Biology subjects

Li, P.

Publications and source records attributed to Li, P..

At least 127 records · Page 7Linked to original sources

bioRxiv2024

Sequence Composition Dictates Condensate Miscibility

Numerous biomolecular condensates coexist within cells, yet the mechanisms governing their mixing and demixing remain elusive. To investigate how the amino acid composition of intrinsically disordered regions (IDRs) affects condensate coexistence, we paired and tested 28 IDRs in 378 different combinations. Our results reveal that IDRs enriched in serine or aromatic amino acids tend to form miscible condensates. Conversely, IDRs with high charge levels form immiscible condensates, even when the serine levels are artificially boosted. Additionally, phosphorylation acts as a switch, modulating condensate miscibility. We also observed that the miscibility between transcription factor condensates and Pol II condensates profoundly influences transcription. We engineered transcription factors by increasing serine content, enhancing both their miscibility with Pol II and their transcriptional activity. However, introducing high levels of charge had the opposite effect. These findings shed light on the fundamental mechanisms controlling condensate miscibility and offer insights for designing specific functional condensates.

molecular biology↗

bioRxiv2024

Priming Epigenetic Landscape at Gene Promoters through Transcriptional Activation in Mammalian Germ Cells

In mammalian germ cells, a cycle of erasing and resetting epigenetic information is crucial for sex-specific gametogenesis and early embryogenesis. Specific chromatin states at promoters allow genes to be expressed at the appropriate time during germ cell development, however, the mechanism that establishes such characteristic chromatin states remains unclear. Here, we show that, in mouse male embryonic germ cells, promoters of developmental and housekeeping genes are selectively protected from de novo DNA methylation, coinciding with their transient upregulation and genome-wide erasure of H3K27me3. Importantly, a specific level of H3K4me3 density at the promoters serves as a potent probe that distinguishes between hypo- and hyper-DNA methylation states. Subsequent restoration of H3K27me3 contributes to establishing bivalent chromatin states that prime genes for activation at later developmental stages. These findings reveal a molecular framework shaping the epigenetic landscape at promoters with long-term effects beyond germ cell development.

genomics↗

bioRxiv2024

Dual-timescale motor circuit dynamics underlies fast head exploratory behavior and efficient locomotion

Motor systems must balance flexibility and structure to enable efficient and adaptive movements. Traditional hierarchical descending models struggle to explain the intrinsic dynamism in natural behaviors. Here, we investigate the head exploratory behavior of Caenorhabditis elegans, a minimal system capable of intricate motor patterns. Using variational mode decomposition, we identified two distinct motor dynamics: slow rhythmic bends propagating along the body and fast, phase-specific head casts influencing directional bias. Combinatorial ablations of three types of cholinergic motor neurons, in conjunction with dynamical systems analysis, revealed their distinct and overlapping roles: RMD contributes to head casts, SMD sustains bending states, SMB and SMD enable slow rhythmic bending and head-body coupling. Collectively, these neurons form a central pattern generator (CPG) driving forward locomotion. In addition, RMD subgroups displayed unique calcium dynamics correlated with rapid head movements and slow transitions between behavior states. We propose that dual-proprioceptive feedback underlies these multi-timescale dynamics, with slow feedback coordinating rhythmic bending and fast feedback shaping head casts, thereby optimizing roaming efficiency. These findings highlight how intrinsic dynamics and structured composition emerge from highly interactive low-level circuits.

