Biology subjects

Yi, Z.

Publications and source records attributed to Yi, Z..

At least 19 recordsLinked to original sources

bioRxiv2026

Pan-pediatric brain tumor microRNA networks define immune microenvironment states and responses to CAR T-cell therapy

Pediatric central nervous system (CNS) tumors remain a leading cause of cancer-related mortality in children, yet molecular programs that shape their immune microenvironments and response to immunotherapy remain poorly defined. Because microRNAs (miRNAs) coordinately regulate gene expression across multiple pathways, we hypothesized that miRNA programs may capture broader immune states than individual immune-regulatory molecules. We integrated small RNA and bulk transcriptomic profiles from diffuse midline glioma, medulloblastoma, ependymoma, and low-grade glioma to identify miRNA programs associated with tumor immune states. Across tumor histologies, dysregulated miRNAs were associated with T-cell, natural killer cell, antigen-presentation, and myeloid programs. Diffuse midline glioma exhibited a distinct miRNA program associated with reduced lymphocyte signatures and increased suppressive myeloid features. Longitudinal profiling of immunocompetent glioma models during B7-H3 CAR T-cell therapy revealed dynamic remodeling of miRNA and immune transcriptional programs. Human tumor-associated miRNAs were significantly enriched among miRNAs associated with CAR T response in vivo. Functional interrogation of miR-149 demonstrated enhanced CAR T-cell expansion and sustained antitumor activity during repeated antigen stimulation. Together, these data define miRNA programs associated with immune states across pediatric CNS tumors and identify miR-149 as a candidate regulator of CAR T-cell function, providing a genomic framework for developing miRNA-directed strategies to improve CAR T-cell therapy.

cancer biology↗

bioRxiv2026

SOLAR Mediates Lysosomal Membrane Repair and Redox Defense

Lysosomal damage is increasingly recognized as a hallmark of aging. Understanding lysosomal quality control may open new therapeutic strategies to enhance lysosomal resilience. Here, we identify SOLAR (SQSTM1/p62 Oligomer-mediated Lysosomal Antioxidant Defense And Membrane Repair), a lysosomal quality control pathway that links CASM (conjugation of ATG8 to single membranes) to p62-driven membrane repair and redox signaling. In this pathway, CASM, but not macroautophagy, recruited p62 to damaged lysosomes. Efficient lysosomal recruitment of p62 required its ATG8-binding and self-oligomerizing domains, enabling p62 assemblies to promote membrane repair. p62 mutations associated with neurodegeneration interfered with p62 recruitment and compromised lysosomal repair. Besides membrane repair, the SOLAR pathway also activated the p62-KEAP1-NRF2 redox signaling axis, driving transcriptional upregulation of antioxidative genes and cholesterol biosynthesis. By integrating membrane repair and redox defense, SOLAR establishes a coordinated lysosomal quality control pathway with implications for aging and degenerative disease.

cell biology↗

bioRxiv2026

Evaluating Limits of Machine Learning-Assisted Raman Spectroscopy in Classification of Biological Samples

Machine learning (ML)-assisted Raman spectroscopy has become a powerful analytical tool for the classification and identification of analytes; however, technical challenges impacting its detection accuracy have not been investigated. This study explores experimental factors affecting classification performance. Among the evaluated ML models, ML algorithms show minimal impacts on classification accuracy. Instead, experimental factors, including spectral similarity between tested samples and the data quality, dominate detection performance. Increases in spectral noises and spectral similarity significantly reduce classification accuracy. In well-controlled samples with low experimental noise, ML-assisted Raman spectroscopy can discriminate lipid mixtures with a composition difference of 1.85 mol%. To assess the effect of biological heterogeneity, we analyzed single-cell Raman spectra from Saccharomyces cerevisiae strains carrying single, double, or triple gene mutations. Intrinsic cell-to-cell variability introduced substantial spectral differences, severely reducing the accuracy of multiclass classification of these genetically similar strains at the single-cell level. Averaging Raman spectra across multiple cells improved classification accuracy by reducing this spectral variability. We also assess the effectiveness of transfer learning across different Raman spectrometers, specifically by applying a ML model trained on one instrument to another Raman spectrometer. Transfer learning can be improved with proper instrument calibration, highlighting the importance of instrument standardization. Overall, our results demonstrate that data quality and spectral similarity are the primary bottlenecks in ML-assisted Raman spectroscopy. Careful attention to sample preparation, data acquisition, measurement conditions, and instrument calibration is critical to achieving robust and reliable classification performance.

