Objective:To explore the genotype and the clinical phenotype of SCN2A-related developmental delay in children. Methods:A case series study was adopted. Collect clinical data from 10 cases of children with SCN2A gene variants diagnosed with global developmental delay/intellectual disability who were admitted to the Children′s Hospital between July 2019 and March 2023. Summarize the clinical phenotype and genotype based on clinical data such as general information, clinical manifestations, imaging examinations, laboratory tests, genetic testing results, and comprehensive pediatric neuropsychological development assessment. Results:A total of 10 patients were recruited, including 7 males and 3 females, with an age range of 27 days to 5 years and 9 months. 9 patients underwent children′s neuropsychological and behavioral assessments, and the results were consistent with global developmental delay, including 2 mild cases, 4 moderate cases, and 3 severe cases. 3 cases had autism spectrum disorder, and 2 cases had epilepsy. 6 patients underwent complete head MRI examination, and 4 of them showed abnormalities, including delayed myelination, widening of the local extra brain space in the frontal lobe, and abnormal frontal lobe morphology. All 10 cases had point variants. Among them, 9 cases are de novo and 1 case is maternal inheritance. Out of 10 cases, there were 5 cases with copy number variations, but all of them were of unknown significance. Among the 10 variants, 8 have been reported and 2 have not been reported, namely c.4145A>T(p.N1382I) and c.4937T>A(p.I1646N). In this study, 4 out of 10 patients with SCN2A variants had variation sites located in the S4 segment of domain which constitute Nav1.2, the sodium ion channel encoded by SCN2A. The developmental quotient level was lower when the variation sites were located in the S4 segment of domain, and the difference was statistically significant ( t=-3.101, P=0.017), indicating that the severity of developmental delay may be related to the localization of amino acids corresponding to variant sites within the protein domain. Conclusion:SCN2A mutations are strongly associated with diverse neurodevelopmental disorders. In this study, the phenotypic spectrum of SCN2A variants encompassed epilepsy, global developmental delay, and autism spectrum disorder. Affected individuals exhibited early-onset developmental delays, predominantly moderate to severe in severity. Voltage-sensing domain dysfunction in sodium channels may constitute a critical pathomechanism underlying neurodevelopmental impairments. Further electrophysiological characterization and molecular mechanistic studies are warranted todelineate the genotype-phenotype correlations between specific variant loci and clinical severity.

Objective:To explore the genotype and the clinical phenotype of SCN2A-related developmental delay in children. Methods:A case series study was adopted. Collect clinical data from 10 cases of children with SCN2A gene variants diagnosed with global developmental delay/intellectual disability who were admitted to the Children′s Hospital between July 2019 and March 2023. Summarize the clinical phenotype and genotype based on clinical data such as general information, clinical manifestations, imaging examinations, laboratory tests, genetic testing results, and comprehensive pediatric neuropsychological development assessment. Results:A total of 10 patients were recruited, including 7 males and 3 females, with an age range of 27 days to 5 years and 9 months. 9 patients underwent children′s neuropsychological and behavioral assessments, and the results were consistent with global developmental delay, including 2 mild cases, 4 moderate cases, and 3 severe cases. 3 cases had autism spectrum disorder, and 2 cases had epilepsy. 6 patients underwent complete head MRI examination, and 4 of them showed abnormalities, including delayed myelination, widening of the local extra brain space in the frontal lobe, and abnormal frontal lobe morphology. All 10 cases had point variants. Among them, 9 cases are de novo and 1 case is maternal inheritance. Out of 10 cases, there were 5 cases with copy number variations, but all of them were of unknown significance. Among the 10 variants, 8 have been reported and 2 have not been reported, namely c.4145A>T(p.N1382I) and c.4937T>A(p.I1646N). In this study, 4 out of 10 patients with SCN2A variants had variation sites located in the S4 segment of domain which constitute Nav1.2, the sodium ion channel encoded by SCN2A. The developmental quotient level was lower when the variation sites were located in the S4 segment of domain, and the difference was statistically significant ( t=-3.101, P=0.017), indicating that the severity of developmental delay may be related to the localization of amino acids corresponding to variant sites within the protein domain. Conclusion:SCN2A mutations are strongly associated with diverse neurodevelopmental disorders. In this study, the phenotypic spectrum of SCN2A variants encompassed epilepsy, global developmental delay, and autism spectrum disorder. Affected individuals exhibited early-onset developmental delays, predominantly moderate to severe in severity. Voltage-sensing domain dysfunction in sodium channels may constitute a critical pathomechanism underlying neurodevelopmental impairments. Further electrophysiological characterization and molecular mechanistic studies are warranted todelineate the genotype-phenotype correlations between specific variant loci and clinical severity.

