Biology subjects

Jing, H.

Publications and source records attributed to Jing, H..

At least 19 recordsLinked to original sources

bioRxiv2026

Discrete depolarisations of chordotonal organ neurons propagate toward the soma and are independent of the sensory TRP channels NompC and Nanchung-Inactive.

The electrophysiological process of auditory transduction in insects remains largely conjecture due to the unknown role of ion channels localised to the cilia, but experimental evidence supports either NompC or Nan-Iav as the auditory mechanotransduction ion channel. Here, we knocked down two key genes that code for the two candidate sound-activated ion channels using dsRNA-mediated RNA interference. We measured sound-evoked activity of the auditory nerve and intracellular electrical currents from the ciliated ending of individual auditory receptors. We found that the sound-evoked nerve activity was reduced in nompC, nan and ift88 knockdown. Using whole-cell patch clamp recordings we found that nompC and nan knockdown resulted in reduced sound-evoked transduction current. Stochastic depolarisations hypothesised to be mediated from one of the candidate mechanotransduction ion channels, either NompC or Nan-Iav, where not affected by knockdown of either channel. The discrete depolarisations are therefore mediated through another unidentified ion channel. We test the hypothesis that discrete depolarisations are graded action potentials that travel toward the soma through noise analysis of the transduction current and analysis of discrete depolarisations to voltage-steps. As a positive control we also knocked down ift88, a protein essential for transporting proteins, including ion channels, along the cilium and found both the transduction current and the discrete depolarisations decreased. Key pointsO_LIInjection of dsRNA decreased RNA of nompC and nan C_LIO_LISound-evoked nerve activity is reduced for RNAi-mediated knockdown of nompC and nan C_LIO_LINompC and Nan both contribute to the transduction current C_LIO_LIThe stochastic discrete depolarisations are not due to NompC or Nan-Iav ion channel but to a third unidentified ion channel. C_LIO_LINoise analysis of the transduction current and the discrete depolarisations suggests they are graded action potentials that travel in the direction of the soma. C_LIO_LIKnockdown of ift88 reduced both the transduction current and discrete depolarisations. C_LI Significance StatementInsects are important to understand, economically, agriculturally and medically. However, we still do not understand fundamental aspects of how insects detect their own body movements, vibrations and sound. These senses are detected by insect chordotonal organs, specialised miniaturised mechanoreceptors that convert movements into electrical signals through specialised ion channels. Previous experimental work has advocated either NompC or Nan-Iav as the mechanosensitive ion channel. Here, for the first time, we reduced the expression of both nompC and nan and measured the sound-evoked transduction current directly from neurons in a specialised auditory chordotonal organ. In contradiction to previous studies, we show that both ion channels contribute to the transduction current and find that electrical signals termed "discrete depolarisations" travel toward the soma.

neuroscience↗

bioRxiv2026

Bone Mechanosensing Dictates Hematopoietic Stem Cell Fate and Immune Homeostasis

The vertebrate water-to-land transition was accompanied by a six-fold increase in gravitational force, followed by the migration of hematopoietic stem cells (HSCs) from kidney or liver to the bone marrow, and the acquisition of enhanced immune functions to cope with novel environmental pressures. Bone senses mechanical loading and provides a microenvironment for HSC development, yet whether bone mechanosensation affects immune cell development and immune homeostasis remains unclear. Here, we unveil bone as a mechanosensory organ that translates mechanical force into hematopoietic instructions. Mechanical loading of bone directs HSCs toward lymphoid lineages in mice and non-human primates, whereas unloading favors myeloid commitment. This process requires osteocyte mechanosensor Piezo1, which induces loading-responsive bone-derived factors such as IL1R2, SERPINC1 and INMT, thereby restraining inflammatory signaling and guiding HSC differentiation. Osteocyte Piezo1 deficiency recapitulates the hematopoietic and immune alterations observed during unloading. Functionally, this pathway enhances acute infection resistance and suppresses immunosenescence in mice and in aged long-tailed macaques. Notably, skeletal mechanoregulation of immune homeostasis is conserved across vertebrate species. Our research defines the mechano-bone-immune axis (mechano-osteoimmunology), offering a novel evolutionary perspective on the interconnected development of the skeletal and immune systems and presenting a promising non-pharmacological target to address immune dysfunction.

immunology↗

bioRxiv2026

Heterotrimeric G protein αi2 Sequesters RasGAP to Control Neutrophil Sensitivity and Chemotaxis

