Parishin alleviates vascular ageing in mice by upregulation of Klotho.

Senescence of vascular endothelial cells is the major risk of vascular dysfunction and disease among elderly people. Parishin, which is a phenolic glucoside derived from Gastrodia elata, significantly prolonged yeast lifespan. However, the action of parishin in vascular ageing remains poorly understood. Here, we treated human coronary artery endothelial cells (HCAEC) and naturally aged mice by parishin. Parishin alleviated HCAEC senescence and general age-related features in vascular tissue in naturally aged mice. Network pharmacology approach was applied to determine the compound-target networks of parishin. Our analysis indicated that parishin had a strong binding affinity for Klotho. Expression of Klotho, a protein of age-related declines, was upregulated by parishin in serum and vascular tissue in naturally aged mice. Furthermore, FoxO1, on Klotho/FoxO1 signalling pathway, was increased in the parishin-intervened group, accompanied by the downregulated phosphorylated FoxO1. Taken together, parishin can increase Klotho expression to alleviate vascular endothelial cell senescence and vascular ageing.

Exome sequencing identifies genetic variants in anophthalmia and microphthalmia.

Anophthalmia and microphthalmia (A/M) are rare birth defects affecting up to 2 per 10,000 live births. These conditions are manifested by the absence of an eye or reduced eye volumes within the orbit leading to vision loss. Although clinical case series suggest a strong genetic component in A/M, few systematic investigations have been conducted on potential genetic contributions owing to low population prevalence. To overcome this challenge, we utilized DNA samples and data collected as part of the National Birth Defects Prevention Study (NBDPS). The NBDPS employed multi-center ascertainment of infants affected by A/M. We performed exome sequencing on 67 family trios and identified numerous genes affected by rare deleterious nonsense and missense variants in this cohort, including de novo variants. We identified 9 nonsense changes and 86 missense variants that are absent from the reference human population (Genome Aggregation Database), and we suggest that these are high priority candidate genes for A/M. We also performed literature curation, single cell transcriptome comparisons, and molecular pathway analysis on the candidate genes and performed protein structure modeling to determine the potential pathogenic variant consequences on PAX6 in this disease.

CD44 deficiency represses neuroinflammation and rescues dopaminergic neurons in a mouse model of Parkinson's disease.

CD44 is a transmembrane protein that transduces extracellular stimuli to immune response. Neuroinflammation is a causative factor in neurodegenerative diseases, such as Parkinson's disease (PD). Owing to its role in inflammation, this study investigated whether CD44 is involved in the pathological progression of PD. Our data showed that CD44 deficiency largely abolished proinflammatory cytokine expression in primary microglia and astrocytes. In PD model mice, CD44 knockout improved behavioral defects, prevented TH loss in the SNpc and striatum, and blocked activation of microglia and astrocytes. Moreover, CD44 neutralization by anti-CD44 antibody recapitulated the phenotypes observed in CD44 knockout mice. Mechanistically, CD44 neutralization blocked TLR4 expression and NF-κB p65 nuclear translocation induced by lipopolysaccharide in BV2 cells. Overall, our results indicate that CD44 deficiency has a beneficial role against PD, which is likely due to repression of the TLR4/NF-κB axis, leading to reduced neuroinflammation. Therefore, CD44 might be a therapeutic target for the development of anti-PD agents.

Genome-wide binding analysis reveals that ANAC060 directly represses sugar-induced transcription of ABI5 in Arabidopsis.

The sugar status of a plant acts as a signal affecting growth and development. The phenomenon by which high levels of sugars inhibit seedling establishment has been widely used to gain insight into sugar-signaling pathways. Natural allelic variation has been identified at the ANAC060 locus. The Arabidopsis Columbia ecotype produces a short ANAC060 protein without a transmembrane domain that is constitutively located to the nucleus, causing sugar insensitivity when overexpressed. In this study, we generated a genome-wide DNA-binding map of ANAC060 via chromatin immunoprecipitation sequencing using transgenic lines that express a functional ANAC060-GFP fusion protein in an anac060 background. A total of 3282 genes associated with ANAC060-binding sites were identified. These genes were enriched in biotic and abiotic stress responses, and the G-box binding motif was highly enriched in ANAC060-bound genomic regions. Expression microarray analysis resulted in the identification of 8350 genes whose activities were altered in the anac060 mutant and upon sugar treatment. Cluster analysis revealed that ANAC060 attenuates sugar-regulated gene expression. Direct target genes of ANAC060 included equivalent numbers of genes that were upregulated or downregulated by ANAC060. The various functions of these target genes indicate that ANAC060 has several functions. Our results demonstrate that ANAC060 directly binds to the promoter of ABI5 and represses the sugar-induced transcription of ABI5. Genetic data indicate that ABI5 is epistatic to ANAC060 in both sugar and abscisic acid responses.

