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Chen, W.

Publications and source records attributed to Chen, W..

At least 181 records · Page 10Linked to original sources

Sequencing-based Spatial Transcriptomics with scRNA-seq Sensitivity

The advent of spatial transcriptomics has dramatically expanded our ability to study the vast network of cell-cell interactions at the molecular level in tissue. Among current methods, sequencing-based approaches have great potential in discovering because of its unbiased capture. In the last couple of years, the spatial resolution for the capture addresses has been significantly improved from 100 m to <1 m, well below the size of a mammalian cell. However, the capture efficiency has always been a pain point, [~]one order of magnitude lower than that of single cell RNA sequencing (scRNA-seq). The low capture efficiency limits the depth and breadth of its applications in the study of complex biological systems and diseases. Here, we introduce Salus Spatial transcriptomic system (Salus-STS), which provides [~]1 m capture resolution and a capture efficiency [~]1 order of magnitude higher than other current methods. Analysis with sub-cellular resolution becomes practical for sequencing-based spatial transcriptomics.

molecular biology↗

Evolutionary trajectories of immune escape across cancers

Immune escape is a critical hallmark of cancer progression and underlies resistance to multiple immunotherapies. However, it remains unclear when the genetic events associated with immune escape occur during cancer development. Here, we integrate functional genomics studies of immunomodulatory genes with a tumor evolution reconstruction approach to infer the evolution of immune escape across 38 cancer types from the Pan-Cancer Analysis of Whole Genomes dataset. Different cancers favor mutations in different immunomodulatory pathways. For example, the antigen presentation machinery is highly mutated in colorectal adenocarcinoma, lung squamous cell carcinoma, and chromophobe renal cell carcinoma, and the protein methylation pathway is highly mutated in bladder transitional cell carcinoma and lung adenocarcinoma. We also observe different timing patterns in multiple immunomodulatory pathways. For instance, mutations impacting genes involved in cellular amino acid metabolism were more likely to happen late in pancreatic adenocarcinoma. Mutations in the glucocorticoid receptor regulatory network pathway tended to occur early, while mutations in the TNF pathways were more likely to occur late in B-cell non-Hodgkin lymphoma. Mutations in the NOD1/2 signaling pathway and DNA binding transcription factor activity tended to happen late in breast adenocarcinoma and ovarian adenocarcinoma. Together, these results delineate the evolutionary trajectories of immune escape in different cancer types and highlight opportunities for improved immunotherapy of cancer. SignificanceDespite its critical role in cancer progression, the evolution of immune escape is poorly understood. We integrate functional genomics and tumor evolution reconstruction and infer immune escape trajectories across cancer types. Our results have important implications for developing biomarkers for immunoprevention and treatment strategies for immune escape of cancer.

evolutionary biology↗

Phosphorylation patterns modulate the transient secondary structure of RNA polymerase II CTD without altering its global conformation

The intrinsically disordered C-terminal domain (CTD) of RNA polymerase II coordinates transcription and co-transcriptional events through dynamic phosphorylation patterns. While it has been long hypothesized that phosphorylation induces structural changes in the CTD, a direct comparison of how different phosphorylation patterns modulate the CTD conformation has been limited. Here, we generated two distinct phosphorylation patterns in an essential Drosophila CTD region with the kinase Dyrk1a: one where Ser2 are primarily phosphorylated, mimicking the state near transcription termination, and a hyperphosphorylation state where most Ser2, Ser5, and Thr4 residues are phosphorylated, expanding on our work on Ser5 phosphorylation, which mimics early transcription elongation. Using 13C Direct-Detect NMR, we show that the CTD has a tendency to form transient beta strands and beta turns, which is altered differently by Ser2 and Ser5 phosphorylation. Small angle x-ray scattering (SAXS) revealed no significant changes in the CTD global dimensions even at high levels of phosphorylation, contradicting the common assumption of phosphorylation-induced chain expansion. Our findings support a transient beta model in which unphosphorylated CTD adopts transient beta strands at Ser2 during transcription pre-initiation. These transient structures are disrupted by Ser5 phosphorylation in early elongation, and later restored by Ser2 phosphorylation near termination for recruiting beta turn-recognizing termination factors.

