Biology subjects

Lu, B.

Publications and source records attributed to Lu, B..

At least 37 records · Page 2Linked to original sources

bioRxiv2025

AtSDR4L and its paralog DIG2 repress somatic embryogenesis during post-embryonic development in Arabidopsis

Somatic embryogenesis, a developmental process advantageous as an alternative means for plant propagation due to the lack of maternal tissues and the ease of in vivo to in vitro knowledge transfer of embryogenesis, has been applied in studies on the regulatory mechanisms governing the developmental plasticity in plants. Core and accessory components of the polycomb repressive complexes (PRCs), the epigenetic regulatory machinery, are known to repress the transcription of genes that positively regulate the somatic embryogenesis in seedlings. Recent studies revealed that Arabidopsis thaliana SEED DORMANCY 4-LIKE (AtSDR4L), an interactor of a PRC accessory, represses the embryo developmental program for a successful switch from seed to seedling. However, little is known about the regulation of cell differentiation by AtSDR4L in seedlings. Here, we show that AtSDR4L, its paralog Dynamic Influencer of Gene expression 2 (DIG2), and PRC components share similar transcriptional regulatory dynamics, particularly on somatic embryogenesis-related genes. We further demonstrate that mutations in AtSDR4L and DIG2 lead to the formation of somatic embryo-like structures and a delay in cellular differentiation. Thus, transcriptional changes reflected by morphological defects associated with somatic embryogenesis in Atsdr4l dig2 mutants suggest that AtSDR4L and DIG2 prevent the dedifferentiation of cells for proper seedling growth through the transcriptional control of cell identity.

plant biology↗

bioRxiv2025

JointMap identified SERPINA3+ chondrocytes as a therapeutic target for osteoarthritis

BackgroundOsteoarthritis (OA) is a prevalent degenerative joint disease that affects nearly half of the population aged over 65. Recent single-cell transcriptional studies have identified heterogeneous OA-specific chondrocyte subtypes, yet a unified subtype-classification remains incomplete. MethodsIn this study, we integrated a total of 545,946 cells to develop JointMap, an interspecies atlas. The chondrocyte subtypes were analyzed using machine learning algorithms were validated via human samples, animal models, and in vitro cell culture. We performed KAS-seq and analyzed the spatial characters for JointMap. ResultsBased on clinical diagnosis and cross-omic indexes, we identified a novel OA-elevated chondrocyte subtype, SERPINA3+ chondrocytes. Notably, we uncovered their upregulated chondrogenesis function and intercellular communication patterns as potential therapeutic targets. ConclusionsIn summary, JointMap provides a unified framework for the systematic annotation of chondral tissues across species and helps in the identification of druggable networks for articular diseases.

bioinformatics↗

bioRxiv2025

Genomic heterogeneity inflates the performance of variant pathogenicity predictions

Recent studies have reported unprecedented accuracy predicting pathogenic variants across the genome, including in noncoding regions, using large AI models trained on vast genomic data. We present a comprehensive evaluation of these frontier models, showing that performance is inflated by differences in the prevalence of pathogenic variants across genomic contexts. We identify the best-performing models for each variant type and establish a benchmark to guide future progress.

bioinformatics↗

bioRxiv2025

Modular striatal dynamics and reciprocal inhibition orchestrate skilled action sequencing

The basal ganglia, particularly the striatum, are critical for orchestrating skilled behavioral sequences, yet the precise mechanisms underlying this process remain unclear. Using high-resolution kinematic tracking and neural recordings in mice performing a water-reaching task, we found spatially distributed modules of striatal projection neurons whose activity corresponded to the generation of each element in the sequence--aiming, reaching, and drinking. They are activated sequentially and exhibit reciprocal inhibition, ensuring a strict serial order. Optogenetic activation of the direct pathway of the orofacial module promoted licking while suppressing reaching. Reaching could in turn suppress stimulation-evoked licking, revealing bidirectional inhibitory interactions. Our findings demonstrate that the striatums modular organization, coupled with lateral inhibition, sculpts the temporal progression of actions, providing a mechanistic framework for understanding how the basal ganglia coordinate complex behaviors.

neuroscience↗

bioRxiv2025

Quantitative RNA pseudouridine landscape reveals dynamic modification patterns and evolutionary conservation across bacterial species