Plant Regulomics: a data-driven interface for retrieving upstream regulators from plant multi-omics data.

High-throughput technology has become a powerful approach for routine plant research. Interpreting the biological significance of high-throughput data has largely focused on the functional characterization of a large gene list or genomic loci that involves the following two aspects: the functions of the genes or loci and how they are regulated as a whole, i.e. searching for the upstream regulators. Traditional platforms for functional annotation largely help resolving the first issue. Addressing the second issue is essential for a global understanding of the regulatory mechanism, but is more challenging, and requires additional high-throughput experimental evidence and a unified statistical framework for data-mining. The rapid accumulation of 'omics data provides a large amount of experimental data. We here present Plant Regulomics, an interface that integrates 19 925 transcriptomic and epigenomic data sets and diverse sources of functional evidence (58 112 terms and 695 414 protein-protein interactions) from six plant species along with the orthologous genes from 56 whole-genome sequenced plant species. All pair-wise transcriptomic comparisons with biological significance within the same study were performed, and all epigenomic data were processed to genomic loci targeted by various factors. These data were well organized to gene modules and loci lists, which were further implemented into the same statistical framework. For any input gene list or genomic loci, Plant Regulomics retrieves the upstream factors, treatments, and experimental/environmental conditions regulating the input from the integrated 'omics data. Additionally, multiple tools and an interactive visualization are available through a user-friendly web interface. Plant Regulomics is available at http://bioinfo.sibs.ac.cn/plant-regulomics.

SFRP2 enhances dental pulp stem cell-mediated dentin regeneration in rabbit jaw.

OBJECTIVES: Dental tissue-derived mesenchymal stem cell (MSC)-mediated tooth regeneration may be a useful therapeutic tool for repairing tooth loss. However, the low success rate of tooth regeneration restricts its clinical application. Identifying key factors for enhancing dentinogenesis in MSCs is crucial for promoting tooth regeneration. MATERIALS AND METHODS: Human dental pulp stem cells (DPSCs) were transfected with retrovirus to obtain SFRP2-over-expressing DPSCs. Alkaline phosphatase (ALP) activity assay, Alizarin red staining, quantitative analysis of calcium, and dentinogenesis-related genes were detected. Additionally, transplantation in a rabbit tooth extraction model was used to explore the role of SFRP2 in dentin regeneration. RESULTS: We found SFRP2 over-expression greatly enhanced ALP activity, and mineralization in DPSCs. Real-time RT-PCR revealed SFRP2 over-expression promoted the expressions of OSX, RUNX2, DSPP, DMP1, and BSP. Moreover, Micro CT analysis showed high-density calcification occurred to a much higher extent in SFRP2 over-expressing group compared to control group in vivo. Additionally, HE staining, immmunohistochemistry staining, and scanning electron microscopy results showed much more dentin-like tissue formed in SFRP2 over-expressing group compared to control group. CONCLUSIONS: Our findings revealed SFRP2 is an important regulator that enhances the dentinogenesis of DPSCs and dentin regeneration in the jaw, which may have clinical applications.

Polycomb repressive complex 2 attenuates ABA-induced senescence in Arabidopsis.

The phytohormone abscisic acid (ABA)-induced leaf senescence facilitates nutrient reuse and potentially contributes to enhancing plant stress tolerance. However, excessive senescence causes serious reductions in crop yield, and the mechanism by which senescence is finely tuned at different levels is still insufficiently understood. Here, we found that the double mutant of core enzymes of the polycomb repressive complex 2 (PRC2) is hypersensitive to ABA in Arabidopsis thaliana. To elucidate the interplay between ABA and PRC2 at the genome level, we extensively profiled the transcriptomic and epigenomic changes triggered by ABA. We observed that H3K27me3 preferentially targets ABA-induced senescence-associated genes (SAGs). In the double, but not single, mutant of PRC2 enzymes, these SAGs were derepressed and could be more highly induced by ABA compared with the wild-type, suggesting a redundant role for the PRC2 enzymes in negatively regulating ABA-induced senescence. Contrary to the rapid transcriptomic changes triggered by ABA, the reduction of H3K27me3 at these SAGs falls far behind the induction of their expression, indicating that PRC2-mediated H3K27me3 contributed to long-term damping of ABA-induced senescence to prevent an oversensitive response. The findings of this study may serve as a paradigm for a global understanding of the interplay between the rapid effects of a phytohormone such as ABA and the long-term effects of the epigenetic machinery in regulating plant senescence processes and environmental responses.

