Biology subjects

Li, P.

Publications and source records attributed to Li, P..

At least 109 records · Page 6Linked to original sources

bioRxiv2025

Molecular Mechanisms of Chinese Medicine in Regulating Colorectal Cancer Immune Microenvironment: Insights from Single-Cell Transcriptomics and Network Pharmacology

BackgroundThe molecular mechanisms underlying the efficacy of Traditional Chinese Medicine (TCM) in colorectal cancer treatment remain largely unexplored. We developed a computational systems biology approach integrating single-cell transcriptomics with network pharmacology to elucidate the potential mechanisms of TCM in modulating colorectal cancer progression. MethodsWe developed an integrated computational pipeline for multi-omics data analysis combining single-cell transcriptomics with network pharmacology. Raw single-cell RNA-seq data from 3 normal tissues and 3 colorectal tumors were obtained from GEO database and processed using a customized workflow in R. Quality control, normalization, and dimensionality reduction were performed using the Seurat v4.0 algorithm, followed by unsupervised clustering to identify cell subpopulations. Differentially expressed genes (DEGs) were identified using MAST algorithm with adjusted p-value < 0.05 and |log2FC| > 1.0. These computationally identified DEGs were subsequently mapped to a comprehensive Traditional Chinese Medicine (TCM) database using a network pharmacology approach to predict herb-target interactions. In parallel, we integrated TCGA RNA-seq data (STAR-counts) with clinical information, applying log2(TPM+1) transformation for normalization. We then implemented a machine learning-based correlation analysis to construct gene-cell-immunity-pathway networks, using weighted gene co-expression network analysis (WGCNA) to identify key regulatory modules. ResultsOur computational analysis of single-cell RNA-seq data identified 109 differentially expressed genes (DEGs) that define the molecular signature of colorectal cancer microenvironment. Clustering algorithms revealed 14 distinct cell subpopulations, with predominant immune cell infiltration, particularly B and T lymphocytes, suggesting a complex immune regulatory network. Network pharmacology analysis mapped these DEGs to potential therapeutic targets, computationally predicting interactions with 140 traditional Chinese herbs. These herbs were classified into 8 functional categories. Through integrative multi-omics analysis and pathway enrichment algorithms, we identified core regulatory networks comprising 23 genes and 39 significantly enriched signaling pathways (FDR < 0.01) that orchestrate immune cell function in the tumor microenvironment. Notably, our analysis in silico revealed previously uncharacterized gene-pathway interactions that may explain the immunomodulatory effects of specific herbal compounds. ConclusionsOur systems biology and computational analysis revealed a potential mechanism by which 8 categories of Chinese herbal medicines and 23 genes across 39 signaling pathways may regulate colorectal cancer progression through modulation of specific gene regulatory networks and immune cell functions. These findings demonstrate the value of integrative computational approaches in elucidating complex biological mechanisms of traditional medicines

immunology↗

bioRxiv2025

A large-scale method to measure the absolute stoichiometries of protein Poly-ADP-Ribosylation

Poly-ADP-ribosylation (PARylation) is a reversible posttranslational modification that occurs in higher eukaryotes. While thousands of PARylated substrates have been identified, the specific biological functions of most PARylated proteins remain elusive. PARylation stoichiometry is a critical parameter to assess the potential functions of a PARylated protein. Here, we developed a large-scale strategy to measure the absolute stoichiometries of protein PARylation. By integrating mild cell lysis, boronate enrichment and carefully designed titration experiments, we were able to determine the PARylation stoichiometries for a total of 235 proteins. This approach enables the capture of all PARylation events on various amino acid acceptors. We revealed that PARylation occupancy spans over three orders of magnitude. However, most PARylation events occur at low stoichiometric values (median 0.578%). Notably, we observed that high stoichiometry PARylation (>1%) predominantly targets proteins involved in transcription regulation and chromatin remodeling. Thus, our study provides a systems-scale, quantitative view of PARylation stoichiometries under genotoxic conditions, which serves as invaluable resources for future functional studies of this important protein posttranslational modification.