Pseudouridine ({Psi}) modifications are the most abundant RNA modifications; however, their distribution and functional significance in bacteria remain largely unexplored compared to eukaryotic systems. In this study, we present the first transcriptome-wide and quantitative mapping of {Psi} modifications across five diverse bacterial species (Bacillus cereus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Pseudomonas syringae) at single-base resolution, utilizing the optimized BID-seq method for bacterial RNA. Our analysis revealed growth phase-dependent dynamics of pseudouridylation in bacterial tRNA and mRNA, particularly in genes enriched in core metabolic pathways. Comparative analysis demonstrated evolutionarily conserved features of {Psi} modifications, such as dominant motif contexts, {Psi} clustering within operons, etc. Functional analysis indicated {Psi} modifications influence bacterial mRNA stability, translation, and interactions with specific RNA-binding proteins (RBPs) in response to changing cellular demands during growth phase transitions. The integrated computational analysis on local RNA architecture was conducted to elucidate the structure-dependent {Psi} modifications in bacterial RNA. Furthermore, we developed an integrated deep learning framework, combining Transformer-GNN-based neural networks (pseU_NN) to capture both RNA sequence and structural features for effective prediction of {Psi}-modified sites. Overall, our study provides valuable insights into the landscapes of bacterial RNA {Psi} modifications and establishes a foundation for future mechanistic investigations into the functions of {Psi} in bacterial RNA regulation.

microbiology↗

bioRxiv2025

Forest biogeochemical monitoring indicates altered microbial communities, macronutrient availability, CO2 emissions and litter chemistry in root zone soil of oak trees with Acute Decline symptoms

Acute and Chronic Oak Decline (AOD & COD) widely impact oak woodlands across Europe. AOD is known to cause rapid decline in tree health in a short span of 3-5 years. However, the interactions between such oak decline and soil biogeochemical dynamics are not fully understood. We selected three oak trees for each of the three treatments for biogeochemical monitoring: 1. No symptoms (Healthy), 2. AOD & 3. COD symptoms, in Writtle woodlands, Essex, UK. The selected trees were used for quarterly root zone soil sampling (cores to depth of 40 cm), and monthly surface soil (0-10 cm), leaf litter and GHG emissions sampling over a year (2022-23). Soil samples were characterised for their physico-chemical properties, total nutrient content & availability. Leaf litter samples were sorted into branches, leaves, seeds and flowers, weighed and their chemistry characterised. Soil microbial communities were characterised using phospholipid fatty acid analyses. Almost all the measured properties showed significant changes with season and depth, indicating a strong temporal and depth effect on forest soil biogeochemical dynamics. Notably macro-nutrient contents of leaf litter were greater in the summer period, which resulted in increased soil nutrient availability in autumn. This pattern was particularly exaggerated in AOD trees, which had greater nutrient content in litterfall in summer and greater nutrient availability in root zone soil in autumn than those of COD and Healthy trees. We found that AOD root zone soil have altered microbial communities, decreased CO2 emissions and increased macronutrient availability. Taken together, our study shows poor physiological nutrient management by diseased AOD trees revealed by greater nutrient concentration in AOD leaf litter indicating the lack of nutrient resorption and re-allocation before leaf senescence, and less active root zone soil under AOD trees, shown by reduced soil CO2 emissions and increased nutrient availability in oak root influenced zones. Hence, we conclude that the biogeochemical dynamics of AOD root zone soils are significantly different to that of healthy and COD trees, however controlled experiments are needed alongside these field observations to disentangle the causes from effects in understanding the relationship between soil health and oak decline. HighlightsO_LIWe monitored forest soil biogeochemical dynamics under oak trees of different health status C_LIO_LIAcute Oak Decline (AOD) trees had greater macronutrient availability in root zone soils C_LIO_LIAOD trees had greater nutrient content in litter added to the root zone soil C_LIO_LIAOD root zone soils had altered microbial community structure & reduced CO2 emissions C_LIO_LIWe conclude that AOD trees have poor physiological nutrient management and less active rhizosphere compared to healthy trees. C_LI

ecology↗

bioRxiv2025

Deconvoluting single-cell transcriptomics reveals cellular programs regulated by cell-cell communication in colorectal cancer

