Short-term exposure to ambient air pollution and atrial fibrillation hospitalization: A time-series study in Yancheng, China.

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.

Dopa-Responsive Dystonia in Han Chinese Patients: One Novel Heterozygous Mutation in GTP Cyclohydrolase 1 (GCH1) and Three Known Mutations in TH.

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.

Clinical study of the pronator quadratus muscle: anatomical features and feasibility of pronator-sparing surgery.

BACKGROUND: No clinical data for the relationship of pronator quadratus (PQ) muscle to distal radius had been reported. The aim of this study was to investigate the anatomical features of the PQ muscle related to plate osteosynthesis for distal radius fractures in clinical cases. The feasibility of PQ muscle sparing surgery was investigated as well. METHODS: Fifty two distal radius fractures (23-A2) were enclosed in this study. The whole width of the muscle and the distance from the distal edge of the muscle to the joint surface of the distal radius were measured. The distance from the fracture site of the radius to the joint surface was measured as well. RESULTS: The average width of the pronator quadratus muscle was 37.6 mm. The average distance from the pronator quadratus muscle to the lunate fossa surface was 12.2 mm, and the average distance from the pronator quadratus muscle to the scaphoid fossa surface was 13.6 mm. The average distance from the lunate fossa of the distal radius to the fracture site was 12.2 mm (range, 7.3-17 mm), and the scaphoid fossa of the distal radius to the fracture site was 13.2 mm (range, 9.4-18.8 mm). CONCLUSIONS: This PQ muscle sparing surgery is feasible and can be performed without difficulty. The data might provide a useful basis for the preservation of pronator quadratus muscle applied to a functionally reduced fracture regarding the potential efficacy of conventional volar plate osteosynthesis.

Mapping conservation priorities for wild yak (Bos mutus) habitats on the Tibetan Plateau, China.

The wild yak (Bos mutus) is a cold-tolerant herbivore native to the Tibetan Plateau and has been categorized as vulnerable by the International Union for Conservation of Nature and Natural Resources. Low population densities within currently fragmented habitats and unclear landscape conservation priorities warrant attention. Herein, we employed the maximum entropy (MaxEnt) model using over 900 wild yak occurrence records to model wild yak habitat suitability. Our analysis revealed unprotected wild yak landscapes covering 30.79 % of the habitat area, indicating a conservation gap between protected areas (PAs) and wild yak habitats. To protect metapopulation dynamics and mitigate high risks of poaching, habitat degradation and fragmentation, resource competition, and degenerated genetic characterization of wild yaks in fragmented and degraded habitat, we identified eight habitat patches as landscape conservation units (LCUs) and 14 linkages among the LCUs, enhancing the connectivity between LCUs to decrease negative effects of genetic threats. A centrality analysis demonstrated that Changtang, Arjinshan, and Hoh Xil national nature reserves and their linkages are all critical for the maintenance of habitat connectivity. Here, we suggest that habitat- and LCU-specific conservation strategies should be highlighted during the establishment of PAs and transboundary cooperation. Ultimately, our results can assist conservationists and land managers in comprehending wild yak distribution, movement, and habitat requirements, as well as for the development of effective protection strategies. Furthermore, the combined modeling method (MaxEnt-Zonation-InVEST) could be utilized as a component for identifying conservation priorities and linkages between core patches for species and assessing the efficiency of PAs, core habitats, and corridors in achieving conservation goals. Our study can provide a framework in identifying priority conservation and connectivity between habitat patches to facilitate effectively conservation and genetic resilience for endangered species in fragmented habitats.

Injectable and Conductive Nanomicelle Hydrogel with α-Tocopherol Encapsulation for Enhanced Myocardial Infarction Repair.

