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Skin cutaneous melanoma (SKCM), a malignant melanocyte-derived skin cancer, potentially leads to fatal outcomes without effective treatment. The variability in immunotherapy responses among melanoma patients is significantly influenced by the intricate immune microenvironment, particularly due to the status of tumor T cells, encompassing their activity, exhaustion levels, and antigen recognition capabilities. This study utilized single-cell RNA sequencing (scRNA-seq) to analyze 34 melanoma samples from two public datasets (GSE215120 and GSE115978). Herein, we extracted 706 marker genes associated with immune checkpoint (ICP) therapy from these T cells, 509 markers of T cells from 11 melanoma tissues, and eventually identified 33 candidate genes. These genes underwent LASSO and COX regression analyses to identify the signature genes. Of the initial 33 candidate genes, we successfully isolated six distinct T cell-associated immunotherapy-related genes (IRTGs). Additionally, the computation of each patient risk score proved beneficial in evaluating the immune cell infiltration level and functions as an independent prognostic factor for melanoma patient survival. The risk score results revealed promising predictive outcomes in determining the response of melanoma patients to immunotherapy. Notably, our study is the first to reveal the potential correlation between signature gene PEB4B and the immune microenvironment in melaoma, which was explored with multiple immunofluorescence (IF) and Immune Infiltration Assessment. In a conclusion, our findings demonstrate the potential utility of a risk score dependent on signature genes as a predictive tool for assessing the prognosis and response to immunotherapeutic interventions in melanoma patients.
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Freckle is a prevalent pigmentary dermatosis with an obvious hereditary component. Dozens of freckles risk loci have been discovered through research on multiple traits or other diseases, rather than as an independent trait. To discover novel variants associated with freckles, we performed GWAS and meta-analysis in 4813 Chinese individuals. We conducted GWAS and meta-analysis of two cohorts: 197 patients and 1603 controls (Cohort I), and 336 patients and 2677 controls (Cohort II), both from China. Then we performed linkage disequilibrium (LD) analysis, eQTL study, and enrichment analysis with association results for functional implications. Finally, we discovered 59 new SNPs and 13 novel susceptibility genes associated with freckles (Pmeta <5 × 10-8), which has enriched the genetic research on freckles.
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Pyroelectric nanostructures can effectively generate temperature-mediated reactive oxygen species (ROS) through the pyroelectric effect, providing promise for treating hypoxic tumors; and therefore, the synergistic application of photothermal therapy (PTT) and pyroelectric dynamic therapy (PEDT) presents an intriguing approach for cancer therapy. However, this method still faces challenges in improving pyroelectric catalysis and achieving precise tumor localization. In this study, a nano-heterojunction based on CeO2-BaTiO3 nanorods (IR1061@PCBNR) is reported, which exhibits highly effective pyroelectric catalysis for simultaneous tumor-targeted dynamic therapy and gentle photothermal therapy through the utilization of the rich oxygen vacancies. The oxygen vacancies create active sites that facilitate the migration of pyroelectrically-induced charge carriers, improving charge separation and ROS generation. IR1061@PCBNR also demonstrates high tumor penetration; while, minimizing damage to normal cells. This precise nanomedicine strategy holds great potential for advancing dynamic cancer therapies by overcoming the limitations of conventional approaches.
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BACKGROUND: Acute urticaria is a prevalent inflammatory dermatosis characterized by fulminant wheals, often accompanied by severe pruritis. It may also cause nausea, vomiting, and abdominal pain. Numerous studies have substantiated the pivotal involvement of double-stranded DNA (dsDNA) in autoimmunity. However, the role of dsDNA in the pathogenesis of acute urticaria is unclear. METHODS: We measured serum dsDNA levels in patients and controls. The relationship between dsDNA levels and environmental exposures (temperature, ultraviolet [UV] index, and season) was investigated by correlating disease onset dates with archived meteorological data. Finally, we used quantitative PCR to determine the expressions of genes encoding dsDNA receptors, single-stranded RNA (ssRNA) receptors, exosome formation, and type I interferon in the peripheral blood of patients and controls. RESULTS: Serum dsDNA levels were significantly higher in patients with acute urticaria compared with controls (mean values 1.38 and 0.94 ng/ml, respectively, P < 0.001). dsDNA levels were higher in patients exposed to higher environmental temperatures and UV indices and were higher during the summer months. We also found that the expressions of genes encoding dsDNA receptors, ssRNA receptors, absent in melanoma factor 2 (AIM2)-related inflammatory factors, and interferon alpha were up-regulated in patients. CONCLUSIONS: We demonstrated that serum dsDNA levels are elevated in acute urticaria and are influenced by climatic factors such as temperature, ultraviolet index, and season. We also found that elevated dsDNA promotes the expression of AIM2-related factors and type I interferons. This study generates new hypotheses regarding the pathogenesis of acute urticaria and suggests novel therapeutic targets.
