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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inheritable cardiac disorder, which is characterized by life-threatening cardiac arrhythmias, syncope, seizures, or sudden cardiac death in response to physical exercise or emotional stress. This inherited disease is predominantly caused by mutations in the ryanodine receptor type 2 (RYR2). To minimize the cell line variations for disease modeling, we generated two induced pluripotency stem cell lines (hiPSCs: isCPVTA2254V1-2 and isCPVTA2254V1-3) from skin fibroblasts of one CPVT patient carrying the p.A2254V mutation using CytoTune2.0 Sendai virus cocktail for non-integration reprogramming. All generated iPSCs maintained pluripotency, normal karyotype, and spontaneous in vivo and in vitro differentiation capacity.

An imprinted polymer layer was easily modified on the Au electrode surface by spontaneous oxidative polymerization of dopamine in the presence of theophylline to fabricate a novel imprinted electrochemical sensor. The results of scanning electron microscopy and cyclic voltammetry measurements demonstrated the successfully preparation of the imprinted sensor. The effects of ratio between theophylline and dopamine, polymerization pH and time were optimized. The prepared sensor exhibited specific adsorption, selective recognition, and sensitive detection capacities toward theophylline. The linear response to theophylline ranged from 2.0 x 10-7 -1.6 x 10-4 mol L-1 with a detection limit of 1.0 x 10-7 mol L-1. Moreover, the sensor could be applied in the detection of theophylline in real samples with satisfactory results. It can be reasonably expected that this simple, novel, and efficient strategy for imprinted sensor preparation based on dopamine self-polymerization provides a promising platform for other molecule recognition and detection. [ABSTRACT FROM AUTHOR]

The degradation of toxic gases and liquids using a catalyst and solar energy is an ideal method, compared with landfill and combustion methods. The search for active semiconductor photocatalysts that efficiently decompose contaminations under light irradiation remains one of the most challenging tasks for solar-energy utilization. In this work, free-supporting three-dimensional (3D) nanosheeted hierarchical porous tungsten, titanium, and tin oxide networks were obtained by a facile Lewis acid catalytic binary template route. These networks possess large macroscopic scale (millimeter-sized) and hierarchical macro/ mesoporous nanostructure with high surface area and large pore volume. Photocatalytic degradation of Azo dyes demonstrated that the nanosheets-constructed hierarchical porous networks have high photocatalytic activity and stability. The present synthetic route can serve as the new design concept for functional 3D layered porous nanostructures. [ABSTRACT FROM AUTHOR]

Brugada syndrome (BrS) is one of the major causes of sudden cardiac death in young people, while the underlying mechanisms are not completely understood. Here, we investigated the pathophysiological phenotypes and mechanisms using induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) from two BrS patients (BrS-CMs) carrying a heterozygous SCN5A mutation p.S1812X. Compared to CMs derived from healthy controls (Ctrl-CMs), BrS-CMs displayed a 50% reduction of INa density, a 69.5% reduction of NaV1.5 expression, and the impaired localization of NaV1.5 and connexin 43 (Cx43) at the cell surface. BrS-CMs exhibited reduced action potential (AP) upstroke velocity and conduction slowing. The Ito in BrS-CMs was significantly augmented, and the ICaL window current probability was increased. Our data indicate that the electrophysiological mechanisms underlying arrhythmia in BrS-CMs may involve both depolarization and repolarization disorders. Cilostazol and milrinone showed dramatic inhibitions of Ito in BrS-CMs and alleviated the arrhythmic activity, suggesting their therapeutic potential for BrS patients.

In adult cardiomyocytes (CMs), the type 2 ryanodine receptor (RYR2) is an indispensable Ca2+ release channel that ensures the integrity of excitation-contraction coupling, which is fundamental for every heartbeat. However, the role and importance of RYR2 during human embryonic cardiac development are still poorly understood. Here, we generated two human induced pluripotent stem cell (iPSC)-based RYR2 knockout (RYR2–/–) lines using the CRISPR/Cas9 gene editing technology. We found that RYR2–/–-iPSCs could differentiate into CMs with the efficiency similar to control-iPSCs (Ctrl-iPSCs); however, the survival of iPSC-CMs was markedly affected by the lack of functional RYR2. While Ctrl-iPSC-CMs exhibited regular Ca2+ handling, we observed significantly reduced frequency and intense abnormalities of Ca2+ transients in RYR2–/–-iPSC-CMs. Ctrl-iPSC-CMs displayed sensitivity to extracellular Ca2+ ([Ca2+ ]o) and caffeine in a concentration-dependent manner, while RYR2–/–-iPSC-CMs showed inconsistent reactions to [Ca2+ ]o and were insensitive to caffeine, indicating there is no RYR2-mediated Ca2+ release from the sarcoplasmic reticulum (SR). Instead, compensatory mechanism for calcium handling in RYR2–/–-iPSC-CMs is partially mediated by the inositol 1,4,5-trisphosphate receptor (IP3R). Similar to Ctrl-iPSC-CMs, SR Ca2+ refilling in RYR2–/–-iPSC-CMs is mediated by SERCA. Additionally, RYR2–/–-iPSC-CMs showed a decreased beating rate and a reduced peak amplitude of L-type Ca2+ current. These findings demonstrate that RYR2 is not required for CM lineage commitment but is important for CM survival and contractile function. IP3R-mediated Ca2+ release is one of the major compensatory mechanisms for Ca2+ cycling in human CMs with the RYR2 deficiency.