MiR-137 knockdown promotes the osteogenic differentiation of human adipose-derived stem cells via the LSD1/BMP2/SMAD4 signaling network.

MicroRNAs are a group of endogenous regulators that participate in several cellular physiological processes. However, the role of miR-137 in the osteogenic differentiation of human adipose-derived stem cells (hASCs) has not been reported. This study verified a general downward trend in miR-137 expression during the osteogenic differentiation of hASCs. MiR-137 knockdown promoted the osteogenesis of hASCs in vitro and in vivo. Mechanistically, inhibition of miR-137 activated the bone morphogenetic protein 2 (BMP2)-mothers against the decapentaplegic homolog 4 (SMAD4) pathway, whereas repressed lysine-specific histone demethylase 1 (LSD1), which was confirmed as a negative regulator of osteogenesis in our previous studies. Furthermore, LSD1 knockdown enhanced the expression of BMP2 and SMAD4, suggesting the coordination of LSD1 in the osteogenic regulation of miR-137. This study indicated that miR-137 negatively regulated the osteogenic differentiation of hASCs via the LSD1/BMP2/SMAD4 signaling network, revealing a new potential therapeutic target of hASC-based bone tissue engineering.

UNC-5 netrin receptor B mediates osteogenic differentiation by modulating bone morphogenetic protein signaling in human adipose-derived stem cells.

UNC-5 netrin receptor B (UNC5B) is a dependence receptor of netrin-1 that plays an essential role in mediating angiogenesis and tumorigenesis. Despite its significant roles, there is limited knowledge about the role played by UNC5B in osteogenesis. In the present study, we first demonstrated that UNC5B was required for osteogenic differentiation of human adipose-derived stem cells (hASCs), both in vitro and in vivo. We also found that mechanistically, UNC5B promotes osteogenic differentiation by activating bone morphogenetic protein signaling. These findings point to a new important function of UNC5B and provide a potential basis for hASCs-mediated bone regeneration.

Rapid and efficient one-step purification of a serralysin family protease by using a p-aminobenzamidine-modified affinity medium.

The metalloproteinase MP belongs to the serralysin family, which is involved in important functions such as nutrient acquisition and infection pathogenesis. Serralysin proteases in highly purified form are commonly used at the industrial level with several purposes. In this study, we set up an efficient and rapid purification protocol for MP using a p-aminobenzamidine-modified affinity chromatography. The affinity medium was synthesized by using p-aminobenzamidine as affinity ligand immobilized via cyanuric chloride spacer to Sepharose 6B sorbent carrier. According to the adsorption analysis, the dissociation constant Kd and theoretical maximum adsorption Qmax of this medium were 24.2 µg/mL and 24.1 mg/g wet sorbent, respectively. The purity of MP was assessed by a high-performance liquid chromatography on a TSK3000SW column and sodium dodecyl sulfate polyacrylamide gel electrophoresis, revealing values of 98.7 and ∼98%, respectively. The specific activity of purified MP was 95.6 U/mg, which is similar to values obtained through traditional purification protocols. In conclusion, our protocol could be easily employed for the rapid isolation of MP with high purity, and could be implemented for other serralysin family proteases.

Demethylation of IGFBP5 by Histone Demethylase KDM6B Promotes Mesenchymal Stem Cell-Mediated Periodontal Tissue Regeneration by Enhancing Osteogenic Differentiation and Anti-Inflammation Potentials.