biophysics↗

The genetic diversity and populational specificity of the human gut virome at single nucleotide resolution

Large-scale characterization of gut viral genomes provides strain-resolved insights into host-microbe interactions. However, existing viral genomes are mainly derived from Western populations, limiting our understanding of global gut viral diversity and functional variations necessary for personalized medicine and addressing regional health disparities. Here, we introduce the Chinese Gut Viral Reference (CGVR) set, consisting of 120,568 viral genomes from 3,234 deeply sequenced fecal samples collected nationwide, covering 72,751 viral species-level clusters (VSCs), nearly 90% of which are absent from current databases. Analysis of single nucleotide variations (SNVs) in 233 globally prevalent VSCs revealed that 18.9% showed significant genetic stratification between Chinese and non-Chinese populations, potentially linked to bacterial infection susceptibility. The predicted bacterial hosts of population-stratified viruses exhibit distinct genetic components associated with health-related functions, including multidrug resistance. Additionally, viral strain diversity at the SNV level correlated with human phenotypic traits, such as age and gastrointestinal issues like constipation. Our analysis also indicates that the human gut bacteriome is specifically shaped by the virome, which mediates associations with human phenotypic traits. This foundational resource underscores the unique genetic makeup of the gut virome across populations and emphasizes the importance of recognizing gut viral genetic heterogeneity for deeper insights into regional health implications.

microbiology↗

Elastase mediated white matter damage in cerebral small vessel disease: Microglia - neutrophils pas de deux

Cerebral small vessel disease (CSVD) leads to an extensive white matter damage associated with cognitive decline, yet the underlying damaging mechanisms remain incompletely understood. Here we established a positive correlation between plasma levels of serine proteinase elastase ELANE and periventricular white matter hyperintensity (PV-WMH) in a cohort of CSVD patients. In a CSVD murine model induced by bilateral carotid artery stenosis (BCAS), upregulated ELANE was detected both in microglia and peripheral blood neutrophils. Genetic ELANE deficiency significantly alleviated oligodendrocyte loss, thereby reducing white matter lesions (WMLs) as well as ameliorating sensorimotor and cognitive impairments in BCAS mice. In vitro studies demonstrated that ELANE triggered time-dependent and dose-dependent oligodendrocyte lineage cell death. Bone marrow transplantation showed that ELANE from microglia and peripheral blood both contributed to WML development and BCAS-induced neurological deficits. Mechanistically, ELANE, accumulated by oligodendrocytes, cleaved the phosphodiesterase domain of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase). Pharmacological inhibition of ELANE with Sivelestat reduced oligodendrocyte loss and WMLs leading to the restoration of white matter integrity and neurological improvements in BCAS mice. In post-mortem brain specimens of CSVD patients ELANE accumulated within WMLs being predominantly localized in microglia (and hence defined as microglial ELANE) rather than in the brain-infiltrating neutrophils. We therefore posit microglial ELANE as an instigator of whiter matter injury in CSVD and suggest its potential therapeutic relevance.

neuroscience↗

A Witches' Broom Phytoplasma effector induces stunting by stabilizing a bHLH transcription factor in plants

O_LIPhytoplasmas are specialized phloem-limited bacteria that cause diseases on various crops resulting in significant agricultural losses. This research focuses on the jujube Witches Broom (JWB) phytoplasma and investigates the host-manipulating activity of the effector SJP39. C_LIO_LIWe found that SJP39 directly interacts with the plant transcription factor bHLH87 in the nuclei. SJP39 stabilizes the bHLH87 homologs in A. thaliana and jujube, leading to growth defects in the plants. C_LIO_LITranscriptomic analysis indicates that SJP39 affects the gibberellin (GA) pathway in jujube. We further demonstrate that ZjbHLH87 regulates GA signalling as a negative regulator and SJP39 enhances this regulation. C_LIO_LIThe research offers important insights into the pathogenesis of JWB disease and identified SJP39 as a virulence factor that can contribute to the growth defects caused by JWB phytoplasma infection. These findings open new opportunities to manage JWB and other phytoplasma diseases. C_LI

plant biology↗

Phosphotyrosine Signal Profiling of Clinical CAR-T Reveals Tonic Signaling Associated with Therapeutic Efficacy