Substantial advancements have been achieved in the realm of cardiac tissue repair utilizing functional hydrogel materials. Additionally, drug-loaded hydrogels have emerged as a research hotspot for modulating adverse microenvironments and preventing left ventricular remodeling after myocardial infarction (MI), thereby fostering improved reparative outcomes. In this study, diacrylated Pluronic F127 micelles were used as macro-cross-linkers for the hydrogel, and the hydrophobic drug α-tocopherol (α-TOH) was loaded. Through the in situ synthesis of polydopamine (PDA) and the incorporation of conductive components, an injectable and highly compliant antioxidant/conductive composite FPDA hydrogel was constructed. The hydrogel exhibited exceptional stretchability, high toughness, good conductivity, cell affinity, and tissue adhesion. In a rabbit model, the material was surgically implanted onto the myocardial tissue, subsequent to the ligation of the left anterior descending coronary artery. Four weeks postimplantation, there was discernible functional recovery, manifesting as augmented fractional shortening and ejection fraction, alongside reduced infarcted areas. The findings of this investigation underscore the substantial utility of FPDA hydrogels given their proactive capacity to modulate the post-MI infarct microenvironment and thereby enhance the therapeutic outcomes of myocardial infarction.

Continuous contractile force and electrical signal recordings of 3D cardiac tissue utilizing conductive hydrogel pillars on a chip.

Heart-on-chip emerged as a potential tool for cardiac tissue engineering, recapitulating key physiological cues in cardiac pathophysiology. Controlled electrical stimulation and the ability to provide directly analyzed functional readouts are essential to evaluate the physiology of cardiac tissues in the heart-on-chip platforms. In this scenario, a novel heart-on-chip platform integrating two soft conductive hydrogel pillar electrodes was presented here. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and cardiac fibroblasts were seeded into the apparatus to create 3D human cardiac tissues. The application of electrical stimulation improved functional performance by altering the dynamics of tissue structure and contractile development. The contractile forces that cardiac tissues contract was accurately measured through optical tracking of hydrogel pillar displacement. Furthermore, the conductive properties of hydrogel pillars allowed direct and non-invasive electrophysiology studies, enabling continuous monitoring of signal changes in real-time while dynamically administering drugs to the cardiac tissues, as shown by a chronotropic reaction to isoprenaline and verapamil. Overall, the platform for acquiring contractile force and electrophysiological signals in situ allowed monitoring the tissue development trend without interrupting the culture process and could have diverse applications in preclinical drug testing, disease modeling, and therapeutic discovery.

Skin sympathetic nerve activity as a biomarker for outcomes in spontaneous intracerebral hemorrhage.

OBJECTIVE: A rapid and accurate forecast for the early prognosis of ICH patients is challenging. This study investigated whether heart rate variability (HRV) and skin sympathetic nerve activity (SKNA) could prognosticate poor neurological outcomes in ICH patients. METHODS: Between November 2020 and November 2021, we studied 92 spontaneous ICH patients in the First Affiliated Hospital of Nanjing Medical University. Glasgow Outcome Scale (GOS) score at 2 weeks after the ICH was used to categorize patients into good and poor outcome groups. The modified Rankin Scale (mRS) assessed patients' ability to live independently for 1 year. We utilized a portable high-frequency electrocardiogram (ECG) recording system to record the HRV and SKNA information in ICH patients and control participants. RESULTS: 77 patients were eligible for the prediction of neurological outcome and were allocated into the good (n = 22) or poor (n = 55) outcome groups based on the GOS grade. In univariate logistic regression analysis, significant variables that could differentiate the outcomes were age, hypertension, tracheal intubation, Glasgow Coma Scale (GCS) score, existing intraventricular hemorrhage, white blood cells, neutrophil, lnVLF, lnTP, and aSKNA. Variables in the best fit multivariable logistic regression model were age, hypertension, GCS score, neutrophils, and aSKNA. The GCS score was the only independent risk factor for poor outcomes. At 30 days and 1 year of follow-up, patients with lower aSKNA had poor outcomes. INTERPRETATION: ICH patients had reduced aSKNA, which could be a prognostic indicator. A lower aSKNA suggested a worse prognosis. The present data indicate that ECG signals could be helpful for prognosticating ICH patients.

Evaluation of skin sympathetic nervous activity for classification of intracerebral hemorrhage and outcome prediction.