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DNA , Estações do Ano , Raios Ultravioleta , Urticária , Humanos , Masculino , Adulto , Feminino , Urticária/sangue , Urticária/genética , Urticária/etiologia , DNA/sangue , DNA/genética , Doença Aguda , Pessoa de Meia-Idade , Estudos de Casos e Controles , Raios Ultravioleta/efeitos adversos , Adulto Jovem , Temperatura , Adolescente , Exposição Ambiental/efeitos adversos , Interferon Tipo I/sangue , Interferon Tipo I/genética , Interferon Tipo I/imunologiaRESUMO
Vitiligo is an autoimmune disease involving loss of melanocytes. Although several genetic studies have confirmed that genetic factors play an important role, its pathogenesis remains incompletely characterized. In this study, a genome-wide meta-analysis was conducted to search for more susceptibility variants of vitiligo. Tang et al performed a GWAS for cohort I (1117 vitiligo cases and 1701 healthy controls) previously, and we conducted a GWAS for cohort II (3323 vitiligo cases and 7186 healthy controls) in this study, with the results subjected to a genome-wide meta-analysis and linkage disequilibrium analysis. We identify, to our knowledge, 11 previously unreported susceptibility variants, of which 6 variants are located in the intronic regions, and the remaining 5 variants are located within intergenic regions between genes. In addition, the results of polygenic risk score show that the best evaluated effect for target data is among significant SNVs of the base data. The susceptibility genes of vitiligo are mainly enriched in the immune-related functions and pathways. The susceptibility variants expand the role of genetic factors associated with vitiligo. The bioinformatics analysis for risk genes provides further insight into the pathogenesis of vitiligo.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Vitiligo , Feminino , Humanos , Masculino , Estudos de Casos e Controles , China/epidemiologia , População do Leste Asiático/genética , Desequilíbrio de Ligação , Vitiligo/genéticaRESUMO
OBJECTIVE: Inflammation and vascular smooth muscle cell (VSMC) phenotypic switching are implicated in the pathogenesis of abdominal aortic aneurysm (AAA). Trimethylamine N-oxide (TMAO) has emerged as a crucial risk factor in cardiovascular diseases, inducing vascular inflammation and calcification. We aimed to evaluate the effect of TMAO on the formation of AAA. APPROACH AND RESULTS: Here, we showed that TMAO was elevated in plasma from AAA patients compared with nonaneurysmal subjects by liquid chromatographyâmass spectrometry (LCâMS) detection. Functional studies revealed that increased TMAO induced by feeding a choline-supplemented diet promoted Ang II-induced AAA formation. Immunohistochemistry, enzyme-linked immunosorbent assay (ELISA), and Western blot analyses revealed that TMAO induced macrophage infiltration and inflammatory factor release. Conversely, inhibition of TMAO by supplementation with DMB suppressed AAA formation and the inflammatory response. Molecular studies revealed that TMAO regulated VSMC phenotypic switching. Flow cytometry analyses showed that TMAO induces macrophage M1-type polarization. Furthermore, pharmacological intervention experiments suggested that the nuclear factor-κB (NF-κB) signaling pathway was critical for TMAO to trigger AAA formation. CONCLUSIONS: TMAO promotes AAA formation by inducing vascular inflammation and VSMC phenotypic switching through activation of the NF-κB signaling pathway. Thus, TMAO is a prospective therapeutic AAA target.