Mesenchymal stem cell (MSC)-mediated periodontal tissue regeneration is considered a promising method for periodontitis treatment. The molecular mechanism underlying directed differentiation and anti-inflammatory actions remains unclear, thus limiting potential MSC application. We previously found that insulin-like growth factor binding protein 5 (IGFBP5) is highly expressed in dental tissue-derived MSCs compared with in non-dental tissue-derived MSCs. IGFBP5 is mainly involved in regulating biological activity of insulin-like growth factors, and its functions in human MSCs and tissue regeneration are unclear. In this study, we performed gain- and loss-of-function assays to test whether IGFBP5 could regulate the osteogenic differentiation and anti-inflammatory potential in MSCs. We found that IGFBP5 expression was upregulated upon osteogenic induction, and that IGFBP5 enhanced osteogenic differentiation in MSCs. We further showed that IGFBP5 prompted the anti-inflammation effect of MSCs via negative regulation of NFκB signaling. Depletion of the histone demethylase lysine (K)-specific demethylase 6B (KDM6B) downregulated IGFBP5 expression by increasing histone K27 methylation in the IGFBP5 promoter. Moreover, IGFBP5 expression in periodontal tissues was downregulated in individuals with periodontitis compared with in healthy people, and IGFBP5 enhanced MSC-mediated periodontal tissue regeneration and alleviated local inflammation in a swine model of periodontitis. In conclusion, our present results reveal a new function for IGFBP5, provide insight into the mechanism underlying the directed differentiation and anti-inflammation capacities of MSCs, and identify a potential target mediator for improving tissue regeneration.

Structure-Based Design and Synthesis of a New Phenylboronic-Modified Affinity Medium for Metalloprotease Purification.

Metalloproteases are emerging as useful agents in the treatment of many diseases including arthritis, cancer, cardiovascular diseases, and fibrosis. Studies that could shed light on the metalloprotease pharmaceutical applications require the pure enzyme. Here, we reported the structure-based design and synthesis of the affinity medium for the efficient purification of metalloprotease using the 4-aminophenylboronic acid (4-APBA) as affinity ligand, which was coupled with Sepharose 6B via cyanuric chloride as spacer. The molecular docking analysis showed that the boron atom was interacting with the hydroxyl group of Ser176 residue, whereas the hydroxyl group of the boronic moiety is oriented toward Leu175 and His177 residues. In addition to the covalent bond between the boron atom and hydroxyl group of Ser176, the spacer between boronic acid derivatives and medium beads contributes to the formation of an enzyme-medium complex. With this synthesized medium, we developed and optimized a one-step purification procedure and applied it for the affinity purification of metalloproteases from three commercial enzyme products. The native metalloproteases were purified to high homogeneity with more than 95% purity. The novel purification method developed in this work provides new opportunities for scientific, industrial and pharmaceutical projects.

Application of iron magnetic nanoparticles in protein immobilization.

Due to their properties such as superparamagnetism, high surface area, large surface-to-volume ratio, easy separation under external magnetic fields, iron magnetic nanoparticles have attracted much attention in the past few decades. Various modification methods have been developed to produce biocompatible magnetic nanoparticles for protein immobilization. This review provides an updated and integrated focus on the fabrication and characterization of suitable magnetic iron nanoparticle-based nano-active materials for protein immobilization.

METTL7A-mediated m6A modification of corin reverses bisphosphonates-impaired osteogenic differentiation of orofacial BMSCs.

Bisphosphonate-related osteonecrosis of jaw (BRONJ) is characterized by impaired osteogenic differentiation of orofacial bone marrow stromal cells (BMSCs). Corin has recently been demonstrated to act as a key regulator in bone development and orthopedic disorders. However, the role of corin in BRONJ-related BMSCs dysfunction remains unclarified. A m6A epitranscriptomic microarray study from our group shows that the CORIN gene is significantly upregulated and m6A hypermethylated during orofacial BMSCs osteogenic differentiation. Corin knockdown inhibits BMSCs osteogenic differentiation, whereas corin overexpression or soluble corin (sCorin) exerts a promotion effect. Furthermore, corin expression is negatively regulated by bisphosphonates (BPs). Corin overexpression or sCorin reverses BPs-impaired BMSCs differentiation ability. Mechanistically, we find altered expression of phos-ERK in corin knockdown/overexpression BMSCs and BMSCs under sCorin stimulation. PD98059 (a selective ERK inhibitor) blocks the corin-mediated promotion effect. With regard to the high methylation level of corin during osteogenic differentiation, we apply a non-selective m6A methylase inhibitor, Cycloleucine, which also blocks the corin-mediated promotion effect. Furthermore, we demonstrate that METTL7A modulates corin m6A modification and reverses BPs-impaired BMSCs function, indicating that METTL7A regulates corin expression and thus contributes to orofacial BMSCs differentiation ability. To conclude, our study reveals that corin reverses BPs-induced BMSCs dysfunction, and METTL7A-mediated corin m6A modification underlies corin promotion of osteogenic differentiation via the ERK pathway. We hope this brings new insights into future clinical treatments for BRONJ.