Cells within a tissue microenvironment communicate through intricate cell-cell communication (CCC) networks. In this meta-analysis of eight single-cell cohorts encompassing 153 patients and 279 samples, we advance the understanding of CCC networks in colorectal cancers through a novel analytical framework. Employing hierarchical topic modeling, we identify gene expression modules (GEMs) that mirror single-cell signaling states, crucial for deciphering the complexity of intercellular interactions. By applying causal discovery methods, we systematically uncover GEMs likely regulated by ligand-receptor signaling and cross-cell-type communication. This analysis reveals cross-cell-type CCC programs, marked by highly correlated GEMs across various cell types, shedding light on the intricate CCC networks within the tumor microenvironment. Spatial transcriptomics further validate these findings by demonstrating the co-localization of GEMs within CCC programs in distinct spatial domains, emphasizing the spatial dynamics of tumor intercellular communication. Our interactive website (http://44.192.10.166:3838/) and analytical framework equip researchers with powerful tools to explore these complex mechanisms, potentially uncovering novel drug targets and refining strategies for precision immunotherapies. This comprehensive study not only presents a detailed catalog of CCC networks driven by ligand-receptor interactions in colorectal cancer but also highlights the significance of integrating multi-sample and patient data to unravel the molecular underpinnings of cancer communication pathways.

bioinformatics↗

bioRxiv2025

Distinguish risk genes functioning at presynaptic or postsynaptic regions and key connectomes associated with pathological α-synuclein spreading

Previous studies have suggested that pathological -synuclein (-Syn) mainly transmits along the neuronal network, but several key questions remain unanswered: (1) How many and which connections in the connectome are necessary for predicting the progression of pathological -Syn? (2) How to identify risk gene that affects pathology spreading functioning at presynaptic or postsynaptic regions, and are these genes enriched in different cell types? Here, we addressed these key questions with novel mathematical models. Strikingly, the spreading of pathological -Syn is predominantly determined by the key subnetworks composed of only 2% of the strongest connections in the connectome. We further explored the genes that are responsible for the selective vulnerability of different brain regions to transmission to distinguish the genes that play roles in presynaptic from those in postsynaptic regions. Those risk genes were significantly enriched in microglial cells of presynaptic regions and neurons of postsynaptic regions. Gene regulatory network analyses were then conducted to identify key drivers of genes responsible for selective vulnerability and overlapping with Parkinsons disease risk genes. By identifying and discriminating between key gene mediators of transmission operating at presynaptic and postsynaptic regions, our study has demonstrated for the first time that these are functionally distinct processes.

neuroscience↗

bioRxiv2025

Enhanced Detection of RNA Modifications in Escherichia coli Utilizing Nanopore RNA004 Technology

RNA modifications are critical regulators of diverse cellular processes, yet their roles in prokaryotic mRNAs remain poorly understood. Recent advances in Oxford Nanopore sequencing--especially the RNA004 kit--have enabled higher yields, reduced signal-to-noise ratio, and improved read accuracy, making them promising tools for investigating bacterial epitranscriptomes. Here, we presented a comprehensive walkthrough for Escherichia coli RNA modification analysis based on RNA004. Using both native (WT) and in vitro-transcribed (IVT) RNA samples, we first evaluated the Dorado modification detection models ({Psi}, mA, mC, and A-to-I). While each model successfully identified known rRNA modification sites, it also generated many false positives, emphasizing the need for careful data interpretation. To address these limitations, we introduced nanoSundial (https://github.com/lrslab/nanoSundial), a new comparative method that leveraged raw current features from WT and IVT samples to detect multiple types of RNA modifications in prokaryotes. We optimized nanoSundial on well-studied rRNA sites and validated its effectiveness with tRNA modifications. Through technical and biological replicate analyses, nanoSundial demonstrated reproducibility exceeding 95% in tRNA, rRNA, and ncRNA regions, albeit with lower reproducibility ([~]61%) in mRNA. We further found enrichment of mRNA modifications at the start or end of coding sequences. In total, 190 stably modified CDS regions were identified in E. coli, many of which cluster near the end of highly expressed transcriptional units (TUs) in each operon. Overall, this study highlighted the strengths and limitations of current nanopore-based modification detection methods on bacterial RNA, introduced a robust new comparative tool, and elucidated previously uncharacterized mRNA modification landscapes. Our findings open new avenues for understanding the functional impacts of bacterial RNA modifications and advancing epitranscriptomic research in prokaryotes.

bioinformatics↗

bioRxiv2025

Dynamic Transcriptomic Remodeling in Human Neural Progenitor Cells Reveals Mechanisms for Vision Preservation in Retinitis Pigmentosa Model

