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Atrial fibrillation (AF) is an important cardiovascular disease that causes a great burden of disease. However, there is limited evidence of a link between air pollution exposure and AF. This study aimed to explore the short-term association between air pollution and AF. We obtained daily hospitalization of AF in two major hospitals of Yancheng, China from May, 2015 to May, 2020. Generalized additive models with quasi-Poisson regression were used to assess the associations between six criteria air pollutants and AF hospitalization. We explored the lag patterns, and visualized the concentration-response relationships. The robustness of the association was tested by two-pollutant model, and we explored potential effect modification by age, sex and season. A total of 15,171 inpatients from two hospitals were collected in this study with an average daily count of eight patients. We observed consistent and significant associations between six air pollutants and AF on lag 0–4 days. A 10 ug/m3 increase in PM2.5 was associated with 2.81% (95%CI: 1.44%, 4.20%) changes in AF, and the effect estimate was 1.67% (95%CI: 0.77%, 2.59%) for PM10, 4.90% (95%CI: 1.69%, 8.22%) for NO2, 6.81% (95%CI: 0.46%, 13.57%) for SO2, 1.82% (95%CI: 0.60%, 3.06%) for O3; a 0.1 mg/m3 increase in CO was associated with 2.55% (95%CI: 0.91%, 4.21%) increments in AF. Associations of PM2.5 and PM10 were robust after adjusting for SO2, NO2, CO, and O3, but not vice versa. Female patients and those aged less 70 years had larger risk of AF associated with air pollution exposure. The concentration-response curves of the six pollutants were almost linear and increasing with no obvious thresholds. This time-series study in Yancheng demonstrated increased risk of AF and a delayed effect over lag 0–4 days. Our findings suggested need of prevention and protection against these environmental risk factors for AF in health departments.

The gene encoding collagen like tail subunit of asymmetric acetylcholinesterase (COLQ) is responsible for the transcription of three strands of collagen of acetylcholinesterase, which is attached to the endplate of neuromuscular junctions. Mutations in the COLQ gene are inherited in an autosomal-recessive manner and can lead to type V congenital myasthenia syndrome (CMS), which manifests as decreased muscle strength at birth or shortly after birth, respiratory failure, restricted eye movements, drooping of eyelids, and difficulty swallowing. Here we reported three variants within COLQ in two unrelated children with CMS. An intronic variant (c.393+1G>A) and a novel missense variant (p.Q381P) were identified as compound heterozygous in a 13-month-old boy, with the parents being carriers of each. An intragenic deletion including exons 14 and 15 was found in a homozygous state in a 12-year-old boy. We studied the relative expression of the COLQ and AChE gene in the probands' families, performed three-dimensional protein structural analysis, and analyzed the conservation of the missense mutation c.1142A>C (p.Q381P). The splicing mutation c.393+1G>A was found to affect the normal splicing of COLQ exon 5, resulting in a 27-bp deletion. The missense mutation c.1142A>C (p.Q381P) was located in a conserved position in different species. We found that homozygous deletion of COLQ exons 14–15 resulted in a 241-bp deletion, which decreased the number of amino acids and caused a frameshift translation. COLQ expression was significantly lower in the probands than in the probands' parents and siblings, while AChE expression was significantly higher. Moreover, the mutations were found to cause significant differences in the predicted three-dimensional structure of the protein. The splicing mutation c.393+1G>A, missense mutation c.1A>C (p.Q381P), and COLQ exon 14–15 deletion could cause CMS.

Mental retardation, X-linked 21/34 (MRX21/34), is a rare intellectual disability disease caused by mutations in the IL1RAPL1 (Interleukin-1 Receptor Accessory Protein-Like 1) gene. Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from PBMCs collected from a ten-year-old boy with MRX21/34. The iPSCs showed stable amplification, expressed pluripotent genes, displayed a normal karyotype, and had characteristics of trilineage differentiation potential in an in vitro differentiation assay.

Human-induced pluripotent stem cell (hiPSC) technology and directed cardiac differentiation technology can provide a continuous supply of cells for disease modeling, drug screening, and cell therapy. However, two-dimensional (2D) cells often fail to faithfully reflect the physiological structure and function of the heart. Considering the contractile function is the most critical and easy-to-understand function of cardiomyocytes, the engineered cardiac tissues (ECT) with mechanical properties may serve as an appropriate three-dimensional (3D) platform for drug evaluation. At present, there are various methods to generate ECTs, some of which are quite costly. In the present study, we proposed that human foreskin fibroblast (HFF) cells, as a cost-effective and accessible cell source, can promote the compaction and remodeling of ECTs. The HFFs derived ECTs displayed stable structural and functional characteristics with a higher performance-to-price ratio. Moreover, both ECTs made from atrial and ventricular cardiomyocytes showed an excellent drug response, demonstrating that the ECT with HFFs as an easy and reliable platform for drug evaluation.