neuroscience↗

bioRxiv2024

scCompass: An integrated cross-species scRNA-seq database for AI-ready

Emerging single-cell sequencing technology has generated large amounts of data, allowing analysis of cellular dynamics and gene regulation at the single-cell resolution. Advances in artificial intelligence enhance life sciences research by delivering critical insights and optimizing data analysis processes. However, inconsistent data processing quality and standards remain to be a major challenge. Here we propose scCompass, which provides a data quality solution to build a large-scale, cross-species and model-friendly single-cell data collection. By applying standardized data pre-processing, scCompass integrates and curates transcriptomic data from 13 species and nearly 105 million single cells. Using this extensive dataset, we are able to archieve stable expression genes (SEGs) and organ-specific expression genes (OSGs) in human and mouse. We provide different scalable datasets that can be easily adapted for AI model training and the pretrained checkpoints with state-of-the-art (SOTA) single-cell foundataion models. In summary, the AI-readiness of scCompass, which combined with user-friendly data sharing, visualization and online analysis, greatly simplifies data access and exploitation for researchers in single cell biology(http://www.bdbe.cn/kun).

bioinformatics↗

bioRxiv2024

Immune Evasion, Cell-Cell Fusion, and Spike Stability of the SARS-CoV-2 XEC Variant: Role of Glycosylation Mutations at the N-terminal Domain

SARS-CoV-2 continues to evolve, producing new variants that drive global COVID-19 surges. XEC, a recombinant of KS.1.1 and KP.3.3, contains T22N and F59S mutations in the spike proteins N-terminal domain (NTD). The T22N mutation, similar to the DelS31 mutation in KP.3.1.1, introduces a potential N-linked glycosylation site in XEC. In this study, we examined the neutralizing antibody (nAb) response and mutation effects in sera from bivalent-vaccinated healthcare workers, BA.2.86/JN.1 wave-infected patients, and XBB.1.5 monovalent-vaccinated hamsters, assessing responses to XEC alongside D614G, JN.1, KP.3, and KP.3.1.1. XEC demonstrated significantly reduced neutralization titers across all cohorts, largely due to the F59S mutation. Notably, removal of glycosylation sites in XEC and KP.3.1.1 substantially restored nAb titers. Antigenic cartography analysis revealed XEC to be more antigenically distinct from its common ancestral BA.2.86/JN.1 compared to KP.3.1.1, with the F59S mutation as a determining factor. Similar to KP.3.1.1, XEC showed reduced cell-cell fusion relative to its parental KP.3, a change attributed to the T22N glycosylation. We also observed reduced S1 shedding for XEC and KP.3.1.1, which was reversed by ablation of T22N and DelS31 glycosylation mutations, respectively. Molecular modeling suggests that T22N and F59S mutations of XEC alters hydrophobic interactions with adjacent spike protein residues, impacting both conformational stability and neutralization. Overall, our findings underscore the pivotal role of NTD mutations in shaping SARS-CoV-2 spike biology and immune escape mechanisms.

molecular biology↗

bioRxiv2024

Imaging of live bacterial whole-cell biosensors illuminates spatial sialic acid availability within the inflamed mammalian gut

Host mucin-derived sialic acids are key drivers of microbial colonisation, growth and pathogenicity within the mammalian gut. However, their study is hindered by complex spatiotemporal dynamics: Many gut metabolites, including sialic acids, are rapidly consumed, transformed or absorbed by the microbiota or host, meaning that conventional measurements of faeces or bulk digesta often fail to capture their true local availability. In contrast, engineered bacterial-whole cell biosensors provide an in situ read-out of metabolite exposure at the point and time of use, before these molecules are depleted. Here, we demonstrate increases in the bioavailability of sialic acid in the inflamed mouse gut using an engineered Escherichia coli biosensor that reports on sialic acid exposure via NanR-regulated transcriptional circuit. The biosensor robustly colonises the mouse gut and remains functional for at least six weeks. Through organ-scale imaging at single bacterial resolution we observe strong correlations between disease status and biosensor response in two inflammation models. Profiling along the length of the gut uncovers regional variations between the maximal sialic acid sensing and the peak inflammatory response within host tissues in a murine colitis model. Simultaneous tracking of host and microbial markers of inflammation informs the therapeutic response to sialidase inhibition, which accelerates disease recovery. Together, these data illuminate the complex spatial dynamics involved in shared host-microbiome metabolism and demonstrate the broader power of using engineered bacterial biosensors to monitor in situ bioavailability of rapidly turned-over metabolites within the gut.

