Biology subjects

Xu, Y.

Publications and source records attributed to Xu, Y..

At least 505 records · Page 28Linked to original sources

bioRxiv2023

2D and 3D multiplexed subcellular profiling of nuclear instability in human cancer

Nuclear atypia, including altered nuclear size, contour, and chromatin organization, is ubiquitous in cancer cells. Atypical primary nuclei and micronuclei can rupture during interphase; however, the frequency, causes, and consequences of nuclear rupture are unknown in most cancers. We demonstrate that nuclear envelope rupture is surprisingly common in many human cancers, particularly glioblastoma. Using highly-multiplexed 2D and super-resolution 3D-imaging of glioblastoma tissues and patient-derived xenografts and cells, we link primary nuclear rupture with reduced lamin A/C and micronuclear rupture with reduced lamin B1. Moreover, ruptured glioblastoma cells activate cGAS-STING-signaling involved in innate immunity. We observe that local patterning of cell states influences tumor spatial organization and is linked to both lamin expression and rupture frequency, with neural-progenitor-cell-like states exhibiting the lowest lamin A/C levels and greatest susceptibility to primary nuclear rupture. Our study reveals that nuclear instability is a core feature of cancer, and links nuclear integrity, cell state, and immune signaling.

cancer biology↗

bioRxiv2023

TRAFICA: Improving Transcription Factor Binding Affinity Prediction using Large Language Model on ATAC-seq Data

AO_SCPLOWBSTRACTC_SCPLOWIn silico transcription factor and DNA (TF-DNA) binding affinity prediction plays a vital role in examining TF binding preferences and understanding gene regulation. The existing tools employ TF-DNA binding profiles from in vitro high-throughput technologies to predict TF-DNA binding affinity. However, TFs tend to bind to sequences in open chromatin regions in vivo, such TF binding preference is seldomly considered by these existing tools. In this study, we developed TRAFICA, an open chromatin language model to predict TF-DNA binding affinity by integrating the characteristics of sequences from open chromatin regions in ATAC-seq experiments and in vitro TF-DNA binding profiles from high-throughput technologies. We applied self-supervised learning to pre-train TRAFICA on over 13 million nucleotide sequences from the peaks in ATAC-seq experiments to learn the TF binding preference in vivo. TRAFICA was further fine-tuned using the TF-DNA binding profiles from PBM and HT-SELEX technologies to learn the association between TFs and their target DNA sequences. We observed that TRAFICA significantly outperformed both machine learning-based and deep learning-based tools in predicting in vitro and in vivo TF-DNA binding affinity. These findings indicate that considering the characteristics of sequences from open chromatin regions could significantly improve TF-DNA binding affinity prediction, particularly when limited TF-DNA binding profiles from high-throughput technologies are available for specific TFs.

bioinformatics↗

bioRxiv2023

Multimodal single cell-resolved spatial proteomics reveals pancreatic tumor heterogeneity

Despite the advances in antibody-guided cell typing and mass spectrometry-based proteomics, their integration is hindered by challenges for processing rare cells in the heterogeneous tissue context. Here, we introduce Spatial and Cell-type Proteomics (SCPro), which combines multiplexed imaging and flow cytometry with ion exchange-based protein aggregation capture technology to characterize spatial proteome heterogeneity with single cell resolution. The SCPro was employed to explore the pancreatic tumor microenvironment and revealed the spatial alternations of over 5,000 proteins by automatically dissecting up to 100 single cells guided by multi-color imaging of centimeter-scale formalin-fixed, paraffin-embedded tissue slide. To enhance cell-type resolution, we characterized the proteome of 14 different cell types by sorting up to 1,000 cells from the same tumor, which allows us to deconvolute the spatial distribution of immune cell subtypes and leads to the discovery of a novel subtype of regulatory T cells. Together, the SCPro provides a multimodal spatial proteomics approach for profiling tissue proteome heterogeneity.

systems biology↗

bioRxiv2023

Loss of TREM2 exacerbates parenchymal amyloid pathology but diminishes CAA in Tg-SwDI mice