Heart failure (HF) is a global public health problem of increasing importance. The association between acute exposure to air pollution and HF has been well established in developed countries, but little evidence is available in developing countries where air pollution levels are much higher. To explore the associations between PM2.5 and HF hospitalizations in Yancheng, China. In this time-series study, daily HF hospitalizations admitted in three major hospitals in Yancheng from May 1, 2015 to Apr 30, 2020 were collected. We used a generalized additive model with quasi-Poisson regression to investigate the association between PM2.5 and HF hospitalizations. The robustness of the associations was tested using two-pollutant models, and we examined the potential effect modification by age, gender, and season via stratification analyses. Lastly, we pooled the concentration-response curves. A total of 10,466 HF hospitalizations were recorded, with a daily average of 6 cases. We observed the most robust estimates on lag 0 day, and the associated increment in HF was 1.28% (95% CI 0.45%, 2.11%) for a 10-μg/m3 increase of PM2.5. The association remained after adjustment of O3, but not for NO2, CO, and SO2. The PM2.5-HF associations were positive in females, patients aged ≥ 65 years, and in cold season. The C-R relationship curve was generally increasing below 30 μg/m3. This study provided evidence on the association of PM2.5 with acute exacerbation of chronic heart failure, which may benefit future prevention strategy and policymaking.

Background: Brugada syndrome (BrS) is an autosomal dominant disorder that causes a high predisposition to sudden cardiac death. Several genes have been reported to be associated with BrS. Considering that the heterogeneity in clinical manifestations may result from genetic variations, the application of patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes (CMs) may help to reveal cell phenotype characteristics resulting from different genetic backgrounds. The present study was to compare the structural and electrophysiological characteristics of sodium channel subunits with different genetic variations and evaluate the safety of quinidine for use with BrS patient-specific iPSC-derived cardiomyocytes.Methods: Two BrS patient-specific iPS cell lines were constructed that carried missense mutations in SCN5A and SCN1B. One iPS cell line from a healthy volunteer was used as a control. The differentiated cardiomyocytes from the three groups were evaluated by flow cytometry, immunofluorescence staining, electron microscopy, as well as calcium transient and patch clamp analyses to assess different pathological phenotypes. Finally, we evaluated the drug responses to varying concentrations of quinidine by measuring the action potential.Results: Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration and varying degrees of decreased Vmax, but no structural difference was observed. After applying different concentrations of quinidine, the disease-specific groups and the control group had a downward trend in maximal upstroke velocity, resting membrane potential and action potential amplitude, and exhibited prolonged action potential duration without increasing incidence of arrhythmic events.Conclusion: Both patient-specific iPSC-CMs recapitulated the BrS phenotype at the cellular level. Although the SCN5A variation led to a markedly lower sodium current than what was observed with the SCN1B variation, their responses to quinidine were quite similar. The present study provides an advantageous platform for exploring disease mechanisms and evaluating drug safety in vitro.

Allan-Herndon-Dudley syndrome (AHDS) is a rare, X-chromosome-linked inherited disorder that affects brain development and is caused by a mutation in SLC16A2. Herein, we generated an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells of a one-year-old male infant with AHDS using Sendai-virus-mediated reprogramming. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro. Additionally, this iPSC line was found to maintain a normal karyotype and retain the pathogenic mutation in SLC16A2, facilitating the study of disease mechanisms and development of new therapies of AHDS.

Mitochondrial DNA depletion syndrome-13 (MTDPS13) is a rare autosomal recessive mitochondrial disease caused by mutations in the FBXL4 (F-box and leucine-rich repeat protein 4) gene. Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from PBMCs collected from a one-year-old female patient with MTDPS13. The iPSCs were stable during amplification, expressed pluripotent genes, maintained a normal karyotype, and showed characteristics of the three germs layers in an in vitro differentiation assay.

