👤 Xiao-Li Ma

Postnatal respiration requires bulk formation of alveoli that produces extensive surface area for gas diffusion from epithelium to the circulatory system. Alveolar morphogenesis initiates at late gestation or postnatal stage during mammalian development and is mediated by coordination among multiple cell types. Here we show that fibroblast-derived Heparan Sulfate Glycosaminoglycan (HS-GAG) is essential for maintaining a niche that supports alveolar formation by modulating both biophysical and biochemical cues. Gli1-CreER mediated deletion of HS synthase gene Ext1 in lung fibroblasts results in enlarged and simplified alveolar structures. Ablation of HS results in loss of a subset of PDGFRα Show less

Men, despite having a lower likelihood of longevity compared to women, generally exhibit better health status when they achieve longevity. The role of DNA methylation in this paradox remains unclear. We performed whole-genome bisulfite sequencing on long-lived men (LLMs), long-lived women (LLWs), younger men (YMs) and younger women (YWs) to explore specific methylation characteristics in LLMs. Despite an accelerated methylation aging rate in LLMs compared to LLWs, we identify thousands of differentially methylated genomic units (DMUs) in LLMs independent of age and sex. These DMUs, validated by an elastic net classifier, can serve as methylation markers for discriminating longevity potential in men. Many are located near health-related genes. Genes like PIWIL1 and EXT1, with promoters featuring DMUs, exemplify the potential role of LLM-specific methylation patterns in suppressing age-related diseases by regulating gene transcription. Our findings provide evidence of a distinct methylation feature contributing to healthy aging and longevity of LLMs. Show less

Gastrointestinal (GI) cancers exhibit aberrant lipid metabolism, yet the causal mechanisms remain elusive. Here, we integrated Mendelian randomization (MR) and multi-omics data to dissect metabolic drivers of 20 GI diseases. Focusing on colorectal (CC) and esophageal cancer (EC), we identified five metabolites (e.g., 1,2-di-palmitoyl-sn-glycero-3-phosphocholine) and arachidonic acid ethyl ester as causal drivers. Summary-data-based MR and colocalization analysis (PP.H4 > 0.75) revealed FADS1 as a master regulator of these metabolites, with genetic variants exhibiting tissue-specific lipidomic effects. Functional validation using FADS1-knockout cell lines and mouse models demonstrated that FADS1 inhibition suppresses tumor cell proliferation, migration, and invasion while promoting apoptosis. In vivo, FADS1 deletion reduced chemically induced CC/EC tumor burden by 62-75%, accompanied by decreased Ki-67/MMP-9 expression and inflammatory infiltration. Mechanistically, FADS1 ablation disrupted lipid metabolism (reduced linoleic acid and arachidonic acid) and attenuated PI3K/AKT and MAPK signaling. Multi-omics integration further corroborated FADS1-mediated epigenetic regulation (e.g., mQTL-driven DNA methylation). This study establishes FADS1 as a pivotal orchestrator of GI carcinogenesis via metabolic reprogramming and signaling dysregulation, offering a compelling therapeutic target for precision oncology in CC and EC. Regulatory mechanisms of FADS1 in CC and EC. Show less

Fibroblast growth factor receptor 1 (FGFR1) is crucial in the progression of various cancers, participating in the processes of cell proliferation, survival, and differentiation. FGFR1 plays a role in the resistance to immune checkpoint inhibitors (ICIs) such as pembrolizumab and nivolumab. Therefore, using monoclonal antibodies and tyrosine kinase inhibitors to target FGFR1 and enhancing ICIs by modifying the tumor microenvironment and combating immune suppression represents a potential therapeutic strategy. Based on the FGFR1-related research and the active targeting strategy, we believe that modifying the surface of nanomedicines with anti-FGFR1 antibodies (such as OM-RCA-01) is an effective targeted treatment method for tumors with high expression of FGFR1. Although there have been relevant studies confirming the feasibility of this approach, there are challenges in clinical application, especially in terms of maintaining uniform quality during large-scale production. Therefore, we suggest conducting further optimization studies in the future to accelerate the clinical application of such drug delivery systems and provide more efficient and cost-effective options for tumor treatment. Show less