Chimeric Antigen Receptor T (CAR-T) therapies have revolutionized the treatment of cancers such as relapsed and refractory B cell malignancies. However, the precise therapeutic mechanism of CAR-T action remain to be elucidated. In this study, we systematically analyzed CAR signaling via phosphotyrosine (pTyr) proteomics in CAR-T cells from both clinical patients and healthy donors. We found that CAR-T products from clinical patients displayed heightened tyrosine phosphorylation, particularly in the JAK-STAT, MAPK and TCR signaling cascades. We also identified the significantly regulated pTyr sites in primary CAR-T cells under tonic signaling or upon stimulation by antigen-presenting CD19-K562 cells. Although both CD28{zeta} and 4-1BB{zeta} CAR-T cells exhibited comparable pTyr changes, CD28{zeta} CAR-T cells displayed a more pronounced activation in the TCR signaling pathway. Additionally, comparative analysis between clinical and primary CAR-T cells suggested that CAR-T products were subject to heightened tonic signaling, which may be related to therapeutic relapse. Our findings reveal the state of clinical CAR-T products and refine the CAR-T signal transduction network, providing comprehensive insights and informed guidance for CAR-T therapies.

immunology↗

Mechanical force regulates the inhibitory function of PD-1

The immune checkpoint molecule, programmed cell death 1 (PD-1), plays a pivotal role in regulating T-cell function. Upon binding to its ligands, PD-L1 or PD-L2, PD-1 suppresses T-cell receptor signaling, thereby preventing T-cell activation, making it a critical target in cancer immunotherapy. Although extensively studied, the molecular mechanism of PD-1s inhibitory function is still not fully understood, especially at the atomic level. Using the biomembrane force probe (BFP), we discovered that interactions between PD-1 and PD-L1/PD-L2 exhibit catch-slip bond behavior under force. At lower forces, catch bonds are observed, transitioning to slip bond as the force increases. Steered molecular dynamics (SMD) simulations revealed a force-induced bond state between PD-1 and its ligands, distinct from the force-free state observed in solved complex structures. Disrupting interactions that stabilize either state weakens the catch bond and diminishes PD-1s inhibitory function. Interestingly, soluble forms of PD-L1 and PD-L2 compete with their surface-bond counterparts, attenuating PD-1s suppression of T-cell activation. This suggests that soluble PD-1 ligands could potentially serve as anti-PD-1 drugs. Tumor growth studies in mice confirmed the anti-cancer activity of soluble PD-L1. Our findings highlight the critical role of mechanical force in PD-1s inhibitory function, suggesting that PD-1 may act as a mechanical sensor in suppressing T-cell activation. These insights indicate that mechanical regulation should be considered when designing PD-1 blocking inhibitors and other PD-1 related cancer immunotherapies. TeaserThis study shows that the interaction between PD-1 and its ligands is force-dependent, and soluble forms of PD-1 ligands can potentially serve as PD-1 blockers in cancer immunotherapy.

biophysics↗

Identification and genomic characterization of a novel bisegmented coronavirus in the lesser panda

Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses and are renowned for their capacity to infect a diverse range of animals, including humans. In this study, we report the identification and characterization of a novel bisegmented coronavirus, designated LpCoV, from a dead lesser panda, which exhibited severe clinical manifestations and lesions in multiple organs. The LpCoV represents the first documented coronavirus with a unique bisegmented genome while maintaining the typical coronavirus morphology. One genomic segment encodes the ORF1ab polyprotein, while the other segment encodes the spike and nucleocapsid proteins, notably lacking the envelope (E) and membrane (M) genes. The pairwise patristic distances of the five concatenated domains in the replicase region (3CLpro, NiRAN, RdRP, ZBD, and HEL1) between LpCoV and -{delta} coronaviruses range from 1.19 to 1.70. Based on the classification criteria established by the International Committee on Taxonomy of Viruses (ICTV), LpCoV is proposed to constitute a new genus within the Coronaviridae family. An epidemiological investigation identified five LpCoV-like viruses in lesser pandas from two different provinces (Sichuan and Jiangsu) indicating the long-term circulation and expansion of bisegmented coronaviruses in wildlife. These findings highlight the imperative for comprehensive viral surveillance in wildlife, which is essential for understanding and mitigating the risk of animal diseases and zoonotic spillover.

