Validating Performance Models for Hybrid Power Plant Control Assessment

The need for simple, but accurate performance models of wind turbine generators (WTGs), photovoltaic (PV) plants, and battery energy storage systems (BESS) for various hybrid power plant (HPP) studies motivates the present work. Particularly, the development and verification stage of HPP controls requires reduced-order models to minimize the complexity and computation effort of simulation platforms. In this paper, such models are proposed, and the most essential parts of the models are validated through field measurements. The models target power system integration studies involving active and reactive power, as well as frequency and voltage regulation where detailed models, as proposed in the standards, can be cumbersome. Field measurements of two Vestas WTGs, one 1-MW PV plant, and one 1-MW/1-MWh BESS are used for model validation. The results show that the WTG and PV performance models correctly estimate the power generation variability according to fluctuations in wind speed and solar irradiance. The BESS performance model provides satisfactory results related to grid-forming control performance and estimation of state-of-charge. The presented validation work enables using the proposed performance models for power system studies and HPP control design in all model-based design stages, that is, preliminary analysis, design, verification, and validation with a high level of confidence

Ibrutinib impairs IGF-1-dependent activation of intracellular Ca handling in isolated mouse ventricular myocytes

BackgroundThe Bruton tyrosine kinase (BTK) inhibitor Ibrutinib is associated with a higher incidence of cardiotoxic side effects including heart failure (HF).ObjectivesIbrutinib is capable of inhibiting PI3K/Akt signaling in neonatal rat ventricular cardiomyocytes when stimulated with insulin-like growth factor 1 (IGF-1). We therefore hypothesized that Ibrutinib might disrupt IGF-1-mediated activation of intracellular Ca handling in adult mouse cardiomyocytes by inhibiting PI3K/Akt signaling.MethodsIsolated ventricular myocytes (C57BL6/J) were exposed to IGF-1 at 10 nmol/L in the presence or absence of Ibrutinib (1 µmol/L) or Acalabrutinib (10 µmol/L; cell culture for 24 ± 2 h). Intracellular Ca handling was measured by epifluorescence (Fura-2 AM) and confocal microscopy (Fluo-4 AM). Ruptured-patch whole-cell voltage-clamp was used to measure ICa. Levels of key cardiac Ca handling proteins were investigated by immunoblots.ResultsIGF-1 significantly increased Ca transient amplitudes by ∼83% as compared to vehicle treated control cells. This was associated with unaffected diastolic Ca, enhanced SR Ca loading and increased ICa. Co-treatment with Ibrutinib attenuated both the IGF-1-mediated increase in SR Ca content and in ICa. IGF-1 treated cardiomyocytes had significantly increased levels of pS473Akt/Akt and SERCA2a expression as compared to cells concomitantly treated with IGF-1 and Ibrutinib. SR Ca release (as assessed by Ca spark frequency) was unaffected by either treatment. In order to test for potential off-target effects, second generation BTK inhibitor Acalabrutinib with greater BTK selectivity and lower cardiovascular toxicity was tested for IGF1-mediated activation of intracellular Ca handling. Acalabrutinib induced similar effects on Ca handling in IGF-1 treated cultured myocytes as Ibrutinib in regard to decreased Ca transient amplitude and slowed Ca transient decay, hence implying a functional class effect of BTK inhibitors in cardiac myocytes.ConclusionsInhibition of BTK by Ibrutinib impairs IGF-1-dependent activation of intracellular Ca handling in adult ventricular mouse myocytes in the face of disrupted Akt signaling and absent SERCA2a upregulation

A Pilot Trial to Compare the Long-Term Efficacy of Pulmonary Vein Isolation with High-Power Short-Duration Radiofrequency Versus Laser Energy with Rapid Ablation Mode