biochemistry↗

bioRxiv2025

A tissue-scale strategy for sensing threats in barrier organs

Barrier organs rely on a limited set of pattern recognition receptors (PRRs) to detect diverse immunogenic challenges. How organs assess threats and adjust immune responses to balance host protection with collateral tissue damage remains unclear. Here, by analyzing influenza infection in the lung using single-molecule imaging and spatial transcriptomics, we discovered a tiered threat-sensing strategy at the tissue scale, where the probability of detecting and responding to infection is lowest in the outermost epithelia and highest in the inner stroma. This strategy emerges from spatially graded PRR expression that results in cell-type-specific probabilities of threat-sensing across the tissue, a design broadly adopted by barrier organs. Selectively increasing PRR expression in lung epithelia in vivo exacerbated tissue damage upon inflammatory challenge. These results reveal a spatially tiered strategy to tolerate threats restricted within the epithelia, and yet enable progressively potent immune responses as threats invade deeper into the tissue.

immunology↗

bioRxiv2025

Reconstructing signaling histories of single cells via perturbation screens and transfer learning

Manipulating the signaling environment is an effective approach to alter cellular states for broad-ranging applications, from engineering tissues to treating diseases. Such manipulation requires knowing the signaling states and histories of the cells in situ, for which high-throughput discovery methods are lacking. Here, we present an integrated experimental-computational framework that learns signaling response signatures from a high-throughput in vitro perturbation atlas and infers combinatorial signaling activities in in vivo cell types with high accuracy and temporal resolution. Specifically, we generated signaling perturbation atlas across diverse cell types/states through multiplexed sequential combinatorial screens on human pluripotent stem cells. Using the atlas to train IRIS, a neural network-based model, and predicting on mouse embryo scRNAseq atlas, we discovered global features of combinatorial signaling code usage over time, identified biologically meaningful heterogeneity of signaling states within each cell type, and reconstructed signaling histories along diverse cell lineages. We further demonstrated that IRIS greatly accelerates the optimization of stem cell differentiation protocols by drastically reducing the combinatorial space that needs to be tested. This framework leads to the revelation that different cell types share robust signal response signatures, and provides a scalable solution for mapping complex signaling interactions in vivo to guide targeted interventions.

developmental biology↗

bioRxiv2025

Bacterial Vaginosis Toxins Impair Sperm Capacitation and Fertilization

Study questionWhat effect do toxins produced by bacterial vaginosis (BV) bacteria have on sperm function? Summary answerBacterial vaginosis toxins dysregulate sperm capacitation and intracellular calcium homeostasis and impair the ability of sperm to fertilize oocytes. What is known alreadyIn bacterial vaginosis, which is linked to infertility, overgrowth of Prevotella and Gardnerella in the vagina is accompanied by elevated concentrations of the toxins lipopolysaccharide (LPS) and vaginolysin (VLY). Study design, size, durationThis was a laboratory study in which human semen samples were collected from consenting healthy donors with normal semen parameters. Mouse sperm samples were obtained from the caudal epididymis. Participants/materials, setting, methodsMotile mouse and human sperm were isolated via swim-up and treated under non-capacitating or capacitating conditions. LPS from Escherichia coli was commercially available. VLY was produced by cloning the Gardnerella VLY protein in the ClearColi expression system. Mouse sperm were pre-incubated in in vitro fertilization medium with LPS or VLY and then co-cultured with ovulated cumulus-oocyte complexes. The effects of LPS and VLY on sperm motility and hyperactivation were assessed with computer-assisted sperm analysis. Effects on viability were assessed by Hoechst staining. Acrosomal exocytosis was assessed in sperm from transgenic Acr-eGFP mice and in human sperm stained with Pisum sativum agglutinin FITC. Intracellular calcium dynamics were assessed by staining sperm with the calcium-sensitive dye Fluo-4 AM and fluorescent imaging several sperm at the single-cell level. The effects of LPS on sperm from CatSper knock-out mice were assessed. Additionally, sperm were treated with a toll-like receptor 4 antagonist and further exposed to LPS. Main results and the role of chanceExposure of mouse sperm to LPS or VLY significantly decreased in vitro fertilization (P < 0.05). Under capacitating conditions, both toxins initially increased mouse and human sperm hyperactivation, then significantly decreased sperm motility (P < 0.05), hyperactivation (P < 0.05), and acrosomal exocytosis (P < 0.01). These changes were accompanied by a rapid and irreversible increase in intracellular calcium concentration. Effects of LPS, but not VLY, were prevented by polymyxin-B, which aggregates LPS. The LPS-induced intracellular calcium increase required external calcium but not the calcium channel CatSper and was inhibited by the Toll-like receptor 4 antagonist. Limitations, reasons for cautionFirst, the commercially available LPS we used was isolated from Escherichia coli, rather than from the BV-associated bacteria Prevotella bivia. Second, we did not quantify the absolute sperm intracellular calcium concentration before or after LPS or VLY treatment. Third, all of our experiments were in vitro. Wider implications of the findingsThese studies suggest that BV-associated toxins contribute to infertility by, in part, impairing sperm capacitation and reducing their fertilizing ability. Study funding/competing interest(s)This work was supported by the National Institutes of Health (grant #R01 HD069631). The authors declare that they have no conflict of interest.