microbiology↗

Cryo-EM structures of human ClpXP reveal mechanisms of assembly and proteolytic activation

The human ClpXP complex (hClpXP) plays a central role in mitochondrial protein quality control by degrading misfolded or unneeded proteins. While bacterial ClpXP complexes have been extensively characterized, the molecular determinants underlying hClpXP assembly and regulation are not as well understood. We determined cryo-electron microscopy (cryo-EM) structures of hClpP in isolation and in complex with hClpX, revealing how hClpX binding promotes rearrangement of an asymmetric hClpP heptamer to assemble as a symmetric tetradecamer. Our hClpXP structure also highlights the stabilizing role of a previously uncharacterized eukaryotic ClpX sequence, referred to as the E-loop, and its importance in ATPase activity and hexamer assembly. We further show that peptide interaction with the hClpP proteolytic active site promotes the complex to adopt a proteolytically competent conformation. Together, these findings advance our understanding of the molecular mechanisms defining hClpXP activation and function.

molecular biology↗

Distinct Binding Modes of Inter-Spike Cross-Linking Suggest a Supplementary Mechanism for SARS-CoV-2 Antibody Neutralization

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its Omicron subvariants drastically amplifies transmissibility, infectivity, and immune escape, mainly due to their resistance to most neutralizing antibodies. Thus, exploring the mechanisms underlying antibody evasion is crucial. Although the full-length native form of antibody, immunoglobulin G (IgG), offers valuable insights into the neutralization, structural investigations primarily focus on the fragment of antigen-binding (Fab). Here, we employ single-particle cryo-electron microscopy (cryo-EM) to characterize a W328-6H2 antibody, in its native IgG form complexed with severe acute respiratory syndrome (SARS), severe acute respiratory syndrome coronavirus 2 wild-type (WT) and Omicron variant BA.1 spike protein (S). Three high-resolution structures reveal that the full-length IgG forms a centered head-to-head dimer of trimer when bound fully stoichiometrically with both SARS and WT S, while adopting a distinct offset configuration with Omicron BA.1 S. Combined with functional assays, our results suggest that, beyond the binding affinity between the RBD epitope and Fab, the higher-order architectures of S trimer and full-length IgG play an additional role in neutralization, elucidate a potential molecular basis of Omicron immune escape, and expand our understanding on antibody evasion mechanisms.

immunology↗

Immunologic and Biophysical Features of the BNT162b2 JN.1- and KP.2-Adapted COVID-19 Vaccines

Vaccines remain a vital public health tool to reduce the burden of COVID-19. COVID-19 vaccines that are more closely matched to circulating SARS-CoV-2 lineages elicit more potent and relevant immune responses that translate to improved real-world vaccine effectiveness. The rise in prevalence of the Omicron JN.1 lineage, and subsequent derivative sublineages such as KP.2 and KP.3, coincided with reduced neutralizing activity and effectiveness of Omicron XBB.1.5-adapted vaccines. Here, we characterized the biophysical and immunologic attributes of BNT162b2 JN.1- and KP.2-adapted mRNA vaccine-encoded spike (S) protein immunogens. Biophysical interrogations of S revealed the structural consequences of hallmark amino acid substitutions and a potential molecular mechanism of immune escape employed by JN.1 and KP.2. The vaccine candidates were evaluated for their immunogenicity when administered as fourth or fifth doses in BNT162b2-experienced mice or as a primary series in naive mice. In both vaccine-experienced and naive settings, JN.1- and KP.2-adapted vaccines conferred improved neutralizing responses over the BNT162b2 XBB.1.5 vaccine against a broad panel of emerging JN.1 sublineages, including the predominant KP.3.1.1 and emerging XEC lineages. Antigenic mapping of neutralizing responses indicated greater antigenic overlap of JN.1- and KP.2-adapted vaccine responses with currently circulating sublineages compared to an XBB.1.5-adapted vaccine. CD4+ and CD8+ T cell responses were generally conserved across all three vaccines. Together, the data support the selection of JN.1- or KP.2-adapted vaccines for the 2024-25 COVID-19 vaccine formula. ONE-SENTENCE SUMMARYThe Omicron JN.1- and KP.2-adapted BNT162b2 mRNA vaccines encoding prefusion S proteins elicit similar preclinical neutralizing antibody responses against circulating JN.1 sublineage pseudoviruses that are more potent than those elicited by past iterations of BNT162b2 licensed vaccines, thus demonstrating the importance of annual strain changes to the COVID-19 vaccine.