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Aneurisma da Aorta Abdominal , Metilaminas , NF-kappa B , Humanos , Animais , NF-kappa B/metabolismo , Músculo Liso Vascular , Aneurisma da Aorta Abdominal/patologia , Inflamação/metabolismo , Miócitos de Músculo Liso , Angiotensina II/farmacologia , Modelos Animais de DoençasRESUMO
Psychological stress has long been considered to cause the aggravation and recurrence of psoriasis, but the underlying mechanism remains largely unknown. Here, we used a mouse model of restraint-induced stress and imiquimod (IMQ)-induced psoriasiform inflammation to investigate the crosstalk between stress and the skin immune system and their functions in the pathogenesis of psoriasis. We found that stress aggravated skin inflammation and elevated serum corticosterone (CORT) levels in mice. Stress also increased the number of macrophages and glucocorticoid receptor (GR) expression in IMQ-treated mouse skin. GR agonist CORT upregulated the phosphorylation of STAT1 to promote M1 macrophage polarization in vitro. Additionally, GR deletion in macrophages and pharmacologic inhibition of GR improved skin inflammation and reduced M1 macrophage polarization under stress. Taken together, these results indicate that stress aggravates psoriasiform inflammation by promoting CORT/GR signaling-induced M1 macrophage polarization, suggesting that blocking the GR signaling has great potential as an adjuvant treatment for psoriasis patients with chronic stress.
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X-ray imaging based on a single gray level shows visual blind parts and affects accurate judgment in some situations. Color-cognized x-ray imaging will boost the recognition capability, which has not yet been reported. Here, we propose a quartz-assisted chromatic x-ray imaging model based on metal halide nanocrystal (NC) stacked scintillators. Mutually inactive (BA)2PbBr4:Mn and Cs3Cu2I5:Tl enable x-ray energy- or density-dependent radioluminescence (RL) color variation. The upper scintillator light yield and the bottom scintillator transmittance are enhanced by elaborate in situ passivation of phenethylamine bromide and NC orientation regulation, respectively. Imaging targets with different densities are distinguished on RL spectra, and the color coordinates shift linearly on CIE 1931. An algorithm balances the image details of different gray areas and enhances the visual perception by color filling. This work provides color recognition between objects with different densities and takes a step toward chromatic x-ray imaging applied to practical scenarios.
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Developing a straightforward method to produce conductive hydrogels with excellent mechanical properties, self-adhesion, and biocompatibility remains a significant challenge. While current approaches aim to enhance mechanical performance, they often require additional steps or external forces for fixation, leading to increased production time and limited practicality. A novel lignin-grafted polyacrylamide/hydroxypropyl cellulose hydrogel (L-g-PAM/HPC hydrogel) with a semi-interpenetrating polymer network structure had been developed in this research that boasted exceptional adhesion to the skin (â¼68 kPa) and stretchability properties (â¼1637 %) compared to PAM-based hydrogels. By incorporating conductive additives such as silver nanowires and carbon nanocages to construct a bridge-like structure within the hydrogel matrix, the resulting AgC@L-g-PAM/HPC hydrogel exhibited impressive electrical conductivity, surpassing that of other PAM-based hydrogels relying on MXene, with a maximum value of 0.76 S/m. Furthermore, the AgC@L-g-PAM/HPC hydrogel retained its efficient electrical signal transmission capability even under mechanical stress. These make it an ideal flexible strain sensor capable of detecting various human motions. In this study, a smart real-time monitoring system was successfully developed for tracking cervical spine bending, serving as an extension for monitoring human activities.
