Biology subjects

Bi, R.

Publications and source records attributed to Bi, R..

11 recordsLinked to original sources

bioRxiv2026

Host recovery after skin barrier disruption is individual-specific and associated with microbial functions

The human skin is repeatedly exposed to mechanical and environmental stress, particularly in common skin diseases such as eczema, and yet the determinants of recovery remain poorly understood. Using longitudinal, multimodal profiling of skin physiology, structure (Raman spectroscopy), and microbial communities (shotgun metagenomics), we investigated in a human cohort (n=36 subjects, x2 sites, x6 timepoints) how host-microbe interactions could jointly shape recovery. Despite baseline variability in physiological parameters, we established that our protocol enables a defined disruption of the stratum corneum. While recovery trajectories for host attributes were notably consistent across age groups and body sites, individual-specific differences in recovery timelines were observed. To assess the role of the skin microbiome, several key time-dependent changes in microbial species were identified including enrichment of select Cutibacterium and Staphylococcus species and depletion of Corynebacterium and Malassezia species. Clustering of microbiome stability profiles across subjects and sites identified 6 distinct groups which associate with varying host-recovery patterns and microbial functions. Finally, joint hazards modelling of recovery timing revealed significant contributions from microbial taxa, functions and stability groups, highlighting the under-appreciated role of host-microbial interactions in response to skin stress and in the recovery process.

genomics↗

bioRxiv2025

FlexRibbon: Joint Sequence and Structure Pretraining for Protein Modeling

AO_SCPLOWBSTRACTC_SCPLOWProtein foundation models have advanced rapidly, with most approaches falling into two dominant paradigms. Sequence-based language models (e.g., ESM-2) capture sequence semantics at scale, and a number of recent works incorporate structural signals into sequence encoders. MSA-based predictors (e.g., AlphaFold 2/3) achieve accurate folding by exploiting evolutionary couplings, but their reliance on homologous sequences makes them less reliable in highly mutated or alignment-sparse regimes. We present FlexRibbon{ddagger}, a pretrained protein model that jointly learns from amino acid sequences and three-dimensional structures. Our pretraining strategy combines masked language modeling with diffusion-based denoising, enabling bidirectional sequence-structure learning without requiring MSAs. Trained on both experimentally resolved structures and AlphaFold 2 predictions, FlexRibbon captures global folds as well as flexible conformations critical for biological function. Evaluated across diverse tasks spanning interface design, intermolecular interaction prediction, and protein function prediction, FlexRibbon establishes new state-of-the-art performance on 12 different tasks, with particularly strong gains in mutation-rich settings where MSA-based methods often struggle.

molecular biology↗

bioRxiv2024

Inhibitor of cardiolipin biosynthesis-related enzyme MoGep4 confers broad-spectrum anti-fungal activity

Plant pathogens cause devastating diseases, leading to serious losses to agriculture. Mechanistic understanding of pathogenesis of plant pathogens lays the foundation for the development of fungicides for disease control. Mitophagy, a specific form of autophagy, is important for fungal virulence. The role of cardiolipin, mitochondrial signature phospholipid, in mitophagy and pathogenesis is largely unknown in plant pathogenic fungi. The functions of enzymes involved in cardiolipin biosynthesis and relevant inhibitors were assessed using a set of assays, including genetic deletion, plant infection, lipidomics, chemical-protein interaction, chemical inhibition, and field trials. Our results showed that the cardiolipin biosynthesis-related gene MoGEP4 of the rice blast fungus Magnaporthe oryzae regulates growth, conidiation, cardiolipin biosynthesis, and virulence. Mechanistically, MoGep4 regulated mitophagy and Mps1-MAPK phosphorylation, which are required for virulence. Chemical alexidine dihydrochloride (AXD) inhibited the enzyme activity of MoGep4, cardiolipin biosynthesis and mitophagy. Importantly, AXD efficiently inhibited the growth of 10 plant pathogens and controlled rice blast and Fusarium head blight in the field. Our study demonstrated that MoGep4 regulates mitophagy, Mps1 phosphorylation and pathogenesis in M. oryzae. In addition, we found that the MoGep4 inhibitor, AXD, displays broad-spectrum antifungal activity and is a promising candidate for fungicide development.

microbiology↗

bioRxiv2023

High-resolution ultrastructure and morphology of marine ammonia-oxidizing archaea Nitrosopumilus maritimus SCM1 revealed by Cryo-ET and STEM-EDS

