Genetic analysis of different subtypes of Aseptic pustulosis in the Chinese population.

Aseptic pustulosis involves inflammatory skin conditions with non-bacterial pustules on red skin, accompanied by neutrophil and eosinophil infiltration in the epidermis. Dysregulation of the IL-36 pathway leads to neutrophil aggregation and pustule formation. Variants in IL36RN, CARD14, AP1S3, MPO, SERPINA3, and BTN3A3 genes have been identified in GPP in the past. Some patients with ACH, PPP, and AGEP also exhibit mutations in IL36RN, CARD14, and AP1S3 genes, albeit with regional and population-specific variations. This study aims to explore a shared genetic foundation among aseptic pustulosis. We performed Sanger sequencing on six genes in 126 aseptic pustulosis patients. Genetic analysis identified IL36RN variants strongly associated with ACH, AGEP, and SPD. Immunohistochemistry revealed elevated inflammatory cytokines in all subtypes. This study establishes a significant association between IL36RN variants and ACH, AGEP, and SPD, emphasizing the IL-1/IL-36 chemokine-neutrophil axis as a common pathogenic mechanism. Targeting this axis holds promise for therapeutic interventions in aseptic pustulosis.

Early onset of pathological polyploidization and cellular senescence in hepatocytes lacking RAD51 creates a pro-fibrotic and pro-tumorigenic inflammatory microenvironment.

BACKGROUND AND AIMS: RAD51 recombinase (RAD51) is a highly conserved DNA repair protein and is indispensable for embryonic viability. As a result, the role of RAD51 in liver development and function is unknown. Our aim was to characterize the function of RAD51 in postnatal liver development. APPROACH AND RESULTS: RAD51 is highly expressed during liver development and during regeneration following hepatectomy and hepatic injury, and is also elevated in chronic liver diseases. We generated a hepatocyte-specific Rad51 deletion mouse model using Alb -Cre ( Rad51 -conditional knockout (CKO)) and Adeno-associated virus 8-thyroxine-binding globulin-cyclization recombination enzyme to evaluate the function of RAD51 in liver development and regeneration. The phenotype in Rad51 -CKO mice is dependent on CRE dosage, with Rad51fl/fl ; Alb -Cre +/+ manifesting a more severe phenotype than the Rad51fl/fl ; Alb -Cre +/- mice. RAD51 deletion in postnatal hepatocytes results in aborted mitosis and early onset of pathological polyploidization that is associated with oxidative stress and cellular senescence. Remarkable liver fibrosis occurs spontaneously as early as in 3-month-old Rad51fl/fl ; Alb -Cre +/+ mice. While liver regeneration is compromised in Rad51 -CKO mice, they are more tolerant of carbon tetrachloride-induced hepatic injury and resistant to diethylnitrosamine/carbon tetrachloride-induced HCC. A chronic inflammatory microenvironment created by the senescent hepatocytes appears to activate ductular reaction the transdifferentiation of cholangiocytes to hepatocytes. The newly derived RAD51 functional immature hepatocytes proliferate vigorously, acquire increased malignancy, and eventually give rise to HCC. CONCLUSIONS: Our results demonstrate a novel function of RAD51 in liver development, homeostasis, and tumorigenesis. The Rad51 -CKO mice represent a unique genetic model for premature liver senescence, fibrosis, and hepatocellular carcinogenesis.

CYBB-Mediated Ferroptosis Associated with Immunosuppression in Mycobacterium leprae-Infected Monocyte-Derived Macrophages.