Background: Pulmonary vein (PV) reconnection is the major cause of atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). The probability of reconnection is higher if the primary lesion is not sufficiently effective, which can be unmasked with an adenosine provocation test (APT). High-power short-duration radiofrequency energy (HPSD) guided with ablation index (AI) and the third generation of the visually guided laser balloon (VGLB) are new methods for PVI. Methods: A total of 70 participants (35 in each group) who underwent a PVI with either AI-guided HPSD (50 W; AI 500 for the anterior and 400 for the posterior wall, respectively) or VGLB ablation were included in this observational pilot trial. Twenty minutes after each PVI, an APT was performed. The primary endpoint was the event-free survival from AF after three years. Results: A total of 137 (100%) PVs in the HPSD arm and 131 PVs (98.5%) in the VGLB arm were initially successfully isolated (p = 0.24). The overall procedure duration was similar in both arms (155 ± 39 in HPSD vs. 175 ± 58 min in VGLB, p = 0.191). Fluoroscopy time, left atrial dwelling time and duration from the first to the last ablation were longer in the VGLB arm (23 ± 8 vs. 12 ± 3 min, p < 0.001; 157 (111–185) vs. 134 (104–154) min, p = 0.049; 92(59–108) vs. 72 (43–85) min, p = 0.010). A total of 127 (93%) in the HPSD arm and 126 (95%) PVs in the VGLB arm remained isolated after APT (p = 0.34). The primary endpoint was met 1107 ± 68 days after ablation in 71% vs. 66% in the VGLB and HPSD arms, respectively (p = 0.65). Conclusions: HPSD and VGLB did not differ with respect to long-term outcome of PVI. A large, randomized study should be conducted to compare clinical outcomes with respect to these new ablation techniques

Organizaciones Agrarias y Cooperativas: Transformaciones en trabajo, producción, y acceso a la tierra en Misiones. 16H351

Las actividades agropecuarias en Misiones, vienen sufriendo profundas transformaciones que impactan de manera diferencial sobre los trabajadores y sobre los productores agrarios, pero también en el proceso manufacturero y de comercialización. Con el objetivo de identificar y analizar éstas transformaciones recientes, intentaremos generar conocimiento sobre cambios productivos y en la organización del trabajo en encadenamientos agroindustriales del té y la yerba mate, relevar las estrategias económicas de las cooperativas agroindustriales, identificando sus particularidades respecto a la organización del trabajo, a las modalidades de incorporación de tecnologías y normas de calidad, y en relación con las políticas públicas. También investigaremos la incidencia de organizaciones de productores agrarios sobre los cambios en la implementación de políticas agropecuarias, en especial respecto a la producción, comercialización de alimentos y acceso a la tierra. Considerando las interacciones complejas en las transformaciones en curso, al mismo tiempo las limitaciones contextuales y las estrategias de los actores, exploraremos canales de circulación de insumos y de productos, mecanismos de fijación de precios, para analizar relaciones económicas y de poder, así como transferencias entre los distintos sectores. Desde una perspectiva metodológica cualitativa, tomaremos algunas experiencias de producción y comercialización, por parte de pequeños productores en forma asociativa, como referencia empírica para reflexionar sobre las posibilidades y dificultades de las organizaciones agrarias