Classification and outcome prediction of intracerebral hemorrhage (ICH) is critical for improving the survival rate of patients. Early or delayed neurological deterioration is common in ICH patients, which may lead to changes in the autonomic nervous system (ANS). Therefore, we proposed a new framework for ICH classification and outcome prediction based on skin sympathetic nervous activity (SKNA) signals. A customized measurement device presented in our previous papers was used to collect data. 117 subjects (50 healthy control subjects and 67 ICH patients) were recruited for this study to obtain their 5-min electrocardiogram (ECG) and SKNA signals. We extracted the signal's time-domain, frequency-domain, and nonlinear features and analyzed their differences between healthy control subjects and ICH patients. Subsequently, we established the ICH classification and outcome evaluation model based on the eXtreme Gradient Boosting (XGBoost). In addition, heart rate variability (HRV) as an ANS assessment method was also included as a comparison method in this study. The results showed significant differences in most features of the SKNA signal between healthy control subjects and ICH patients. The ICH patients with good outcomes have a higher change rate and complexity of SKNA signal than those with bad outcomes. In addition, the accuracy of the model for ICH classification and outcome prediction based on the SKNA signal was more than 91% and 83%, respectively. The ICH classification and outcome prediction based on the SKNA signal proved to be a feasible method in this study. Furthermore, the features of change rate and complexity, such as entropy measures, can be used to characterize the difference in SKNA signals of different groups. The method can potentially provide a new tool for rapid classification and outcome prediction of ICH patients. Index Terms-intracerebral hemorrhage (ICH), skin sympathetic nervous activity (SKNA), classification, outcome prediction, cardiovascular and cerebrovascular diseases.

Autonomic nervous activity analysis based on visibility graph complex networks and skin sympathetic nerve activity.

Background: Autonomic nerve system (ANS) plays an important role in regulating cardiovascular function and cerebrovascular function. Traditional heart rate variation (HRV) and emerging skin sympathetic nerve activity (SKNA) analyses from ultra-short-time (UST) data cannot fully reveal neural activity, thereby quantitatively reflect ANS intensity. Methods: Electrocardiogram and SKNA from sixteen patients (seven cerebral hemorrhage (CH) patients and nine control group (CO) patients) were recorded using a portable device. Ten derived HRV (mean, standard deviation and root mean square difference of sinus RR intervals (NNmean, SDNN and RMSSD), ultra-low frequency (<0.003 Hz, uLF), very low frequency ([0.003 Hz, 0.04 Hz), vLF), low frequency ([0.04 Hz, 0.15 Hz), LF) and high frequency power ([0.15 Hz, 0.4 Hz), HF), ratio of LF to HF (LF/HF), the standard deviation of instantaneous beat-to-beat R-R interval variability (SD1), and approximate entropy (ApEn)) and ten visibility graph (VG) features (diameter (Dia), average node degree (aND), average shortest-path length (aSPL), clustering coefficient (CC), average closeness centrality (aCC), transitivity (Trans), average degree centrality (aDC), link density (LD), sMetric (sM) and graph energy (GE) of the constructed complex network) were compared on 5-min and UST segments to verify their validity and robustness in discriminating CH and CO under different data lengths. Besides, their potential for quantifying ANS-Load were also investigated. Results: The validation results of HRV and VG features in discriminating CH from CO showed that VG features were more clearly distinguishable between the two groups than HRV features. For effectiveness evaluation of analyzing ANS on UST segment, the NNmean, SDNN, RMSSD, LF, HF and LF/HF in HRV features and the CC, Trans, Dia and GE of VG features remained stable in both activated and inactivated segments across all data lengths. The capability of HRV and VG features in quantifying ANS-Load were evaluated and compared under different ANS-Load, the results showed that most HRV features (SDNN, LFHF, RMSSD, vLF, LF and HF) and almost all VG features were correlated to sympathetic nerve activity intensity. Conclusions: The proposed autonomic nervous activity analysis method based on VG and SKNA offers a new insight into ANS assessment in UST segments and ANS-Load quantification.