Nitrososphaerota, formerly known as Thaumarchaeota, constitute a diverse and widespread group of ammonia-oxidizing archaea (AOA) inhabiting ubiquitously in marine and terrestrial environments, playing a pivotal role in global nitrogen cycling. Despite their significance in Earths ecosystems, the cellular organization of AOA remains largely unexplored, leading to a significant question unanswered of how the machinery of these organisms underpins metabolic functions. In this study, we combined chromatic-aberration-corrected cryo-electron tomography (cryo-ET), scanning transmission electron microscopy (STEM), and energy dispersive X-ray spectroscopy (EDS) to unveil the cellular organization and elemental composition of Nitrosopumilus maritimus SCM1, a representative member of marine Nitrososphaerota. Our tomograms show the native ultrastructural morphology of SCM1 and one to several dense storage granules in the cytoplasm. STEM-EDS analysis identifies two types of storage granules in which one type is possibly composed of polyphosphate, while the other type is polyhydroxyalkanoate. Collectively, these findings provide visual evidence for the resilience of AOA in the vast oligotrophic marine environment.

microbiology↗

bioRxiv2023

Melatonin Targets MoIcl1 and Works Synergistically with Fungicide Isoprothiolane in Rice Blast Control

Melatonin-a natural harmless molecule-displays versatile roles in human health and crop disease control such as for rice blast. Rice blast, caused by the filamentous fungus Magnaporthe oryzae, is one devastating disease of rice. Application of fungicides is one of the major measures in the control of various crop diseases. However, fungicide resistance in the pathogen and relevant environmental pollution are becoming serious problems. By screening for possible synergistic combinations, here, we discovered an eco-friendly combination for rice blast control, melatonin and the fungicide isoprothiolane. These compounds together exhibited significant synergistic inhibitory effects on vegetative growth, conidial germination, appressorium formation, penetration, and plant infection by M. oryzae. The combination of melatonin and isoprothiolane reduced the effective concentration of isoprothiolane by over 10-fold as well as residual levels of isoprothiolane. Transcriptomics and lipidomics revealed that melatonin and isoprothiolane synergistically interfered with lipid metabolism by regulating many common targets, including the predicted isocitrate lyase-encoding gene MoICL1. Furthermore, we show that melatonin and isoprothiolane interact with MoIcl1 using different techniques. This study demonstrates that melatonin and isoprothiolane function synergistically and can be used to reduce the dosage and residual level of isoprothiolane, potentially contributing to the environment-friendly and sustainable control of crop diseases.

pathology↗

bioRxiv2023

Doxorubicin inhibits phosphatidylserine decarboxylase and confers broad-spectrum antifungal activity

O_LIAs phospholipids of cell membranes, phosphatidylethanolamine (PE) and phosphatidylserine (PS) play crucial roles in glycerophospholipid metabolism. Broadly, some phospholipid biosynthesis enzymes serve as potential fungicide targets. Therefore, revealing the functions and mechanism of PE biosynthesis in plant pathogens would provide potential targets for crop disease control. C_LIO_LIWe performed analyses including phenotypic characterizations, lipidomics, enzyme activity, site-directed mutagenesis, and chemical inhibition assays to study the function of PS decarboxylase-encoding gene MoPSD2 in rice blast fungus Magnaporthe oryzae. C_LIO_LIThe Mopsd2 mutant was defective in development, lipid metabolism and plant infection. The PS level increased while PE decreased in Mopsd2, consistent with the enzyme activity. Furthermore, chemical doxorubicin inhibited the enzyme activity of MoPsd2 and showed antifungal activity against ten phytopathogenic fungi including M. oryzae and reduced disease severity of two crop diseases in the field. Three predicted doxorubicin-interacting residues are important for MoPsd2 functions. C_LIO_LIOur study demonstrates that MoPsd2 is involved in de novo PE biosynthesis and contributes to the development and plant infection of M. oryzae and that doxorubicin shows broad-spectrum antifungal activity as a fungicide candidate. The study also implicates that bacterium Streptomyces peucetius, which biosynthesizes doxorubicin, could be potentially used as an eco-friendly biocontrol agent. C_LI

pathology↗

bioRxiv2022

Creating an atlas of the bone microenvironment during oral inflammatory-related bone disease using single-cell profiling

Oral inflammatory diseases such as apical periodontitis are common bacterial infectious diseases that may affect the periapical alveolar bone tissues. A protective healing process occurs simultaneously with the inflammatory tissue destruction, in which mesenchymal stem cells (MSCs) play a primary role. However, a systematic and precise description of the cellular and molecular composition of the microenvironment of bone affected by inflammation is lacking. In this study, we created a single cell atlas of cell populations that compose alveolar bone in healthy and inflammatory disease states. We investigated changes in expression frequency and patterns related to apical periodontitis, as well as the interactions between MSCs and immunocytes. Our results highlight an enhanced self-supporting network and osteogenic potential within MSCs during apical periodontitis-associated inflammation. MSCs not only differentiated towards osteoblast lineage cells, but also expressed higher levels of osteogenic related markers, including SPARC and Col11. This was confirmed by lineage tracing in transgenic mouse models and human samples from oral inflammatory-related alveolar bone lesions. In summary, the current study provides an in-depth description of the microenvironment of MSCs and immunocytes in both healthy and disease states. We also identified key apical periodontitis-associated MSC subclusters and their biomarkers, which could further our understanding of the healing process and the underlying mechanisms of oral inflammatory-related bone disease. Taken together, these results enhance our understanding of heterogeneity and cellular interactions of alveolar bone cells under pathogenic and inflammatory conditions. We provide these data as a tool for investigators not only to better appreciate the repertoire of progenitors that are stress responsive but importantly to help design new therapeutic targets to restore bone lesions caused by apical periodontitis and other inflammatory-related bone diseases.

