Genome-wide meta-analysis and fine-mapping prioritize potential causal variants and genes related to leprosy.

To date, genome-wide association studies (GWASs) have discovered 35 susceptible loci of leprosy; however, the cumulative effects of these loci can only partially explain the overall risk of leprosy, and the causal variants and genes within these loci remain unknown. Here, we conducted out new GWASs in two independent cohorts of 5007 cases and 4579 controls and then a meta-analysis in these newly generated and multiple previously published (2277 cases and 3159 controls) datasets were performed. Three novel and 15 previously reported risk loci were identified from these datasets, increasing the known leprosy risk loci of explained genetic heritability from 23.0 to 38.5%. A comprehensive fine-mapping analysis was conducted, and 19 causal variants and 14 causal genes were identified. Specifically, manual checking of epigenomic information from the Epimap database revealed that the causal variants were mainly located within the immune-relevant or immune-specific regulatory elements. Furthermore, by using gene-set, tissue, and cell-type enrichment analyses, we highlighted the key roles of immune-related tissues and cells and implicated the PD-1 signaling pathways in the pathogenetic mechanism of leprosy. Collectively, our study identified candidate causal variants and elucidated the potential regulatory and coding mechanisms for genes associated with leprosy.

Combination treatment with antibiotics and photodynamic therapy in refractory mycobacterium marinum infection: A case report.

Mycobacterium marinum can cause skin infection. Treatment of this infection often requires a chronic multidrug regimen. For refractory cases with progression, relapse, or slow recovery, long-term medication may cause problems such as ineffectiveness, poor patient compliance, and drug intolerance. We report a refractory case with a total treatment time of 2 years, successfully cured by the combination of antibiotics and photodynamic therapy. Our case shows that combination treatment with antibiotics and photodynamic therapy may be an effective approach for refractory Mycobacterium marinum infection.

Distribution of tubal endometriosis: A 10-year retrospective study.

AIM: To investigate the distribution of tubal endometriosis (EM) in the right and left sides and four parts of the fallopian tube. METHODS: A retrospective, cross-sectional study was conducted on patients with tubal EM at the Fourth Affiliated Hospital of Guangxi Medical University from October 2011 to September 2021. Chi-square and binomial tests were used for analysis. RESULTS: Thirty-four patients (53.97%) had tubal resection due to EM (EM group). Twenty-nine patients (46.03%) had tubal resection due to non-EM (non-EM group). Thirty-two patients (50.80%) had left fallopian tube EM, 21 (33.33%) had right fallopian tube EM, and 10 (15.87%) had bilateral fallopian tube EM, with significant differences among them (p = 0.000). In the EM group, 15 patients (44.12%) had left fallopian tube EM, 13 (38.23%) had right fallopian tube EM, and 6 (17.65%) had bilateral fallopian tube EM (p = 0.052). In the non-EM group, statistically different (p = 0.001) diagnoses of left fallopian tube EM, right fallopian tube EM, and bilateral fallopian tube EM were 17 (58.62%), 8 (27.59%), and 4 (13.79%), respectively. In the EM group, 18 patients (52.94%) were in the ampullary region; 16 (47.06%) were in the nonampullary region (p = 0.864). In the non-EM group, 22 cases (75.86%) were in the ampullary region and 7 (24.14%) were in the nonampullary region, with a significant difference between them (p = 0.008). CONCLUSIONS: The incidence of left fallopian tube EM was higher than that of right and bilateral fallopian tube EM. The incidence of tubal ampullary EM was higher than that of nonampullary region.

Effects of miR­195­5p on cell proliferation and apoptosis in gestational diabetes mellitus via targeting EZH2.

Gestational diabetes mellitus (GDM) is a type of diabetes mellitus (DM) that occurs during pregnancy. The present study aimed to investigate the roles of microRNA (miR)­195­5p and enhancer of zeste homolog 2 (EZH2) in GDM, and their potential association. Human umbilical vein endothelial cells (HUVECs) were collected from healthy and GDM umbilical cords, and the endothelial properties were detected by flow cytometry. mRNA expression levels of miR­195­5p and EZH2, and EZH2 protein expression levels were detected by reverse transcription­quantitative PCR (RT­qPCR) and western blot analysis, respectively. Cell colony formation and flow cytometry were performed to determine cell proliferation and apoptosis. Furthermore, the target gene of miR­195­5p was predicted and assessed using a dual­luciferase reporter assay. The levels of cell viability, proliferation and apoptosis following the overexpression of miR­195­5p, EZH2 or miR­195­5p + EZH2, were detected using Cell Counting Kit­8, colony formation and flow cytometry assays, respectively. In addition, the mRNA expression levels of miR­195­59 and EZH2, and EZH2 protein expression levels following transfection with overexpression plasmids were detected using RT­qPCR and western blot analysis, respectively. It was identified that high mRNA expression of miR­195­5p, and low EZH2 mRNA and protein expression levels decreased the level of cell proliferation and the high apoptotic rate of GDM­HUVECs. In addition, miR­195­5p was predicted and identified to target EZH2, and miR­195­5p overexpression was identified to inhibit cell proliferation and promote apoptosis. However, it was demonstrated that upregulation of EZH2 could alleviate the inhibition of cell proliferation and the increased apoptotic rate induced by miR­195­5p overexpression. Therefore, the present results suggested that miR­195­5p may inhibit cell viability, proliferation and promote apoptosis by targeting EZH2 in GDM­induced HUVECs.

