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BackgroundSarcoplasmic reticulum Ca2+ leak and post-translational modifications under stress have been implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly lethal inherited arrhythmogenic disorder. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling.ObjectiveThe aims were to obtain functional hiPSC-derived cardiomyocytes from a CPVT patient harboring a novel ryanodine receptor (RyR2) mutation and model the syndrome, drug responses and investigate the molecular mechanisms associated to the CPVT syndrome.MethodsPatient-specific cardiomyocytes were generated from a young athletic female diagnosed with CPVT. The contractile, intracellular Ca2+ handling and electrophysiological properties as well as the RyR2 macromolecular remodeling were studied.ResultsExercise stress electrocardiography revealed polymorphic ventricular tachycardia when treated with metoprolol and marked improvement with flecainide alone. We found abnormal stress-induced contractile and electrophysiological properties associated with sarcoplasmic reticulum Ca2+ leak in CPVT hiPSC-derived cardiomyocytes. We found inadequate response to metoprolol and a potent response of flecainide. Stabilizing RyR2 with a Rycal compound prevents those abnormalities specifically in CPVT hiPSC-derived cardiomyocytes. The RyR2-D3638A mutation is located in the conformational change inducing-central core domain and leads to RyR2 macromolecular remodeling including depletion of PP2A and Calstabin2.ConclusionWe identified a novel RyR2-D3638A mutation causing 3D conformational defects and aberrant biophysical properties associated to RyR2 macromolecular complex post-translational remodeling. The molecular remodeling is for the first time revealed using patient-specific hiPSC-derived cardiomyocytes which may explain the CPVT proband's resistance. Our study promotes hiPSC-derived cardiomyocytes as a suitable model for disease modeling, testing new therapeutic compounds, personalized medicine and deciphering underlying molecular mechanisms.

Fish habitats and reproduction can be significantly altered downstream of hydroelectric power plants operated by hydropeaking and resulting in rapid and frequent changes in river hydrodynamic conditions. To mitigate the impacts, it is necessary to maintain the habitat quality through operational measures. The microhabitat method, coupling 1 D or 2 D hydraulic simulations to biological models, is a useful tool to assess the evolution of hydromorphological parameters and fish habitats and define these mitigation measures. Calibration of the hydraulic model must be carried out carefully because the model must accurately reproduce hydraulic conditions from low to high flows. The objective is therefore to evaluate the sensitivity of the habitat value as a function of the type of calibration and the friction law for shallow habitats. The analysis is performed by estimating the uncertainty in fish habitat values resulting from Strickler's law or Nikuradse's law. The study is carried out on a river in the French Pyrenees based on the modeling of 2 stations with different cross-sectional shapes, one with progressive overflow and the other without these phenomena. Thanks to field measurements at low and high flowrates, the calibration process showed that the friction coefficient can be multiplied by 2. Two dimensionnal simulations give similar results to those obtained with 1 D when the flow remains unidirectional but differ for areas with high overflows. Calibration and models can lead to different conclusions regarding the estimation of habitat modifications due to hydropeaking operation and the definition of base flow and maximum turbine discharge. [ABSTRACT FROM AUTHOR]

Hydropower production can cause migration delay and fish mortality, impeding the safe and timely downstream migration of diadromous fish, such as Atlantic salmon (Salmo salar) and silver eels (Anguilla anguilla). To date, only a few field performance tests, especially for eels, have evaluated the efficiency of fine-spaced angled racks associated to a surface bypass entrance to protect fish. Here, 115 salmon smolts and 65 silver eels were radio-tracked over a 2 yr period to assess passage efficiency and passage time at a hydropower intake (50 m3.s−1) retrofitted with a 20 mm rack associated to a surface bypass (2 m3.s−1). Results showed high impediment (89.6% and 96.9% for smolts and eels, respectively), and passage efficiency for the angled rack (89.1% and 93.3%), with short passage times (median, 3 and 7.5 min). However, our results highlighted a strong influence of hydrological conditions, in enhancing fish passage, especially through the bear-trap gate. We conclude that this fish passage solution, making use of existing spillways on the study site, is highly effective for both species. Special attention must, however, be paid to bar-rack design and its cleaning system to ensure fish guidance and prevent impingement or passage through the rack, especially for salmon smolts.

Hydropower energy can contribute to achieve the carbon neutrality goals, but also needs to reach environmental sustainability. Hydropower plants (HPP) constitute barriers to fish migrations that are essential for accomplishing their complete biological cycle. Fish downstream passage solutions (FDPS) have to be implemented to maximize their survival, guiding them away from the turbine intakes towards a safe passage alternative. Recent telemetry studies confirmed the efficiency of 26° inclined low bar spacing (20 mm) rack associated to surface bypasses, installed upstream HPPs, to protect downstream migrating Atlantic salmon smolts. Here we tested the efficiency of such FDPS for eel protection using radiotelemetry at four successive HPPs (with intake capacities from 28 to 45 m3.s−1) in the Ariège River (southern France). Between 52 and 74 eels, longer than 550 mm, entered the HPP intakes and 100% of them were protected from turbine passage. All eels crossed the HPP water intake using the surface bypasses, and the great majority in few minutes from their first presentation in front of the rack. These results showed that in such rack configuration, it is not necessary to add a specific bottom bypass, usually recommended for eels. We also showed the importance of optimal hydraulic conditions, mainly tangential (parallel to the rack) velocity and bypass discharge, to efficiently guide the eels towards the surface bypasses, reducing their passage time. Overall, our study provided key elements to water managers for designing an efficient FDPS for eels.