Objective To explore the applicability of four risk assessment methods in evaluating occupational health risks associated with low-level benzene homologues exposure in key work sites within the automobile manufacturing industry. Methods The work sites (paint mixing and spray painting) with exposure to benzene homologues among six automobile manufacturing enterprises in Guangdong Province were selected as the study subjects using the judgmental sampling method. Qualitative risk assessment, exposure index method, non-carcinogenic risk assessment, and the International Council on Mining and Metals risk rating method were independently applied to evaluate the occupational health risks of benzene homologues at these work sites. Accuracy, consistency, and correlation of the four methods were compared. Results The air levels of benzene, toluene, xylene, and ethylbenzene in work sites of paint mixing and spray painting across all six enterprises met national occupational health standards. The median ratios of occupational exposure limits for benzene and toluene in spray painting site were higher than those in paint mixing site (0.017 vs 0.010, P<0.05). Using this ratio as a reference for evaluating method accuracy, the non-carcinogenic risk assessment method could distinguish paint mixing site from spray painting site in terms of risk level (P<0.05), whereas the other three methods could not (both P>0.05). The result of consistency testing revealed that the Kappa coefficients between the four methods ranged from -0.13-0.26, indicating poor consistency. The result of Spearman correlation analysis showed that the non-carcinogenic risk assessment and exposure index methods had higher correlation with occupational exposure limits ratios (Spearman correlation coefficients were 0.501 and 0.656, respectively, all P<0.05). Conclusion Occupational health risk assessment can serve as a supplementary tool to evaluate the hazard level of key work sites in the automobile manufacturing industry. Non-carcinogenic risk assessment shows higher accuracy.

Objective To analyze the status of occupational disease hazards in Shantou City for 2019 to 2022 and propose corresponding management measures. Methods Technical reports on various occupational-disease-specific activities in Shantou City from 2019 to 2022 were collected and the data were comprehensively analyzed. Results Among the 3 066 enterprises surveyed in the 2020 occupational disease hazard investigation in Shantou City, occupational hazards were reported in 2 982 enterprises (accounting for 97.3%), with 2 955 being small and micro enterprises, accounted for 99.1%(2 955/2 982). The exposure rate of occupational hazards was 58.7% (42 894/73 054) among workers in the surveyed enterprises, with dust and noise exposure rates of 59.7% and 77.8%, respectively. The reported rate of occupational disease hazard projects by employers, regular detection rate of workplace occupational hazards, detection rate of occupational medical examination among workers, and occupational health training rate of key responsible personnel and occupational health management staff were 8.4%, 1.4%, 2.4%, and 4.3%, respectively. The results of occupational hazards monitoring of workplace in key industries from 2019 to 2022 showed that noise had the highest rate of exceeding national standards workplace, followed by silica dust, accounting for 34.2% and 13.8%, with the on-site exceedance rate of 32.2% and 10.0%, respectively. From 2019 to 2022, 31 suspected occupational disease cases were identified in key occupational disease monitoring, including 27 suspected cases of occupational pneumoconiosis and four suspected cases of occupational noise-induced deafness. Conclusion The workers in Shantou City have a high exposure rate to occupational hazards, and the occupational health management level of employers remains low, with noise and silica dust being the most severe occupational hazards. It is essential to improve technical support and service system development for occupational disease prevention and treatment, strengthen supervision and management in key industries and positions, explore occupational health assistance mechanisms for small and micro enterprises, and enforce employers' responsibility in occupational disease prevention to protect workers' occupational health and safety.

