Mutation-specific differences in arrhythmias and drug responses in CPVT patients : simultaneous patch clamp and video imaging of iPSC derived cardiomyocytes

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease characterized by arrhythmias under adrenergic stress. Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for CPVT. We characterized electrophysiological properties of CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying different mutations in RYR2 and evaluated effects of carvedilol and flecainide on action potential (AP) and contractile properties of hiPSC-CMs. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion (E3D) and L4115F mutation in RYR2. APs and contractile movement were recorded simultaneously from the same hiPSC-CMs. Differences in AP properties of ventricular like CMs were seen in CPVT and control CMs: APD90 of both E3D (n = 20) and L4115F (n = 25) CPVT CMs was shorter than in control CMs (n = 15). E3D-CPVT CMs had shortest AP duration, lowest AP amplitude, upstroke velocity and more depolarized diastolic potential than controls. Adrenaline had positive and carvedilol and flecainide negative chronotropic effect in all hiPSC CMs. CPVT CMs had increased amount of delayed after depolarizations (DADs) and early after depolarizations (EADs) after adrenaline exposure. E3D CPVT CMs had the most DADs, EADs, and tachyarrhythmia. Discordant negatively coupled alternans was seen in L4115F CPVT CMs. Carvedilol cured almost all arrhythmias in L4115F CPVT CMs. Both drugs decreased contraction amplitude in all hiPSC CMs. E3D CPVT CMs have electrophysiological properties, which render them more prone to arrhythmias. iPSC-CMs provide a unique platform for disease modeling and drug screening for CPVT. Combining electrophysiological measurements, we can gain deeper insight into mechanisms of arrhythmias.Peer reviewe

Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients

Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and IA115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to this study, the arrhythmia-abolishing effect of neither of the drugs is optimal. iPSC-CMs provide a unique platform for testing drugs for CPVT.Peer reviewe

Polarization beating of random electromagnetic beams

We consider temporal interference of two stationary, quasi-monochromatic, partially polarized optical beams with different mean frequencies. We show that both the intensity and the polarization state, represented by the Stokes parameters, exhibit beating, i.e., periodic temporal variation with frequency specified by the difference of the mean frequencies. The contrasts, or visibilities, of the Stokes-parameter changes are characterized by the equal-time electromagnetic degree of coherence between the beams. If the beams are otherwise identical random processes, but with spectra centered at different frequencies, then the polarization modulation is characterized by the degree of polarization, consistently with a recent interferometric interpretation of this quantity. Our results provide insight into the role of polarization in beating of electromagnetic waves

Development of the Surface Urban Energy and Water balance Scheme (SUEWS) for cold climate cities

The Surface Urban Energy and Water Balance Scheme (SUEWS) is developed to include snow. The processes addressed include accumulation of snow on the different urban surface types: snow albedo and density aging, snow melting and re-freezing of meltwater. Individual model parameters are assessed and independently evaluated using long-term observations in the two cold climate cities of Helsinki and Montreal. Eddy covariance sensible and latent heat fluxes and snow depth observations are available for two sites in Montreal and one in Helsinki. Surface runoff from two catchments (24 and 45 ha) in Helsinki and snow properties (albedo and density) from two sites in Montreal are also analysed. As multiple observation sites with different land-cover characteristics are available in both cities, model development is conducted independent of evaluation. The developed model simulates snowmelt related runoff well (within 19% and 3% for the two catchments in Helsinki when there is snow on the ground), with the springtime peak estimated correctly. However, the observed runoff peaks tend to be smoother than the simulated ones, likely due to the water holding capacity of the catchments and the missing time lag between the catchment and the observation point in the model. For all three sites the model simulates the timing of the snow accumulation and melt events well, but underestimates the total snow depth by 18–20% in Helsinki and 29–33% in Montreal. The model is able to reproduce the diurnal pattern of net radiation and turbulent fluxes of sensible and latent heat during cold snow, melting snow and snow-free periods. The largest model uncertainties are related to the timing of the melting period and the parameterization of the snowmelt. The results show that the enhanced model can simulate correctly the exchange of energy and water in cold climate cities at sites with varying surface cover