Aging is an inevitable process integrating chronological alterations of multiple organs. A growing aging population necessitates feasible anti-aging strategies to deal with age-associated health problems. We previously performed a proteomics analysis in a healthy-aging cohort, and revealed an age-related downregulation of ARMH4. Here we generate a whole-body Armh4-knockout mouse line, and investigate its impact on systemic aging. Under normal feeding conditions, Armh4 deficiency significantly lowers spontaneous mortality and extends maximum lifespan. In the female mice, Armh4 deficiency postpones sexual maturity for one week. At the organ level, the age-related pathologies of the heart, liver, kidney, and spleen are substantially alleviated by Armh4 deletion. Mechanistically, ARMH4 interacts with IGF1R/FGFR1 to sensitize the activation of PI3K-Akt-mTORC1 and Ras-MEK-ERK pathways, consequently promoting protein synthesis and inhibiting autophagy. Moreover, ARMH4 is required for the maintenance of IGF1R/FGFR1 expressions through regulating the transcription factor c-Myc. Therefore, ARMH4 maintains a positive-feedback growth signaling to promote aging. Show less

During the formation of hypertrophic scars (HS), there is often a notable abnormal proliferation and differentiation of cells, especially fibroblasts, but it remains ambiguous whether a causal relationship exists between fibroblast growth factor receptors (FGFRs) and hypertrophic scar. This study explored the causal impact of FGFR1, FGFR2, FGFR3, and FGFR4 on HS utilizing a two-sample Mendelian randomization (MR) analyses. The elevated expression of FGFR1 and FGFR 4 emerged as two potential risk factors against HS in the inverse-variance weighted analysis. Conversely, FGFR2 and FGFR3 exhibited no significant causal relationship with hypertrophic scars. Rigorous analyses including assessments of heterogeneity, genetic horizontal pleiotropy, and leave-one-out sensitivity collectively affirmed the stability and reliability of the findings in this study. Taken together, the elevated expression of FGFR1 and FGFR 4 act as two key regulatory factors in preventing the formation of HS and serves as a crucial modulator in impeding scar formation. Show less

Despite the increasing approval and ongoing clinical trials of FGFR-targeted therapies, accurately detecting FGFR fusions remains a challenge due to limited research, low incidence rates, complex fusion partner distribution, and unique kinase domain distribution. We conducted a multicenter study to comprehensively profile FGFR fusions in the largest Chinese pan-cancer cohort to date, comprising 118 FGFR fusions from 114 individuals. Both DNA- and RNA-based sequencing approaches were utilized to reveal novel and fundamental features of FGFR fusion. Our research reveals an incidence rate of 0.96% for FGFR rearrangements within this Chinese cohort, including a high incidence rate of FGFR fusions (40%) in parotid gland carcinoma. However, this is based on a small sample size of 5 tumors and should be interpreted cautiously pending validation in larger cohorts. We also uncovered distinct breakpoint distribution patterns across various FGFR rearrangements. For example, a primary breakpoint in intron17 of FGFR2 was predominant (21/22), while FGFR1/3 breakpoints displayed substantial diversity. For the first time, we identified "hot" breakpoints in FGFR1 intron17, exon18, and FGFR3's 3' untranslated region. These findings underline the importance of incorporating these regions in targeted sequencing to ensure comprehensive detection of FGFR1/3 fusions. Notably, we observed a predilection for intrachromosomal distribution in common FGFR1/2/3 fusions. In contrast, most novel fusions (12/15) exhibited an interchromosomal distribution pattern, indicating variations in the fusion formation mechanism. Importantly, our study demonstrates the substantial incremental value of RNA-NGS or other orthogonal methods in confirming the functionality of FGFR rearrangements initially identified by DNA sequencing. In our cohort, 46% (6/13) of rare FGFR1/2/3 fusions lacked detectable RNA transcripts; however, this does not definitively indicate non-functionality as factors such as low RNA quality, expression below detection limits, or nonsense-mediated decay may contribute. Therefore, RNA-based validation is critical for accurately identifying potentially targetable FGFR fusions and guiding therapy. Our findings offer critical novel insights into functional FGFR fusions and bear considerable clinical implications for identifying individuals whose tumors are most likely to respond favorably to FGFR-targeted therapies. Show less