synthetic biology↗

bioRxiv2024

Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis

Cancer-associated adipocytes (CAAs) reprogram metabolic status of tumor microenvironment (TME). The metabolic crosstalk between CAAs and CD8+T cells in TME remains unclear. Here we report that CAAs undergo lipolysis, releasing free fatty acids that promote lipid peroxidation and disturb mitochondrial homeostasis in CD8+T cells, leading to their functional exhaustion. Importantly, we uncover that fibroblast growth factor 21 (FGF21) autocrinally drives CAA lipolysis through upregulating adipose triglyceride lipase (ATGL) via FGFR1/KLB-p38 signaling. FGF21 deletion in adipose tissue or ATGL inhibition impedes CAA lipolysis, mitigates lipid peroxidation, normalizes mitochondrial dynamics of CD8+T cells, and restores their effector function, consequently blunting tumor growth. Moreover, combining ATGL inhibitor with anti-PD-1 therapy synergistically enhances the antitumor activity of CD8+T cells, yielding greater therapeutic efficacy. Our findings highlight the pivotal role of CAA lipol ysis in CD8+T cell dysfunction within TME, suggesting that targeting CAA lipolysis represents a valuable avenue for improving cancer immunotherapy.

cancer biology↗

bioRxiv2024

Mid1 deletion leads to cognitive dysfunction in Opitz syndrome by regulates neural rhythms through the inhibition of p-Creb by PP2Ac

MID1 is an E3 ubiquitin ligase of the tripartite motif (TRIM) subfamily of RING-containing protein1. MID1 is involved in many basic biological processes, especially during embryonic development. Mutation, truncation or complete deletion of MID1 gene is the cause of Opitz G/BBB syndrome (OS). OS is a rare genetic disease of nervous system, which is characterized by midline structural development defects during embryogenesis, including structural brain abnormalities, developmental retardation and mental retardation2. Although the function of MID1 has been studied for many years, the effect and mechanism of complete deletion of MID1 gene on OS nervous system still need to be further explored. Here we find that Mid1 gene is necessary for the normal development of hippocampus (HPC), and Mid1 gene knockout (Mid1-/y) mice showed a significant decrease in rhythm in HPC and abnormal synchronization of {gamma} rhythm in prefrontal cortex and hippocampus (PFC-HPC), showing decreased synaptic plasticity and learning and memory dysfunction.

neuroscience↗

bioRxiv2024

Novel and optimized mouse behavior enabled by fully autonomous HABITS: Home-cage Assisted Behavioral Innovation and Testing System

Mice are among the most prevalent animal models used in neuroscience, benefiting from the extensive physiological, imaging and genetic tools available to study their brain. However, the development of novel and optimized behavioral paradigms for mice has been laborious and inconsistent, impeding the investigation of complex cognitions. Here, we present a home-cage assisted mouse behavioral innovation and testing system (HABITS), enabling free-moving mice to learn challenging cognitive behaviors in their home-cage without any human involvement. Supported by the general programming framework, we have not only replicated established paradigms in current neuroscience research but also developed novel paradigms previously unexplored in mice, resulting in more than 300 mice demonstrated in various cognition functions. Most significantly, HABITS incorporates a machine-teaching algorithm, which comprehensively optimized the presentation of stimuli and modalities for trials, leading to more efficient training and higher-quality behavioral outcomes. To our knowledge, this is the first instance where mouse behavior has been systematically optimized by an algorithmic approach. Altogether, our results open a new avenue for mouse behavioral innovation and optimization, which directly facilitates investigation of neural circuits for novel cognitions with mice.

animal behavior and cognition↗

bioRxiv2024

Unveiling allopolyploidization-driven genome duplications through progressive analysis of deep genome skimming data