G protein-coupled receptors (GPCRs) direct neutrophil chemotaxis through heterotrimeric G proteins, yet the downstream effectors of the predominant Gai isoform, Gai2, remain incompletely defined. Here we identify the Ras GTPase-activating protein CAPRI (RASA4) as a functional effector of Gai2 that links GPCR signaling to Ras adaptation. Using AlphaFold3-based structural modeling and binding free-energy calculations and experimental verification, we reveal that constitutively active and structurally altered Gai2 mutants (Q205L and T182A) exhibit enhanced binding to CAPRI. Neutrophils expressing these mutants display elevated basal Ras activity, heightened sensitivity to chemoattractant, and improved chemotaxis in low- or subsensitive-concentration gradients. However, these cells exhibit excessive Ras activation and impaired chemotaxis at high, saturating chemoattractant concentrations, while maintaining near-normal responses at intermediate concentrations. These results reveal an upward shift in the concentration range for efficient chemotaxis. Our findings not only establish a previously unrecognized Gai2-CAPRI signaling axis that tunes Ras adaptation but also define a mechanism by which heterotrimeric G proteins calibrate leukocyte navigation across diverse chemoattractant gradients.

immunology↗

bioRxiv2026

Immunoregulatory gene GIMAP6 suppresses lethal atherosclerotic vasculopathy and ischemic heart failure

Controlling hyperlipidemia has reduced but not eliminated atherosclerotic cardiovascular disease as a predominant cause of human mortality. Here, we report that loss of the immunoregulatory gene GTPase of immunity-associated protein 6 (GIMAP6), causes an inflammatory vasculopathy and accelerated atherosclerosis in the absence of hyperlipidemia. These pathologic changes in turn result in progressive cardiac ischemia, myocardial infarction, and heart failure, culminating in early death. In humans, rare deleterious GIMAP6 variants are associated with premature severe cardiovascular disease. These findings reveal GIMAP6 to play an important protective role against atherosclerotic cardiovascular disease whose identification offers opportunities for improved risk management and a target for new therapies.

immunology↗

bioRxiv2025

A Unified Multi-modal LLM for Dynamic Protein-Ligand Interactions and Generative Molecular Design

BioDynaGen (Biological Dynamics and Generation) is a novel multi-modal framework unifying protein sequences, dynamic binding site conformations, small molecule ligand SMILES, and natural language text into a single discrete token representation. Built upon a general large language model, BioDynaGen employs continuous pre-training and instruction fine-tuning via next-token prediction to address critical gaps in modeling protein dynamics and ligand interactions. This framework enables a diverse range of tasks, including small molecule-protein binding prediction, dynamic pocket design, and ligand-assisted functional generation. By comprehensively integrating these modalities, BioDynaGen offers an advanced framework for understanding and designing complex biological molecular interactions.

bioinformatics↗

bioRxiv2025

De Novo Design of Anti-Aging Peptides

Aging, a universal biological process in complex organisms, is increasingly recognized to be driven by progressive loss of epigenetic information, as proposed in the Information Theory of Aging (ITOA). However, research on anti-aging peptides remains scarce, with most existing efforts confined to derivatives of natural proteins, while systematic design attempts are virtually absent. This limitation not only restricts discovery within the evolutionary sequence space but also hampers the identification of candidates with novel mechanisms and improved efficacy. Here, we present ElixirSeeker2, the first computational framework for de novo design of anti-aging peptides. By integrating modeling of known anti-aging peptides, activity scoring from the IC50 database, and penalty constraints from toxic peptides, ElixirSeeker2 enables large-scale virtual screening and identification of novel peptide candidates. Several lead peptides demonstrated significant effects in delaying cellular senescence, restoring cellular functions in vitro and in enhancing locomotor activity of aged Caenorhabditis elegans. This study not only validates the feasibility of de novo design in anti-aging interventions but also establishes a strategy for the development of next-generation biologics.

bioinformatics↗

bioRxiv2024

Superresolution Imaging Reveals the Spatial Organization of CD81 Microdomains in Regulating Membrane Signaling on Jurkat T Cell Microvilli