bioinformatics↗

bioRxiv2026

Early developmental placental defects and pregnancy loss in lupus mice expressing human TLR8

Anti-phospholipid (APL) autoantibodies confer a high risk for adverse pregnancy outcomes, especially in Systemic Lupus Erythematosus (SLE). While human TLR8 (huTLR8) has been implicated in APL antibody-mediated placental injury in vitro, its in vivo role in pregnancy is unexplored. We report a novel mouse model of pregnancy loss in SLE-prone mice expressing huTLR8. Placental analysis revealed early developmental defects starting post-implantation, including a thin junctional zone, impaired vascularization, infarcts, and inflammation. Profound immune dysregulation was evident at E8.5 including increased myeloid cells and CD8 T cells and decreased uterine natural killer (uNK) cells. RNA sequencing revealed downregulated pregnancy-specific glycoproteins, reduced uNK cell-associated genes, and an upregulated myeloid cell signature. Bone marrow chimera studies demonstrated preferential activation of huTLR8-expressing placental Ly6C+ monocytes. Spatial transcriptomics at E9.5 confirmed uNK cell loss, decreased IL15 expression by both stromal and myeloid cells, and discrete inflammatory aggregates in the maternal layers containing myeloid cells and IFN{gamma}-expressing CD8 T cells. We propose that huTLR8, likely through myeloid cell activation and cytolytic T cell recruitment, drives placental injury in the context of SLE and APL autoantibodies. This model provides a valuable platform to dissect early pathogenic events in APL-associated pregnancy loss and identify new therapeutic targets.

immunology↗

bioRxiv2026

DIVERGENT TRAJECTORIES FOR ANAEROBIC MITOCHONDRIAL EVOLUTION IN BREVIATE PROTISTS

Mitochondrion-related organelles (MROs) have evolved as adaptations to low oxygen conditions multiple times in the eukaryote tree of life. However, the evolutionary steps by which aerobic mitochondrial functions were replaced by anaerobic pathways are still poorly understood. The breviate Pygsuia biforma is particularly interesting because it is the only protist known to have replaced the canonical mitochondrial iron-sulfur cluster (ISC) system with a horizontally acquired SUF-like minimal system (SMS) protein. This functions within an MRO possessing a uniquely configured electron transport chain (ETC). To investigate the evolutionary path by which the P. biforma MRO evolved these features, we conducted a comparative transcriptomic study of eight diverse marine breviate species and predicted their MRO proteomes. We found three distinct patterns of iron-sulfur cluster biosynthesis machinery across the breviates where organisms would encode: the canonical ISC system alone, the ISC system and cytoplasmic SMS system, and a cytoplasmic and MRO-localized SMS system. Phylogenetic analyses suggests that the SMS system was acquired via lateral gene transfer in an ancestor of all breviates and later duplicated, with one copy gaining mitochondrial targeting and replacing the ISC system in a subset of breviates. We observed similarly divergent evolutionary trajectories for quinone-utilizing proteins. Two species have completely lost the ETC while the remaining lineages retain a partial ETC and mitochondrial contact site and cristae organizing system (MICOS), previously thought to be absent in breviates. These patterns reflect divergent biochemical configurations of MROs shaped by gene transfer, loss, and duplication within a single eukaryotic lineage and underscores dynamic remodeling of organellar metabolism in response to marine hypoxic environments.

evolutionary biology↗

bioRxiv2026

Magnetically activatable insect viral vectors promote anticancer immunity through spatially confined gene disruption

Precise control of genome editing activity in vivo remains a major barrier to the clinical translation of CRISPR-based therapeutics, as current approaches cannot reliably restrict editing activity to target tissues 1,2,3. Here we show that a magnetically gated baculoviral CRISPR platform enables spatial control of genome editing activity 4. By coupling magnetic activation of viral transduction at target sites with complement-mediated inactivation of circulating vectors, this system functionally confines genome editing activity to defined spatial contexts, effectively decoupling editing activity from biodistribution. We further show that spatially confined genome editing can be coupled with endogenous antiviral sensing to drive coordinated immune modulation within tumours. In a syngeneic murine tumour model, local administration combined with magnetic activation restricts genome editing to tumours without detectable editing in major organs, remodels dendritic cell and CD8{square} T cell states, suppresses tumour growth, and extends survival. Together, these findings establish a generalizable strategy for spatial control of genome editing and localized immunomodulation in cancer.

