnerabilities.

cancer biology↗