Mycobacterium leprae-infected macrophages preferentially exhibit the regulatory M2 phenotype in vitro, which helps the immune escape unabated growth of M leprae in host cells. The mechanism that triggers macrophage polarization is still unknown. In this study, we performed single-cell RNA sequencing to determine the initial responses of human monocyte-derived macrophages against M leprae infection of 4 healthy individuals and found an increase in a major alternative-activated macrophage type that overexpressed NEAT1, CCL2, and CD163. Importantly, further functional analysis showed that ferroptosis was positively correlated with M2 polarization of macrophages, and in vitro experiments have shown that inhibition of ferroptosis promotes the survival of M leprae within macrophages. In addition, further joint analysis of our results with mutisequencing data from patients with leprosy and in vitro validation identified that CYBB was the pivotal molecule for ferroptosis that could promote the M2 polarization of M leprae-infected macrophages, resulting in the immune escape and unabated growth of pathogenic bacteria. Overall, our results suggest that M leprae facilitated its survival by inducing CYBB-mediated macrophage ferroptosis leading to its alternative activation and might reveal the potential for a new therapeutic strategy of leprosy.

Nitric oxide-dependent immunosuppressive function of thymus-derived mesenchymal stromal/stem cells.

BACKGROUND: The thymus is required for T cell development and the formation of the adaptive immunity. Stromal cells, which include thymic epithelial cells (TECs) and mesenchymal stromal cells (MSCs), are essential for thymic function. However, the immunomodulatory function of thymus-derived MSCs (T-MSCs) has not been fully explored. METHODS: MSCs were isolated from mouse thymus and their general characteristics including surface markers and multi-differentiation potential were characterized. The immunomodulatory function of T-MSCs stimulated by IFN-γ and TNF-α was evaluated in vitro and in vivo. Furthermore, the spatial distribution of MSCs in the thymus was interrogated by using tdTomato-flox mice corssed to various MSC lineage Cre recombinase lines. RESULTS: A subset of T-MSCs express Nestin, and are mainly distributed in the thymic medulla region and cortical-medulla junction, but not in the capsule. The Nestin-positive T-MSCs exhibit typical immunophenotypic characteristics and differentiation potential. Additionally, when stimulated with IFN-γ and TNF-α, they can inhibit activated T lymphocytes as efficiently as BM-MSCs, and this function is dependent on the production of nitric oxide (NO). Additionally, the T-MSCs exhibit a remarkable therapeutic efficacy in acute liver injury and inflammatory bowel disease (IBD). CONCLUSIONS: Nestin-positive MSCs are mainly distributed in medulla and cortical-medulla junction in thymus and possess immunosuppressive ability upon stimulation by inflammatory cytokines. The findings have implications in understanding the physiological function of MSCs in thymus.

Single-cell sequencing analysis reveals development and differentiation trajectory of Schwann cells manipulated by M. leprae.

BACKGROUND: M. leprae preferentially infects Schwann cells (SCs) in the peripheral nerves leading to nerve damage and irreversible disability. Knowledge of how M. leprae infects and interacts with host SCs is essential for understanding mechanisms of nerve damage and revealing potential new therapeutic strategies. METHODOLOGY/PRINCIPAL FINDINGS: We performed a time-course single-cell sequencing analysis of SCs infected with M. leprae at different time points, further analyzed the heterogeneity of SCs, subpopulations associated with M. leprae infection, developmental trajectory of SCs and validated by Western blot or flow cytometry. Different subpopulations of SCs exhibiting distinct genetic features and functional enrichments were present. We observed two subpopulations associated with M. leprae infection, a stem cell-like cell subpopulation increased significantly at 24 h but declined by 72 h after M. leprae infection, and an adipocyte-like cell subpopulation, emerged at 72 h post-infection. The results were validated and confirmed that a stem cell-like cell subpopulation was in the early stage of differentiation and could differentiate into an adipocyte-like cell subpopulation. CONCLUSIONS/SIGNIFICANCE: Our results present a systematic time-course analysis of SC heterogeneity after infection by M. leprae at single-cell resolution, provide valuable information to understand the critical biological processes underlying reprogramming and lipid metabolism during M. leprae infection of SCs, and increase understanding of the disease-causing mechanisms at play in leprosy patients as well as revealing potential new therapeutic strategies.

TAP2 Drives HLA-B∗13:01‒Linked Dapsone Hypersensitivity Syndrome Tolerance and Reactivity.

