Biology subjects

li, H.

Publications and source records attributed to li, H..

4 recordsLinked to original sources

bioRxiv2026

A Deep Learning Framework for Predicting Gut Microbe-Host Receptor Interactions

MotivationGut microbiota regulates host health through complex protein-protein interactions. However, deciphering this specific interactions between microbiota and human receptors remains a significant challenge due to the lack of specialized computational tools. ResultsLeveraging the hypothesis of cell communication and relevant data, HMI-Pred initially builds an ensemble classifier to screen for potential ligand sequences within microbial genomes. It then jointly evaluates sequence semantics and molecular docking to predict potential microbe-host receptor interactions.HMI-Pred achieved robust performance with F1-scores of 0.901 for microbial ligand identification and 0.883 for interaction prediction. Application to 332,381 microbial proteins revealed distinct interaction patterns: histone deacetylases (HDACs) served as broad-spectrum targets (mean score > 0.80), while G protein-coupled receptors (GPCRs) exhibited high specificity (scores 0.42-0.61). Furthermore, literature mining validated over 47% of the functional predictions, and specific immunomodulatory interactions were confirmed in Akkermansia muciniphila.HMI-Pred provides a valuable computational tool for decoding host-microbe signaling networks and facilitating the discovery of microbiome-based therapeutic targets. AvailabilityThe source code and documentation are available at https://github.com/YangLab-BUPT/HMI-Pred. Contactlihm@bupt.edu.cn

microbiology↗

bioRxiv2025

Hydrogen-Induced Calcium Influx via the TRPC4-TRPC4AP Axis

BackgroundCalcium ions (Ca{superscript 2}) serve as universal intracellular messengers regulating diverse physiological processes, while dysregulated Ca{superscript 2} homeostasis triggers cytotoxicity. Molecular hydrogen (H2) exhibits protective effects against oxidative stress-related pathologies, but its mechanism of action remains incompletely understood. Transient receptor potential canonical 4 (TRPC4) channels and their associated protein TRPC4AP are critical mediators of Ca{superscript 2} influx ( [Ca{superscript 2}]i), yet their role in H2-mediated calcium signaling is unexplored. This study investigates the molecular mechanism by which H2 modulates Ca{superscript 2} dynamics through the TRPC4-TRPC4AP axis, aiming to establish its therapeutic potential for calcium-related disorders. MethodsThe study employed heterogeneous cellular models (e.g., mesenchymal stem cells, neurons, fibroblasts) and in vivo two-photon calcium imaging in C57BL/6J mice. Techniques included CRISPR-Cas9 knockout, siRNA-mediated gene silencing, molecular docking (AlphaFold 3), and protein-protein interaction analysis. Calcium flux was quantified via fluorescence imaging, while mitochondrial integrity and cytoskeletal dynamics were assessed using JC-1 staining, ATPase activity assays, and live-cell imaging. Structural validation of TRPC4-TRPC4AP binding sites utilized mutagenesis and complementation experiments. ResultsH2 selectively enhanced extracellular Ca{superscript 2} influx via TRPC4-TRPC4AP, with no cytotoxicity or mitochondrial dysfunction observed. Key arginine residues (730Arg-731Arg) in the TRPC4 CIRB domain formed hydrogen-bond networks essential for channel activation. In vivo, H2 increased neuronal Ca{superscript 2} transient frequency and amplitude in the primary motor cortex. TRPC4AP knockout abolished H2-induced Ca{superscript 2} influx, while mutagenesis of 730Arg/731Arg disrupted channel activity. H2 also promoted cytoskeletal remodeling and cell motility, dependent on TRPC4AP-mediated Ca{superscript 2} signaling. ConclusionsThis study identifies H2 as a novel calcium agonist that activates the TRPC4-TRPC4AP axis to regulate extracellular Ca{superscript 2} influx. The 730Arg-731Arg motif in TRPC4 serves as a critical H2-sensitive site, enabling dynamic calcium homeostasis without overload. These findings provide a mechanistic basis for H2-based therapies targeting calcium dysregulation in neurodegenerative, inflammatory, and metabolic diseases, while highlighting TRPC4AP as a pivotal molecular switch for gasotransmitter signaling.