Objective:To investigate the phenotypes of Rubinstein-Taybi syndrome (RSTS) caused by variants in the CREBBP or EP300 gene, and the correlation between genotype and phenotype.Methods:This case series study was performed on pediatric patients who were referred to the Children′s Hospital of Capital Institute of Pediatrics between January 2013 and July 2022. Both point variant and copy number deletion in CREBBP or EP300 gene were detected by whole exome sequencing, chromosomal microarray analysis, or copy number variation sequencing (CNV-seq). The variant categories were summarized and phenotype numbers were re-visited for RSTS patients. Based on variant types, the patients were divided into different groups (point variant or copy number deletion, EP300 or CREBBP point variant, and loss of function or missense variant). Phenotype counts between different groups were compared using the rank-sum test of two independent samples.Results:A total of 21 RSTS patients were recruited, including 12 males and 9 females, with ages ranging from 1 month to 14 years and 2 months. Among them, 67% (14/21) had point variants, and 33% (7/21) had copy number deletions. Out of these, 20 variants (95%) were de novo. Among 20 patients finishing phenotype count during re-visit, 95% (19/20) of the patients exhibited developmental delays before the age of 2 years. Additionally, 80% (16/20) of the patients had distinctive facial features. Considering phenotype count, no statistically significant difference was found between point variant (14 cases) and copy number deletion (6 cases) (5.0 (3.0, 7.0) vs. 5.0 (2.5, 5.3), Z=0.75, P=0.452), CREBBP (10 cases) and EP300 gene (4 cases) point variant (5.0 (3.8, 7.0) vs. 4.0 (2.0, 6.0), Z=1.14, P=0.253), and loss of function (9 cases) and missense (5 cases) variant (6.0 (4.5, 7.0) vs. 3.0 (2.5, 5.5), Z=1.54, P=0.121). Conclusions:Patients with RSTS primarily exhibit developmental delays in early childhood. Specific facial features serve as suggested signs of genetic testing. However, no significant genotype-phenotype correlation is found.

IgA nephropathy is a common primary glomerular disease,and autophagy plays an important role in maintaining the homeostasis of the internal environment.Dysfunction of cellular autophagy can affect the occurrence and development of IgA nephropathy.This article focused on the molecular mechanism of TCM regulating autophagy in renal intrinsic cells,and found that TCM extracts and formulas mainly regulate autophagy through PI3K/Akt/mTOR,TLR4/NF-κB,MAPK,Nrf2/HO-1,NLRP3 and other signaling pathways.Furthermore,it could intervene in pathological damage such as renal fibrosis,inflammation,and oxidative stress,delaying the progression of IgA nephropathy,in order to provide reference for the clinical treatment and new drug development of IgA nephropathy.