Dapsone hypersensitivity syndrome (DHS) is restricted to HLA-B∗13:01. However, the positive predictive value for HLA-B∗13:01 is only 7.8%. To explore the potential coexisting factors involved in the occurrence of DHS, we carried out a GWAS and a genome-wide DNA methylation profile analysis comparing patients with DHS with dapsone-tolerant control subjects (all carrying HLA-B∗13:01). No non-HLA SNPs associated with DHS were identified at the genome-wide level. However, the pathway of antigen processing and presentation was enriched in patients with DHS, and the gene TAP2 was identified. Expression of TAP2 and its molecular chaperone, TAP1, were validated by quantitative PCR, and in vitro functional experiments were performed. The results showed that patients with DHS have higher mRNA levels of TAP1 and TAP2 and an enhanced capacity for antigen-presenting cells activating dapsone-specific T cells compared with dapsone-tolerant controls. Activation of dapsone-specific T cells was inhibited when TAP function of antigen-presenting cells was impaired. This study shows that epigenetic regulation of TAP1 and TAP2 affects the function of antigen-presenting cells and is a critical factor that mediates the development of DHS.

Induction of IL-32 in the immune response of keratinocytes to Mycobacterium marinum infection.

Keratinocytes are the predominant cell type in the skin epidermis, and they not only protect the skin from the influence of external physical factors but also function as an immune barrier against microbial invasion. However, little is known regarding the immune defence mechanisms of keratinocytes against mycobacteria. Here, we performed single-cell RNA sequencing (scRNA-seq) on skin biopsy samples from patients with Mycobacterium marinum infection and bulk RNA sequencing (bRNA-seq) on M. marinum-infected keratinocytes in vitro. The combined analysis of scRNA-seq and bRNA-seq data revealed that several genes were upregulated in M. marinum-infected keratinocytes. Further in vitro validation of these genes by quantitative polymerase chain reaction and western blotting assay confirmed the induction of IL-32 in the immune response of keratinocytes to M. marinum infection. Immunohistochemistry also showed the high expression of IL-32 in patients' lesions. These findings suggest that IL-32 induction is a possible mechanism through which keratinocytes defend against M. marinum infection; this could provide new targets for the immunotherapy of chronic cutaneous mycobacterial infections.

IL-23/IL-23R Promote Macrophage Pyroptosis and T Helper 1/T Helper 17 Cell Differentiation in Mycobacterial Infection.

Pathogen-induced epigenetic modifications can reshape anti-infection immune processes and control the magnitude of host responses. DNA methylation profiling has identified crucial aberrant methylation changes associated with diseases, thus providing biological insights into the roles of epigenetic factors in mycobacterial infection. In this study, we performed a genome-wide methylation analysis of skin biopsies from patients with leprosy and healthy controls. T helper 17 differentiation pathway was found to be significantly associated with leprosy through functional enrichment analysis. As a key gene in this pathway, IL-23R was found to be critical to mycobacterial immunity in leprosy, according to integrated analysis with DNA methylation, RNA sequencing, and GWASs. Functional analysis revealed that IL-23/IL-23R-enhanced bacterial clearance by activating caspase-1/GSDMD-mediated pyroptosis in a manner dependent on NLRP3 through signal transducer and activator of transcription 3 signaling in macrophages. Moreover, IL23/IL-23R promoted T helper 1 and T helper 17 cell differentiation and proinflammatory cytokine secretion, thereby increasing host bactericidal activity. IL-23R knockout attenuated the effects and increased susceptibility to mycobacterial infection mentioned earlier. These findings illustrate the biological functions of IL-23/IL-23R in modulating intracellular bacterial clearance in macrophages and further support their regulatory effects in T helper cell differentiation. Our study highlights that IL-23/IL-23R might serve as potential targets for the prevention and treatment of leprosy and other mycobacterial infections.

Barriers and facilitators to lower extremity orthotic compliance in the pediatric population: A scoping review of the literature.