Incidence of Post-Liver Transplant Hepatic Dysfunction After Sustained Virologic Response Following Direct-Acting Anti-Hepatitis C Therapy.

OBJECTIVES: Newly developed, direct-acting antiviral therapy is effective in over 90% of cases to eradicate hepatitis C virus infection. Direct-acting antiviral therapy is also effective in liver transplant recipients with recurrent hepatitis C virus infection. However, hepatic function after sustained virologic response in transplant recipients is unknown. Here, we aimed to uncover the incidence of hepatic dysfunction in this patient group at our center. MATERIALS AND METHODS: Our study included 40 consecutive (January 2014 to February 2016) and compliant posttransplant recipients who achieved sustained viral response from direct-acting antiviral therapy. Patients were investigated for incidence and causes of hepatic dysfunction. RESULTS: In our patient group, 4 (10%) experienced hepatic dysfunction with stable baseline immunosuppression, with 2 having drastic increases in alanine aminotransferase at 15 and 32 weeks after direct-acting antiviral therapy. Biopsies showed hepatitis, and both patients were treated with hydrocortisone, which increased their baseline immunosuppression. The 3rd patient had an increase in bilirubin at 21 weeks posttherapy, with biopsy showing macrovascular steatosis. The 4th patient had a rapid increase in bilirubin at 7 weeks after direct-acting antiviral therapy, with biopsy showing significant duct loss. CONCLUSIONS: During the study period, 10% of patients experienced hepatic dysfunction after sustained viral response. Presumed causative factors included partial immune reconstitution and nonalcoholic fatty liver disease.

Genetic Association of Pulmonary Surfactant Protein Genes, SFTPA1, SFTPA2, SFTPB, SFTPC, and SFTPD With Cystic Fibrosis.

Surfactant proteins (SP) are involved in surfactant function and innate immunity in the human lung. Both lung function and innate immunity are altered in CF, and altered SP levels and genetic association are observed in Cystic Fibrosis (CF). We hypothesized that single nucleotide polymorphisms (SNPs) within the SP genes associate with CF or severity subgroups, either through single SNP or via SNP-SNP interactions between two SNPs of a given gene (intragenic) and/or between two genes (intergenic). We genotyped a total of 17 SP SNPs from 72 case-trio pedigree (SFTPA1 (5), SFTPA2 (4), SFTPB (4), SFTPC (2), and SFTPD (2)), and identified SP SNP associations by applying quantitative genetic principles. The results showed (a) Two SNPs, SFTPB rs7316 (p = 0.0083) and SFTPC rs1124 (p = 0.0154), each associated with CF. (b) Three intragenic SNP-SNP interactions, SFTPB (rs2077079, rs3024798), and SFTPA1 (rs1136451, rs1059057 and rs4253527), associated with CF. (c) A total of 34 intergenic SNP-SNP interactions among the 4 SP genes to be associated with CF. (d) No SNP-SNP interaction was observed between SFTPA1 or SFTPA2 and SFTPD. (e) Equal number of SNP-SNP interactions were observed between SFTPB and SFTPA1/SFTPA2 (n = 7) and SP-B and SFTPD (n = 7). (f) SFTPC exhibited significant SNP-SNP interactions with SFTPA1/SFTPA2 (n = 11), SFTPB (n = 4) and SFTPD (n = 3). (g) A single SFTPB SNP was associated with mild CF after Bonferroni correction, and several intergenic interactions that are associated (p < 0.01) with either mild or moderate/severe CF were observed. These collectively indicate that complex SNP-SNP interactions of the SP genes may contribute to the pulmonary disease in CF patients. We speculate that SPs may serve as modifiers for the varied progression of pulmonary disease in CF and/or its severity.

Contributions of the σ(W) , σ(M) and σ(X) regulons to the lantibiotic resistome of Bacillus subtilis.

In Bacillus subtilis, the extracytoplasmic function (ECF) σ factors σ(M) , σ(W) and σ(X) all contribute to resistance against lantibiotics. Nisin, a model lantibiotic, has a dual mode of action: it inhibits cell wall synthesis by binding lipid II, and this complex also forms pores in the cytoplasmic membrane. These activities can be separated in a nisin hinge-region variant (N20P M21P) that binds lipid II, but no longer permeabilizes membranes. The major contribution of σ(M) to nisin resistance is expression of ltaSa, encoding a stress-activated lipoteichoic acid synthase, and σ(X) functions primarily by activation of the dlt operon controlling d-alanylation of teichoic acids. Together, σ(M) and σ(X) regulate cell envelope structure to decrease access of nisin to its lipid II target. In contrast, σ(W) is principally involved in protection against membrane permeabilization as it provides little protection against the nisin hinge region variant. σ(W) contributes to nisin resistance by regulation of a signal peptide peptidase (SppA), phage shock proteins (PspA and YvlC, a PspC homologue) and tellurite resistance related proteins (YceGHI). These defensive mechanisms are also effective against other lantibiotics such as mersacidin, gallidermin and subtilin and comprise an important subset of the intrinsic antibiotic resistome of B. subtilis.