Alterations in the fibroblast growth factor receptor 3 (FGFR3) gene have been noted in human diseases, including bladder cancer and urothelial carcinoma (UC). Erdafitinib was approved for the treatment of UC but is limited by the progression of on-target gatekeeper resistance mutations. Several heterobifunctional FGFR degraders have been developed as potential therapeutic agents to block FGFR1 or FGFR2 signaling. However, to date, none of the FGFR3-active degraders have been identified. Herein, we report the discovery of LC-MF-4, the first efficient FGFR3 degrader, for the treatment of cancers harboring FGFR3 alterations. Proteomic analysis revealed that LC-MF-4 exhibits exceptional proteomic selectivity for FGFR3 degradation. In FGFR3-TACC3 fusion-positive cells, LC-MF-4 exerted its effects by suppressing the expression of genes involved in mitochondrial biogenesis and ATP synthesis. This study demonstrated robust antitumor activity of LC-MF-4 in the Ba/F3-FGFR3-TACC3 xenograft model, highlighting its potential for the treatment of FGFR3-altered cancers. Show less

Parkinson's disease (PD), as a neurodegenerative disorder, is characterized primarily by damage to the central nervous system, accompanied by astrocyte dysfunction and the activation of ferroptosis. Recent studies have shown that oligodendrocytes also exhibit functional abnormalities in the brains of PD patients and are involved in the ferroptotic process. However, it remains unclear whether there is an interaction between oligodendrocytes and astrocytes and how they induce neuronal ferroptosis. Here, we employed single-nucleus sequencing and spatial transcriptomics to characterize the intercellular communication network between oligodendrocytes and astrocytes in the PD environment. Among these, astrocytes are the primary recipients of signals sent by oligodendrocytes in the FGF (Fibroblast growth factors) signaling pathway. In PD, the communication intensity is weakened, involving FGF1 and FGF9 and their receptors FGFR1, FGFR2, and FGFR3. Subsequently, we further validated the significant activation of mitochondrial oxidative phosphorylation processes within oligodendrocytes and astrocytes in PD mice, and that astrocytes might also involve the interaction of Mt1 and Ca Show less

Pancreatic cancer is characterized by a poor prognosis and limited responsiveness to conventional therapies, presenting a substantial therapeutic challenge. Although chemotherapy remains the cornerstone of systemic treatment, options become scarce once frontline therapies fail. While targeted therapies and immunotherapies have emerged as potential alternatives, their efficacy in pancreatic cancer is not well established. As research advances, exploring the tumor immune microenvironment (TiME) of pancreatic cancer is crucial and holds significant potential for developing novel treatment strategies.We report a case of a pancreatic cancer patient who, after the failure of frontline and second-line treatments, was treated with a pioneering combination of targeted therapy and immunotherapy to modulate the unique TiME. The targeted agent, surufatinib, is a tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor (VEGFR) 1-3, fibroblast growth factor receptor 1 (FGFR1), and colony-stimulating factor 1 receptor (CSF-1R). The immunotherapy agent, toripalimab, is an immune checkpoint inhibitor targeting programmed cell death protein 1 (PD-1). Remarkably, the patient benefitted from this regimen, exhibiting stable disease, improved clinical symptoms, and prolonged progression-free survival. This case highlights the potential of personalized therapy in treating pancreatic cancer, particularly in patients with distinctive features of the TiME that may predict favorable responses to immunotherapy. Personalized strategies that consider the spatial structure and composition of the TiME may offer a promising avenue for achieving long-term progression-free survival in patients with pancreatic cancer. Show less

The intramuscular fat (IMF) content, as an important meat quality trait, can directly affect the tenderness, juiciness, and flavor of pork. Reasonably increasing the IMF content can improve the palatability of pork. Therefore, identification of important factors for the lipid accumulation among muscles is the breakthrough point for improving meat quality. FGF21, identified as a novel metabolic regulator, has been found to regulate glucose and lipid metabolism in 3T3-L1 adipocytes, but its function in porcine adipocytes remains unclear. In this study, we discovered that the administration of recombinant FGF21 protein promotes adipogenic differentiation and increases triglyceride accumulation in porcine adipocytes. While the expression of FGFR1 in adipocytes under muscle conditions is inhibited, affecting the signal transduction of FGF21. This inhibitory effect is accompanied by activation of the AhR signaling pathway. When treated with the AhR antagonist CH223191, there was a partial restoration of FGFR1 expression levels. This indicates that muscle cells suppress the expression of FGFR1 in adipocytes by activating the AhR signaling pathway, thereby affecting the signal transduction of FGF21. Our results reveal the regulatory role of FGF21 in pig adipocyte differentiation and the regulatory mechanism of muscle environment on FGFR1 expression, providing new theoretical basis for IMF content improvement from the perspective of FGF21-FGFR1 signaling transduction. Show less