immunology↗

Genic and phylogenomic discordances reveal conflicting hybridization episodes in temperate Loliinae grasses

The grass subtribe Loliinae has great ecological and economic importance, as it includes community-dominant species of world mountain grasslands and the most extensively cultivated pasture, fodder and lawn grasses (fescues, ryegrasses). Resolving the phylogeny of recently evolved Loliinae lineages has proven challenging due to frequent introgressions and polyploidizations that occurred throughout their history. Evolutionary reconstruction based on genome-wide data sets is useful for large groups of species, enabling recovering phylogenetic trees, contrasting their topologies, unraveling the origins of the discordances, and testing hypotheses on their reticulate history. Here we present the first target-capture phylogeny of Loliinae using 234 single-copy nuclear coding loci for a large sample of 132 representative taxa, covering all its 29 evolutionary lineages. Additionally, we have completed organelle (plastome) sequences to elucidate the hybridogenic speciation history of the Loliinae from complementary genome sources. Concatenated maximum likelihood and multispecies coalescent trees of single-copy genes showed well-supported relationships for major lineages, which were generally consistent across analyses and genomes, and with previous taxonomic and phylogenetic findings. However, they also revealed high levels of both nuclear and cyto-nuclear discordances. The time-calibrated phylogeny of target-capture data supports an early Miocene origin for Loliinae and Mid-Late Miocene splits for its main broad-leaved and fine-leaved lineages, while current species-rich groups radiated in Plio-Pleistocene times. Hybridization and topological incongruence tests between the nuclear single-copy genes and plastome-based trees using multiple approaches and different sampling subsets confirmed the rampant introgression experienced by Loliinae at deep and shallow nodes. However, hybridization rates differed from lineage to lineage within the major clades and were not correlated with time or ploidy but rather depended on the "hybridogenous" nature of particular lineages. Our analyses detected high hybridization rates in four broad-leaved (Subulatae-Hawaiian, Tropical-South African, Mexico-Central-South American and Leucopoa p.p.) and five fine-leaved Loliinae lineages (American II, Aulaxyper, Afroalpine, American-Neozeylandic) containing rogue species that probably originated from trans-clade crosses and are more likely to hybridize greatly. In contrast, they recovered low hybridization rates in four broad-leaved (Schedonorus-Lolium, Subbulbosae, Drymanthele-Pseudoscariosae-Lojaconoa, Leucopoa pp) and six fine-leaved lineages (Festuca, Psilurus-Vulpia, American I, Exaratae-Loretia, American-Vulpia-Pampas, Eskia), with species derived from single ancestors that hybridize only with close congeners. The levels of intragenomic nuclear discordance could have been magnified by the prevalence of allopolyploids in the Loliinae and by methodological bias in the selection of orthologs; however, our nuclear and plastome trees have revealed key hybrid origins in these grasses. [allopolyploidization, lineage-specific hybridization rates, nuclear and cyto-nuclear discordances, Festuca and related genera, phylogenomics, nuclear single-copy genes, plastome].

evolutionary biology↗

Genomic diversity and underlying metabolic variations of the human gut microbiome between populations at single nucleotide resolution