Tetraspanin proteins are closely associated with high-curvature membrane structures and play key roles in organizing membrane domains and regulating membrane signaling in immune cells. However, their specific roles in regulating T cell membrane signaling, particularly within the microvilli often characteristic of these cells, remain poorly understood. Here, we used Jurkat T cells as a model system and investigated CD81 as a member of the tetraspanin family. Using total internal reflection fluorescence (TIRF) microscopy and structured illumination microscopy (SIM), we identified an enrichment of the tetraspanin CD81 microdomains along the actin-rich membrane microvilli. At the distal end of the microvilli, SIM images revealed the spatial colocalization of CD81 with T cell receptors (TCR) and CD63, implying a potential role for CD81 in regulating TCR signaling in conjunction with CD63. Spatial analysis of CD81 and CD63 microdomains from the dual-color SIM data revealed their preference for associating with each other. Cluster analysis of direct stochastic optical reconstruction microscopy (dSTORM) data revealed that in vitro T cell activation results in reduced domain sizes and increased domain separation of CD81. These findings provide visual evidence of the spatial organization and rearrangement of CD81 on the T cell microvilli, highlighting its potential role in signal regulation on specialized membrane protrusions.

cell biology↗

bioRxiv2024

An Automated High-throughput Affinity Capture-Mass Spectrometry Platform with Data-Independent Acquisition

Affinity capture (AC) combined with mass spectrometry (MS)-based proteomics is highly utilized throughout the drug discovery pipeline to determine small molecule target selectivity and engagement. However, the tedious sample preparation steps and time-consuming MS acquisition process has limited its use in high-throughput format. Here, we report an automated workflow employing biotinylated probes and streptavidin magnetic beads for small molecule target enrichment in 96-well plate format, ending with direct sampling from EvoSep Solid Phase Extraction tips for liquid chromatography (LC)-tandem mass spectrometry (MS/MS) analysis. The streamlined process significantly reduced both overall and hands-on time needed for sample preparation. Additionally, we developed a data-independent acquisition-mass spectrometry (DIA-MS) method to establish an efficient label-free quantitative chemical proteomic kinome profiling workflow. DIA-MS yielded coverage of [~]380 kinases, a >60% increase compared to using a data-dependent acquisition (DDA)-MS method and provided reproducible target profiling of the kinase inhibitor dasatinib. We further showcased the applicability of this AC-MS workflow for assessing the selectivity of two clinical-stage CDK9 inhibitors against [~]250 probe-enriched kinases. Our study here provides a roadmap for efficient target engagement and selectivity profiling in native cell or tissue lysates using AC-MS.

biochemistry↗

bioRxiv2024

BEACON: Benchmark for Comprehensive RNA Tasks and Language Models

RNA plays a pivotal role in translating genetic instructions into functional outcomes, underscoring its importance in biological processes and disease mechanisms. Despite the emergence of numerous deep learning approaches for RNA, particularly universal RNA language models, there remains a significant lack of standardized benchmarks to assess the effectiveness of these methods. In this study, we introduce the first comprehensive RNA benchmark BEACON (BEnchmArk for COmprehensive RNA Task and Language Models). First, BEACON comprises 13 distinct tasks derived from extensive previous work covering structural analysis, functional studies, and engineering applications, enabling a comprehensive assessment of the performance of methods on various RNA understanding tasks. Second, we examine a range of models, including traditional approaches like CNNs, as well as advanced RNA foundation models based on language models, offering valuable insights into the task-specific performances of these models. Third, we investigate the vital RNA language model components from the tokenizer and positional encoding aspects. Notably, our findings emphasize the superiority of single nucleotide tokenization and the effectiveness of Attention with Linear Biases (ALiBi) over traditional positional encoding methods. Based on these insights, a simple yet strong baseline called BEACON-B is proposed, which can achieve outstanding performance with limited data and computational resources. The datasets and source code of our benchmark are available at https://github.com/terry-r123/RNABenchmark.

bioinformatics↗

bioRxiv2023

Accurate Prediction of Antibody Function and Structure Using Bio-Inspired Antibody Language Model

In recent decades, antibodies have emerged as indispensable therapeutics for combating diseases, particularly viral infections. However, their development has been hindered by limited structural information and labor-intensive engineering processes. Fortunately, significant advancements in deep learning methods have facilitated the precise prediction of protein structure and function by leveraging co-evolution information from homologous proteins. Despite these advances, predicting the conformation of antibodies remains challenging due to their unique evolution and the high flexibility of their antigen-binding regions. Here, to address this challenge, we present the Bio-inspired Anti-body Language Model (BALM). This model is trained on a vast dataset comprising 336 million 40% non-redundant unlabeled antibody sequences, capturing both unique and conserved properties specific to antibodies. Notably, BALM showcases exceptional performance across four antigen-binding prediction tasks. Moreover, we introduce BALMFold, an end-to-end method derived from BALM, capable of swiftly predicting full atomic antibody structures from individual sequences. Remarkably, BALMFold outperforms those well-established methods like AlphaFold2, IgFold, ESMFold, and OmegaFold in the antibody benchmark, demonstrating significant potential to advance innovative engineering and streamline therapeutic antibody development by reducing the need for unnecessary trials.