physiology↗

bioRxiv2025

Emergence of isochorismate-based salicylic acid biosynthesis within Brassicales

Salicylic acid (SA) is a major defense phytohormone. In Arabidopsis thaliana, the isochorismate (IC) pathway is the primary route for pathogen-induced SA biosynthesis. First, the IC synthase (ICS) catalyzes the isomerization of chorismate to IC in chloroplasts. Second, the chloroplast-localized MATE transporter EDS5 appears to transport IC from chloroplasts to the cytosol. Cytosolic IC is then further converted to SA via the GH3 amino acid-conjugating enzyme PBS3. While this pathway is genetically well-characterized in A. thaliana, its evolutionary origin and conservation remain controversial. In this study, through comprehensive phylogenetic, structural, and functional analyses, we demonstrate that the IC pathway emerged within the Brassicales order in a time span between the divergence of Carica papaya and Capparis spinosa. The evolution of the IC pathway was driven by three key adaptations during the time span: (1) enhancement of ICS activity, (2) neofunctionalization of EDS5 after duplication of its ancestral gene, and (3) evolution of a PBS3, whose activity is specialized for glutamate-conjugation to IC. Structural modeling and functional assays reveal that an enhanced salt bridge network in ICS enhanced its activity. One of the duplicated genes, EDS5, acquired key amino acid substitutions in the C-lobe, which likely contributed to the EDS5 neofunctionalization. In addition, the functional PBS3 clade, including A. thaliana PBS3, is restricted to a Brassicales clade. Taken together, this study addresses the evolutionary trajectory of IC-based SA biosynthesis.

plant biology↗

bioRxiv2025

D-LMBmapX: Generalized Deep-Learning Pipeline for Automated Whole-brain Neural Circuitry Profiling Across Any Developmental Stages

Understanding whole-brain circuitry development is essential for uncovering the origins of disorders linked to abnormal neural wiring, yet progress has been limited by the lack of tools for accurate, comprehensive analysis. Brain development is highly dynamic and region-specific, with pronounced inter-individual variability during early stages, and no existing method achieves whole-brain profiling at arbitrary stages. The rapidly changing morphology of developing axons further complicates segmentation. Here, we present D-LMBmapX, a deep learning pipeline for automated whole-brain circuitry profiling across postnatal development. D-LMBmapX constructs sample-inferred atlases from flanking anchor stages, enabling accurate registration at any time point. By developing a foundation model for generalised axon and soma segmentation, it supports quantitative mesoscale developmental connectomics, demonstrated through spatial-temporal profiling of catecholaminergic projections. D-LMBmapX also enables robust cross-modality and cross-dimensional registration, including precise alignment of single 2D slices to 3D references, and offers generalizable strategies for 5D analysis of diverse biomedical spatial datasets.

neuroscience↗

bioRxiv2025

Targeting Non-Catalytic Sites of SRC Sensitizes the Efficacy of SRC Kinase Inhibitors in Solid Tumors