While fibroblast growth factor receptor 2 (FGFR2) emerges as an appealing cancer therapeutic target, so far there is no selective FGFR2 inhibitor on the market. Here, we report the discovery of a series of new selective, irreversible FGFR2 inhibitors with compound BW710 being the representative. Compound BW710 potently inhibited the proliferation of BaF3-FGFR2 cells with an IC Show less

Ovarian cancer is a common malignant tumor in women, exhibiting a certain sensitivity to chemotherapy drugs like gemcitabine (GEM). This study, through the analysis of ovarian cancer single-cell RNA sequencing (scRNA-seq) data and transcriptome data post-GEM treatment, identifies the pivotal role of hypoxia-inducible factor 1 alpha (HIF-1α) in regulating the treatment process. The results reveal that HIF-1α modulates the expression of VEGF-B, thereby inhibiting the fibroblast growth factor 2 (FGF2)/FGFR1 signaling pathway and impacting tumor formation. In vitro experiments validate the mechanistic role of HIF-1α in GEM treatment, demonstrating that overexpression of HIF-1α reverses the drug's effects on ovarian cancer cells while silencing fibroblast growth factor receptor 1 (FGFR1) can restore treatment efficacy. These findings provide essential molecular targets and a theoretical foundation for the development of novel treatment strategies for ovarian cancer in the future. Show less

Sepsis is characterized by a life-threatening syndrome caused by an unbalanced host response to infection. Fibroblast growth factor 8 (FGF8) has been newly identified to play important roles in inflammation and innate immunity, but its role in host response to sepsis is undefined. A cecal ligation and puncture (CLP)-induced mouse sepsis model was established to evaluate the immunomodulatory function of FGF8 during sepsis. The underlying molecular mechanisms were elucidated by cell models using relevant molecular biology experiments. The clinical value of FGF8 in the adjuvant diagnosis of sepsis was evaluated using clinical samples. FGF8 protein concentrations were elevated in CLP-induced septic mice compared to controls. In vivo, FGF8 blockade using anti-FGF8 antibody significantly increased mortality and bacterial burden and was paralleled by significantly aggravated tissue injury after CLP. Therapeutic administration of recombinant FGF8 (rFGF8) improved the bacterial clearance and mortality of septic mice in a FGFR1-dependent manner. In vitro, FGF8 directly enhanced bacterial phagocytosis and killing of macrophages by enhancing the phosphorylation of the ERK1/2 signaling pathway, which could be abrogated with the ERK1/2 pathway inhibitor U0126. Clinically, serum FGF8 levels in both adult and pediatric patients with sepsis in an intensive care unit were significantly higher than those in healthy controls. These results present a previously unrecognized role of FGF8 in improving survival of sepsis by enhancing host immune defense. Therefore, targeting FGF8 may provide new strategies for the diagnosis and immunotherapy of sepsis. Show less

Intramuscular fat (IMF) critically governs beef sensory attributes (juiciness, tenderness, flavor). Previous studies have predominantly focused on genomics and transcriptomics, with limited proteomic data available. To gain a more comprehensive understanding of the mechanisms regulating IMF deposition, we integrated proteomic and metabolomic profiling of the Longissimus dorsi across three genetically distinct cattle breeds. A comprehensive analysis of 633 differentially abundant proteins (DAPs) and 1456 differential metabolites (DAMs) identified 20 potential protein regulators (e.g., ACAA1, ACACA, ADIPOQ, and HSD17B12) and 19 candidate metabolites (e.g., hexadecanoic acid, icosadienoic acid, oleic acid, and oxaloacetate) as key molecular markers. Furthermore, HSD17B12 was found to inhibit IMF cell proliferation while promoting differentiation and lipid accumulation. This integrated approach highlights HSD17B12 as a critical regulator in enhancing IMF content, providing a theoretical foundation for improving beef quality. Show less