Downstream migrating fish can be strongly affected by hydroelectric facilities. To set up adapted mitigation measures, it is important to identify these impacts (e.g. induced mortality rates). For Francis turbines, two mortality prediction formulas, developed in 1989 and updated in 2000, are currently used in France for salmonids according to turbine characteristics and fish size (Larinier and Dartiguelongue, 1989, updated by Bosc and Larinier, 2000). However, their use is limited when some parameters are unknown, such as turbine speed. Moreover, the updated version of can be criticized because of its unpublished development procedure and its unknown predictive power. The main purpose of this study is to update the existing formulae to meet the following objectives: (1) a transparent development procedure, (2) formulae simplification, (3) the use of simple (usually the best-known) turbine parameters, and (4) a maximization of the predictive power and an assessment of prediction errors. Based on data from 73 in situ mortality tests available in peer-reviewed and ‘grey’ literature, we developed two new formulae to estimate salmonid mortality rate in Francis turbines. The first one uses turbine peripheral speed, diameter and fish size (correlation between predicted and observed mortality rates r = 0.89, and root mean square error RMSE = 0.11). The second one is based on usually known parameters: turbine discharge, water head and fish size, to allow a broader applicability (r = 0.89, RMSE = 0.10). This study comforts the validity of previous formulae and provides two new ones allowing a satisfactory precision in the estimations.

The insulin IGF-1-PI3K-Akt signaling pathway has been suggested to improve cardiac inotropism and increase Ca(2+) handling through the effects of the protein kinase Akt. However, the underlying molecular mechanisms remain largely unknown. In this study, we provide evidence for an unanticipated regulatory function of Akt controlling L-type Ca(2+) channel (LTCC) protein density. The pore-forming channel subunit Ca(v)alpha1 contains highly conserved PEST sequences (signals for rapid protein degradation), and in-frame deletion of these PEST sequences results in increased Ca(v)alpha1 protein levels. Our findings show that Akt-dependent phosphorylation of Ca(v)beta2, the LTCC chaperone for Ca(v)alpha1, antagonizes Ca(v)alpha1 protein degradation by preventing Ca(v)alpha1 PEST sequence recognition, leading to increased LTCC density and the consequent modulation of Ca(2+) channel function. This novel mechanism by which Akt modulates LTCC stability could profoundly influence cardiac myocyte Ca(2+) entry, Ca(2+) handling, and contractility.

Hydropower plants can profoundly modify the natural morphology and hydrology of rivers and can alter the functionality of habitats for fish living and reproduction. In particular, hydropeaking leads to rapid and frequent changes of the hydrodynamic conditions and it is crucial to ensure aquatic habitat quality is maintained as much as possible during these periods. One present method to determine mitigation measure (minimum and maximum flow, rate of change) is to perform hydraulic simulations in 1D or 2D in the range of flow variation and to evaluate habitat quality for fish with the microhabitat method. The hydraulic model calibration has to be conducted carefully since the model has to reproduce precisely the hydraulic conditions from low to high flow rates (up to several times the mean flow of the rivers). Within this range, the friction coefficient can evolve greatly because at low flows the size of roughness elements become comparable to the water depth.. This phenomenon is observed by performing the modelling and the calibration at 2 stations on a river in French Pyrenees with different cross section shapes, one with progressive overflowing of some banks with large blocks and the other one without such phenomena. Thanks to field measurements of water levels at low and high discharge, the calibration process has shown that the friction coefficient can be multiplied by 2 as a function of the discharge. The paper proposes a methodology to evaluate the most appropriate tool. As water depth is concerned, the 2D simulations (TELEMAC 2D) provide similar results to those obtained with 1D (HEC-RAS) because flow remains unidirectional. Then a sensitivity analysis is carried out to estimate the uncertainty on the fish habitat outputs for a fish species (brown trout in the present study) resulting from several widely used friction laws. These friction laws can lead to different conclusions about habitat suitability depending on the calibrated coefficient. Finally, to perform relevant habitat modelling, it is necessary to measure water levels at several discharges and to describe accurately the spatial variability of roughness height.

Aims Ventricular fibrillation (VF) occurring in the acute phase of ST-elevation myocardial infarction (STEMI) is the leading cause of sudden cardiac death worldwide. Several studies showed that reduced connexin 43 (Cx43) expression and reduced conduction velocity increase the risk of VF in acute myocardial infarction (MI). Furthermore, genetic background might predispose individuals to primary VF (PVF). The primary objective was to evaluate the presence of GJA1 variants in STEMI patients. The secondary objective was to evaluate the arrhythmogenic impact of GJA1 variants in STEMI patients with VF. Methods and results The MAP-IDM prospective cohort study included 966 STEMI patients and was designed to identify genetic predisposition to VF. A total of 483 (50.0%) STEMI patients with PVF were included. The presence of GJA1 variants increased the risk of VF in STEMI patients [from 49.1 to 70.8%, P = 0.0423; odds ratio (OR): 0.40; 95% confidence interval: 0.16–0.97; P = 0.04]. The risk of PVF decreased with beta-blocker intake (from 53.5 to 44.8%, P = 0.0085), atrial fibrillation (from 50.7 to 26.4%, P = 0.0022), and with left ventricular ejection fraction >50% (from 60.2 to 41.4%, P < 0.0001). Among 16 GJA1 variants, three novel heterozygous missense variants were identified in three patients: V236I, H248R, and I327M. In vitro studies of these variants showed altered Cx43 localization and decreased cellular communication, mainly during acidosis. Conclusion Connexin 43 variants are associated with increased VF susceptibility in STEMI patients. Restoring Cx43 function may be a potential therapeutic target to prevent PVF in patients with acute MI. Clinical trial registration Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT00859300 [ABSTRACT FROM AUTHOR]