Alzheimers disease (AD) is a progressive neurodegenerative disease, and it is the most common cause of dementia worldwide. Recent genome-wide association studies (GWAS) identified TREM2 (triggering receptor expressed on myeloid cells 2) as one of the major risk factors for AD. TREM2 is a surface receptor expressed on microglia and largely mediates microglial functions and immune homeostasis in the brain. The functions of TREM2 in AD pathogenesis, including in the formation of the key pathology parenchymal amyloid-{beta} (A{beta}) plaques, have been investigated by introducing Trem2 deficiency in AD mouse models. However, the role of TREM2 in cerebrovascular amyloidosis, in particular cerebral amyloid angiopathy (CAA) remains unexplored. CAA features A{beta} deposition along the cerebral vessels, signifying an intersection between AD and vascular dysfunction. Using a well-characterized CAA-prone, transgenic mouse model of AD, Tg-SwDI (SwDI), we found that loss of TREM2 led to a marked increase in overall A{beta} load in the brain, but a dramatic decrease in CAA in microvessel-rich regions, along with reduced microglial association with CAA. Transcriptomic analysis revealed that in the absence of Trem2, microglia were activated but trapped in transition to the fully reactive state. Like microglia, perivascular macrophages were activated with upregulation of cell junction related pathways in Trem2-deficient SwDI mice. In addition, vascular mural cells and astrocytes exhibited distinct responses to Trem2 deficiency, contributing to the pathological changes in the brain of Trem2-null SwDI mice. Our study provides the first evidence that TREM2 differentially modulates parenchymal and vascular A{beta} pathologies, which may have significant implications for both TREM2- and A{beta}-targeting therapies for AD.

neuroscience↗

bioRxiv2023

Berberine impairs spermatogenesis in mice by modulating ornithine metabolism via gut microbiota regulation

Berberine (BBR) is used to treat diarrhea clinically, its reproductive toxicity, however, is poorly documented. This study aims to investigate the impact of BBR on the male reproductive system. Gradient doses of BBR were administered orally to experimental mice for consecutive 14 days. The gut microbiota, sperm concentration of cauda epididymis, and serum testosterone levels were measured after the last dose for assessing the effects of BBR. Moreover, the metabolome and transcriptome of the mice and microbiota were also investigated. Intragastric BBR administration resulted in a significant decrease in serum testosterone levels and epididymal sperm concentration in mice, which was attributed to a dramatic decrease of Muribaculaceae abundance in the gut microbiota of mice. Both fecal microbiota transplantation (FMT) and polyethylene glycol (PEG) treatment experiments also demonstrated that Muribaculaceae is necessary for spermatogenesis. Metabolomic analysis revealed that BBR affected the arginine and proline metabolism pathways, of which ornithine levels were downregulated after BBR administration. Intragastric administration of M.intestinale and its metabolite ornithine to BBR-treated mice achieved a recovery of sperm concentration and testosterone levels. RNA sequencing of testes showed the genes related to the LDLR-mediated cholesterol-synthesis testosterone pathway were downregulated after BBR administration. The levels of testosterone increased and Ldlr gene became more transcriptionally active in TM3 cells cultured in media supplemented with ornithine. This study for the first time revealed an association between BBR-induced gut Muribaculaceae dysbiosis and defects in spermatogenesis via ornithine metabolism, which provided a candidate and strategy for the treatment of infertility caused by a decreased serum testosterone level-induced by gut microbiota dysbiosis.

pharmacology and toxicology↗

bioRxiv2023

A foundation model for bioactivity prediction using pairwise meta-learning

Compound bioactivity plays an important role in different stages of drug development and discovery. Existing machine learning approaches have poor generalization ability in compound bioactivity prediction due to the small number of compounds in each assay and incompatible measurements among assays. Here, we propose ActFound, a foundation model for bioactivity prediction trained on 2.3 million experimentally-measured bioactivity compounds and 50, 869 assays from ChEMBL and BindingDB. The key idea of ActFound is to employ pairwise learning to learn the relative value differences between two compounds within the same assay to circumvent the incompatibility among assays. ActFound further exploits meta-learning to jointly optimize the model from all assays. On six real-world bioactivity datasets, ActFound demonstrates accurate in-domain prediction and strong generalization across datasets, assay types, and molecular scaffolds. We also demonstrated that ActFound can be used as an accurate alternative to the leading computational chemistry software FEP+(OPLS4) by achieving comparable performance when only using a few data points for fine-tuning. The promising results of ActFound indicate that ActFound can be an effective foundation model for a wide range of tasks in compound bioactivity prediction, paving the path for machine learning-based drug development and discovery.