Whole-genome duplication (WGD) events are widespread across the Web of Life (WoL). Given the prevalence of WGDs in the polyploid Prunus (Rosaceae), this economically- and agriculturally-important angiosperm lineage provides an excellent model for exploring this mode of reticulation. We used the polyploid Prunus to demonstrate a progressive strategy for analyzing Deep Genome Skimming (DGS) data in the presence of WGDs. Phylogenomic discordance analyses indicated that allopolyploidization, rather than Incomplete Lineage Sorting (ILS), played a dominant role in the origin and dynamics of polyploid Prunus. This study underscores how a progressive strategy to identify WGD events at different depths in a phylogenetic tree reveals the nuances of evolutionary mechanisms driving allopolyploidization. We inferred that the continued uplift of the Himalayas from the Middle to Late Miocene drove the rapid diversification of the Eastern Asia endemic Maddenia clade, by facilitating frequent hybridization and allopolyploidization, specifically introgression between the Himalayas-Hengduan and the Central-Eastern China clades.

systems biology↗

bioRxiv2024

Involvement of 5' and 3' UTRs on SARS-CoV-2 Genome Packaging

The SARS-CoV-2 virus, responsible for the COVID-19 pandemic, packages its large single-stranded RNA genome through a precise yet enigmatic mechanism. A packaging signal (PS) within its genome was proposed to facilitate the assembly of new viral particles. Here in this study, we report the role of the 5 and 3 untranslated regions (UTRs) in PS-mediated genome packaging. Utilizing proximity ligation data, we demonstrate direct interactions between the UTRs and the PS9 element, a key packaging signal within the SARS-CoV-2 genome. Multiple evidence confirmed that the presence of UTRs enhance the packaging efficiency of infectious virus-like particles (iVLPs) and recruits more nucleocapsid (N) protein, suggesting a critical role in genome compaction and packaging. These insights into the regulatory mechanisms of SARS-CoV-2 genome packaging provide novel targets for antiviral therapeutics and contribute to the broader understanding of coronavirus assembly.

microbiology↗

bioRxiv2024

DNFE: Directed-network flow entropy for detecting the tipping points during biological processes

There generally exists a critical state or tipping point from a stable state to another in dynamic biological processes, beyond which a significant qualitative transition occurs. Identifying this tipping point and its driving network is essential to prevent or delay catastrophic consequences. However, most traditional approaches based on undirected networks still suffer from the problem of the robustness and effectiveness when applied to high-dimensional small sample data, especially for single-cell data. To address this challenge, we developed a directed-network flow entropy (DNFE) method which can transform measured omics data into a directed network. This method is applicable to both single-cell RNA-sequencing (scRNA-seq) and bulk data. By applying this method to five real datasets, including three single-cell datasets and two bulk tumor datasets, the method can not only successfully detect the critical states as well as their dynamic network biomarkers, but also help explore regulatory relationships between genes. Numerical simulation indicates that the DNFE method is robust and superior to existing methods. Furthermore, DNFE has predicted active transcription factors (TFs), and further identified dark genes, which are usually overlooked by traditional methods.

cancer biology↗

bioRxiv2024

Molecular and spatiotemporal characterization of cells in murine atherosclerotic plaques