bioengineering↗

bioRxiv2025

LazyNet: Interpretable ODE Modeling of Sparse CRISPR Single-Cell Screens Reveals New Biological Insights

We present LazyNet, a compact one-step neural-ODE model for single-cell CRISPR A/I that operates directly on two-snapshot ("pre [->] post") measurements and yields parameters with clear mechanistic meaning. The core log-linear-exp residual block exactly represents multiplicative effects, so synergistic multi-locus responses appear as explicit components rather than opaque composites. On a 53k-cell x 18k-gene neuronal Perturb-seq matrix, a three-replica LazyNet ensemble trained under a matched 1-hour budget achieved strong threshold-free ranking and competitive error (genome-wide r{approx}0.67) while running on CPUs, compared with transformer and state-space baselines trained on a single V100 with the same time cap. A T-cell screen included only for generalization showed the same ranking advantage under the identical evaluation pipeline. Beyond prediction, LazyNet exposes directed, local elasticities; averaging Jacobians across replicas produces a consensus interaction matrix from which compact subgraphs are extracted and evaluated at the module level. The resulting networks show coherent enrichment against authoritative resources (e.g., large-scale co-expression and curated functional associations) and concordance with orthogonal GPX4-knockout proteomes, recovering known ferroptosis regulators and nominating testable links in a lysosomal-mitochondrial-immune module.

bioinformatics↗

bioRxiv2024

Effects of combined application of organic fertilizer and inorganic fertilizer on soil and yield of Gaodan grass

Using Sorghum bicolor x sudanense as test material, the effects of inorganic fertilizer and different proportions of organic fertilizer application on soil properties, yield and quality of sorghum were studied under conventional nitrogen application levels, aiming to provide data support for efficient production of green cycle forage. Five treatments were set up in the experiment, namely blank treatment (CK), conventional fertilization (HF), equivalent cow manure organic fertilizer (NF2), equivalent sheep manure organic fertilizer (YF2), 150% equivalent cow manure organic fertilizer (NF5) and 150% equivalent sheep manure organic fertilizer (YF5). In general, NF5 treatment was excellent in improving soil organic matter, enzyme activity and nutrient content, and the yield of Gaodan grass was significantly increased.

plant biology↗

bioRxiv2024

Engineered mitochondrial A-to-G editors with enhanced efficiency and targeting scope

Mitochondrial base editing is a powerful technology, but the current A-to-G mitochondrial DNA (mtDNA) base editors are reluctant to achieve high efficiency, which is critical for mtDNA engineering. Through laboratory evolution, TadA-8e variants were discovered with substantially increased activity and expanded targeting compatibility, especially for previously unfavorite sequence contexts, when applied to both nuclear and mitochondrial ABEs. Further engineering of the mtDNA editors (eTd-mtABEs) dramatically reduced both DNA and RNA off-targeting effects and enhanced strand-selective A-to-G editing with substitution of DddA to DNA nickases. Moreover, the eTd-mtABEs induced up to 145-fold editing frequencies compared to previous mtDNA adenine base editors in rat cells, and installed targeted mutations in all injected rat embryos with up to 74% efficiency in founders, resulting generation of SNHL and Leigh syndrome models with severe defects. It suggests that eTd-mtABEs are promising mtDNA engineering technology for basic research and for translational studies. HighlightsO_LIEngineered TadA variants enhance nuclear and mitochondrial ABE activity in all sequence contexts. C_LIO_LIAdditional mutations in eTd-mtABEs further minimize both DNA and RNA off-targeting effects. C_LIO_LIEngineered TadA variants are compatible to DNA nickase assisted strand-selective mtDNA editing. C_LIO_LIeTd-mtABEs enable highly efficient generation of rat mtDNA disease models with severe phenotypes. C_LI

bioengineering↗

bioRxiv2024

Maternal total sleep deprivation causes oxidative stress and mitochondrial dysfunction in oocytes associated with fertility decline in mice