The non-receptor tyrosine kinase SRC promotes the progression of hematologic malignancies and numerous solid tumors. Several SRC kinase inhibitors have been approved for the treatment of hematologic malignancies. However, drug resistance to sole ATP pocket-targeted kinase inhibition, coupled with low potency for solid tumors and insufficient selectivity, has limited the clinical application of SRC kinase inhibitors. The non-catalytic functions of kinases have provided crucial mechanisms underlying kinase inhibitor resistance, thereby presenting new opportunities for discovery SRC-targeted strategies. In this study, we discovered that upon abrogation of phosphorylation by SRC kinase inhibitors, non-catalytic SRC promotes the transcription of the oncogenes TRIB3 and SPC24 transcription by binding to their promoter sequence. Simultaneously, it interacts with TRIB3 and prevents their proteasome-mediated degradation by the E3 ligase CHIP, ultimately inducing resistance to SRC kinase inhibitors. The peptide TS1-2, blocking SRC/TRIB3 interaction in non-catalytic regions, inhibits the tumor progression of pancreatic ductal adenocarcinoma (PDAC), kidney renal clear cell carcinoma (KIRC), liver hepatocellular carcinoma (LIHC), and breast invasive carcinoma (BRCA), and enhances the efficacy of SRC kinase inhibitors in solid tumors. This study provides the insights of non-catalytic functions of SRC, validates the tumor-promoting function and mechanism of nuclear accumulation of SRC/TRIB3 following SRC kinase inhibitor treatment, identifies SRC/TRIB3 interaction as a potential non-catalytic target, and offers the candidate peptide TS1-2 as a potential combination strategy for overcoming SRC kinase inhibitor resistance. SignificanceThe scaffolding functions of SRC reduced the efficacy of SRC kinase inhibitors, and targeting SRC/TRIB3 non-catalytic functions synergizes the therapeutic effects of SRC kinase inhibitors in SRC-dependent solid tumors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/638389v2_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@17aa618org.highwire.dtl.DTLVardef@12e86eeorg.highwire.dtl.DTLVardef@19c8d82org.highwire.dtl.DTLVardef@10e6c46_HPS_FORMAT_FIGEXP M_FIG C_FIG SRC kinase inhibitors block myristoylation-dependent membrane location and catalytic phosphorylation of SRC. Phosphorylated SRC activates STAT1 and thereby represses TRIB3 transcription. Accumulated non-catalytic SRC promotes TRIB3, SPC24 transcription. Upregulated TIRB3 interacts with SRC to reduce CHIP-mediated ubiquitin-proteasomal degradation. The peptide TS1-2 disrupts TRIB3/SRC complex by targeting Non-kinase regions of SRC, consequently enhancing the therapeutic efficacy of SRC kinase inhibitors.

cancer biology↗

bioRxiv2025

Tet3 Mediates O-GlcNAcylation-Induced Remyelination

The failure of oligodendrocyte precursor cells (OPCs) to generate mature oligodendrocytes represents a major hurdle impeding myelin repair. However, the cellular determinants for OPC differentiation and the pharmacological targets driving remyelination remain rudimentary. Here, we demonstrate that O-GlcNAcylation intrinsically drives remyelination, in which Tet3 is one downstream effector. Enhanced O-GlcNAcylation significantly promotes OPC differentiation, whereas conditional depletion of Ogt in OPCs seriously impairs myelin formation in the developing central nervous system (CNS). Intriguingly, O-GlcNAcylation in OPCs positively correlates with the myelin status, and enhanced O-GlcNAcylation dramatically accelerates remyelination. Proteomic analyses reveal a cohort of proteins uniquely O-GlcNAcylated in OPCs. Among these, Tet3 is exclusively O-GlcNAcylated in OPCs within CNS, which in turn modulates its demethylation activity, thereby regulating myelin gene expression and remyelination. Our findings highlight the crucial role of the Ogt-Tet3 axis in OPC differentiation and suggest O-GlcNAcylation as a druggable target for treating demyelinating diseases.

developmental biology↗

bioRxiv2025

GEI-17-Mediated SUMOylation of GDI-1 Regulates Apoptotic Cell Clearance

Apoptotic cell clearance represents the final stage of apoptosis, and involves phagosome formation, maturation, and digestion. Here, we found that SUMO modifications participate in apoptotic cell clearance by influencing phagosomal degradation activity in C. elegans. The SUMO E3 ligase, GEI-17, SUMOylates GDP dissociation inhibitor (GDI-1) at K270 to trigger phagosomal degradation. Upon SUMOylation, GDI-1 facilitates release of GDP-bound RAB-1, which is subsequently converted to the GTP-bound form in a manner dependent on GDI displacement factor, PRAF-3. RAB-1 conversion enables binding and translocation of RAB-7 from the endoplasmic reticulum to Golgi to promote phagosome maturation and degradation activity. In the absence of GDI-1 SUMOylation, GDI-1 binds to GDP-RAB-1, sequestering it in the cytoplasm, resulting in impaired phagosomal degradation. Furthermore, we found SUMOylation of GDI1 at a conserved site plays a crucial role in efferocytosis regulation in mammals. This study defines a previously unrecognized mechanism by which SUMOylation drives apoptotic cell clearance.