bioinformatics↗

bioRxiv2023

Humanized CD36 mouse model supports the preclinical evaluation of therapeutic candidates targeting CD36

CD36 (also known as scavenger receptor B2) is a multifunctional receptor that mediates lipid uptake, advanced oxidation protein products, and immunological recognition, and has roles in lipid accumulation, apoptosis, as well as in metastatic colonization in cancer. CD36 is involved in tumor immunity, metastatic invasion, and therapy resistance through various molecular mechanisms. Targeting CD36 has emerged as an effective strategy for tumor immunotherapy. In this study, we have successfully generated a novel CD36 humanized mouse strain where the sequences encoding the extracellular domains of the mouse Cd36 gene were replaced with the corresponding human sequences. The results showed that CD36 humanized mice expressed only human CD36, and the proportion of each lymphocyte was not significantly changed compared with wild-type mice. Furthermore, CD36 monoclonal antibody could significantly inhibit tumor growth after treatment. Therefore, the CD36 humanized mice provided a validated preclinical mouse model for the evaluation of tumor immunotherapy targeting CD36.

immunology↗

bioRxiv2022

S-nitrosylation of Aux/IAA protein represses auxin signaling

Auxin plays crucial roles in nearly every aspect of plant growth and development. Auxin signaling activation is mediated through degradation of Auxin/INDOLE-3-ACETIC ACID (Aux/IAA) family. Nitric oxide (NO) regulates diverse cellular bioactivities through S-nitrosylation of target protein at specific cysteine residues. NO-auxin interplay has an important role in regulation plant growth. However, little is known about the molecular mechanism of how NO effects Aux/IAA proteins stability. Here we show that NO negatively regulates the IAA17 protein stability to repress auxin signaling. We found that NO directly inhibits IAA17 protein degradation. S-nitrosylation of IAA17 at Cys-70 represses the TIR-IAA17 co-receptor interaction to attenuate auxin responsiveness. Our data suggest a model in which S-nitrosylation of IAA17 at Cys-70 negatively regulates auxin signaling to effect plant development, providing a mechanism for redox-phytohormones networks.

plant biology↗

bioRxiv2022

Membrane compression by synaptic vesicle exocytosis triggers ultrafast endocytosis

Compensatory endocytosis keeps the surface area of secretory cells constant following exocytosis. At chemical synapses, clathrin-independent ultrafast endocytosis maintains such homeostasis. This endocytic pathway is temporally and spatially coupled to exocytosis, initiating within 50 ms at the region immediately next to where vesicles fuse: the active zone. How synaptic vesicle exocytosis induces ultrafast endocytosis is unknown. Here, we demonstrate that actin filaments are enriched in the region surrounding active zone at mouse hippocampal synapses and that the membrane area conservation due to this actin corral is necessary for exo-endocytic coupling. Simulations suggest that flattening of fused vesicles exerts lateral membrane pressure in the plasma membrane against the actin corral, resulting in rapid formation of endocytic pits at the border between the active zone and the surrounding actin-enriched region. Consistent with our simulations, ultrafast endocytosis does not initiate when actin organization is disrupted, either pharmacologically or by ablation of the actin-binding protein Epsin1. These data suggest that endocytosis is mechanically coupled to exocytosis at synapses.

cell biology↗

bioRxiv2021

FastQTLmapping: an ultra-fast package for mQTL-like analysis

SummaryHere we describe fastQTLmapping, a C++ package that is computationally efficient not only for mQTL-like analysis but as a generic solver also for conducting exhaustive linear regressions involving extraordinarily large numbers of dependent and explanatory variables allowing for covariates. Compared to the state-of-the-art MatrixEQTL, fastQTLmapping was an order of magnitude faster with much lower peak memory usage. In a large dataset consisting of 3,500 individuals, 8 million SNPs, 0.8 million CpGs and 20 covariates, fastQTLmapping completed the mQTL analysis in 7 hours with 230GB peak memory usage. Availability and ImplementationFastQTLmapping is implemented in C++ and released under a GPL license. FastQTLmapping can be downloaded from https://github.com/TianTTL/xQTLmapping. Contactliufan@big.ac.cn

bioinformatics↗

bioRxiv2021

Global patterns and rates of habitat transitions across the eukaryotic tree of life