BackgroundA comprehensive and representative reference database is crucial for accurate taxonomic and functional profiling of the human gut microbiome in population-level studies. However, with 70% of current microbial reference data derived from Europeans and the Americans, East Asia, especially China, remain underrepresented. MethodsWe constructed the human Gut Microbiome Reference (GMR), comprising 478,588 high-quality microbial genomes from Chinese (247,134) and non-Chinese (231,454) populations. Species-level clustering and protein annotations were performed to characterize microbial diversity and function. We further integrated novel genomes into taxonomic profiling database and validated the improvements using independent cohort data. ResultsThe GMR dataset spans 6,664 species, including 26.4% newly classified species, and encodes over 20 million unique proteins, with 47% lacking known functional annotations. Notably, we observed that 35.35% and 32.46% of species unique to Chinese and non-Chinese populations, respectively. For 2,145 species shared between populations, 74% of 304 species with balanced prevalence between populations exhibited population-specific phylogenetic stratification, involving health relevant functionalities such as antibiotic resistance. Integration of novel genomes into taxonomic improved population-level species profiling by up to 23% and uncovered replicable associations between novel species and host physiological traits. ConclusionsOur study largely expands the compositional and functional landscape of the human gut microbiome, providing a crucial resource for studying the role of gut microbiome for regional health disparities.

genomics↗

Mechanical control of germ cell specification in Arabidopsis anthers

A central question in developmental biology is how the germline is established. We have studied the specification of the male germ cells (GCs) within the anther1-3. Hereby, we have focused on the potential role of mechanics, an aspect of anther development which has been very poorly characterized2,4. Using a combination of live imaging and mechanical measurements, we provide evidence that GCs originate in a special micro-mechanical niche, where inner tissues exert push on outer cell layers, placing them under compression. Mechanical perturbations significantly disrupted the GC specification and patterning. Moreover, we found that the master genetic regulator SPOROCYTELESS/NOZZLE (SPL/NZZ)5,6 is central in establishing this micro-mechanical environment by softening the cell wall. The mechanical cues, in turn, stabilize the transcription of SPL/NZZ. We propose here an intrinsic growth-derived mechano-chemical feedback loop that drives germ-cell fate acquisition.

developmental biology↗

Integration of the DD-genome reshapes gene transcription, chromatin architecture and metabolome of allohexaploid wheat leading to enhanced adaptability

The integration, through hybridization, of the DD genome into domesticated tetraploid wheat gave rise to allohexaploid wheat, the most cultivated wheat globally growing across diverse environmental conditions. However, the regulatory basis of this integration on increased environmental adaptability in allohexaploid remains largely unexplored. Here, we investigated the change of transcriptome, epigenome as well as the chromatin interactome, and metabolome in three independent polyploidization events representing DD genome integration. Our findings reveal that polyploidization events induce the activation of defense-related genes through comprehensive reorganization of epigenome and chromatin architecture. DD integration not only brings an additional gene copy but also activates the homoeologs existing in the A and B subgenomes through chromatin interactions. Furthermore, secondary metabolites represented by alkaloids and flavonoids that are crucial for environmental adaptation, are significantly enriched following polyploidization. Thus, hexaploid wheat exhibits enhanced tolerance to alkalinity, UV-B light stress and high salt conditions was observed. These results highlight the indispensable role of DD genome integration in the adaptability of allohexaploid wheat during its evolution.

plant biology↗

CD4+ tissue resident memory Th17 cells drive IL-17A-mediated joint pathology in Spondyloarthritis