bioinformatics↗

bioRxiv2023

Three-dimensional visualization of blood vessels in human gliomas based on tissue clearing and deep learning

Gliomas, with their intricate and aggressive nature, call for a detailed visualization of their vasculature. While many studies lean towards 2D imaging of thin sections, this method often overlooks the full spatial heterogeneity inherent to tumors. To overcome this limitation, our study melded state-of-the-art techniques, encompassing tissue clearing technology, 3D confocal microscopy imaging, and deep learning-aided vessel extraction, resulting in a comprehensive 3D visualization of glioma vasculature in intact human tissue. Specifically, we treated formalin-fixed thick human glioma tissue sections (500 m) with OPTIClear for transparency and subsequently performed immunofluorescent labeling using CD31. Using confocal microscopy, we obtained 3D images of the glioma vasculature. For vessel extraction, we employed a specialized 3D U-Net, enriched with image preprocessing and post-processing methods, and benchmarked its performance against the Imaris software. Our findings indicated that OPTIClear-enabled tissue clearing yielded a holistic 3D representation of immunolabeled vessels in clinical human glioma samples. Impressively, our deep learning technique outshined the traditional Imaris approach in terms of accuracy and efficiency in vessel extraction. Further, discernible variations in vascular metrics, such as mean diameter, branching point count, and volume ratio, were observed between low-grade and high-grade gliomas. In essence, our innovative blend of tissue clearing and deep learning not only enables enhanced 3D visualization of human glioma vasculature but also underscores morphological disparities across glioma grades, potentially influencing pathological grading, therapeutic strategies, and prognostic evaluations.

neuroscience↗

bioRxiv2023

Auditory cues modulate the short timescale dynamics of STN activity during stepping in Parkinson's disease

BackgroundGait impairment has a major impact on motor performance and quality of life in patients with Parkinsons disease (PD). The neurophysiological mechanisms of gait impairment remain poorly understood, meaning that treatment options are currently limited. It is believed that basal ganglia oscillatory activity at {beta} frequencies (15-30 Hz) may be a contributor to gait impairment in PD, but the precise dynamics of this oscillatory activity during gait remain unclear. Auditory cues are known to lead to improvements in gait kinematics in PD. If the neurophysiological mechanisms of this cueing effect were better understood they could be leveraged to treat gait impairments using brain-computer interface (BCI) technologies. ObjectiveWe aimed to characterize the dynamics of subthalamic nucleus (STN) oscillatory activity during stepping movements in PD and to establish the neurophysiological mechanisms by which auditory cues modulate gait. MethodsWe used local field potentials (LFPs) to study STN oscillatory activity in eight PD patients while stepping in place with auditory cueing. Hidden Markov Models (HMMs) were used to discover dynamic brain states that occurred pre-sound, on-sound, and post-sound cues. ResultsThe occurrence of {beta} bursts was suppressed during and after auditory cues. This manifested as a decrease in their fractional occupancy and state lifetimes. Interestingly, transients showed the opposite effect, with fractional occupancy and state lifetimes increasing during and after auditory cues. ConclusionsWe found transient oscillatory states in the STN LFP during stepping and showed that and {beta} oscillations are differentially modulated by auditory cues during stepping in PD.

neuroscience↗

bioRxiv2023

Transcriptional Control of Neocortical Size and Microcephaly

The mammalian neocortex differs vastly in size and complexity between mammalian species, yet the mechanisms that lead to an increase in brain size during evolution are not known. We show here that two transcription factors coordinate gene expression programs in progenitor cells of the neocortex to regulate their proliferative capacity and neuronal output in order to determine brain size. Comparative studies in mice, ferrets and macaques demonstrate an evolutionary conserved function for these transcription factors to regulate progenitor behaviors across the mammalian clade. Strikingly, the two transcriptional regulators control the expression of large numbers of genes linked to microcephaly suggesting that transcriptional deregulation as an important determinant of the molecular pathogenesis of microcephaly, which is consistent with the finding that genetic manipulation of the two transcription factors leads to severe microcephaly.