cell biology↗

bioRxiv2025

PERK orchestrates MERCS formation and mitochondrial remodelling promoting physiological adaptations during adaptive UPR signalling

The transfer of information and metabolites between mitochondria and the ER is mediated by mitochondria-ER contact sites (MERCS), facilitating adaptations following changes in cellular homeostasis. MERCS are dynamic structures, essential for maintaining cellular homeostasis through modulation of calcium transfer, redox signalling, lipid transfer, autophagy and mitochondrial dynamics. Acute ER stress in myoblasts promoted myogenesis that required the PERK arm of the UPRER for increased MERCS assembly, mitochondrial turnover and function. Similarly, induction of acute UPRER during early development in C. elegans resulted in increased lifespan and healthspan. Adaptive UPRER signalling in myoblasts and C. elegans, increased MERCS assembly and activated autophagy, ultimately promoting mitochondrial remodelling. Adaptations were dependent on the developmental stage, as treatment of myotubes or adult C. elegans resulted in a maladaptive response. The results identify that PERK is required for increased mitochondrial ER communication in response to adaptive UPR signalling, promoting mitochondrial remodelling and improved physiological function. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/633960v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@66c0f2org.highwire.dtl.DTLVardef@57814org.highwire.dtl.DTLVardef@10e87d5org.highwire.dtl.DTLVardef@f7b69e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Multicilia dynamically transduce Shh signaling to regulate choroid plexus functions

Choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or Intraflagellar transport yields neonatal hydrocephalus, at least in part, due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Shh signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by Smo/Gi/cAMP pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and motile cilia. Unlike most cilia that elongate during maturation, choroid plexus ciliary length decreases during development, causing a decline of Shh signaling intensity in developing choroid plexus, a derepression of Aqp1 and Atp1a2, and ultimately, an increased CSF production. Hence, developmental dynamics of choroid plexus multicilia dampens the Shh signaling intensity to promote CSF production.

developmental biology↗

bioRxiv2025

Triple-effect correction for Cell Painting data with contrastive and domain-adversarial learning

Cell Painting (CP), as a high-throughput imaging technology, generates extensive cell-stained imaging data, providing unique morphological insights for biological research. However, CP data contains three types of technical effects, referred to as triple effects, including batch effects, gradient-influenced row and column effects (well position effects). The interaction of various technical effects can obscure true biological signals and complicate the characterization of CP data, making correction essential for reliable analysis. Here, we propose cpDistiller, a triple-effect correction method specially designed for CP data, which leverages a pre-trained segmentation model coupled with a semi-supervised Gaussian mixture variational autoencoder utilizing contrastive and domain-adversarial learning. Through extensive qualitative and quantitative experiments across various CP profiles, we demonstrate that cpDistiller effectively corrects triple effects, especially well position effects, a challenge that no current methods address, while preserving cellular heterogeneity. Moreover, cpDistiller effectively captures system-level phenotypic responses to genetic perturbations and reliably infers gene functions and interactions both when combined with scRNA-seq data and independently. cpDistiller also excels at identifying gene and compound targets, which is a critical step in drug discovery and broader biological research.

bioinformatics↗

bioRxiv2025

The protein translation initiation machinery is targetable for developing fast-killing therapeutics against the zoonotic Cryptosporidium parvum