The gene expression for interleukin-2 receptor subunit alpha (CD25/IL2RA) is frequently altered in adults with acute myeloid leukemia (AML). Increasing evidence indicates that the elevated expression of CD25 may be correlated with poor survival for AML patients. Thus, we performed this meta-analysis to further evaluate the prognostic value of elevated CD25 in AML. Eligible studies were gathered by searching on PubMed, Web of Science, and Embase. Using the R language 3.6.0 software, Pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs) of overall survival (OS) and disease-free survival (DFS)/relapse-free survival (RFS)/event-free survival (EFS) for total and subgroup analyses were calculated to investigate the association of elevated CD25 and outcomes of AML patients. Ten studies with a total of 1640 participants were enrolled in this meta-analysis. Pooled HRs suggested that overexpression of CD25 predicted poor outcomes on both OS (HR = 2.27, 95%CI 1.95-2.64) and DFS/RFS/EFS (HR = 1.77, 95%CI 1.44-2.17) in overall population. Subgroup analyses stratified by ethnicity, AML subtype, cut-off value, statistical methodologies and detection method draw similar results. Our meta-analysis indicates that elevated CD25 expression is a poor prognostic factor for AML patients. Considering limited number of samples, further relevant studies are warranted.

Adverse effects of drug combinations and their underlying mechanisms are highly relevant for safety evaluation, but often not fully studied. Hydroxychloroquine (HCQ) and azithromycin (AZM) were used as a combination therapy in the treatment of COVID-19 patients at the beginning of the pandemic, leading to higher complication rates in comparison to respective monotherapies. Here, we used human-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to systematically investigate the effects of HCQ, AZM, and their combination on the structure and functionality of cardiomyocytes, and to better understand the underlying mechanisms. Our results demonstrate synergistic adverse effects of AZM and HCQ on electrophysiological and contractile function of iPSC-CMs. HCQ-induced prolongation of field potential duration (FPDc) was gradually increased during 7-day treatment period and was strongly enhanced by combination with AZM, although AZM alone slightly shortened FPDc in iPSC-CMs. Combined treatment with AZM and HCQ leads to higher cardiotoxicity, more severe structural disarrangement, more pronounced contractile dysfunctions, and more elevated conduction velocity, compared to respective monotreatments. Mechanistic insights underlying the synergistic effects of AZM and HCQ on iPSC-CM functionality are provided based on increased cellular accumulation of HCQ and AZM as well as increased Cx43- and Nav1.5-protein levels.

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have evolved into widely used and reliable cell sources for modeling cardiovascular channelopathies and for drug safety pharmacology. However, the electrophysiological and pharmacological applications of hiPSC-CMs are hampered by manual patch-clamp technique, which is labor-intensive and generates low output. The automated patch-clamp technique is showing potential to overcome this problem. Here, we describe a new dissociation method, with which we can harvest a vast number of single relaxed hiPSC-CMs with smooth membrane suited for automated patch-clamp. Using the automated whole-cell patch-clamp technology, we report a high success rate for cell capture and whole-cell access (around 70%). We are able to identify and record several currents and paced action potentials (APs) with different success rates, including Na+ current (INa), L-type Ca2+ current (ICaL), two specific K+ currents, the transient outward K+ current (Ito) and the inward rectifier K+ current (IK1). Moreover, we successfully applied dynamic current-clamp to virtually increase IK1 for AP recordings. Our study suggests that automated patch-clamp technology could be used to investigate the relevant ionic currents and APs in hiPSC-CMs. The combination of automated patch-clamp and hiPSC-CM technologies promises a wide range of applications in the future. Keywords: Automated patch-clamp, Human induced pluripotent stem cell-derived cardiomyocyte, Na+ current, Ca2+ current, Transient outward and inward rectifier K+ currents, Dynamic current-clamp