neuroscience↗

bioRxiv2023

ZNF397 Loss Triggers TET2-driven Epigenetic Rewiring, Lineage Plasticity, and AR-targeted Therapy Resistance in AR-dependent Cancers

Cancer cells exhibit phenotypical plasticity and epigenetic reprogramming, which allows them to evade lineage-dependent targeted treatments by adopting lineage plasticity. The underlying mechanisms by which cancer cells exploit the epigenetic regulatory machinery to acquire lineage plasticity and therapy resistance remain poorly understood. We identified Zinc Finger Protein 397 (ZNF397) as a bona fide co-activator of the androgen receptor (AR), essential for the transcriptional program governing AR-driven luminal lineage. ZNF397 deficiency facilitates the transition of cancer cell from an AR-driven luminal lineage to a Ten-Eleven Translocation 2 (TET2)-driven lineage plastic state, ultimately promoting resistance to therapies inhibiting AR signaling. Intriguingly, our findings indicate that TET2 inhibitor can eliminate the AR targeted therapies resistance in ZNF397-deficient tumors. These insights uncover a novel mechanism through which prostate and breast cancers acquire lineage plasticity via epigenetic rewiring and offer promising implications for clinical interventions designed to overcome therapy resistance dictated by lineage plasticity. Statement of SignificanceThis study reveals a novel epigenetic mechanism regulating tumor lineage plasticity and therapy response, enhances understanding of drug resistance and unveils a new therapeutic strategy for prostate cancer and other malignancies. Our findings also illuminate TET2s oncogenic role and mechanistically connect TET2-driven epigenetic rewiring to lineage plasticity and therapy resistance.

cancer biology↗

bioRxiv2023

Integrating population-level and cell-based signatures for drug repositioning

Drug repositioning presents a streamlined and cost-efficient way to expand the range of therapeutic possibilities. Drugs with human genetic evidence are more likely to advance successfully through clinical trials towards FDA approval. Single gene-based drug repositioning methods have been implemented, but approaches leveraging a broad spectrum of molecular signatures remain underexplored. We propose a framework called "TReD" (Transcriptome-informed Reversal Distance) that integrates population-level disease signatures robust to reverse causality and cell-based, drug-induced transcriptome response profiles. TReD embeds the disease signature and drug response profiles in a high-dimensional normed space, quantifying the reversal potential of candidate drugs in a disease-related cell-based screening. Here, we implemented this framework to identify potential therapeutics relevant to COVID-19 and type 2 diabetes (T2D). For COVID-19, we identified 36 drugs showing potential reversal roles. Notably, nearly 70% (25/36) of the drugs have been linked to COVID-19 from other studies, with seven drugs supported by ongoing/completed clinical trials. For T2D, we observed reversal signals for 16 compounds on multiple disease signatures. Five drugs are supported by published literature, affirming potential therapeutic value. In summary, we propose a comprehensive genetics-anchored framework integrating population-level signatures and cell-based screening that has the potential to accelerate the search for new therapeutic strategies.

bioinformatics↗

bioRxiv2023

Mammalian circadian clock proteins form dynamic interacting microbodies distinct from phase separation

Liquid-liquid phase separation (LLPS) underlies diverse biological processes. Because most LLPS studies were performed in vitro or in cells that overexpress protein, the physiological relevance of LLPS is unclear. PERIOD proteins are central mammalian circadian clock components and interact with other clock proteins in the core circadian negative feedback loop. Different core clock proteins were previously shown to form large complexes. Here we show that when transgene was stably expressed, PER2 formed nuclear phosphorylation-dependent LLPS condensates that recruited other clock proteins. Super-resolution microscopy of endogenous PER2, however, revealed formation of circadian-controlled, rapidly diffusing microbodies that were resistant to protein concentration changes, hexanediol treatment, and loss of phosphorylation, indicating that they are distinct from the LLPS condensates caused by overexpression. Surprisingly, only a small fraction of endogenous PER2 microbodies transiently interact with endogenous BMAL1 and CRY1, a conclusion that was confirmed in cells and in mice tissues, suggesting an enzyme-like mechanism in the circadian negative feedback process. Together, these results demonstrate that the dynamic interactions of core clock proteins is a key feature of mammalian circadian clock mechanism and the importance of examining endogenous proteins in LLPS and circadian studies.