Human neural progenitor cells (hNPCs) have shown promise in slowing down retinal degeneration in animal models and are currently being tested in clinical trials for treating retinitis pigmentosa (RP). However, the status of grafted hNPCs and their interaction with host retinal cells over time is largely unknown. Here, we investigated single-cell transcriptomic changes in grafted hNPCs and host retinal cells following injection into a rodent model for RP. Grafted hNPCs and host retinal cells undergo dynamic transcriptomic changes in the degenerative retinal environment. Grafted hNPCs protect vision through multiple mechanisms, including trophic factor support, modulation of metabolic activity, reduction of apoptosis, oxidative stress, and inflammation, alongside extracellular matrix remodeling. CellChat analysis revealed a progressive decline in intercellular signaling and communication strength between hNPCs and host retinal cells over time. This study indicates that enhancing trophic factor supports and improving host retinal environment are key targets to enable long-term vision preservation.

neuroscience↗

bioRxiv2024

A2A-positive neurons in the nucleus accumbens core regulate effort exertion

Previous work has implicated the nucleus accumbens (NAc) in the regulation of effort, defined as the amount of work an animal is willing to perform for a given reward, but little is known about the specific contributions of neuronal populations within the NAc to effort regulation. In this study, we examined the contributions of direct pathway and indirect pathway neurons in the NAc core using an operant effort regulation task, in which the effort requirement is the number of lever presses needed for earning a food reward. Using optogenetics, we manipulated the activity of direct pathway spiny projection neurons (dSPNs, D1+) and indirect pathway SPNs (iSPNs, A2A+). Activating dSPNs reduced lever pressing regardless of the effort requirement, as it elicited gnawing, a competing consummatory behavior. On the other hand, activating iSPNs in the NAc core (but not in the shell) reduced lever pressing in an effort-dependent manner: stimulation-inducted reduction in performance was greater at higher press-to-reward ratio requirements. In contrast, optogenetically inhibiting NAc core iSPN output resulted in increased levels of effort exertion. Our results show that the indirect pathway output from the NAc core can bidirectionally regulate effort exertion.

neuroscience↗

bioRxiv2024

GABAergic neurons from the ventral tegmental area represent and regulate force vectors

The ventral tegmental area (VTA), a midbrain region associated with motivated behaviors, consists predominantly of dopaminergic (DA) neurons and GABAergic (GABA) neurons. Previous work has suggested that VTA GABA neurons provide a reward prediction, which is used in computing a reward prediction error. In this study, using in vivo electrophysiology and continuous quantification of force exertion in head-fixed mice, we discovered distinct populations of VTA GABA neurons that exhibited precise force tuning independently of learning, reward prediction, and outcome valence. Their activity usually preceded force exertion, and selective optogenetic manipulations of these neurons systematically modulated force exertion without influencing reward prediction. Together, these findings show that VTA GABA neurons continuously regulate force vectors during motivated behavior.

neuroscience↗

bioRxiv2024

Current transcriptome database and biomarker discovery for immunotherapy by immune checkpoint blockade

Immune checkpoint blockade (ICB) has revolutionized the current immuno-oncology and significantly improved clinical outcome for cancer treatment. Despite the advancement in clinics, only a small subset of patients derives immune response to the ICB therapy. Therefore, a robust predictive biomarker that identifies potential candidate becomes increasingly crucial in delivering this technology to the public. In this review, we first discuss the biomarkers that focus on tumor genome, tumor microenvironment and tumor-host interaction. Then, we compare existing databases for biomarker discovery for ICB response. We also present IOhub - an interactive web portal that incorporates 36 bulk and 10 single-cell transcriptome datasets for benchmark analysis of the current biomarkers. Finally, we highlight the trending interest in antibody drug conjugate and combination treatment and their use in precision immuno-oncology.

bioinformatics↗

bioRxiv2024

AtSDR4L and paralog promote seed-to-seedling transition in multiple seed compartments

Development is a series of decision-making events. Success of seed plants at individual and population levels strongly depends on the timing of germination and the rapidness of seedling establishment. Arabidopsis thaliana SEED DORMANCY 4-LIKE (AtSDR4L) and its paralog Dynamic Influencer of Gene Expression 2 (DIG2) are transcriptional co-repressors that promote seed-to-seedling phase transition. Their regulatory roles in promoting germination at the temporal and tissue-specific scales remain elusive. We show that strong germination arrest of Atsdr4l dig2 is alleviated by ABA antagonists. Isolated mutant embryos develop faster than intact seeds, but still exhibit delayed growth. Atsdr4l dig2 seeds show extensive changes in gene expression in both the seed coat and the embryo, with a subset of the genes differentially expressed tissue-specifically. MIKC-type MADS-box genes are the top-enriched transcription factor family among up-regulated genes in both seed compartments of Atsdr4l dig2, and AGAMOUS-LIKE44 (AGL44) is a dirct target of both AtSDR4L and DIG2. Many hormonal genes and hypoxia-responsive genes are misregulated in the double mutant seeds, accompanied by an over-accumulation of abscisic acid, auxin, their derivatives, as well as the immediate precursor of ethylene. Together, these results provide new mechanistic insights into how AtSDR4L and DIG2 work in concert to coordinate multiple pathways and prepare seeds for germination.