ObjectiveSingle-cell technologies have revolutionized our understanding of the phenotypic and transcriptional diversity of aortic leukocytes in atherosclerotic humans and mice. However, enzymatically dissociated tissues lose the spatial context of plaque cells in situ. Here we utilized imaging mass cytometry (IMC) combining with single-cell RNA sequencing (scRNA-seq) to characterize the spatial distribution dynamics, phenotypic transitions, metabolic and functional phenotypes, and the intercellular interaction networks of plaque cells during atherosclerotic progression. Additionally, the dynamic immune landscape of circulating leukocytes associated with atherosclerosis was characterized using cytometry of time of flight (CyTOF). Approach and ResultsA highly multiplexed IMC panel with 33 metal-conjugated antibodies was designed to generate 11 highly multiplexed histology images of aortic root tissues from ApoE-/- mice on high-fat diet at different stage of atherosclerosis. Using histoCAT, we identified 8 principal cell subtypes with distinct phenotypic and geographic dynamics. Furthermore, IMC-defined cell subsets partially corresponded to scRNA-seq-annotated aortic cell subtypes, including 4 macrophage subsets, neutrophils, smooth muscle cells (SMCs) and SMC-derived SEMs (Stem cell, endothelial cell and macrophage-like cell). Activation of inflammatory pathways, increased oxidative phosphorylation and augmented osteoclast differentiation were observed in macrophage populations, SMCs and SEMs from an early stage to advanced stage of atherosclerosis. Notably, cell neighborhood analysis by IMC uncovered multifaceted cell-cell interactions within the plaque, in particular in neutrophil-mediated interactions with smooth muscle cells and macrophages, which were confirmed by ligand-receptor interactions based on scRNA-seq data. Additionally, characterization of the peripheral immune cells by CyTOF revealed an increased ratio of myeloid cells to lymphocytes, and certain neutrophil and monocyte subpopulations also exhibited enhanced lipid metabolism and glycolysis as well as activated inflammatory signaling. ConclusionThis study provides a dynamic spatiotemporal landscape of atherosclerotic lesions and peripheral leukocytes. The new information based on IMC may help understand atherosclerotic pathology and develop novel therapeutic strategies.

pathology↗

bioRxiv2024

Mapping HIV-1 RNA Structure, Homodimers, Long-Range Interactions and persistent domains by HiCapR

Human Immunodeficiency Virus (HIV) persists as a leading global health issue. A significant gap in knowledge exists in our understanding of long-range interactions within the HIV-1 RNA genome. To bridge this gap, we introduce HiCapR, incorporating a psoralen crosslinking RNA proximity ligation and post-library hybridization for capturing HIV RNA-RNA interactions. Leveraging HiCapR, we confirm the presence of stem structures in the key regions, such as the 5-untranslated region(5-UTR) and Rev Response Element (RRE) stems, and dimer sites in 5-UTR region, which is responsible for HIV packaging. Importantly, we reveal multiple previously unknown homodimers along the HIV genome, which may have important implications for viral RNA splicing and packaging processes. Also, we uncover a wealth of unprecedented long-range interactions, particularly within the 5-UTR of infected cells. Intriguingly, our findings indicate a pronounced reduction in long-range RNA-RNA interactions, signifying a transition from a state of abundant interactions, hence a relative loose state within infected cells to a condensed structure within virions. Concurrently, we have demonstrated the presence of stable genomic domains within virions that are instrumental in the dimerization process. These domains are preserved throughout the packaging process. Our findings shed light on the functional significance of RNA organization, including stable and persistent genomic domains, homodimerization, and long-range RNA-RNA interactions, in the splicing, packaging as well as assembly of HIV. HighlightsHiCapR is a new proximity ligation method for mapping RNA structures and homodimers in the HIV genome with sufficient reliability and efficiency. Multiple homodimers were discovered along the genome, with potential implications for splicing and packaging processes. Long-range RNA-RNA interactions are abundant in infected cells but significantly reduced in virions. Stable genomic domains encluding homodimer sites are persistent in virions and are involved in dimerization.

genomics↗

bioRxiv2024

Flexible use of conserved motif vocabularies constrains genome access in cell type evolution

Cell types evolve into a hierarchy with related types grouped into families. How cell type diversification is constrained by the stable separation between families over vast evolutionary times remains unknown. Here, integrating single-nucleus multiomic sequencing and deep learning, we show that hundreds of sequence features (motifs) divide into distinct sets associated with accessible genomes of specific cell type families. This division is conserved across highly divergent, early-branching animals including flatworms and cnidarians. While specific interactions between motifs delineate cell type relationships within families, surprisingly, these interactions are not conserved between species. Consistently, while deep learning models trained on one species can predict accessibility of other species sequences, their predictions frequently rely on distinct, but synonymous, motif combinations. We propose that long-term stability of cell type families is maintained through genome access specified by conserved motif sets, or vocabularies, whereas cell types diversify through flexible use of motifs within each set.