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Lignina , Nanofios , Humanos , Prata , Vértebras Cervicais , Condutividade Elétrica , HidrogéisRESUMO
BACKGROUND: Nonsyndromic orofacial clefts (NSOFCs) are the most common craniofacial birth malformations in humans and are generally classified as nonsyndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO). Genome-wide association studies (GWASs) of NSOFCs have demonstrated multiple risk loci and candidate genes; however, published risk factors are able to explain only a small fraction of the observed NSOFCs heritability. METHODS: Here, we performed GWASs of 1615 NSCPO cases and 2340 controls, and then conducted genome-wide meta-analyses of NSOFCs, totaling 6812 NSCL/P cases, 2614 NSCPO cases, and 19,165 controls from the Chinese Han population. RESULTS: We identify 47 risk loci with genome-wide pmeta -value <5.0 × 10-8 , 5 risk loci (1p32.1, 3p14.1, 3p14.3, 3p21.31, and 13q22.1) of which are new. All of the 47 susceptibility loci conjointly account for 44.12% of the NSOFCs' heritability in the Chinese Han population. CONCLUSION: Our results improve the comprehending of genetic susceptibility to NSOFCs and provide new views into the genetic etiology of craniofacial anomalies.
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CaMK4 has an important function in autoimmune diseases, and the contribution of CaMK4 in psoriasis remains obscure. Here, we show that CaMK4 expression is significantly increased in psoriatic lesional skin from psoriasis patients compared to healthy human skin as well as inflamed skin from an imiquimod (IMQ)-induced mouse model of psoriasis compared to healthy mouse skin. Camk4-deficient (Camk4-/-) mice treated with IMQ exhibit reduced severity of psoriasis compared to wild-type (WT) mice. There are more macrophages and fewer IL-17A+γδ TCR+ cells in the skin of IMQ-treated Camk4-/- mice compared to IMQ-treated WT mice. CaMK4 inhibits IL-10 production by macrophages, thus allowing excessive psoriatic inflammation. Deletion of Camk4 in macrophages alleviates IMQ-induced psoriatic inflammation in mice. In keratinocytes, CaMK4 inhibits apoptosis as well as promotes cell proliferation and the expression of pro-inflammatory genes such as S100A8 and CAMP. Taken together, these data indicate that CaMK4 regulates IMQ-induced psoriasis by sustaining inflammation and provides a potential target for psoriasis treatment.
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Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina , Psoríase , Animais , Cálcio , Proteína Quinase Tipo 4 Dependente de Cálcio-Calmodulina/genética , Modelos Animais de Doenças , Humanos , Imiquimode , Inflamação , Queratinócitos/metabolismo , Macrófagos/metabolismo , Camundongos , Psoríase/induzido quimicamente , Psoríase/genéticaRESUMO
Backround: Leprosy is very prevalent in many populations around the world, which is well known that both alleles for human leukocyte antigen (HLA) as well as single nucleotide polymorphisms (SNPs) in the HLA region are common in leprosy patients. Previous studies have identified leprosy-associated susceptibility genes that explain only part of disease risk and heritability. In view of the complicated characteristics of the major histocompatibility complex (MHC) region, this study aimed to explore the development and variation of HLA in leprosy and its possible mechanism. Methods: Previous genome-wide association data were extracted from Han and minority populations in southern China for HLA fine-mapping studies. Insertion and deletion (INDEL), SNP, and copy number variation (CNV) imputation were determined by using the Thousand People Database (1KGP Phase 3 Dataset) as a reference panel. The HAN-MHC database was used to input the HLA classical alleles and amino acids in the MHC region, and further step-regression analysis was performed to analyze independent variation signals associated with leprosy. Results: The most significant locus rs75324027 (the same locus as rs602875 in the HLA-DR region) [p = 7.49E-09, OR= 0.62, 95%,CI: 0.52-0.73] in the intergene region between HLA-DQA1 and HLA-DRB1 was related with leprosy in M-S(Han leprosy patients in south China)disease. In M-SM (Leprosy patients of ethnic minorities in south China)disease, one of the most significant loci of the HLA-DQB1 gene was 6-32626438-A-T (p = 4.49E-08, OR = 0.36, 95%,CI: 0.25-0.52). Therefore, rs75324027 is a locus in M-S disease, and 6-32626438-a-T may be a new locus in M-SM disease. The interaction between 6 and 32626438-A-T and RS75324027 was analyzed, and A significant interaction relationship was found. In the optimal model, the accuracy of prediction was 0.5974, cross-validation Consistency:10, p = 0.0107. Conclusion: In conclusion, this study is the first to assess the association between HLA and leprosy susceptibility in Han and other minority populations in southern China using the Thousand Population database and the Han MHC database. In addition, our analysis validated the previously reported locus rs602875 in the HLA-DR region and for the first time identified an unreported independent locus in leprosy among ethnic minorities in southern China.