[Objectives] The study aimed to discuss effects of major meteorological disasters on national economic construction as well as people's lives and property in Ningxia. [Method] Based on data about meteorological disasters over the past 50 years and their direct economic losses during 2003 -2011 in Ningxia, effects of major meteorological disasters on national economic construction as well as people's lives and property were discussed, and some defense countermeasures of meteorological disasters were put forward. [Result] In Ningxia, drought, rainstorm and flood, gale and dust, hail and thunderstorm had done considerable harm to national economic construction as well as people's lives and property. Since 2003, total direct economic losses caused by all meteorological disasters in Ningxia changed from 1 .28 billion to 1 . 97 billion yuan and accounted for 0.8% -3.1% of GDP of Ningxia. Among them, the direct economic losses caused by drought were the highest and annual average value during 2003 -2011 reached 1 .22 billion yuan, accounting for 77. 6% of total direct economic losses caused by all meteorological disasters in Ningxia. The direct economic losses caused by rainstorm, flood and hail ranked second, and their annual average values were 0.11 billion and 0.12 billion yuan, accounting for 7. 4% and 7. 6% of total direct economic losses. Meanwhile, annual average direct economic losses caused by thunderstorm in Ningxia reached 1.18 million yuan. In addition, annual average value of the direct economic losses caused by gale and dust totaled 0.01 billion yuan, with a proportion of 1 . 0%. [Conclusion] The research could provide scientific references for the defense of meteorological disasters in future. [ABSTRACT FROM AUTHOR]

Purpose -- The purpose of the studies was to test if extent of prior social media activity could predict likelihood that a consumer would post reviews on a new review website. Design/methodology/approach -- Two online surveys were conducted presenting scenarios in which users were asked about prior social media activity, the number of social networks they belonged to in study one, and how actively they had posted reviews in study two. These questions were followed by descriptions of new review websites, a general local merchant review website in study one and a local restaurant review website in study two. Findings -- Although demographics did a poor job of predicting who would post reviews on the new review websites, prior active social media use and review posting did modestly predict intention to post reviews on the new review websites. Research limitations/implications -- This is not an experimental study and so causality cannot be claimed. Descriptively, although the results were consistent in two studies using different stimuli, other factors might prove to be better predictors of active user-generated content for other types of sites. Practical implications -- The findings suggest a simple and effective way for two-sided platform managers to identify potential active reviewers so that they can target them through marketing strategies to encourage their essential participation and less-active users can be similarly targeted to encourage modest use. Originality/value -- No other studies can be found that focus on this aspect of managing two-sided platforms. The results might be important for managers of other similar websites that depend on user-generated content for their value. [ABSTRACT FROM AUTHOR]

A novel flow injection procedure has been developed for the determination of tannic acid based on the inhibition of the chemiluminescences in luminol-H2O2-Manganese tetrasulfonatophthalocyanine (MnTSPc) system by tannic acid. The method is simple, rapid and sensitive with a detection limit of 8 × 10−10 mol·L−1 and a linear range of 7 × 10−9–5 × 10−6 mol·L−1. The relative standard deviation is 1.9% for eleven measurements of 5 × 10−7 mol·L−1 tannic acid. The method has been successfully applied to the determination of tannic acid in real Chinese gall and hop pellets samples. [ABSTRACT FROM AUTHOR]

Patients with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) can present with life-threatening cardiac arrhythmias. The pathophysiological mechanism is unknown. We reprogrammed fibroblasts from one mildly and one severely affected VLCADD patient, into human induced pluripotent stem cells (hiPSCs) and differentiated these into cardiomyocytes (VLCADD-CMs). VLCADD-CMs displayed shorter action potentials (APs), more delayed afterdepolarizations (DADs) and higher systolic and diastolic intracellular Ca2+ concentration ([Ca2+]i) than control CMs. The mitochondrial booster resveratrol mitigated the biochemical, electrophysiological and [Ca2+]i changes in the mild but not in the severe VLCADD-CMs. Accumulation of potentially toxic intermediates of fatty acid oxidation was blocked by substrate reduction with etomoxir. Incubation with etomoxir led to marked prolongation of AP duration and reduced DADs and [Ca2+]i in both VLCADD-CMs. These results provide compelling evidence that reduced accumulation of fatty acid oxidation intermediates, either by enhanced fatty acid oxidation flux through increased mitochondria biogenesis (resveratrol) or by inhibition of fatty acid transport into the mitochondria (etomoxir), rescues pro-arrhythmia defects in VLCADD-CMs and open doors for new treatments.

Pure bismuth nanoflowers were synthesized for the first time with remarkable productivity through a low-temperature hydrothermal method. The obtained nanostructures were used to prepare modified electrodes, which showed high sensitivity for the detection of heavy metal ions in aqueous solution by stripping analysis. [ABSTRACT FROM AUTHOR]