Although somatic cells can be reprogrammed to pluripotent stem cells (PSCs) with pure chemicals, authentic pluripotency of chemically induced pluripotent stem cells (CiPSCs) has never been achieved through tetraploid complementation assay. Spontaneous reprogramming of spermatogonial stem cells (SSCs) was another non-transgenic way to obtain PSCs, but this process lacks mechanistic explanation. Here, we reconstructed the trajectory of mouse SSC reprogramming and developed a five-chemical combination, boosting the reprogramming efficiency by nearly 80- to 100-folds. More importantly, chemical induced germline-derived PSCs (5C-gPSCs), but not gPSCs and chemical induced pluripotent stem cells, had authentic pluripotency, as determined by tetraploid complementation. Mechanistically, SSCs traversed through an inverted pathway of in vivo germ cell development, exhibiting the expression signatures and DNA methylation dynamics from spermatogonia to primordial germ cells and further to epiblasts. Besides, SSC-specific imprinting control regions switched from biallelic methylated states to monoallelic methylated states by imprinting demethylation and then re-methylation on one of the two alleles in 5C-gPSCs, which was apparently distinct with the imprinting reprogramming in vivo as DNA methylation simultaneously occurred on both alleles. Our work sheds light on the unique regulatory network underpinning SSC reprogramming, providing insights to understand generic mechanisms for cell-fate decision and epigenetic-related disorders in regenerative medicine.
Male ; Mice ; Animals ; Cellular Reprogramming/genetics* ; Tetraploidy ; Pluripotent Stem Cells/metabolism* ; Induced Pluripotent Stem Cells/metabolism* ; DNA Methylation ; Spermatogonia/metabolism* ; Germ Cells/metabolism*

Diabetic kidney disease is one of the complications of diabetes,which can progress to end-stage renal disease.In recent years,it has been found that miRNAs have become a research hotspot,with miRNA-21 regulating transforming growth factor β1(TGF-β1)/Smads,phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT),Wnt/β-catenin and other signaling pathways to promote the progress of diabetic kidney disease.Studies have showed that traditional Chinese medicine has a regulatory effect on the expression of miRNA-21 and can target miRNA-21 to regulate TGF-β1/Smads,phosphatase and tensin homolog/PI3K/AKT/mammalian target of rapamycin(mTOR),peroxisome proliferator activated receptors and other signal transduction pathways to trigger signal cascade reactions,which intervene in pathological processes such as fibrosis,inflammation,oxidative stress and autophagy.In this article,the role of miRNA-21 in diabetic kidney disease and the intervention of traditional Chinese medicine were summarized,in order to provide some reference for the treatment of diabetic kidney disease and the development of new drugs.

OBJECTIVE: To analyze the clinical characteristics and spectrum of SPTB gene variants among 16 Chinese children with Hereditary spherocytosis (HS) and explore their genotype-phenotype correlation. METHODS: Sixteen children who were diagnosed with HS at the Affiliated Hospital of Capital Institute of Pediatrics from November 2018 to July 2022 were selected as the research subjects. Genetic testing was carried out by whole exome sequencing. Candidate variants were verified by Sanger sequencing and subjected to bioinformatic analysis and prediction of 3D structure of the protein. Correlation between the SPTB genotypes and clinical phenotypes was analyzed using Chi-squared test. RESULTS: The male-to-female ratio of the HS patients was 6 : 10, with the median age being 7-year-and-10-month. Clinical features of the patients have included anemia, reticulocytosis and gradual onset of splenomegaly. Mild, moderate and severe anemia have respectively occurred in 56.25% (9/16), 31.25% (5/16) and 12.50% (2/16) of the patients. SPTB gene variants were detected in all patients, among which 10 were unreported previously and 7 were de novo in origin. Loss of function (LOF) variants accounted for 93.75% (15/16). Only one missense variant was detected. Eleven, 4 and 1 of the variants had occurred in the repeat domain, CH1 domain, and dimerization domain, respectively. There was no significant correlation between the type or domain of the SPTB gene variants with the clinical features such as severity of anemia (x² = 3.345, P > 0.05). All of the variants were predicted to be pathogenic or likely pathogenic based on the guidelines from the American College of Medical Genetics and Genomics. CONCLUSION Mild to moderate anemia are predominant clinical features of the HS children harboring a SPTB gene variant, for which LOF variants are the main mutational type. The clinical feature of HS is unaffected by the type of the variants.
Child ; Female ; Humans ; Male ; Computational Biology ; Genetic Testing ; Genomics ; Genotype ; Spherocytosis, Hereditary/genetics* ; East Asian People/genetics* ; Spectrin/genetics*