plant biology↗

bioRxiv2024

Post-translational modifications orchestrate the intrinsic signaling bias of orphan receptor GPR52

Despite recent advances in GPCR structure and pharmacology, the regulation of GPCR activation, signaling, and functioning by diverse post-translational modifications (PTMs) has been largely unexplored. Furthermore, for a special category of self-activating orphan GPCRs, it is completely unknown whether and how specific PTMs control their unique signaling profiles and cellular functions. In this study of GPR52, an orphan GPCR with exceedingly high constitutive G protein signaling activity and emerging as a neurotherapeutic target, we discovered its disproportionately low arrestin recruitment activity. Through profiling the N-glycosylation and phosphorylation patterns of the receptor and clarifying their roles in G protein versus arrestin coupling, we found these two types of PTMs in specific motifs differentially shape the intrinsic signaling bias of GPR52. While N-terminal N-glycosylation promotes constitutive Gs signaling possibly through favoring the self-activating conformation, phosphorylation in helix 8, to our great surprise, suppresses arrestin recruitment and thus attenuates receptor internalization. In addition, we uncovered the counteracting roles of N-glycosylation and phosphorylation in modulating GPR52-dependent accumulation of the huntingtin protein (HTT) in brain striatal cells. Thus, our study provides novel insights into the regulation of intrinsic signaling bias and cellular function of an orphan GPCR via distinct PTMs in different motifs.

cell biology↗

bioRxiv2024

Global transcription factors analyses reveal hierarchy and synergism of regulatory networks and master virulence regulators in Pseudomonas aeruginosa

The transcription factor (TF) regulatory network in Pseudomonas aeruginosa is complex and involves multiple regulators that respond to various environmental signals and physiological cues by regulating gene expression. However, the biological functions of at least half of its 373 putative TFs remain uncharacterised. Herein, chromatin immunoprecipitation sequencing (ChIP-seq) was used to investigate the binding sites of 172 TFs in the P. aeruginosa PAO1 strain. The results revealed 81,009 significant binding peaks in the genome, more than half of which were located in the promoter regions. To further decode the diverse regulatory relationships among TFs, a hierarchical network was assembled into three levels: top, middle, and bottom. Thirteen ternary regulatory motifs revealed flexible relationships among TFs in small hubs, and a comprehensive co-association atlas was established, showing the enrichment of seven core associated clusters. Twenty-four TFs were identified as the master regulators of virulence-related pathways. The pan-genome analysis revealed the conservation and evolution of TFs in P. aeruginosa complex and other species. A Web-based database combining existing and new data from ChIP-seq and the high-throughput systematic evolution of ligands by exponential enrichment was established for searching TF-binding sites. This study provides important insights into the pathogenic mechanisms of P. aeruginosa and related bacteria and is expected to contribute to the development of effective therapies for infectious diseases caused by this pathogen.

microbiology↗

bioRxiv2024

The genomic trajectory of ovarian high grade serous carcinoma is determined in STIC lesions

Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinomas (STIC) lesions, which, in turn, progress into invasive HGSC that readily spread to the ovary and disseminate around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole genome duplication observed in late-stage disease are determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded samples (FFPE) from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of whole genome duplication, arises early in HGSC, and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development.

cancer biology↗

bioRxiv2024

Mechanisms mediating arylidene-indolinones induced degradation: thoughts on "Discovery of a Drug-like, Natural Product-Inspired, DCAF11 Ligand Chemotype"

In the recent issue of Nature Communications (2023 Nov 30;14(1):7908), Xue et. al. reported a very interesting and significant discovery of a possible DCAF11 ligand chemotype that could be used as the "warhead" to design bifunctional compounds for targeted degradation via engaging the E3 ligase DCAF11 1 (annotated as ref 1 hereafter). The discovery is of importance to the targeted protein degradation field and was inspired by previous reports suggesting that similar compounds may also engage the autophagosome protein LC3 for degradation and function as autophagy-tethering compounds (ATTECs) 2, 3, 4, 5, 6, 7, which seem to be inconsistent with ref 1. We think that the conclusions based on these data are not necessarily mutually exclusive. After performing additional experiments and analyses, we would like to discuss some possibilities explaining such discrepancies and make a few points of clarification.

biochemistry↗