genetics↗

bioRxiv2023

Keratin 17- and PKCα-dependent transient amplification of neutrophil influx after repeated stress to the skin

Neutrophils contribute to the pathogenesis of chronic inflammatory skin diseases. Little is known about the source and identity of the signals mediating their recruitment in inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin and assess whether keratinocyte-derived signals impact neutrophil recruitment. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12h and resolves within 24h. A second TPA treatment or a UVB challenge, when applied at 24h but not 48h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated in ex vivo culture, and involves the K17-dependent sustainment of protein kinase C (PKC) activity and release of neutrophil chemoattractants by stressed keratinocytes. We show that K17 binds RACK1, a scaffold essential for PKC activity. Finally, analyses of RNAseq data reveal the presence of a transcriptomic signature consistent with TAR and PKC activation in chronic inflammatory skin diseases. These findings uncover a novel, transient, and keratin-dependent mechanism that amplifies neutrophil recruitment to the skin under stress, with direct implications for inflammatory skin disorders.

immunology↗

bioRxiv2023

MSIsensor-RNA: microsatellite instability detection for bulk and single-cell gene expression data

Microsatellite instability (MSI) is an indispensable biomarker in cancer immunotherapy. Currently, MSI scoring methods by high-throughput omics methods have gained popularity and demonstrated better performance than the gold standard method for MSI detection. However, the MSI detection method on expression data, especially single-cell expression data, is still lacking, limiting the scope of clinical application and prohibiting the investigation of MSI at a single-cell level. Herein, we developed MSIsensor-RNA, an accurate, robust, adaptable, and standalone software to detect MSI status based on expression values of MSI-associated genes. We demonstrated the favorable performance and promise of MSIsensor-RNA in both bulk and single-cell gene expression data in multiplatform technologies including RNA-seq, microarray, and single-cell RNA-seq. MSIsensor-RNA is a versatile, efficient, and robust method for MSI status detection from both bulk and single-cell gene expression data in clinical studies and applications. MSIsensor-RNA is available at https://github.com/xjtu-omics/msisensor-rna.

bioinformatics↗

bioRxiv2023

Data-driven optimization yielded a highly-efficient CRISPR/Cas9 system for gene editing in Arabidopsis

The CRISPR/Cas9 technology is widely used for plant gene editing. In Arabidopsis, the early CRISPR/Cas9 systems using constitutive promoters to drive Cas9 expression usually have low heritable mutation efficiencies in the T1 generation. Germ cell-specific or cell division-specific promoters, like EC1.2en-EC1.1p fusion, YAO and CDC45, have been used as alternatives to direct Cas9 expression, but the efficiency of getting nonchimeric mutations is still not high. To further improve gene editing efficiency, we used gene co-expression network analysis to identify NUC1 as a candidate promoter for driving Cas9 expression. NUC1 has expression patterns similar to YAO, but expresses at a much higher level. We constructed a CRISPR/Cas9 system pHY07 that uses the NUC1 promoter to drive Cas9 and carries the mCherry protein as a fluorescent marker for selecting transgenic seeds. Using this system to edit the GL2 gene, we obtained apparently nonchimeric mutations in 55% of the T1 transgenic plants. Among the Cas9-free T2 plants 99% harbored mutations that are stably inherited from the previous generation. Therefore, our system exhibited extremely high editing efficiency, and through fluorescent screening of transgenic seeds, it become easy to obtain Cas9-free and stable genetic mutants in the T2 generation.

plant biology↗

bioRxiv2023

A Specialized Epithelial Cell Type Regulating Mucosal Immunity and Driving Human Crohn's Disease