biochemistry↗

bioRxiv2024

Induction of Senescence During Postpartum Mammary Gland Involution supports tissue remodeling and promotes postpartum tumorigenesis

Cellular senescence is an evolutionarily conserved stress response1, yet its roles during physiological processes remain underexplored2,3. Senescent cells are known to promote tissue repair4,5 and suppress tumorigenesis6, but their accumulation contributes to various pathological and physiological processes, including cancer and ageing7-9. However, it is currently unknown whether physiological senescence can be co-opted by oncogenic events to promote tumorigenesis. Postpartum mammary gland involution is a major tissue remodelling event in adulthood10,11, resembling the wound healing process, and is closely linked to postpartum breast cancer (PPBC)12 providing a compelling context to investigate this question. Here, we show that senescence is induced in alveolar luminal cells during involution in a p16-dependent manner. Reducing senescent cells hinders tissue remodeling and delays involution, underscoring their physiological importance. However, using a PPBC mouse model where the oncogenic event coincides with involution, we demonstrate that eliminating involution-associated senescent cells markedly extended the cancer latency. Mechanistically, we reveal that senescent cells enhance tumor-initiating cell plasticity in a paracrine manner, promoting tumor invasion and metastasis. Collectively, our findings uncover a dual role of senescence in mediating postpartum tissue remodeling and promoting tumorigenesis, highlighting a scenario where physiological senescence is hijacked to drive cancer progression. This work underscores that senescence might be a unifying mechanism linking tissue repair to tumorigenesis.

cell biology↗

bioRxiv2020

Conductance mechanisms of rapidly desensitizing cation channelrhodopsins from cryptophyte algae

Channelrhodopsins guide algal phototaxis and are widely used as optogenetic probes for control of membrane potential with light. "Bacteriorhodopsin-like" cation channelrhodopsins (BCCRs) from cryptophytes differ in primary structure from other CCRs, lacking usual residues important for their cation conductance. Instead, BCCR sequences match more closely those of rhodopsin proton pumps, containing residues responsible for critical proton transfer reactions. We report 19 new BCCRs, which, together with the earlier 6 known members of this family, form three branches (subfamilies) of a phylogenetic tree. Here we show that the conductance mechanisms in two subfamilies differ with respect to involvement of the homolog of the proton donor in rhodopsin pumps. Two BCCRs from the genus Rhodomonas generate photocurrents that rapidly desensitize under continuous illumination. Using a combination of patch clamp electrophysiology, absorption and Raman spectroscopy, and flash photolysis, we found that the desensitization is due to rapid accumulation of a long-lived nonconducting intermediate of the photocycle with unusually blue-shifted absorption with a maximum at 330 nm. These observations reveal diversity within the BCCR family and contribute to deeper understanding of their independently evolved cation channel function. IMPORTANCECation channelrhodopsins, light-gated channels from flagellate green algae, are extensively used as optogenetic photoactivators of neurons in research and recently have progressed to clinical trials for vision restoration. However, the molecular mechanisms of their photoactivation remain poorly understood. We recently identified cryptophyte cation channelrhodopsins, structurally different from those of green algae, which have separately evolved to converge on light-gated cation conductance. This study reveals diversity within this new protein family and describes a subclade with unusually rapid desensitization that results in short transient photocurrents in continuous light. Such transient currents have not been observed in the green algae channelrhodopsins and are potentially useful in optogenetic protocols. Kinetic UV-vis spectroscopy and photoelectrophysiology reveal the desensitization is caused by rapid accumulation of a non-conductive photointermediate in the photochemical reaction cycle. The absorption maximum of the intermediate is 330 nm, the shortest wavelength reported in any rhodopsin, indicating a novel chromophore structure.

biochemistry↗