The Benefits and Limits of Urban Tree Planting for Environmental and Human Health

Many of the world's major cities have implemented tree planting programs based on assumed environmental and social benefits of urban forests. Recent studies have increasingly tested these assumptions and provide empirical evidence for the contributions of tree planting programs, as well as their feasibility and limits, for solving or mitigating urban environmental and social issues. We propose that current evidence supports local cooling, stormwater absorption, and health benefits of urban trees for local residents. However, the potential for urban trees to appreciably mitigate greenhouse gas emissions and air pollution over a wide array of sites and environmental conditions is limited. Consequently, urban trees appear to be more promising for climate and pollution adaptation strategies than mitigation strategies. In large part, this is due to space constraints limiting the extent of urban tree canopies relative to the current magnitude of emissions. The most promising environmental and health impacts of urban trees are those that can be realized with well-stewarded tree planting and localized design interventions at site to municipal scales. Tree planting at these scales has documented benefits on local climate and health, which can be maximized through targeted site design followed by monitoring, adaptive management, and studies of long-term eco-evolutionary dynamics.Peer reviewe

Over twenty years farmland reforestation decreases fungal diversity of soils, but stimulates the return of ectomycorrhizal fungal communities

© 2018, Springer International Publishing AG, part of Springer Nature. Background and Aims: Although soil-inhabiting fungi can affect tree health and biomass production in managed and pristine forests, little is known about the sensitivity of the plant-fungal associations to long-term changes in land use. We aimed to investigate how reforestation of farmlands change soil characteristics and affected the recovery of soil fungal functional guilds. Methods: We examined edaphic conditions and fungal communities (Illumina Sequencing) in three land-use types: primary forests (PF), secondary forests (SF, established over two decades ago) and active farmlands during May, July and September in Wuying, China. Results: Edaphic conditions and general fungal communities varied with land-use. Interestingly, overall fungal diversity was higher in soils at the farmland than at the forested sites, possibly as a result of recurring disturbances (tilling) allowing competitive release as described by the intermediate disturbance hypothesis. Although ectomycorrhizal fungal diversity and richness were marginally higher in PF than in SF, the latter still hosted surprisingly diverse and abundant ectomycorrhizal fungal communities. Conclusions: Reforestation largely restored fungal communities that were still in transition, as their composition in SF was distinct from that in PF. Our results highlight the ability of fungi grown in previously strongly managed agricultural land to rapidly respond to reforestation and thus provide support for forest trees

Heterozygous junctophilin-2 (JPH2) p. (Thr161Lys) is a monogenic cause for HCM with heart failure

During the last two decades, mutations in sarcomere genes have found to comprise the most common cause for hypertrophic cardiomyopathy (HCM), but still significant number of patients with dominant HCM in the family are left without molecular genetic diagnosis. Next generation sequencing (NGS) does not only enable evaluation of established HCM genes but also candidate genes for cardiomyopathy are frequently tested which may lead to a situation where conclusive interpretation of the variant requires extensive family studies. We aimed to characterize the phenotype related to a variant in the junctophilin-2 (JPH2) gene, which is less known non-sarcomeric candidate gene. In addition, we did extensive review of the literature and databases about JPH2 variation in association with cardiac disease. We characterize nine Finnish index patients with HCM and heterozygous for JPH2 c.482C>A, p. (Thr161Lys) variant were included and segregation studies were performed. We identified 20 individuals affected with HCM with or without systolic heart failure and conduction abnormalities in the nine Finnish families with JPH2 p.(Thr161Lys) variant. We found 26 heterozygotes with the variant and penetrance was 71% by age 60 and 100% by age 80. Cosegregation of the variant with HCM phenotype was observed in six families. Main clinical features were left ventricular hypertrophy, arrhythmia vulnerability and conduction abnormalities including third degree AV-block. In some patients end-stage severe left ventricular heart failure with normal or mildly enlarged diastolic dimensions was detected. In conclusion, we propose that the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical HCM.Peer reviewe

Distinct electrophysiological and mechanical beating phenotypes of long QT syndrome type 1-specific cardiomyocytes carrying different mutations

Peer reviewe