Crohns disease (CD) is a complex chronic inflammatory disorder that may affect any part of gastrointestinal tract with extra-intestinal manifestations and associated immune dysregulation. To characterize heterogeneity in CD, we profiled single-cell transcriptomics of 170 samples from 65 CD patients and 18 non-inflammatory bowel disease (IBD) controls in both the terminal ileum (TI) and ascending colon (AC). Analysis of 202,359 cells identified a novel epithelial cell type in both TI and AC, featuring high expression of LCN2, NOS2, and DUOX2, and thus is named LND. LND cells, confirmed by high-resolution in-situ RNA imaging, were rarely found in non-IBD controls, but expanded significantly in active CD. Compared to other epithelial cells, genes defining LND cells were enriched in antimicrobial response and immunoregulation. Moreover, multiplexed protein imaging demonstrated that LND cell abundance was associated with immune infiltration. Cross-talk between LND and immune cells was explored by ligand-receptor interactions and further evidenced by their spatial colocalization. LND cells showed significant enrichment of expression specificity of IBD/CD susceptibility genes, revealing its role in immunopathogenesis of CD. Investigating lineage relationships of epithelial cells detected two LND cell subpopulations with different origins and developmental potential, early and late LND. The ratio of the late to early LND cells was related to anti-TNF response. These findings emphasize the pathogenic role of the specialized LND cell type in both Crohns ileitis and Crohns colitis and identify novel biomarkers associated with disease activity and treatment response.

bioinformatics↗

bioRxiv2023

Light-induced trapping of endogenous proteins reveals spatiotemporal roles of microtubule and kinesin-1 in dendrite patterning of Drosophila sensory neurons

Animal development involves numerous molecular events, whose spatiotemporal properties largely determine the biological outcomes. Conventional methods for studying gene function lack the necessary spatiotemporal resolution for precise dissection of developmental mechanisms. Optogenetic approaches are powerful alternatives, but most existing tools rely on exogenous designer proteins that produce narrow outputs and cannot be applied to diverse or endogenous proteins. To address this limitation, we developed OptoTrap, a light-inducible protein trapping system that allows manipulation of endogenous proteins tagged with GFP or split GFP. This system turns on fast and is reversible in minutes or hours. We generated OptoTrap variants optimized for neurons and epithelial cells and demonstrate effective trapping of endogenous proteins of diverse sizes, subcellular locations, and functions. Furthermore, OptoTrap allowed us to instantly disrupt microtubules and inhibit the kinesin-1 motor in specific dendritic branches of Drosophila sensory neurons. Using OptoTrap, we obtained direct evidence that microtubules support the growth of highly dynamic dendrites. Similarly, targeted manipulation of Kinesin heavy chain revealed differential spatiotemporal requirements of kinesin-1 in the patterning of low- and high-order dendritic branches, suggesting that different cargos are needed for the growth of these branches. OptoTrap allows for precise manipulation of endogenous proteins in a spatiotemporal manner and thus holds great promise for studying developmental mechanisms in a wide range of cell types and developmental stages.

developmental biology↗

bioRxiv2023

Trem2 Agonist Reprograms Foamy Macrophages to Promote Atherosclerotic Plaque Stability

ObjectiveTrem2, a surface lipid receptor, is expressed on foamy macrophages within atherosclerotic lesions and regulates cell survival, proliferation, and anti-inflammatory responses. Studies examining the role of Trem2 in atherosclerosis have shown that deletion of Trem2 leads to impaired foamy macrophage lipid uptake, proliferation, survival, and cholesterol efflux. Thus, we tested the hypothesis that administration of a validated Trem2 agonist antibody (AL002a) to atherogenic mice could drive macrophage survival and decrease necrotic core formation to improve plaque stability. Approach and ResultsTo model a therapeutic intervention approach, atherosclerosis-prone mice (Ldlr-/-) were fed a high fat diet (HFD) for 8 weeks, then transitioned to treatment with AL002a or isotype control for an additional 8 weeks while continuing on an HFD. AL002a-treated mice had increased lesion size in both the aortic sinus and whole mount aorta, which correlated with an expansion of plaque macrophage area. This expansion was due to increased macrophage survival and proliferation in plaques. Importantly, plaques from AL002a-treated mice showed improved features of plaque stability, including smaller necrotic cores, increased fibrous caps, and greater collagen deposition. Single cell RNA sequencing of whole aorta suspensions from isotype and AL002a-treated atherosclerotic mice revealed that Trem2 agonism dramatically altered foamy macrophage transcriptome. This included upregulation of oxidative phosphorylation and increased expression of collagen genes. In vitro studies validated that Trem2-agonism with AL002a promoted foamy macrophage oxLDL uptake, survival, and cholesterol efflux in culture. ConclusionsTrem2 agonist expands plaque macrophages by promoting cell survival and proliferation but improves features of plaque stability by rewiring foamy macrophage function to enhance collagen deposition.

immunology↗