Dynamics of Cardiac Autonomic Responses During Hemodialysis Measured by Heart Rate Variability and Skin Sympathetic Nerve Activity: The Impact of Interdialytic Weight Gain.

Background: Autonomic nervous regulation plays a critical role in end-stage kidney disease (ESKD) patients with cardiovascular complications. However, studies on autonomic regulation in ESKD patients are limited to heart rate variability (HRV) analysis. Skin sympathetic nerve activity (SKNA), which noninvasively reflects the sympathetic nerve activity, has not been used in ESKD patients. Methods: Seventy-six patients on maintenance hemodialysis (MHD) treatment (a 4-h HD session, three times a week) were enrolled. Utilizing a noninvasive, single-lead, high-frequency recording system, we analyzed the dynamic change in HRV parameters and SKNA during HD. The different characteristics between the subgroups divided based on interdialytic weight gain (IDWG, <3 kg or ≥3 kg) were also demonstrated. Results: After the HD, values for heart rate (75.1 ± 11.3 to 80.3 ± 12.3 bpm, p < 0.001) and LF/HF (1.92 ± 1.67 to 2.18 ± 2.17, p = 0.013) were significantly higher than baseline. In subgroup analysis, average voltage of skin sympathetic nerve activity (aSKNA) in IDWG ≥3 kg group was lower than the IDWG <3 kg group at the end of MHD (1.06 ± 0.30 vs 1.32 ± 0.61 µV, p = 0.046). Moreover, there was a linear correlation between mean heart rate (HR) and aSKNA in low IDWG patients (p < 0.001), which was not found in high IDWG patients. At the 1-year follow-up, high IDWG patients had a higher incidence of cardiovascular hospitalization (p = 0.046). Conclusions: In MHD patients, a gradual activation of sympathetic nerve activity could be measured by HRV and aSKNA. A lower aSKNA at the end of HD and a loss of HR-aSKNA correlation in overhydrated patients were observed. Extensive volume control is promising to improve the autonomic nervous function and clinical outcomes in this population.

Generation of a human induced pluripotent stem cell line (JSPHi002-A) from a patient with long-QT syndrome type 1 caused by KCNQ1 c.773A > T mutation.

We generated an iPSCs line from the peripheral blood mononuclear cells (PBMCs) collected from a patient with long QT syndrome type 1 (LQT1) via a non-integrating system. We identified and verified a missense mutation in the KCNQ1 gene (c.773A > T) by whole-exome sequencing and Sanger sequencing. The established iPSC line was tested for pluripotency, differentiation potential, and karyotype. This cell-based model can help study the molecular mechanism and develop personalized drug therapies for LQT1.

Novel Mitochondrial Gene Rearrangement and Intergenic Regions Exist in the Mitochondrial Genomes from Four Newly Established Families of Praying Mantises (Insecta: Mantodea).

Long non-coding regions (NCRs) and gene rearrangements are commonly seen in mitochondrial genomes of Mantodea and are primarily focused on three regions: CR-I-Q-M-ND2, COX2-K-D-ATP8, and ND3-A-R-N-S-E-F-ND5. In this study, eight complete and one nearly complete mitochondrial genomes of praying mantises were acquired for the purpose of discussing mitochondrial gene rearrangements and phylogenetic relationships within Mantodea, primarily in the newly established families Haaniidae and Gonypetidae. Except for Heterochaeta sp. JZ-2017, novel mitochondrial gene arrangements were detected in Cheddikulama straminea, Sinomiopteryx graham, Pseudovates chlorophaea, Spilomantis occipitalis. Of note is the fact that one type of novel arrangement was detected for the first time in the Cyt b-S2-ND1 region. This could be reliably explained by the tandem replication-random loss (TDRL) model. The long NCR between trnT and trnP was generally found in Iridopteryginae and was similar to the ND4L or ND6 gene. Combined with gene rearrangements and intergenic regions, the monophyly of Haaniidae was supported, whereas the paraphyly of Gonypetidae was recovered. Furthermore, several synapomorphies unique to some clades were detected that conserved block sequences between trnI and trnQ and gaps between trnT and trnP in Toxoderidae and Iridopteryginae, respectively.

