Dynamic m6 A profiles reveal the role of YTHDC2-TLR2 signaling axis in Talaromyces marneffei infection.

Talaromyces marneffei (TM) immune evasion is an important factor leading to the high mortality rate of Penicilliosis marneffei. N6 -methyladenosine (m6 A) plays important roles in host immune response to various pathogen infections, yet its role in TM and HIV/TM coinfection remains largely unexplored. Here we reported genome-wide transcriptional m6 A profiles of TM mono-infection and HIV/TM coinfection. Our finding revealed dynamic alterations in global m6 A levels and upregulation of the m6 A reader YTH N6 -methyladenosine RNA binding protein C2 (YTHDC2) in TM-infected macrophages. Knockdown of YTHDC2 in TM-infected cells showed an elevated expression of TLR2 through m6 A-dependence, along with upregulation of TNF-α and IL1-ß. Overall, we characterized the m6 A profiles of the host and fungus before and after TM infection, and demonstrated that YTHDC2 mediates the key m6 A site of TLR2 to exert its function. These findings provide new insights into the underlying mechanisms and novel therapeutic approaches for TM diseases.

[Clinical and genetic analysis of five children with Catecholaminergic polymorphic ventricular tachycardia due to variants of RYR2 gene].

OBJECTIVE: To explore the clinical and genetic characteristics of five children with Catecholaminergic polymorphic ventricular tachycardia (CPVT). METHODS: Five children with clinical manifestations consistent with CPVT admitted to the Department of Cardiology of Children's Hospital Affiliated to Zhengzhou University from November 2019 to November 2021 were selected as the study subjects. Their clinical data were collected. Potential variants were detected by whole exome sequencing, and Sanger sequencing was used to verify the candidate variants. All patients were treated with ß-blocker propranolol and followed up. RESULTS: All patients had developed the disease during exercise and presented with syncope as the initial clinical manifestation. Electrocardiogram showed sinus bradycardia. The first onset age of the 5 patients were (10.4 ± 2.19) years, and the time of delayed diagnosis was (1.6 ± 2.19) years. All of the children were found to harbor de novo heterozygous missense variants of the RYR2 gene, including c.6916G>A (p.V2306I), c.527G>C (p.R176P), c.12271G>A (p.A4091T), c.506G>T (p.R169L) and c.6817G>A (p.G2273R). Among these, c.527G>C (p.R176P) and c.6817G>A (p.G2273R) were unreported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.527G>C (p.R176P) was classified as a pathogenic variant (PS2+PM1+PM2_Supporting+PM5+PP3+PP4), and the c.6817G>A (p.G2273R) was classified as a likely pathogenic variant (PS2+PM2_Supporting+PP3+PP4). The symptoms of all children were significantly improved with the propranolol treatment, and none has developed syncope during the follow up. CONCLUSION: Discovery of the c.527G>C (p.R176P) and c.6817G>A (p.G2273R) variants has expanded the mutational spectrum of the RYR2 gene. Genetic testing of CPVT patients can clarify the cause of the disease and provide a reference for their genetic counseling.

Cardiomyopathy in children: a single-centre, retrospective study of genetic and clinical characteristics.

OBJECTIVES: This study aimed to describe the genetic and clinical characteristics of paediatric cardiomyopathy in a cohort of Chinese patients. METHODS: We retrospectively reviewed the clinical history and mutation spectrum of 75 unrelated Chinese paediatric patients who were diagnosed with cardiomyopathy and referred to our hospital between January 2016 and December 2022. RESULTS: Seventy-five children with cardiomyopathy were enrolled, including 32 (42.7%) boys and 43 (57.3%) girls. Dilated cardiomyopathy was the most prevalent cardiomyopathy (61.3%) in the patients, followed by hypertrophic cardiomyopathy (17.3%), ventricular non-compaction (14.7%), restrictive cardiomyopathy (5.3%) and arrhythmogenic right ventricular cardiomyopathy (1.3%). Whole-exome sequencing and targeted next-generation sequencing identified 34 pathogenic/likely pathogenic variants and 1 copy number variant in 14 genes related to cardiomyopathy in 30 children, accounting for 40% of all patients. TNNC1 p.Asp65Asn and MYH7 p.Glu500Lys have not been reported previously. The follow-up time ranged from 2 months to 6 years. Twenty-two children died (mortality rate 29%). CONCLUSIONS: Comprehensive genetic testing was associated with a 40% yield of causal genetic mutations in Chinese cardiomyopathy cases. We found diversity in the mutation profile in different patients, which suggests that the mutational background of cardiomyopathy in China is heterogeneous, and the findings may be helpful to those counselling patients and families.