Despite the purported benefits of lower extremity orthotics in the literature, pediatric compliance rates remain low. This scoping review synthesized the available literature regarding barriers and facilitators to lower extremity orthotic compliance in the pediatric population using the framework of the International Classification of Functioning, Disability and Health: Children and Youth (ICF). A comprehensive search of MEDLINE, EMBASE, and CINAHL was conducted on May 11, 2021, and of PsycInfo on May 12, 2021. Article reference lists and gray literature were also searched. A total of 81 articles were included. Factors described in at least four articles were labeled as universal barriers or facilitators. In the International Classification of Functioning, Disability and Health: Children and Youth domain of Body Functions/Body Structures, universal barriers were present in the global mental functions, experience of self and time, sensory functions, function of joints and bones, and structures related to the skin subcategories, with no universal facilitators identified. For the Activity Limitations/Participation Restrictions domain, one universal facilitator was identified in the mobility subcategory. In the Environmental Contextual Factors domain, universal barriers were found in the attitudes of immediate and extended family and societal attitude subcategories, with both universal barriers and facilitators found in support & relationships: immediate and extended family, support and relationships: health professionals, services, systems, and policies, and products and technology. The reviewed literature strongly emphasizes the importance of proper orthotic fit and comfort, and the child's experience of self, for lower extremity orthotic compliance, along with multiple environmental factors.

Case Report: Lepromatous Leprosy and Psoriasis: An Uncommon Coincidence.

Leprosy, a chronic infectious disease, and psoriasis, an inflammatory disorder, are distinct entities. Epidemiology data show that these two diseases are almost mutually exclusive, with only a few reported cases of their coexistence. Here, we present the case of a patient manifesting intermingled psoriatic and leprosy lesions diagnosed as borderline lepromatous leprosy and plaque psoriasis. Of note, Mycobacterium leprae bacilli were detected not only in the two types of lesions but also in normal-appearing skin and blood.

Single-cell analyses reveal novel molecular signatures and pathogenesis in cutaneous T cell lymphoma.

Sézary syndrome (SS) is a rare and aggressive type of cutaneous T cell lymphoma (CTCL) with a poor prognosis. Intra-tumoral heterogeneity caused by different disease compartments (e.g., skin, blood) and poor understanding of the pathogenesis has created obstacles to the precise diagnosis and targeted treatment of the disease. Here we performed a comprehensive analysis by integrating single-cell transcriptomic data of 40,333 peripheral blood mononuclear cells (PBMCs) and 41,580 skin cells, as well as single-cell chromatin accessibility data of 11,058 PBMCs from an SS patient and matched healthy controls (HCs). Validation and functional investigation were carried out in an independent cohort consisting of SS patients, mycosis fungoides (MF) patients, psoriatic erythroderma patients, and HCs, as well as multiple cell lines. The analysis revealed that skin-derived Sézary cells (SCs) had a shifting trend to more advanced mature phenotypes compared to blood-derived SCs. A series of specific marker genes (TOX, DNM3, KLHL42, PGM2L1, and SESN3) shared in blood- and skin-derived SCs were identified, facilitating the diagnosis and prognosis of MF/SS. Moreover, luciferase reporter assays and gene knockdown assays were used to verify that KLHL42 was transcriptionally activated by GATA3 in SS. Functional assays indicated that KLHL42 silencing significantly inhibited aggressive CTCL cell proliferation and promoted its apoptosis. Therefore, targeting inhibition KLHL42 might serve as a promising therapeutic approach in CTCL.

The immune-suppressive landscape in lepromatous leprosy revealed by single-cell RNA sequencing.