ObjectivesInterleukin (IL)-17A is a key driver of Spondyloarthritis (SpA) joint pathology. We aimed to identify its cellular source in synovial tissue from patients with two forms of SpA namely Axial SpA (AxSpA) and Psoriatic arthritis (PsA). MethodsSynovial tissue from patients with SpA was profiled using single-cell RNA sequencing (scRNA-seq: AxSpA, n=5 and PsA, n=6) or spatial RNA profiling (PsA, n=4). CellPhoneDB was used to infer cell-cell communication. Tissue resident memory Th17 (TRM17)-like cells were generated in vitro using blood memory CD4+ T cells from SpA patients. An epigenetic inhibitor library, siRNA and clustered regularly interspaced short palindromic repeats (CRISPR) were used to identify epigenetic regulator(s) for TRM17. ResultsscRNA-seq showed that CD4+CXCR6+ TRM17 cells are the predominant spontaneous IL17A producers in SpA synovium. Cell-cell communication and single-cell spatial analysis support the interaction between TRM17 and CLEC10A+ dendritic cells, which were activated in SpA. Both sublining and lining fibroblasts in SpA synovium showed evidence of IL-17A activation. In vitro-generated CD4+ TRM17-like cells phenocopied joint tissue TRM17, producing IL-17A/F upon T cell receptor (TCR) stimulation, which was further enhanced by cytokines. Perturbation of BRD1 inhibited the generation of TRM17-like cells. ConclusionsCD4+ TRM17 cells are the predominant source of IL-17A in SpA synovial tissue. TCR stimulation is essential for the secretion of IL-17A by CD4+TRM17-like cells. The epigenetic regulator BRD1 contributes to the generation of CD4+TRM17. Depleting CD4+TRM17 cells in SpA is thus a therapeutic strategy with potential to induce long-term remission. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSInterleukin (IL)-17A plays a key role in the immunopathogenesis of Spondyloarthritis (SpA), but its cellular source in joint tissue has not been determined previously. The induction and accumulation of CD4+ tissue resident memory Th17 (TRM17) cells following the clearance of pathogens has been described in skin, lung and kidney. Whether CD4+ TRM17 cells also accumulate in the joint and contribute to the pathology of SpA is not clear. What this study addsO_LICD4+ TRM17 cells are present in SpA synovial tissue and are the predominant source of IL17A C_LIO_LICD4+ TRM17 cells in SpA joints express IL17A without any in vitro exogenous stimulation C_LIO_LIT cell receptor (TCR) rather than cytokine stimulation is essential for IL-17A production by CD4+ TRM17-like cells C_LIO_LIThe epigenetic regulator BRD1 contributes to the generation of CD4+ TRM17-like cells. C_LI How this study might affect research, practice or policyOur findings identify CD4+ TRM17 cells as the primary source of IL-17A in SpA synovium, a previously unrecognized role for these cells. Key questions remain: How do CD4+ TRM17 cells relate to IL-17A producers in synovial fluid? What mechanisms induce and maintain them in the joint? How do they interact with other cells to promote arthritis? These questions warrant further investigation. In addition, our data suggest that targeting CD4+ TRM17 cells, the "factory" of IL-17A in SpA synovial tissue, has the potential to induce long-term remission, encouraging future efforts to develop new therapies to deplete CD4+ TRM17 cells in SpA.

immunology↗

Analyzing the Molecular Mechanism of Eucalyptol, Limonene and Pinene Enteric Capsules (QIENUO) in the Treatment of Pulmonary cystic fibrosis with Network Pharmacology and Verifying Molecular Docking

ObjectiveTo explore the mechanism of Eucalyptol, Limonene and Pinene Enteric Capsules (QIENUO) in the treatment of pulmonary cystic fibrosis (CPF), analyze the common targets of QIENUO and CPF, and verify the molecular docking of core proteins and small molecules. MethodsThe main active compounds and their corresponding targets were obtained from PubChem, SwissTargetprediction, GeneCards, PharmMapper and TCMSP databases. Targets related to CPF were screened from GeneCards, OMIM, DisGeNET and TTD databases. The common "QIENUO-CPF" targets were analyzed by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) through the website of Weishengxin. Protein-protein interaction (PPI) network and compound-target-pathway network were constructed by Cytoscape, and the network parameters were systematically analyzed. The interaction between core protein and monomer components was evaluated and verified by molecular docking method. Results228 active compounds target and 1354 CPF-related targets were screened out, and 92 common targets were analyzed by GO and KEGG. The results showed that the therapeutic effect of QIENUO on CPF was mainly through AMPK signaling pathway, cGMP-PKG signaling pathway and TGF-{beta} signaling pathway. The results of molecular docking show that the binding energy of 9 of 15 pairs of ligand-receptor pairs is lower than-6 kjmol-1. ConclusionQIENUO exhibits huge potential as a therapeutic agent for the treatment of pulmonary cystic fibrosis. The specific molecular mechanism and effective active components of QIENUO treat CPF were studied and demonstrated, which provided theoretical basis for better clinical application of QIENUO.

bioinformatics↗