evolutionary biology↗

bioRxiv2024

Neutralization and Stability of JN.1-derived LB.1, KP.2.3, KP.3 and KP.3.1.1 Subvariants

During the summer of 2024, COVID-19 cases surged globally, driven by variants derived from JN.1 subvariants of SARS-CoV-2 that feature new mutations, particularly in the N-terminal domain (NTD) of the spike protein. In this study, we report on the neutralizing antibody (nAb) escape, infectivity, fusion, and stability of these subvariants--LB.1, KP.2.3, KP.3, and KP.3.1.1. Our findings demonstrate that all of these subvariants are highly evasive of nAbs elicited by the bivalent mRNA vaccine, the XBB.1.5 monovalent mumps virus-based vaccine, or from infections during the BA.2.86/JN.1 wave. This reduction in nAb titers is primarily driven by a single serine deletion (DelS31) in the NTD of the spike, leading to a distinct antigenic profile compared to the parental JN.1 and other variants. We also found that the DelS31 mutation decreases pseudovirus infectivity in CaLu-3 cells, which correlates with impaired cell-cell fusion. Additionally, the spike protein of DelS31 variants appears more conformationally stable, as indicated by reduced S1 shedding both with and without stimulation by soluble ACE2, and increased resistance to elevated temperatures. Molecular modeling suggests that the DelS31 mutation induces a conformational change that stabilizes the NTD and strengthens the NTD-Receptor-Binding Domain (RBD) interaction, thus favoring the down conformation of RBD and reducing accessibility to both the ACE2 receptor and certain nAbs. Additionally, the DelS31 mutation introduces an N-linked glycan modification at N30, which shields the underlying NTD region from antibody recognition. Our data highlight the critical role of NTD mutations in the spike protein for nAb evasion, stability, and viral infectivity, and suggest consideration of updating COVID-19 vaccines with antigens containing DelS31.

molecular biology↗

bioRxiv2024

PI(4)P recruits CIDE proteins to promote the formation of unilocular lipids droplets

Lipid droplets (LDs) are evolutionarily conserved organelles that play important roles in metabolism. Each LD is enclosed by a monolayer of phospholipids, distinct from bilayer membranes. The composition of LD surface phospholipids and their impact on LD growth and function remain to be clearly defined. Phosphoinositides mark cellular organelles and regulate cell signalling and organellar function. Here, we demonstrate that PI(4)P decorates a subset of LDs to recruit and activate the CIDE proteins. Enhanced expression of ORP2 and ORP5, LD-associated lipid transfer proteins that remove PI(4)P from LDs, abolished the localization and function of CIDE proteins. Blocking the synthesis of PI(4)P on LD surface via knocking down PI4K2A also impaired the localization and function of CIDE proteins. In adipocytes, depleting PI(4)P dramatically reduced the size of LDs, as well as adipose tissue mass. In severe steatotic liver, depleting PI(4)P reduced LD accumulation. Our results thus identify a key function of LD surface PI(4)P under physiological conditions and unveil how CIDE proteins are recruited to LDs.

cell biology↗

bioRxiv2024

MagnoliidsGDB：An integrated functional genomics database for Magnoliids

In this study, we present MagnoliidsGDB, an integrated functional genomics database specifically developed for magnoliids, a group of plants known for their unique characteristics and medicinal properties. As of March 2024, MagnoliidsGDB has collected 31 genome sequences from 24 species, 149 resequencing datastes from 4 species, 842 transcriptomic datasets from 20 species, and metabolomic data from 15 species. This comprehensive resource allows researchers to explore the genomic, transcriptomic, and metabolomic variations of magnoliids. The user-friendly search and analysis functionalities of MagnoliidsGDB facilitate the study of genomic variations, gene functions, plant evolution and key metabolites of magnoliids. We hope this database will contribute to the study of magnoliids and increase our understanding of the origin, variation, and molecular basis of the unique biological features of magnoliids.

evolutionary biology↗