The successful colonisation of new habitats has played a fundamental role during the evolution of life. Salinity is one of the strongest barriers for organisms to cross, which has resulted in the evolution of distinct marine and terrestrial (including both freshwater and soil) communities. Although microbes represent by far the vast majority of eukaryote diversity, the role of the salt barrier in shaping the diversity across the eukaryotic tree is poorly known. Traditional views suggest rare and ancient marine-terrestrial transitions, but this view is being challenged by the discovery of several recently transitioned lineages. Here, we investigate habitat evolution across the tree of eukaryotes using a unique set of taxon-rich environmental phylogenies inferred from a combination of long-read and short-read metabarcoding data spanning the ribosomal DNA operon. Our results show that overall marine and terrestrial microbial communities are phylogenetically distinct, but transitions have occurred in both directions in almost all major eukaryotic lineages, with at least 350 transition events detected. Some groups have experienced relatively high rates of transitions, most notably fungi for which crossing the salt barrier has most likely been an important aspect of their successful diversification. At the deepest phylogenetic levels, ancestral habitat reconstruction analyses suggest that eukaryotes may have first evolved in non-saline habitats, and that the two largest known eukaryotic assemblages (TSAR and Amorphea) arose in different habitats. Overall, our findings indicate that crossing the salt barrier has played an important role in eukaryotic evolution by providing new ecological niches to fill.

evolutionary biology↗

bioRxiv2021

The F-box protein AFF1 regulates ARF protein accumulation to regulate auxin response

Auxin critically regulates nearly every aspect of plant growth and development. Auxin-driven transcriptional responses are mediated through the AUXIN RESPONSE FACTOR (ARF) family of transcription factors. Although ARF protein stability is regulated via the 26S proteasome, molecular mechanisms underlying ARF stability and turnover are unknown. Here, we report the identification and functional characterization of an F-box E3 ubiquitin ligase, which we have named AUXIN RESPONSE FACTOR F-BOX1 (AFF1). AFF1 directly interacts with ARF19 and regulates its accumulation. Mutants defective in AFF1 display ARF19 protein hyperaccumulation, attenuated auxin responsiveness, and developmental defects. Together, our data suggest a new mechanism, namely control of ARF protein stability, in regulating auxin response.

plant biology↗

bioRxiv2021

Calling differential DNA methylation at cell-type resolution: avoiding misconceptions and promoting best practices

The accurate detection of cell-type specific DNA methylation alterations in the context of general epigenome studies is an important task to improve our understanding of epigenomics in disease development. Although a number of statistical algorithms designed to address this problem have emerged, the task remains challenging. Here we show that a recent commentary by Rahmani et al, that aims to address misconceptions and best practices in the field, continues to suffer from critical misconceptions in how statistical algorithms should be compared and evaluated. In addition, we report contradictory results on real EWAS datasets.

bioinformatics↗

bioRxiv2020

Visualizing the cytosolic delivery of bioconjugated QDs into T cell lymphocytes

The aggregation state and endosomal trapping of engineered nanocarriers once internalized into cells remain poorly characterized. Here, we visualized the membrane penetrating dynamics of semiconductor quantum dots (QDs) into the cytosol of T cells on a single-cell and single-nanoparticle basis. We water solubilized CdSe/CdZnS QDs with polymer encapsulants functionalized with a cell-penetrating peptide composed of an Asp-Ser-Ser (DSS) repeat sequence. T cells tolerated the 24-h incubation with QDs at concentrations of 5 nM or lower. Single-particle imaging demonstrated that the number of internalized nanoparticles was dependent upon the concentration of the probes for both control (peptide-free) and DSS-QDs. DSS-QDs were mostly distributed as monomers, whereas the control QDs were aggregated into clusters. Single-particle tracking using total internal reflection and highly inclined illumination showed that DSS-QDs were stationary near the activating surface and mobile within the cytosol of the T cell. A correlation exhibited between the mobility and aggregation state of individual QD clusters, with monomeric DSS-QDs showing the highest mobility. In addition, monomeric DSS-QDs displayed much faster diffusion than the endosomes. A small-molecule endosome marker confirmed the absence of colocalization between endosomes and DSS-QDs, indicating their endosomal escape. The ability to deliver and track individual QDs in the cytosol of live T cells creates inroads for the optimization of drug delivery and gene therapy through the use of nanoparticles.

bioengineering↗