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia and insulin resistance, Migraine is a common chronic neurological disease caused by increased excitability of the central nervous system, both exerting substantial health burdens. However, the shared genetic basis and underlying molecular mechanisms remain largely unexplored. This study integrates single-cell data and Mendelian randomization (MR) analysis to identify comorbidity-associated genes and elucidate potential mechanistic links between these two conditions. Single-cell datasets from T2DM and migraine were analyzed to identify differentially expressed genes (DEGs). MR analysis was employed to prioritize key causal genes, followed by network-based functional characterization, disease-drug association analysis, cell annotation, and pseudo-time trajectory modeling. Analysis of single-cell data identified 2,128 migraine-associated and 3,833 T2DM-associated genes, with 714 genes shared between the two diseases. MR analysis highlighted AP4E1 and HSD17B12 as key regulators implicated in both conditions. Network analysis further linked these genes to lipid metabolism and vesicle transport pathways. Computational predictions revealed common comorbidities, including metabolic dysregulation and chemical-induced liver injury, as well as potential therapeutic agents such as valproic acid and bisphenol A. Single-cell annotation identified six major immune cell types in T2DM (T cells, NK cells, B cells, CD14 monocytes, CD16 monocytes, and dendritic cells), with T cells emerging as central players. In migraine, five immune cell types were identified (CD4 T cells, CD8 T cells, B cells, NK cells, and monocytes), with monocytes being the predominant cell type. Pseudo-time analysis delineated seven subpopulations of T cells and four subpopulations of monocytes, suggesting distinct functional trajectories in disease pathogenesis. However, due to the use of peripheral blood-derived single-cell data, genes primarily expressed in the central nervous system, such as CALCA and RAMP1, could not be detected, limiting the identification of certain migraine-specific pathways. This single-cell data and MR analysis investigation identifies AP4E1 and HSD17B12 as pivotal genetic determinants in T2DM-migraine comorbidity, shedding light on their molecular interplay and potential therapeutic relevance. Show less

Oxymatrine is an alkaloid with the property of immunomodulation. Recent studies have demonstrated that oxymatrine inhibits experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), by promoting the production of interferon-β (IFN-β). However, the mechanism through which oxymatrine regulates the production of IFN-β remains unclear. The aim of this study was to investigate the pharmacological effects and related molecular mechanisms of oxymatrine in the treatment of EAE through in vivo and in vitro experiments. Oxymatrine alleviated neurological dysfunction, demyelination, and inflammation in EAE mice. It reduced microglia/macrophage infiltration and polarization, lowered pro-inflammatory cytokine levels (iNOS, TNF-α), and enhanced the expression of IL-10 and IL-27. Additionally, oxymatrine upregulated the STING/TBK1/IRF3 signaling pathway in EAE mice, promoting IFN-β production by microglia. Similarly, in LPS-induced BV2 cells, oxymatrine suppressed inflammatory factors and activated the STING/TBK1/IRF3 pathway to enhance IFN-β production. Notably, treatment with the STING inhibitor, C176, reversed these effects in both EAE mice and LPS-induced BV2 cells, confirming the pathway's critical role in the mechanism of oxymatrine therapy. Oxymatrine promotes IFN-β production in microglia by upregulating the STING/TBK1/IRF3 signaling pathway, thereby alleviating the neurological dysfunction of EAE and reducing pathological and inflammatory events. This study identifies a novel anti-EAE mechanism of oxymatrine: promoting IFN-β production in microglia by activating the STING/TBK1/IRF3 pathway. However, it lacks clinical sample verification. If validated later, oxymatrine may provide a more economical, convenient endogenous IFN-β induction regimen for MS patients. Show less

Obesity is turning into a more critical problem for public health. Vitamin D The study aims to examine the influence of VD Firstly, a small sample population study was conducted to compare the disparities in serum 25(OH)D A correlation was identified between serum 25(OH)D The study shows that VD Show less