Cryptosporidium parvum is a zoonotic apicomplexan parasite that causes moderate to severe watery diarrhea in humans and animals. It is one of the two major cryptosporidial species that infect humans, particularly those with weak or compromised immunity (e.g., children and AIDS patients). C. parvum is also one of the major pathogens causing diarrhea in neonatal farm ruminants (e.g., calves). However, fully effective drugs are still unavailable for medical or veterinary use to treat cryptosporidiosis. In the past decade or two, a number of key enzymes in the core metabolic pathways of Cryptosporidium have been explored as drug targets (e.g., energy metabolism, fatty acid synthesis, nucleotide synthesis, protein synthesis and modification), while the protein translation initiation machinery has been unexplored. Here, we report that C. parvum eukaryotic initiation factor 4A (CpeIF4A), a DEAD-box RNA helicase and part of the eIF4F complex (composed of eIF4A, eIF4E, and eIF4G), can be targeted for developing anti-cryptosporidial therapeutics. CpeIF4A can be inhibited by the selective inhibitor rocaglamide-A (Roc-A; a natural product from Aglaia plants). The inhibition of CpeIF4A activity by Roc-A impedes protein synthesis in the sporozoites of C. parvum (IC50 = 3.65-3.80 M) via tight binding to the CpeIF4A-RNA complex (Kd = 33.7 nM). This efficaciously lowers parasite growth in vitro (EC50 = 1.77 nM; selectivity index >1000) and oocyst production in vivo in IFN-{gamma} knockout mice (with a rapid drop on the second day post-administration at 0.5 mg/kg/day). These findings indicate that CpeIF4A can serve as a novel drug target, and that Roc-A is a promising anti-cryptosporidial lead compound for therapeutic development and structural optimization. Author summaryCryptosporidium parvum is a globally distributed protozoan parasite that infect both humans and animals. Cryptosporidial infection in hosts with weak or compromised immunity (e.g., AIDS patients, children or calves) can be severe or deadly, but fully effective treatments are yet unavailable. In the past decade or two, a number of potential drug targets in the core metabolic pathways in Cryptosporidium have been explored, but the protein translation machinery has been unexplored. Here, we report that the C. parvum eukaryotic initiation factor 4A (CpeIF4A), one of the key components in the protein translational machinery, can be targeted for developing fast-killing anti-cryptosporidial therapeutics. We show that CpeIF4A can be inhibited by the selective inhibitor rocaglamide-A (Roc-A), consequently suppressing the protein synthesis in the parasite via tight binding to the CpeIF4A-RNA complex. This efficaciously inhibits the parasite growth both in vitro and in vivo. The killing of C. parvum by Roc-A is fast and irreversible (parasiticidal). Our data indicate that the protein translational machinery is a novel drug target for developing fast-killing anti-cryptosporidial therapeutics, and that Roc-A is a promising lead compound for therapeutic development and structural optimization.

microbiology↗

bioRxiv2024

Suaeda Salsa Hyperspectral Index (SSHI) for mapping S. salsa in coastal wetlands using hyperspectral satellite imagery

Suaeda Salsa (S. salsa), a pioneer species with short and red-purplish plants in the intertidal zones, has significant ecological, economic, recreational and tourism values. Timely monitoring of S. salsa is crucial for understanding its dynamics and sustainable management of coastal wetlands. Hyperspectral satellite offers valuable opportunities due to its detailed spectral information. This study proposed a Suaeda Salsa Hyperspectral Index (SSHI) for S. salsa mapping based on hyperspectral satellite imagery. The SSHI was developed by considering the large within-class spectral variations of cover types at coastal wetlands, accounting for the spectral correlations in hyperspectral data, and employing dynamic band selection on a per-pixel basis to optimize the separation of S. salsa from other land covers. [Formula] (1+ L), where i[isin][499nm, 611nm], j[isin][628nm, 851nm], L= 0.5. We applied SSHI on ZY1-02D/E AHSI images over Yellow River Delta (YRD) and Liao River Delta (LRD), China during 2021 to 2023. Based on SSHI, a simple thresholding method and a random forest (RF) model were used to map S. salsa. Our results showed that the overall accuracies of S. salsa maps achieved 87.96%[~]89.43% (YRD) and 92.03%[~]93.36% (LRD) using thresholds, and 92.62%[~]94.05% (YRD) and 94.74%[~]94.79% (LRD) using RF. For RF, incorporating SSHI improves S. salsa producers accuracies (users accuracies) by 1.02%[~]6.85% (2.26%[~]6.25%) compared to those without SSHI, proving the effectiveness of SSHI. The S. salsa maps reveal notable temporal variations, reflecting the impacts of climate change and human activities. SSHI is also applicable to other hyperspectral imagery, such as GF-5B and PRISMA.