Generation of a human induced pluripotent stem cell line (JSPHi003-A) from a patient with atrial fibrillation and ventricular tachycardia carrying LMNA frame shift mutation (c.1304_1307dup).

The iPSC line was generated from the peripheral blood mononuclear cells (PBMCs) from a 53-year-old female patient carrying the LMNA gene mutation (c.1304_1307dup) diagnosed with atrial fibrillation and paroxysmal ventricular tachycardia. Through comprehensive detection, it was verified that the cell line had the LMNA gene mutation, normal karyotype, and the potential to differentiate into the three germ layers. This cell line may reveal potential therapeutic targets for atrial and ventricular arrhythmias caused by LMNA mutations.

Induced pluripotent stem cells (SHCDNi006-A cells) isolated from the peripheral blood mononuclear cells of a five-month-old Chinese girl with the heterozygous missense mutation (c.2800 G>A) in the KCNT1 gene.

Epilepsy of infancy with migrating focal seizures (EIMFS) is a kind of epileptic encephalopathy with high genetic heterogeneity. The most common pathogenic gene for EIMFS is potassium sodium-activated channel subfamily T member 1 (KCNT1). Using Sendai virus-mediated reprogramming, we established an induced pluripotent stem cell (iPSC) line from the peripheral blood mononuclear cells (PBMCs) of a five-month-old Chinese girl with heterozygous missense mutation (c.2800 G>A) in the KCNT1 gene. 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.

Segawa syndrome caused by TH gene mutation and its mechanism.

Dopa-responsive dystonia (DRD), also known as Segawa syndrome, is a rare neurotransmitter disease. The decrease in dopamine caused by tyrosine hydroxylase (TH) gene mutation may lead to dystonia, tremor and severe encephalopathy in children. Although the disease caused by recessive genetic mutation of the tyrosine hydroxylase (TH) gene is rare, we found that the clinical manifestations of seven children with tyrosine hydroxylase gene mutations are similar to dopa-responsive dystonia. To explore the clinical manifestations and possible pathogenesis of the disease, we analyzed the clinical data of seven patients. Next-generation sequencing showed that the TH gene mutation in three children was a reported homozygous mutation (c.698G>A). At the same time, two new mutations of the TH gene were found in other children: c.316_317insCGT, and c.832G>A (p.Ala278Thr). We collected venous blood from four patients with Segawa syndrome and their parents for real-time quantitative polymerase chain reaction analysis of TH gene expression. We predicted the structure and function of proteins on the missense mutation iterative thread assembly refinement (I-TASSER) server and studied the conservation of protein mutation sites. Combined with molecular biology experiments and related literature analysis, the qPCR results of two patients showed that the expression of the TH gene was lower than that in 10 normal controls, and the expression of the TH gene of one mother was lower than the average expression level. We speculated that mutation in the TH gene may clinically manifest by affecting the production of dopamine and catecholamine downstream, which enriches the gene pool of Segawa syndrome. At the same time, the application of levodopa is helpful to the study, diagnosis and treatment of Segawa syndrome.

Association between fine particulate matter and heart failure hospitalizations: a time-series analysis in Yancheng, China.

BACKGROUND: 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. OBJECTIVES: To explore the associations between PM2.5 and HF hospitalizations in Yancheng, China. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Pathogenesis and drug response of iPSC-derived cardiomyocytes from two Brugada syndrome patients with different Na v1.5-subunit mutations.

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.

Construction of chamber-specific engineered cardiac tissues in vitro with human iPSC-derived cardiomyocytes and human foreskin fibroblasts.

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.

Mechanisms of Congenital Myasthenia Caused by Three Mutations in the COLQ Gene.

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.

Generation and characterization of the induced pluripotent stem cell line SHCDNi004-A from a ten-year-old Chinese boy with X-linked mental retardation in IL1RAPL1 deficiency.

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.