Renal cell carcinoma (RCC) is a prevalent malignancy characterized by a rising incidence and significant mortality. Interleukins (ILs) are crucial in regulating immune cell trafficking and exhibit anti-tumor properties. However, limited research has explored the expression levels and prognostic significance of interleukins in RCC. In this comprehensive study, we performed a detailed analysis of interleukins in RCC patients using multiple bioinformatics tools, including Oncomine, UALCAN, GEPIA, Kaplan-Meier plotter, cBioPortal, GeneMANIA, TRRUST, STRING, and Linked Omics. Our analysis demonstrated a significant upregulation in the transcriptional levels of IL4, IL7, IL15, IL16, IL23A, IL26, and IL32 were significantly upregulated in RCC tissues, indicating their potential involvement in the pathogenesis of this malignancy. In contrast, IL1A, IL11, and IL27 were downregulated, indicating their potential function as tumor suppressors. Significant correlations were identified between the expression levels of IL11, IL23A, IL27, IL32, and the pathological stage of RCC patients. The expression levels of IL1A, IL4, IL11, IL15, IL16, IL23A, IL26, IL27, and IL32 were significantly correlated with improved prognosis. The differentially expressed interleukins primarily function in cytokine-cytokine receptor interactions and immune response-regulating signaling pathways. homeobox A10 (HOXA10), v-myb myeloblastosis viral oncogene homolog (avian) (MYB), v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA), and nuclear factor of kappa light polypeptide gene enhancer in B-cells 1(NFKB1) are key transcription factors for ILs, while LCK proto-oncogene (LCK), LYN proto-oncogene (LYN), spleen associated tyrosine kinase (SYK), Janus kinase 3 (JAK3), and FER tyrosine kinase (FER) are IL targets. IL expression significantly correlated with the infiltration of six distinct immune cell types. IL1A potentially exerts an anti-tumor effect in RCC prognosis by inducing neutrophil extracellular traps (NETs). Additionally, NFKB1 may positively regulate IL1A, providing a rationale for further In conclusion, our study demonstrates the potential role of IL 1A in the prognosis of RCC and establishes a theoretical foundation for subsequent Show less

Interleukin-27 receptor alpha (IL27RA), a key subunit of the interleukin-27 receptor, plays an essential role in T cell-mediated immunity. However, its relevance in breast cancer and response to immunotherapy remains unexplored. We integrated bulk and single-cell RNA sequencing data from TCGA, GEO, and scRNA-seq datasets to analyze IL27RA expression, prognosis, immune infiltration, and treatment response. TIDE and immune checkpoint-treated clinical cohorts were used to assess immunotherapy responsiveness. Chemotherapy sensitivity was predicted using GDSC data, and IL27RA protein expression was validated by Western blot. IL27RA was downregulated in breast cancer but high expression correlated with favorable survival. It was primarily expressed in T cells, particularly CD8⁺ subsets, and associated with enriched immune infiltration and elevated checkpoint gene expression. IL27RA high-expression patients showed lower TIDE scores, better outcomes in ICI-treated cohorts, and higher sensitivity to multiple chemotherapeutic agents. IL27RA is a potential immune biomarker that reflects an inflamed tumor microenvironment and predicts benefit from immunotherapy and chemotherapy in breast cancer. These findings provide novel insights into immune-based stratification using single-cell transcriptomic data. Show less

Recipients' age has emerged as a key factor that impacts on acute renal allograft rejection and graft survival. Age-related functional and structural changes in the immune system have been observed, yet the precise influence of aged immunity on kidney transplant remains unclear. In an initial retrospective analysis of clinical data gathered from two major centers in China and Germany, we found a correlation between aging and mitigated rejection outcomes in kidney recipients. To study the mechanism, we performed kidney transplantation on mice and observed attenuated allograft rejection in senescent recipients. Single-cell transcriptome analysis of allograft kidneys indicated a protective role of p21 Show less