Lepromatous leprosy (L-LEP), caused by the massive proliferation of Mycobacterium leprae primarily in macrophages, is an ideal disease model for investigating the molecular mechanism of intracellular bacteria evading or modulating host immune response. Here, we performed single-cell RNA sequencing of both skin biopsies and peripheral blood mononuclear cells (PBMCs) of L-LEP patients and healthy controls. In L-LEP lesions, we revealed remarkable upregulation of APOE expression that showed a negative correlation with the major histocompatibility complex II gene HLA-DQB2 and MIF, which encodes a pro-inflammatory and anti-microbial cytokine, in the subset of macrophages exhibiting a high expression level of LIPA. The exhaustion of CD8+ T cells featured by the high expression of TIGIT and LAG3 in L-LEP lesions was demonstrated. Moreover, remarkable enhancement of inhibitory immune receptors mediated crosstalk between skin immune cells was observed in L-LEP lesions. For PBMCs, a high expression level of APOE in the HLA-DRhighFBP1high monocyte subset and the expansion of regulatory T cells were found to be associated with L-LEP. These findings revealed the primary suppressive landscape in the L-LEP patients, providing potential targets for the intervention of intracellular bacteria caused persistent infections.

Lyn Kinase Promotes the Proliferation of Malignant Melanoma Cells through Inhibition of Apoptosis and Autophagy via the PI3K/Akt Signaling Pathway.

Melanoma is a malignant tumor of cutaneous melanocytes that is characterized by high grade malignancy, rapid progression and high mortality. Thus far, its specific etiological mechanism has been unclear. In this study, we discovered that Lyn kinase expression was up-regulated in melanoma tissues and cells. The function of Lyn was determined by knocking down its expression with a lentivirus containing Lyn shRNA and upregulating its expression with pcDNA3.1-Lyn in the melanoma cell lines M14 and A375. The results showed that Lyn knockdown could significantly inhibit the proliferation, migration and invasiveness through its inhibition of apoptosis and autophagy via the PI3K/Akt pathway in melanoma cell lines. This was further confirmed by treatment with PI3K inhibitor BEZ235. Up-regulation of Lyn promoted the expression of p-Akt and Cyclin D1. Additionally, we investigated the effects of Lyn inhibitor Bafetinib on melanoma cells and the results were consistent with Lyn knockdown. Collectively, our results indicated that Lyn plays a carcinogenic role in multiple cellular functions during melanoma development through regulating apoptosis and autophagy via the PI3K/Akt pathway and may be a valuable potential target for the clinical treatment of melanoma.

Association of obstructive sleep apnea with hypertension: A systematic review and meta-analysis.

BACKGROUND: Obstructive sleep apnea (OSA) is a sleep disorder characterized as complete or partial upper airflow cessation during sleep. Although it has been widely accepted that OSA is a risk factor for the development of hypertension, the studies focusing on this topic revealed inconsistent results. We aimed to clarify the association between OSA and hypertension, including essential and medication-resistant hypertension. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed. PubMed and Embase databases were used for searching the relevant studies published up to December 31, 2016. A quantitative approach of meta-analysis was performed to estimate the pooled odds ratio (OR) and 95% confidence interval (CI). RESULTS: Twenty-six studies with 51 623 participants (28 314 men, 23 309 women; mean age 51.8 years) met inclusion criteria and were included in this study. Among them, six studies showed a significant association between OSA and resistant hypertension (pooled OR = 2.842, 95% CI = 1.703-3.980, P < 0.05). Meanwhile, the combination of 20 original studies on the association of OSA with essential hypertension also presented significant results with the pooled ORs of 1.184 (95% CI = 1.093-1.274, P < 0.05) for mild OSA, 1.316 (95% CI = 1.197-1.433, P < 0.05) for moderate OSA and 1.561 (95% CI = 1.287-1.835, P < 0.05) for severe OSA. CONCLUSIONS: Our findings indicated that OSA is related to an increased risk of resistant hypertension. Mild, moderate and severe OSA are associated essential hypertension, as well a dose-response manner relationship is manifested. The associations are relatively stronger among Caucasians and male OSA patients.

Regulator of G protein signaling 4 inhibits human melanoma cells proliferation and invasion through the PI3K/AKT signaling pathway.