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As autoimmune skin diseases, both bullous pemphigoid (BP) and dermatomyositis (DM) show significant associations with the major histocompatibility complex (MHC) region. In fact, the coexistence of BP and DM has been previously reported. Therefore, we hypothesized that there may be a potential genetic correlation between BP and DM. Based on data for 312 BP patients, 128 DM patients, and 6793 healthy control subjects, in the MHC region, we imputed single-nucleotide polymorphisms (SNP), insertions and deletions (INDEL), and copy number variations (CNV) using the 1KGP phase 3 dataset and amino acids (AA) and SNP using a Han-MHC reference database. An association study revealed the most significant SNP associated with BP, namely, rs580921 (p = 1.06E-08, odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.37-1.90), which is located in the C6orf10 gene, and the most significant classic human leukocyte antigen (HLA) allele associated with DM, namely, HLA-DPB1*1701 (p = 6.56E-10, OR = 3.61, 95% CI = 2.40-5.42). Further stepwise regression analyses with rs580921 identified a threonine at position 163 of the HLA-B gene as a new independent disease-associated AA, and HLA-DPB1*1701 indicated that no loci were significant. Three-dimensional ribbon models revealed that the HLA-B AA position 163 (p = 3.93E-07, OR = 1.64, 95% CI = 1.35-1.98) located in the α2 domain of the HLA-B molecule was involved in the process of specific antigen presentation. The calculations showed that there was no significant genetic correlation between BP and DM. Our study identified three significant loci in the MHC region, proving that the HLA region was significantly correlated with BP and DM separately. Our research highlights the key role of the MHC region in disease susceptibility.
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Dermatomiosite , Penfigoide Bolhoso , Humanos , Alelos , Aminoácidos/genética , Povo Asiático/genética , China/epidemiologia , Dermatomiosite/genética , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Antígenos HLA-B/genética , Complexo Principal de Histocompatibilidade/genética , Penfigoide Bolhoso/genética , Polimorfismo de Nucleotídeo Único , Treonina/genéticaRESUMO
Limited knowledge of the long-term effects of excessive iodine (EI) intake on biomolecular signatures in the liver/pancreas/kidney prompted this study. Herein, following 6 months of exposure in mice to 300, 600, 1200 or 2400 µg/L iodine, the biochemical signature of alterations to the liver/pancreas/kidney was profiled using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy coupled with principal component analysis-linear discriminant analysis (PCA-LDA). Our research showed that serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), serum creatinine (Scr), insulin, blood glucose levels and homeostasis model assessment for insulin resistance (HOMA-IR) index in the 1200 and 2400 µg/L iodine-treated groups were significantly increased compared with those in the control group. Moreover, histological analysis showed that the liver/kidney/pancreas tissues of mice exposed to EI treatment displayed substantial morphological abnormalities, such as a loss of hepatic architecture, glomerular cell vacuolation and pancreatic neutrophilic infiltration. Notably, EI treatment caused distinct biochemical signature segregation between EI-exposed versus the control liver/pancreas/kidney. The main biochemical alterations between EI-exposed and control groups were observed for protein phosphorylation, protein secondary structures and lipids. The ratios of amide I-to-amide II (1674 cm-1 /1570 cm-1 ), α-helix-to-ß-sheet (1657 cm-1 /1635 cm-1 ), glycogen-to-phosphate (1030 cm-1 /1086 cm-1 ) and the peptide aggregation (1 630 cm-1 /1650 cm-1 ) level of EI-treated groups significantly differed from the control group. Our study demonstrated that EI induced hepatic, renal and pancreatic injury by disturbing the structure, metabolism and function of the cell membrane. This finding provides the new method and implication for human health assessment regarding long-term EI intake.