Enhanced Heart Failure in Redox‐Dead Cys17Ser PKARIα Knock‐In Mice

Background PKARIα (protein kinase A type I‐α regulatory subunit) is redox‐active independent of its physiologic agonist cAMP. However, it is unknown whether this alternative mechanism of PKARIα activation may be of relevance to cardiac excitation–contraction coupling. Methods and Results We used a redox‐dead transgenic mouse model with homozygous knock‐in replacement of redox‐sensitive cysteine 17 with serine within the regulatory subunits of PKARIα (KI). Reactive oxygen species were acutely evoked by exposure of isolated cardiac myocytes to AngII (angiotensin II, 1 µmol/L). The long‐term relevance of oxidized PKARIα was investigated in KI mice and their wild‐type (WT) littermates following transverse aortic constriction (TAC). AngII increased reactive oxygen species in both groups but with RIα dimer formation in WT only. AngII induced translocation of PKARI to the cell membrane and resulted in protein kinase A–dependent stimulation of ICa (L‐type Ca current) in WT with no effect in KI myocytes. Consequently, Ca transients were reduced in KI myocytes as compared with WT cells following acute AngII exposure. Transverse aortic constriction–related reactive oxygen species formation resulted in RIα oxidation in WT but not in KI mice. Within 6 weeks after TAC, KI mice showed an enhanced deterioration of contractile function and impaired survival compared with WT. In accordance, compared with WT, ventricular myocytes from failing KI mice displayed significantly reduced Ca transient amplitudes and lack of ICa stimulation. Conversely, direct pharmacological stimulation of ICa using Bay K8644 rescued Ca transients in AngII‐treated KI myocytes and contractile function in failing KI mice in vivo. Conclusions Oxidative activation of PKARIα with subsequent stimulation of ICa preserves cardiac function in the setting of acute and chronic oxidative stress

Metabolic syndrome — a new definition and management guidelines

The joint position paper by Polish Society of Hypertension, Polish Society for the Treatment of Obesity, Polish Lipid Association, Polish Association for Study of Liver, Polish Society of Family Medicine, Polish Society of Lifestyle Medicine, Division of Prevention and Epidemiology Polish Cardiac Society, “Club 30” Polish Cardiac Society, and Division of Metabolic and Bariatric Surgery Society of Polish Surgeons Reviewers: Agnieszka Olszanecka, Krzysztof J. Filipia

Ibrutinib impairs IGF-1-dependent activation of intracellular Ca handling in isolated mouse ventricular myocytes

Background: The Bruton tyrosine kinase (BTK) inhibitor Ibrutinib is associated with a higher incidence of cardiotoxic side effects including heart failure (HF). Objectives: Ibrutinib is capable of inhibiting PI3K/Akt signaling in neonatal rat ventricular cardiomyocytes when stimulated with insulin-like growth factor 1 (IGF-1). We therefore hypothesized that Ibrutinib might disrupt IGF-1-mediated activation of intracellular Ca handling in adult mouse cardiomyocytes by inhibiting PI3K/Akt signaling. Methods: Isolated ventricular myocytes (C57BL6/J) were exposed to IGF-1 at 10 nmol/L in the presence or absence of Ibrutinib (1 µmol/L) or Acalabrutinib (10 µmol/L; cell culture for 24 ± 2 h). Intracellular Ca handling was measured by epifluorescence (Fura-2 AM) and confocal microscopy (Fluo-4 AM). Ruptured-patch whole-cell voltage-clamp was used to measure ICa. Levels of key cardiac Ca handling proteins were investigated by immunoblots. Results: IGF-1 significantly increased Ca transient amplitudes by ∼83% as compared to vehicle treated control cells. This was associated with unaffected diastolic Ca, enhanced SR Ca loading and increased ICa. Co-treatment with Ibrutinib attenuated both the IGF-1-mediated increase in SR Ca content and in ICa. IGF-1 treated cardiomyocytes had significantly increased levels of pS473Akt/Akt and SERCA2a expression as compared to cells concomitantly treated with IGF-1 and Ibrutinib. SR Ca release (as assessed by Ca spark frequency) was unaffected by either treatment. In order to test for potential off-target effects, second generation BTK inhibitor Acalabrutinib with greater BTK selectivity and lower cardiovascular toxicity was tested for IGF1-mediated activation of intracellular Ca handling. Acalabrutinib induced similar effects on Ca handling in IGF-1 treated cultured myocytes as Ibrutinib in regard to decreased Ca transient amplitude and slowed Ca transient decay, hence implying a functional class effect of BTK inhibitors in cardiac myocytes. Conclusions: Inhibition of BTK by Ibrutinib impairs IGF-1-dependent activation of intracellular Ca handling in adult ventricular mouse myocytes in the face of disrupted Akt signaling and absent SERCA2a upregulation