Melanoma is a tumor produced by skin melanocytes, which has a high metastatic rate and poor prognosis. So far, plenty of work has been done on melanoma, but mechanisms underlying melanoma development have not been fully elucidated. Here we identified regulator of G protein signaling 4(RGS4) as novel therapeutic target for malignant melanoma and its regulating effect on melanoma. We found that endogenous RGS4 expression was much lower in melanoma tissues and cells. In A375 cell line with low endogenous RGS4 expression, the function of RGS4 was detected by up-regulation its expression with pcDNA3.1-RGS4 and knockdown its expression with siRNA. Our results showed that RGS4 could significantly reduce the proliferation, migration and invasion of melanoma cells. RGS4 is an important regulator for the apoptosis of melanocyte, and the apoptosis rate is significantly decreased in low RGS4 enviroment. RGS4 induced non-activation of PI3K/AKT pathway, resulting in decreased expression of E2F1 and Cyclin D1, thus constraining cell proliferation and invasion. These results were further confirmed in M14 cell lines. Collectively, our findings show that RGS4 plays an important role in multiple cellular functions of melanoma development and is valuable to be a therapeutic target.

Age Differences in the Experience of Daily Life Events: A Study Based on the Social Goals Perspective.

This study examined age differences in daily life events related to different types of social goals based on the socioemotional selectivity theory (SST), and determined whether the positivity effect existed in the context of social goals in older adults' daily lives. Over a course of 14 days, 49 older adults and 36 younger adults wrote about up to three life events daily and rated the valence of each event. The findings indicated that (1) although both older and younger adults recorded events related to both emotional and knowledge-acquisition goals, the odds ratio for reporting a higher number of events related to emotional goals compared to the number of events related to knowledge-acquisition goals was 2.12 times higher in older adults than that observed in younger adults. (2) Considering the number of events, there was an age-related positivity effect only for knowledge-related goals, and (3) older adults' ratings for events related to emotional and knowledge-acquisition goals were significantly more positive compared to those observed in younger adults. These findings supported the SST, and to some extent, the positivity effect was demonstrated in the context of social goals.

[Preliminary experience in treatment of chronic prostatitis/chronic pelvic pain syndrome with Longjintonglin capsule].

OBJECTIVE: To explore the effectiveness of Longjintonglin capsule in treatment of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). METHODS: One hundred and thirty-six patients accorded with the demands of chronic prostatitis type III of National Institute of Health (NIH), among them there were 84 cases of chronic prostatitis type IIIA and 52 cases of type IIIB. All of the patients accepted oral Longjintonglin capsule for 3 tablets, 3 times per day, for 3 months. NIH- chronic prostatitis symptom index (NIH-CPSI) and counting leukocytes in expressed prostatic secretions (EPS) were used as target to evaluate the effectiveness. RESULTS: One hundred and thirty-one cases accomplished treatment, in which there were 81 cases of type IIIA, and 50 cases of type IIIB. Overall scores of NIH-CPSI before and after treatment were(24.8 +/- 5.6) and (13.3 +/- 6.8) points respectively, which dropped significantly (average 11.5 points), (P < 0.01). The symptom scores before and after treatment were (15.4 +/- 4.3) and (8.7 +/- 3.9) respectively, which also decreased significantly (average 6.7 points), (P <0.01). The scores for quality of life before and after treatment were (9.4 +/- 3.7) and (4.6 +/- 2.7) respectively, which dropped significant (average 4.8 points) (P < 0.01). The leukocytes counts before and after treatment in patients with CP/CPPs type IIIA were (21.7 +/- 14.5)/HP and (8.8 +/- 12.6)/HP, respectively. Twenty-four cases(18.3%) got cured, 41 cases (31.3%) notable effect, 40 cases (30.5%) some effect, 26 cases (19.8%) no effect, and total effective rate was 80.1%. No apparent side effect was observed in all patients accepted treatment, especially for their kidney and hepatic function. CONCLUSION: Longjintonglin capsule was a safe and effective medicine in treatment of CP/CPPS without significant side effect.