cell biology↗

bioRxiv2021

IGF1 Signaling in Temporomandibular Joint Fibrocartilage Stem Cells Regulates Cartilage Growth and Homeostasis in Mice

ObjectiveInvestigate functional roles of Igf1 in fibrocartilage stem cell (FCSC) for temporomandibular joint (TMJ) cartilage growth and homeostasis. MethodsGli1-CreER+; RosaTdTomato mice were used for validating FCSCs lineage labeling efficiency. In Gli1-/Col2-CreER+; Igf1fl/fl mice, TMJ cartilage morphological and functional changes were characterized at 4 weeks and 5 months after Igf1 deletion. H&E, Safranine O and immuno-histochemistry staining were performed. FCSCs specificity were characterized using EdU and TUNEL staining. A unilateral anterior crossbite (UAC) mouse model was generated for mimicking TMJ osteoarthritis status. ResultsIn Gli1-CreER+; RosaTdTomato mice, RFP labeled FCSCs showed favorable proliferative capacity. 4 weeks after Igf1 deletion, Gli1+ and Col2+ cell lineages led to distinct pathological changes of TMJ cartilage morphology. A more serious reduction of cartilage thickness and cell density were found in the superficial layers in Gli1-CreER+; Igf1fl/fl mice. 5 months after Igf1 deletion, more severe disordered cell arrangement in TMJ cartilage were found in both groups with Gli1+ and Col2+ specific deletion of Igf1. Immunostaining showed that PI3K/Akt signaling pathway was blocked in the superficial layers of TMJ in Gli1-CreER+; RosaTdTomato mice. Finally, deletion of Igf1 in FCSCs significantly aggravated osteoarthritis (OA) phenotypic changes in TMJ in UAC mice model, characterized in decreased cartilage thickness, cell numbers and loss of extracellular matrix secretion. ConclusionIgf1 deletion disrupted stem cell functions of FCSCs, leading to disordered cell distribution during TMJ growth, as well as exaggerated the OA process in TMJ under pathological condition. In TMJ cartilage, Igf1 expression in FCSCs is critical for PI3K/Akt activation, which may be involved in regulating FCSCs self-renewal and differentiation.

cell biology↗

bioRxiv2021

A multiple-causal-gene-cluster model underlying GWAS signals of Alzheimer's disease

Genome-wide association studies (GWASs) have identified dozens of genetic susceptibility loci for Alzheimers disease (AD). Nevertheless, the underlying causal variants and biological mechanisms remain elusive. Here, we systematically integrated AD GWAS with comprehensive multi-omics data, and distilled 304 potentially functional variants and 166 causal genes from 49 loci. Intriguingly, we found that most of AD GWAS loci contain multiple functional variants and causal genes. In vitro assays showed that one functional variant regulated multiple genes in the 11p11.2 locus (the CELF1/SPI1 locus) and alteration of these target genes contributed to AD-related molecular processes, supporting the co-existence of multiple functional variants and AD-relevant causal genes within a single locus. We thus proposed a multiple-causal-gene-cluster model that co-dysregulation of a cluster of genes within a single GWAS loci individually or synergistically contribute to AD development. This model provides a novel insight into the biological mechanisms underlying the GWAS loci of complex traits.

genetics↗

bioRxiv2020

Local and global dichotomic dysfunction in resting and evoked functional connectivity precedes tauopathy

Functional network activity alterations are one of the earliest hallmarks of Alzheimers disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (early-tauopathy 3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice thus reveal a dichotomic hypo-connected resting/hyper-responsive active phenotype. The strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related deficits in humans.

neuroscience↗

bioRxiv2019

A semi-parametric Bayesian approach, iSBA, for differential expression analysis of RNA-seq data

RNA sequencing (RNA-seq) technologies have been popularly applied to study gene expression in recent years. Identifying differentially expressed (DE) genes across treatments is one of the major steps in RNA-seq data analysis. Most differential expression analysis methods rely on parametric assumptions, and it is not guaranteed that these assumptions are appropriate for real data analysis. In this paper, we develop a semi-parametric Bayesian approach for differential expression analysis. More specifically, we model the RNA-seq count data with a Poisson-Gamma mixture model, and propose a Bayesian mixture modeling procedure with a Dirichlet process as the prior model for the distribution of fold changes between the two treatment means. We develop Markov chain Monte Carlo (MCMC) posterior simulation using Metropolis Hastings algorithm to generate posterior samples for differential expression analysis while controlling false discovery rate. Simulation results demonstrate that our proposed method outperforms other popular methods used for detecting DE genes.

genomics↗