Negative Regulation of LINC01013 by METTL3 and YTHDF2 Enhances the Osteogenic Differentiation of Senescent Pre-Osteoblast Cells Induced by Hydrogen Peroxide.

Senescent pre-osteoblasts have a reduced ability to differentiate, which leads to a reduction in bone formation. It is critical to identify the keys that regulate the differentiation fate of senescent pre-osteoblasts. LINC01013 has an essential role in cell stemness, differentiation, and senescence regulation. This study aims to examine the role and mechanism of LINC01013 in regulating osteogenic differentiation in senescent human embryonic osteoblast cell line (hFOB1.19) cells induced by hydrogen peroxide (H2O2). The results show that LINC01013 decreased alkaline phosphatase activity, mineralization of hFOB1.19 cells in vitro, and the expression of collagen II, osteocalcin, and bone sialoprotein. LINC01013 knockdown enhances the osteogenesis of hFOB1.19 cells and rescues osteogenic differentiation impaired by H2O2. METTL3 negatively regulates LINC01013 expression, enhancing hFOB1.19 cells' osteogenesis in vitro and in vivo. METTL3 overexpression can enhance hFOB1.19 cells' osteogenic differentiation impaired by H2O2. YTHDF2 promotes LINC01013 decay, facilitating osteogenic differentiation. YTHDF2 overexpression rescues hFOB1.19 cells osteogenic differentiation impaired by H2O2. Taken together, METTL3 upregulates osteogenic differentiation by inhibiting LINC01013, and YTHDF2 accelerates LINC01013 degradation, reducing its inhibitory effect. This study highlights LINC01013 as a key regulator in the fate switching process of senescent hFOB1.19 cells, impacting osteogenic differentiation.

miR615-3p inhibited FBLN1 and osteogenic differentiation of umbilical cord mesenchymal stem cells by associated with YTHDF2 in a m6A-miRNA interaction manner.

To investigate the role and mechanism of FBLN1 in the osteogenic differentiation and bone regeneration by using umbilical cord mesenchymal stem cells (WJCMSCs). We found that FBLN1 promoted osteogenic differentiation of WJCMSCs and WJCMSC-mediated bone regeneration. It was showed that there was an m6A methylation site in 3'UTR of FBLN1 mRNA, and the mutation of the m6A site enhanced the stability of FBLN1 mRNA, subsequently fostering the FBLN1 enhanced osteogenic differentiation of WJCMSCs. YTHDF2 was identified as capable of recognizing and binding to the m6A site, consequently inducing FBLN1 instability and repressed the osteogenic differentiation of WJCMSCs. Meanwhile, miR-615-3p negatively regulated FBLN1 by binding FBLN1 3'UTR and inhibited the osteogenic differentiation of WJCMSCs and WJCMSC-mediated bone regeneration. Then, we discovered miR-615-3p was found to regulate the functions of FBLN1 facilitated by YTHDF2 through an m6A-miRNA regulation mechanism. We demonstrated that FBLN1 is critical for regulating the osteogenic differentiation potentials of WJCMSCs and have identified that miR615-3p mediated the decay of FBLN1 mRNA which facilitated by m6A reading protein YTHDF2. This provided a novel m6A-miRNA epigenetic regulatory pattern for MSC regulation and bone regeneration.

Integrative analysis of noncoding mutations identifies the druggable genome in preterm birth.

Preterm birth affects ~10% of pregnancies in the US. Despite familial associations, identifying at-risk genetic loci has been challenging. We built deep learning and graphical models to score mutational effects at base resolution via integrating the pregnant myometrial epigenome and large-scale patient genomes with spontaneous preterm birth (sPTB) from European and African American cohorts. We uncovered previously unidentified sPTB genes that are involved in myometrial muscle relaxation and inflammatory responses and that are regulated by the progesterone receptor near labor onset. We studied genomic variants in these genes in our recruited pregnant women administered progestin prophylaxis. We observed that mutation burden in these genes was predictive of responses to progestin treatment for preterm birth. To advance therapeutic development, we screened ~4000 compounds, identified candidate molecules that affect our identified genes, and experimentally validated their therapeutic effects on regulating labor. Together, our integrative approach revealed the druggable genome in preterm birth and provided a generalizable framework for studying complex diseases.