BACKGROUND This study aimed to clarify the diagnosis and expand the understanding of dopa-responsive dystonia (DRD). MATERIAL AND METHODS Relevant data from clinical diagnoses and genetic mutational analyses in 3 Han Chinese patients with sporadic DRD were collected and analyzed. Protein structure/function was predicted. RESULTS One novel mutation of c.679A>G (p.T227A) in GCH1 and 3 known mutations of c.457C>T (p.R153X), c.739G>A (p.G247S), and c.698G>A (p.R227H) in tyrosine hydroxylase (TH) have been found and predicted to be damaging or deleterious. All of the mutations were localized in conserved sequences. The iterative threading assembly refinement (I-TASSER) server generated three-dimensional (3D) atomic models based on protein sequences from the novel nonsense mutation of c.679A>G (p.T227A) in GCH1, which showed that residue 227 was located in the GCH1 active site. CONCLUSIONS Patients carrying different non-synonymous variants had remarkable variation in clinical phenotype. This study expands the spectrum of genotypes and phenotypes of DRD in the Han Chinese ethnicity, provides new insights into the molecular mechanism of DRD, and helps the diagnosis and treatment of DRD.

Brugada syndrome (BrS) is a complex genetic cardiac ion channel disease that causes a high predisposition to sudden cardiac death. Considering that its heterogeneity in clinical manifestations may result from genetic background, the application of patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) may help to reveal cell phenotype characteristics underlying different genetic variations. Here, to verify and compare the pathogenicity of mutations (SCN5A c.4213G>A andSCN1B c.590C>T) identified from two BrS patients, we generated two novel BrS iPS cell lines that carried missense mutations inSCN5A or SCN1B, compared their structures and electrophysiology, and evaluated the safety of quinidine in patient-specific iPSC-derived CMs. Compared to the control group, BrS-CMs showed a significant reduction in sodium current, prolonged action potential duration, and varying degrees of decreased Vmax, but no structural difference. After applying different concentrations of quinidine, drug-induced cardiotoxicity was not observed within 3-fold unbound effective therapeutic plasma concentration (ETPC). The data presented proved that iPSC-CMs with variants in SCN5A c.4213G>A orSCN1B c.590C>T are able to recapitulate single-cell phenotype features of BrS and respond appropriately to quinidine without increasing incidence of arrhythmic events.

Background/aim: Multiple sclerosis (MS) is a chronic and debilitating inflammatory autoimmune disease of the central nervous system (CNS) that affects the myelinated axons in the CNS. Incomplete remissions occur more commonly with increasing duration of disease. Intravenous immunoglobulin (IVIg) has various functions as an immune modulator via macrophage activation. Clinical trials of immunoglobulin demonstrated remarkable clinical effects in several types of MS, especially in relapsing-remitting type. It is an approved method for the treatment of relapsing-remitting MS that can be used as a supportive therapy. Our study involves the case of a ten year old female patient with relapsing-remitting MS. This study was undertaken to examine the effects of IVIg used almost every 6 months in a patient with relapsing-remitting MS. Results: This case study demonstrated that treatments of IVIg used almost every 6 months in a patient with relapsing-remitting MS have potent therapeutic actions with early beneficial responses. Conclusion: IVIg used almost every 6 months shows a potential positive therapeutic treatment for relapsing-remitting MS and more large-scale clinical studies are required.

This paper contributes to an understanding of the relationship between pollen assemblages and grain-size in north-west China. Based on the relationship, we have reconstructed the environmental and vegetation history from sediments from Zhuye Lake, located in the marginal area of the Asian monsoon. During the Late Glacial (before ~ 13 cal ka BP), the high content of sand is correlated with low pollen concentrations, which implies an arid environment and low vegetation cover in the drainage. The relatively high percentages of Pinus and Quercus pollen, derived from nearby high elevations, may indicate particularly low vegetation cover in the lower part of the watershed. Between 13 and 7.7 cal ka BP, increasing silt content is correlated with high percentages of Picea pollen. Fluvial flow and effective humidity at high elevations, as well as lake-level, all increase. Following this, an abrupt environmental change which is likely caused by some change in lake geomorphology persists for about 300 years. The Holocene Optimum is between 7.4 and 4.7 cal ka BP in this region. Pollen concentrations reach their highest values in the section. The abundant herb pollen reflects the high vegetation cover in the lower part of the watershed. The silt and the fine components in the sediments are high and stable indicating optimal moisture conditions. Between 4.7–1.5 cal ka BP the lake-level fell and silty peat was formed at the site. The pollen concentration decreased in contrast to the high pollen concentration in the Holocene Optimum. In the last 1500 years the lake-level fell while terrestrial sediments were deposited at the site. In this phase Chenopodiaceae, Nitraria and Ephedra reach their highest values in the section reflecting an arid environment. In Zhuye Lake and the surrounding area environmental changes are mainly controlled the combined effects of the East Asian monsoon and the Westerlies since the Late Glacial. In the last ~ 1.5 cal ka BP the intensive arid trend may be correlated with changes in the Westerlies.