Previous studies have shown sleep deprivation has an impact on several aspects of health and disease. Sleep deprivation suppresses melatonin production and excessive HPA activation in women, which may reduce the chances of fertility. However, little is known about how and by what relevant mechanisms it affects female fertility. In this study, female mice underwent 72 hours of total sleep deprivation (TSD) caused by rotating wheel or 2 different controls: a stationary wheel, or forced movement at night. Even though, there was no evident anomaly of natural ovulation, the TSD female mice showed impaired early embryo development . Overall levels of estrogen and FSH were lower throughout the estrus cycle (especially in proestrus). RNA Sequencing (RNA-Seq) was used to discover differentially expressed genes (DEGs) that might be involved in oocyte quality after TSD. A total of 42 genes showed significant differential expression in GV oocytes after TSD. These included genes such as Usmg5, Atp5k, Ccnd2 and Tpm3, which were enriched in gene ontology terms of mitochondrial protein complex, oxidoreductase activity, cell division, cell cycle G1/S phase transition, as well as others. The increased concentrations of reactive oxygen species (ROS) in germinal vesicle (GV) and metaphase II (MII) oocytes from TSD mice were observed, which might be induced by impaired mitochondrial function caused by TSD. The GV oocytes displayed increased mitochondrial DNA (mtDNA) copy number and a significant transient increase in inner mitochondrial membrane potential ({bigtriangleup}{psi}m) from the TSD mice probably due to compensatory effect. In contrast, MII oocytes in the TSD group showed a decrease in the mtDNA copy number and a lower {bigtriangleup} {psi}m compared with the controls. Furthermore, abnormal distribution of mitochondria in the GV and MII oocytes was also observed in TSD mice, suggesting mitochondrial dysfunction. In addition, abnormal spindle and abnormal arrangement of chromosomes in MII oocytes were markedly increased in the TSD mice compared with the control mice. In conclusion, our results suggest that TSD significantly alters the oocyte transcriptome, contributing to oxidative stress and disrupted mitochondrial function, which then resulted in oocyte defects and impaired early embryo development in female mice.

developmental biology↗

bioRxiv2024

Genetic polymorphisms of Leukocyte Immunoglobulin-Like Receptor B3 (LILRB3) gene in African American kidney transplant recipients are associated with post-transplant graft failure

BackgroundAfrican American (AA) kidney transplant recipients exhibit a higher rate of graft loss compared to other racial and ethnic populations, highlighting the need to identify causative factors underlying this disparity. MethodWe analyzed RNA sequences of pretransplant whole blood from subjects followed in three kidney transplant cohorts to identify single nucleotide polymorphisms (SNPs) associated with death censored graft loss (DCGL). We employed a meta-analysis to uncover key transcriptional signatures and pathways associated with the identified SNPs and used single cell RNA to define cellular specificity. We characterized SNP functions using in vitro immunological and survival assays and tested for associations between the identified SNPs and other immune-related diseases using a [~]30,100 subject, electronic health record (EHR)-linked database. ResultsWe uncovered a cluster of four consecutive missense SNPs in the Leukocyte Immunoglobulin-Like Receptor B3 (LILRB3, a negative immune response regulator) gene that strongly associated with DCGL. This LILRB3-4SNPs cluster encodes missense mutations at amino acids 617-618 proximal to a SHP-1/2 phosphatase-binding ITIM motif. LILRB3-4SNPs is specifically enriched within subjects of AA ancestry (8.6% prevalence vs 2.3% in Hispanic and 0.1% in European populations), is not linked to APOL1 G1/G2 alleles, and exhibited a strong association with DCGL. Analysis of PBMC and transplant biopsies from recipients with LILRB3-4SNPs showed evidence of enhanced adaptive immune responsiveness and ferroptosis-associated death in monocytes. Overexpression of the variant allele in THP-1 cells (macrophage line) induced augmented inflammation and ferroptosis, which were attenuated by a ferroptosis inhibitor, verifying a causal link. The LILRB3-4SNPs also associated with multiple systemic and organ-specific immune-related diseases in AAs, consistent with conferring a broadly relevant immune function. Conclusionthe LILRB3-4SNPs represent a functionally important, distinct genetic risk factor for kidney transplant outcome and development/severity of other immune-related diseases in patients of AA ancestry. Pharmacological targeting of ferroptosis should be tested to prevent or treat these disease processes in AA recipients carrying LILRB3-4SNPs.

genetics↗

bioRxiv2024

Personalized composite scaffolds for accelerated cell- and growth factor-free craniofacial bone regeneration