Ribosomal proteins are blood biomarkers and associated with CD4+ T cell activation in Alzheimer's disease: a study based on machine learning strategies and scRNA-Seq data validation.

BACKGROUND: Alzheimer's disease (AD) is a widespread neurodegenerative disease that primarily affects the elderly. Unfortunately, the lack of convenient early diagnostic tools makes it difficult to intervene and treat the disease during its initial stages. METHODS: We obtained four bulk and single-cell RNA-sequencing peripheral blood samples related to AD from public databases. Using Boruta and LASSO machine learning algorithms, we screened the signature genes and constructed a diagnostic model using lightGBM. The model was further validated in a test cohort. Additionally, we extracted hub biomarkers using the protein-protein interactions method and validated them in a single-cell RNA-seq dataset. RESULTS: Our analysis revealed the identification of 37 AD-related peripheral blood signature genes, with their main enrichment in ribosome-related biological functions. Four core biomarkers, RPL24, RPL5, RPS27A, and RPS4X, were identified and exhibited good diagnostic power in the testing cohort. Immune infiltration analysis revealed a higher proportion of CD4+ T cells in AD patients' peripheral blood compared to healthy controls, with a negative correlation with the four ribosome-associated core genes. Validation in a single-cell RNA-seq dataset confirmed these findings. CONCLUSIONS: Ribosomal family proteins have the potential to serve as biomarkers for the diagnosis and treatment of AD, and are associated with CD4+ T cell activation.

Investigating EGF and PAG1 as necroptosis-related biomarkers for diabetic nephropathy: an in silico and in vitro validation study.

The current study aims to understand the mechanisms behind regulated cell death (RCD) in diabetic nephropathy and identify related biomarkers through bioinformatics and experimental validation. Datasets of bulk and single-cell RNA sequencing were obtained from public databases and analyzed using gene set variation analysis (GSVA) with gene sets related to RCD, including autophagy, necroptosis, pyroptosis, apoptosis, and ferroptosis. RCD-related gene biomarkers were identified using weighted gene correlation network analysis (WGCNA). The results were verified through experiments with an independent cohort and in vitro experiments. The GSVA revealed higher necroptosis scores in diabetic nephropathy. Three necroptosis-related biomarkers, EGF, PAG1, and ZFP36, were identified and showed strong diagnostic ability for diabetic kidney disease. In vitro experiments showed high levels of necroptotic markers in HK-2 cells treated with high glucose. Bioinformatics and experimental validation have thus identified EGF and PAG1 as necroptosis-related biomarkers for diabetic nephropathy.

Severe mosquito bite allergy complicated by bacterial infection in a 7-year-old child: a case report and brief review of the literature.

INTRODUCTION: SMBA is a cutaneous form of CAEBV that predominantly affects adolescents and children from East Asian countries. It is characterized by local skin erythema, bullae, ulcers, necrosis, and scarring following a mosquito bite. Affected patients may experience IM-like systemic inflammatory reactions. SMBA mainly involves NK cells and has the potential to progress to NK/T-cell lymphoma or invasive NK-cell leukemia. CASE REPORT: A 7-year-old female was admitted to the hospital owing to recurring fever, skin allergies, and multifocal severe ulcerative necrotic skin lesions affecting both lower limbs. The authors primarily suspected bacterial infection, and debridement was insufficient to manage it. Pathological examination of residual skin tissues around the necrotic lesion revealed EBER-positive T cells. Eventually, the patient was diagnosed with SMBA complicated by bacterial infection based on diagnostic criteria and pathology findings. The patient responded well to timely antiviral and antibacterial treatment, with no deterioration during regular follow-up visits. CONCLUSIONS: SMBA is a subtype of CAEBV that is characterized by severe skin ulceration and is easily missed or misdiagnosed. Based on its mosquito bite history, pathological characteristics, and laboratory indicators, SMBA could expand new diagnostic and therapeutic approaches to the ulcerative skin diseases.