Pan-cancer Analysis Reveals m6A Variation and Cell-specific Regulatory Network in Different Cancer Types.

As the most abundant messenger RNA (mRNA) modification, N6-methyladenosine (m6A) plays a crucial role in RNA fate, impacting cellular and physiological processes in various tumor types. However, our understanding of the role of the m6A methylome in tumor heterogeneity remains limited. Herein, we collected and analyzed m6A methylomes across nine human tissues from 97 m6A sequencing (m6A-seq) and RNA sequencing (RNA-seq) samples. Our findings demonstrate that m6A exhibits different heterogeneity in most tumor tissues compared to normal tissues, which contributes to the diverse clinical outcomes in different cancer types. We also found that the cancer type-specific m6A level regulated the expression of different cancer-related genes in distinct cancer types. Utilizing a novel and reliable method called "m6A-express", we predicted m6A-regulated genes and revealed that cancer type-specific m6A-regulated genes contributed to the prognosis, tumor origin, and infiltration level of immune cells in diverse patient populations. Furthermore, we identified cell-specific m6A regulators that regulate cancer-specific m6A and constructed a regulatory network. Experimental validation was performed, confirming that the cell-specific m6A regulator CAPRIN1 controls the m6A level of TP53. Overall, our work reveals the clinical relevance of m6A in various tumor tissues and explains how such heterogeneity is established. These results further suggest the potential of m6A in cancer precision medicine for patients with different cancer types.

Weighted gene co-expression network analysis revealed T cell differentiation associated with the age-related phenotypes in COVID-19 patients.

The risk of severe condition caused by Corona Virus Disease 2019 (COVID-19) increases with age. However, the underlying mechanisms have not been clearly understood. The dataset GSE157103 was used to perform weighted gene co-expression network analysis on 100 COVID-19 patients in our analysis. Through weighted gene co-expression network analysis, we identified a key module which was significantly related with age. This age-related module could predict Intensive Care Unit status and mechanical-ventilation usage, and enriched with positive regulation of T cell receptor signaling pathway biological progress. Moreover, 10 hub genes were identified as crucial gene of the age-related module. Protein-protein interaction network and transcription factors-gene interactions were established. Lastly, independent data sets and RT-qPCR were used to validate the key module and hub genes. Our conclusion revealed that key genes were associated with the age-related phenotypes in COVID-19 patients, and it would be beneficial for clinical doctors to develop reasonable therapeutic strategies in elderly COVID-19 patients.

Genome-Wide Profiling Reveals Alternative Polyadenylation of Innate Immune-Related mRNA in Patients With COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic has caused many deaths worldwide. To date, the mechanism of viral immune escape remains unclear, which is a great obstacle to developing effective clinical treatment. RNA processing mechanisms, including alternative polyadenylation (APA) and alternative splicing (AS), are crucial in the regulation of most human genes in many types of infectious diseases. Because the role of APA and AS in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unknown, we performed de novo identification of dynamic APA sites using a public dataset of human peripheral blood mononuclear cell (PBMC) RNA-Seq data in COVID-19 patients. We found that genes with APA were enriched in innate immunity -related gene ontology categories such as neutrophil activation, regulation of the MAPK cascade and cytokine production, response to interferon-gamma and the innate immune response. We also reported genome-wide AS events and enriched viral transcription-related categories upon SARS-CoV-2 infection. Interestingly, we found that APA events may give better predictions than AS in COVID-19 patients, suggesting that APA could act as a potential therapeutic target and novel biomarker in those patients. Our study is the first to annotate genes with APA and AS in COVID-19 patients and highlights the roles of APA variation in SARS-CoV-2 infection.