Tuberculosis (TB) is a serious public health concern in many regions of the world and the only approved vaccine to prevent TB is the live-attenuated BCG vaccine. Despite being widely used, the BCG vaccine fails to prevent pulmonary TB in adults. The BCG vaccine is administered during the neonatal period when levels of the immunosuppressive cytokine interleukin (IL)-27 are elevated, and previous studies have demonstrated that the source of IL-27 can impact downstream immune responses. We therefore sought to characterize the specific subpopulations of myeloid cells that produce IL-27 following BCG vaccination. To investigate this, we administered the BCG vaccine to neonatal IL-27p28eGFP mice that report IL-27 production. Our studies demonstrated that BCG vaccination steadily increased IL-27 production throughout the weeks post-vaccination. We also showed that a predominantly CD11b+ F4/80+ population of IL-27 producers increased MHC class II expression following BCG vaccination in both the spleen and the lung. However, producers of IL-27 in these tissues differ, with a population of CD11c+ MHC II+ cells emerging in the spleen and a subset of Ly6G/C+ MHC II+ emerging in the lung. 10x scMultiome analysis further validated the increase in MHC class II expression and demonstrated improved antigen presentation functionality following vaccination. The sequencing analysis also revealed subpopulations of IL-27 producers with immunosuppressive functions such as a population of macrophages with increased Mrc1 expression post-vaccination. Our findings suggest that IL-27 producers are a heterogenous population of myeloid cells that impact the development of protective immune responses induced by the BCG vaccine. Show less

To clarify the causal association between cardiovascular proteins and diabetic nephropathy (DN) in Europeans. The large genome-wide association study data of cardiovascular proteins and DN were used for this two-sample Mendelian randomization (MR) analysis. We took the Inverse variance weighted (IVW) as the primary method. Moreover, MR-Egger, weighted median, weighted mode, and simple mode were also performed as supplementary methods. Further, Cochrane's Q test, MR-Egger, and MR-PRESSO were conducted for sensitivity analysis. According to the IVW method, the results indicated that Galanin peptide was a protective factor for DN (OR: 0.835, 95% CI 0.700, 0.996, P = 0.045) and seven cardiovascular proteins were identified as the risk factors for DN, including CX3CL1 (OR: 1.288, 95% CI 1.012, 1.639, P = 0.039), stem cell factor (OR: 1.228, 95%CI: 1.013, 1.489, P = 0.036), tumor necrosis factor receptor 2 (OR: 1.633, 95% CI 1.141, 2.338, P = 0.007), myeloperoxidase (OR: 1.412, 95% CI 1.103, 1.808, P = 0.006), galectin-3 (OR: 1.297, 95% CI 1.095, 1.537, P = 0.003), platelet-derived growth factor subunit B (OR: 1.338, 95% CI 1.020, 1.756, P = 0.035), and interleukin-27 (OR: 1.248, 95% CI 1.033, 1.509, P = 0.022). Moreover, the reverse MR study did not observe the causal effect of DN on cardiovascular proteins. The results of sensitivity analysis suggested no significant pleiotropy and heterogeneity. This MR analysis first evaluated the causal relationship between cardiovascular protein and DN at the genetic level, which could be of great significance for the prevention and treatment of DN. Show less

Traumatic defects or non-union fractures presents a substantial challenge in the fields of tissue engineering and regenerative medicine. Although synthetic calcium phosphate-based biomaterials (CaPs) such as dibasic calcium phosphate anhydrate (DCPA) are commonly employed for bone repair, their inadequate cellular immune responses significantly impede sustained degradation and optimal osteogenesis. In this study, drawing inspiration from the key structure of an acidic non-collagenous protein-CaP complex (ANCPs-CaP) essential for natural bone formation, we prepared biomimetic mineralized dibasic calcium phosphate (MDCPA). This preparation utilized plant-derived non-collagenous protein Zein as the organic template and acidic artificial saliva as the mineralization medium. Physicochemical property analysis revealed that MDCPA is a complex of Zein and DCPA, which mimics the composite of the natural ANCP-CaP. Moreover, MDCPA exhibited enhanced biodegradability and osteogenic potential. Mechanistic insight revealed that MDCPA can be phagocytized and degraded by macrophages via the FCγRIII receptor, leading to the release of interleukin 27 (IL-27), which promotes osteogenic differentiation by osteoimmunomodulation. The critical role of IL-27 in osteogenesis is further confirmed using IL-27 gene knockout mice. Additionally, MDCPA demonstrates effective healing of critical-sized defects in rat cranial bones within only 4 w, providing a promising basis and valuable insights for critical-sized bone defects regeneration. Show less