Approaches to regenerating bone often rely on the integration of biomaterials and biological signals in the form of cells or cytokines. However, from a translational point of view, these approaches face challenges due to the sourcing and quality of the biologic, unpredictable immune responses, complex regulatory paths, and high costs. We describe a simple manufacturing process and a material-centric 3D-printed composite scaffold system (CSS) that offers distinct advantages for clinical translation. The CSS comprises a 3D-printed porous polydiolcitrate-hydroxyapatite composite elastomer infused with a polydiolcitrate-graphene oxide hydrogel composite. Using a continuous liquid interface production 3D printer, we fabricate a precise porous ceramic scaffold with 60% hydroxyapatite content resembling natural bone. The resulting scaffold integrates with a thermoresponsive hydrogel composite, customizable in situ to fit the defect. This hybrid phasic porous CSS mimics the bone microenvironment (inorganic and organic) while allowing independent control of each material phase (rigid and soft). The CSS stimulates osteogenic differentiation in vitro and in vivo. Moreover, it promotes M2 polarization and blood vessel ingrowth, which are crucial for supporting bone formation. Our comprehensive micro-CT analysis revealed that within 4 weeks in a critical-size defect model, the CSS accelerated ECM deposition (8-fold) and mineralized osteoid (69-fold) compared to the untreated. Our material-centric approach delivers impressive osteogenic properties and streamlined manufacturing advantages, potentially expediting clinical application for bone reconstruction surgeries.

bioengineering↗

bioRxiv2024

TLR9 activation in large wound induces tissue repair and hair follicle regeneration via gamma delta T cells

The mechanisms underlying tissue repair in response to damage have been one of main subjects of investigation. In this study, we leveraged the wound-induced hair neogenesis (WIHN) models in adult mice to explore the inner correlation. Our investigation revealed that heightened release of mitochondrial DNA (mtDNA) accompanying tissue damage activated the toll-like receptor 9 (TLR9) pathway, influencing the repair process and the ultimate number of regenerated hair follicles. Furthermore, our analysis of single-cell RNA sequencing comparisons demonstrated increased TLR9 activation was associated with the recruitment of gamma delta T cells ({gamma}{delta}T). Inhibition of {gamma}{delta}T cell recruitment led to a reduction in the population of {gamma}{delta}T cells and a more fibrotic healing outcome. Notably, these {gamma}{delta}T cells exhibited distinctive high production of AREG, contributing to the rapid increase of local AREG levels around the epidermis and influencing the fate commitment of keratinocytes. These findings provide new insights into the roles of TLRs as critical mediators in the sense of tissue damage, the modulation of immune cell activity, and the ultimate influence on healing outcomes. TeaserStarting with how tissue injury stimulates downstream tissue repair and regeneration through relevant signals, this study explored the phenomenon and correlation between tissue damage and TLR9, and the effect of TLR9 on {gamma}{delta}T, keratinocytes and the healing outcomes.

cell biology↗

bioRxiv2024

Rbbp8nl contributes to resistance to anticancer immunotherapy by creating a non-inflamed tumor microenvironment and attenuating CD8+ T cell infiltration

Immune checkpoint blockade (ICB) monotherapy has limited efficacy, and it is crucial to explore predictive markers for the efficacy of immunotherapy and its use as new therapeutic targets or sensitization targets in combination with immunotherapy. Pan-cancer research using RNA sequencing data from The Cancer Genome Atlas (TCGA) revealed that RBBP8NL is particularly overexpressed in the tumor microenvironment (TME) of different malignancies. Additionally, there is a negative correlation between RBBP8NL and immune modulators, T cell inflammatory scores, immunological checkpoints, cancer immune cycle, and tumor-infiltrating immune cells (TIICs), so it can be inferred that RBBP8NL shapes the non-inflammatory TME in BLCA. BLCA patients with high RBBP8NL expression have a low response rate to immunotherapy, and they are more likely to experience hyperprogression of the illness. Interestingly, anti-RBBP8NL with immunotherapy could work better together than they do separately. According to the results of the multi-omics analysis, RBBP8NL inhibits the recruitment of cytotoxic lymphocytes. Furthermore, RBBP8NLs predictive significance for immunotherapy success has been confirmed across several immunotherapy cohorts. In summary, RBBP8NL is a crucial component of the TME and a developing target for binding to ICB as well as a biomarker to direct precision medicine.

cancer biology↗

bioRxiv2024

Integrating Residual Networks and Symbolic Regression for Biological ODE System Modeling