SR Ca 2+ -leak and disordered excitation-contraction coupling as the basis for arrhythmogenic and negative inotropic effects of acute ethanol exposure

Aims: Ethanol has acute negative inotropic and arrhythmogenic effects. The underlying mechanisms, however, are largely unknown. Sarcoplasmic reticulum Ca2+-leak is an important mechanism for reduced contractility and arrhythmias. Ca2+-leak can be induced by oxidative stress and Ca2+/Calmodulin-dependent protein kinase II (CaMKII). Therefore, we investigated the influence of acute ethanol exposure on excitation-contraction coupling in atrial and ventricular cardiomyocytes. Methods and results: Isolated human atrial and murine atrial or ventricular cardiomyocytes were preincubated for 30 min and then superfused with control solution or solution containing ethanol. Ethanol had acute negative inotropic and positive lusitropic effects in human atrial muscle strips and murine ventricular cardiomyocytes. Accordingly, Ca2+-imaging indicated lower Ca2+-transient amplitudes and increased SERCA2a activity, while myofilament Ca2+-sensitivity was reduced. SR Ca2+-leak was assessed by measuring Ca2+-sparks. Ethanol induced severe SR Ca2+-leak in human atrial cardiomyocytes (calculated leak: 4.60 +/- 0.45 mF/F0 vs 1.86 +/- 0.26 in control, n = 80). This effect was dose-dependent, while spontaneous arrhythmogenic 2+-waves increased similar to 5-fold, as investigated in murine cardiomyocytes. Delayed afterdepolarizations, which can result from increased SR Ca2+-leak, were significantly increased by ethanol. Measurements using the reactive oxygen species (ROS) sensor CM-H2DCFDA showed increased ROS-stress in ethanol treated cells. ROS-scavenging with N-acetylcysteine prevented negative inotropic and positive lusitropic effects in human muscle strips. Ethanol-induced Ca2+-leak was abolished in mice with knockout of NOX2 (the main source for ROS in cardiomyocytes). Importantly, mice with oxidation-resistant CaMKII (Met281/282Val mutation) were protected from ethanol-induced Ca2+-leak. Conclusion: We show for the first time that ethanol acutely induces strong SR Ca2+-leak, also altering excitation-contraction coupling. Acute negative inotropic effects of ethanol can be explained by reduced systolic Ca2+-release. Mechanistically, ROS-production via NOX2 and oxidative activation of CaMKII appear to play central roles. This provides a mechanism for the arrhythmogenic and negative inotropic effects of ethanol and suggests a druggable target (CaMKII)

Chronic Exposure to Fluoride Affects GSH Level and NOX4 Expression in Rat Model of This Element of Neurotoxicity

Exposure of neural cells to harmful and toxic factors promotes oxidative stress, resulting in disorders of metabolism, cell differentiation, and maturation. The study examined the brains of rats pre- and postnatally exposed to sodium fluoride (NaF 50 mg/L) and activity of NADPH oxidase 4 (NOX4), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), concentration of glutathione (GSH), and total antioxidant capacity (TAC) in the cerebellum, prefrontal cortex, hippocampus, and striatum were measured. Additionally, NOX4 expression was determined by qRT&ndash;PCR. Rats exposed to fluorides (F-) showed an increase in NOX4 activity in the cerebellum and hippocampus, a decrease in its activity in the prefrontal cortex and hippocampus, and upregulation of NOX4 expression in hippocampus and its downregulation in other brain structures. Analysis also showed significant changes in the activity of all antioxidant enzymes and a decrease in TAC in brain structures. NOX4 induction and decreased antioxidant activity in central nervous system (CNS) cells may be central mechanisms of fluoride neurotoxicity. NOX4 contributes to blood&ndash;brain barrier damage, microglial activation, and neuronal loss, leading to impairment of brain function. Fluoride-induced oxidative stress involves increased reactive oxygen speciaes (ROS) production, which in turn increases the expression of genes encoding pro-inflammatory cytokines