ecology↗

bioRxiv2024

Potent antitumor activity of a designed interleukin-21 mimic

Long-standing goals of cancer immunotherapy are to activate cytotoxic antitumor T cells across a broad range of affinities while dampening suppressive regulatory T (Treg) cell responses, but current approaches achieve these goals with limited success. Here, we report a de novo IL-21 mimic, 21h10, designed to have augmented stability and high signaling potency in both humans and mice. In multiple animal models and in ex vivo human melanoma patient derived organotypic tumor spheroids (PDOTS), 21h10 showed robust antitumor activity. 21h10 generates significantly prolonged STAT signaling in vivo compared with native IL-21, and has considerably stronger anti-tumor activity. Toxicities associated with systemic administration of 21h10 could be mitigated by TNF blockade without compromising antitumor efficacy. In the tumor microenvironment, 21h10 induced highly cytotoxic antitumor T cells from clonotypes with a range of affinities for endogenous tumor antigens, robustly expanding low-affinity cytotoxic T cells and driving high expression of interferon- (IFN-) and granzyme B compared to native IL-21, while increasing the frequency of IFN-+ Th1 cells and reducing that of Foxp3+ Tregs. As 21h10 has full human/mouse cross-reactivity, high stability and potency, and potentiates low-affinity antitumor responses, it has considerable translational potential.

biochemistry↗

bioRxiv2024

Reduced expression of PER2 protein contrbutes to β1-AA induced cardiac autophagy rhythm disorder

It has been confirmed that heart failure may be linked to fluctuations in autophagy rhythm of cardiomyocytes throughout the day. It is known that circadian rhythms depend on the regulation of core biological clock proteins, with PER2 playing a crucial role. Our previous research has confirmed the presence of {beta}1-Adrenergic receptor autoantibodies ({beta}1-AA) could induce inhibition of myocardial autophagy, leading to cell death and heart failure. However, it remains unclear whether {beta}1-AA induces cardiac autophagy rhythm disorder by affecting PER2 expression. This study find that {beta}1-AA disrupts the autophagy rhythm in cardiomyocytes, primarily indicates by the decreased expression of the autophagy marker protein LC3; {beta}1-AA induces disruption of the rhythmic expression of PER2 protein in myocardial cells, mainly manifests by a decrease in PER2 protein expression; Metoprolol is employed to verify that the {beta}1-adrenergic receptor contributes to the reduction of Per2 protein caused by {beta}1-AA. Knocking down Per2 with lentivirus reduces the inhibition of LC3 expression caused by {beta}1-AA, while overexpressing Per2 in cardiomyocytes using lentivirus significantly restores {beta}1-AA-induced decline in LC3 expression. At the same time, mTORC1 activation is found to participate in {beta}1-AA-induced autophagy inhibition of cardiomyocytes after pretreatment with the mTORC1 inhibitor rapamycin. Furthermore, it is confirmed that the decreased expression of PER2 protein caused by {beta}1-AA disrupts the myocardial autophagy rhythm by promoting mTORC1 activation through lentiviruses that knock down or overexpress the Per2 gene. This study provides experimental basis for the precision treatment of cardiovascular diseases from the perspective of biological rhythm.

molecular biology↗

bioRxiv2024

Retrieval Augmented Protein Language Models for Protein Structure Prediction

The advent of advanced artificial intelligence technology has significantly accelerated progress in protein structure prediction, with AlphaFold2 setting a new benchmark for prediction accuracy by leveraging the Evoformer module to automatically extract co-evolutionary information from multiple sequence alignments (MSA). To address AlphaFold2s dependence on MSA depth and quality, we propose two novel models: AIDO.RAGPLM and AIDO.RAGFold, pretrained modules for Retrieval-AuGmented protein language model and structure prediction in an AI-driven Digital Organism (Song et al., 2024). AIDO.RAGPLM integrates pre-trained protein language models with retrieved MSA, surpassing single-sequence protein language models in perplexity, contact prediction, and fitness prediction. When sufficient MSA is available, AIDO.RAGFold achieves TM-scores comparable to AlphaFold2 while operating up to eight times faster, and significantly outperforms AlphaFold2 when MSA is insufficient ({Delta}TM-score=0.379, 0.116 and 0.059 for 0, 5 and 10 MSA sequences as input). Additionally, we developed an MSA retriever using hierarchical ID generation that is 45 to 90 times faster than traditional methods, expanding the MSA training set for AIDO.RAGPLM by 32%. Our findings suggest that AIDO.RAGPLM provides an efficient and accurate solution for protein structure prediction, particularly in scenarios with limited MSA data. The AIDO.RAGPLM model has been open-sourced and is available on https://huggingface.co/genbio-ai/AIDO.Protein-RAG-3B.

bioinformatics↗