Traditional biological research heavily relies on experimental methodologies, which often lead to inefficiencies in communication and knowledge transfer. These methodologies frequently result in redundant trial-and-error experiments, posing challenges in standardizing results and impeding rapid knowledge dissemination. The complexity of biological systems and the sheer volume of experimental data generate a demand for precise mathematical models like Ordinary Differential Equations (ODEs) to articulate biological interactions. However, practical implementation of ODE-based models is hampered by their need for data curation, making them less feasible for everyday research applications. To address these limitations, we introduce LazyNet, a novel computational model that employs logarithmic and exponential functions embedded within a Residual Network (ResNet) architecture to approximate ODEs. LazyNet simplifies complex mathematical operations, reducing the dependency on large datasets and extensive computational resources. This study tests LazyNet across various biological scenarios, including HIV dynamics, gene regulatory networks, and mass spectrometry analysis of small molecules. Our results demonstrate that LazyNet can efficiently assimilate and predict complex biological processes, significantly enhancing model training speed and reducing the reliance on empirical experimentation. Therefore, a promising tool for advancing biological research and fostering more accurate and efficient scientific explorations.

systems biology↗

bioRxiv2023

Chromosome-level scaffolding of haplotype-resolved assemblies using Hi-C data without reference genomes

Scaffolding is crucial for constructing most chromosome-level genomes. The high-throughput chromatin conformation capture (Hi-C) technology has become the primary scaffolding strategy due to its convenience and cost-effectiveness. As sequencing technologies and assembly algorithms advance, constructing haplotype-resolved genomes is increasingly preferred because haplotypes can provide additional genetic information on allelic and non-allelic variations. ALLHiC is a widely used allele-aware scaffolding tool designed for this purpose. However, its dependence on chromosome-level reference genomes and a higher chromosome misassignment rate still impede the unraveling of haplotype-resolved genomes. In this paper, we present HapHiC, a reference-independent allele-aware scaffolding tool with superior performance on chromosome assignment as well as contig ordering and orientation. Additionally, we provide new insights into the challenges in allele-aware scaffolding by conducting comprehensive analyses on various adverse factors. Finally, with the help of HapHiC, we constructed the haplotype-resolved allotriploid genome for Miscanthus x giganteus, an important lignocellulosic bioenergy crop. HapHiC is available at https://github.com/zengxiaofei/HapHiC.

bioinformatics↗

bioRxiv2023

Monocytes reprogrammed by 4-PBA potently contribute to the resolution of inflammation and atherosclerosis

BackgroundChronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis. MethodsSystems analyses integrating single-cell RNA-sequencing and complementary immunological approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming was assessed by integrated biochemical and genetic approaches. The inter-cellular propagation of homeostasis resolution was evaluated by co-culture assays with donor monocytes trained by 4-PBA and recipient naive monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high fat diet-fed ApoE-/- mouse model with i.p. 4-PBA administration. Furthermore, the selective efficacy of 4-PBA trained monocytes were examined by i.v. transfusion of ex vivo trained monocytes by 4-PBA into recipient high fat diet-fed ApoE-/- mice. ResultsIn this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 via reducing peroxisome stress and attenuating SYK-mTOR signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPAR{gamma} neddylation mediated by TOLLIP. 4-PBA trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo. ConclusionOur study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision-therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes.

immunology↗

bioRxiv2023

Magnetic nanocomplexes coupled with an external magnetic field modulate macrophage phenotype: a non-invasive strategy for bone regeneration.

Chronic inflammation is a major cause for the pathogenesis of musculoskeletal diseases such as fragility fracture, and nonunion. Studies have shown that modulating the immune phenotype of macrophages from proinflammatory to prohealing mode can heal recalcitrant bone defects. Current therapeutic strategies predominantly apply biochemical cues, which often lack target specificity and controlling their release kinetics in vivo is challenging spatially and temporally. We show a magnetic iron-oxide nanocomplexes (MNC)-based strategy to resolve chronic inflammation in the context of promoting fracture healing. MNC internalized pro-inflammatory macrophages, when coupled with an external magnetic field, exert an intracellular magnetic force on the cytoskeleton, which promotes a prohealing phenotype switch. Mechanistically, the intracellular magnetic force perturbs actin polymerization, thereby significantly reducing nuclear to cytoplasm redistribution of MRTF-A and HDAC3, major drivers of inflammatory and osteogenic gene expressions. This significantly reduces Nos2 gene expression and subsequently downregulates the inflammatory response, as confirmed by quantitative PCR analysis. These findings are a proof of concept to develop MNC-based resolution-centric therapeutic intervention to direct macrophage phenotype and function towards healing and can be translated either to supplement or replace the currently used anti-inflammatory therapies for fracture healing.

bioengineering↗