Comprehensive analyses of the inotropic compound omecamtiv mecarbil in rat and human cardiac preparations

Omecamtiv mecarbil (OM), a myosin activator, was reported to induce complex concentration- and species-dependent effects on contractile function and clinical studies indicated a low therapeutic index with diastolic dysfunction at concentrations above 1 µM. To further characterize effects of OM in a human context and under different preload conditions, we constructed a setup that allows isometric contractility analyses of human induced pluripotent stem cell (hiPSC)-derived engineered heart tissues (EHTs). The results were compared to effects of OM on the very same EHTs measured under auxotonic conditions. OM induced a sustained, concentration-dependent increase in time-to-peak under all conditions (maximally 2-3 fold). Peak force, in contrast, was increased by OM only in human, but not rat EHTs and only under isometric conditions, varied between hiPSC lines and showed a biphasic concentration-dependency with maximal effects at 1 µM. Relaxation time tended to fall under auxotonic and strongly increase under isometric conditions, again with biphasic concentration-dependency. Diastolic tension concentration-dependently increased under all conditions. The latter was reduced by an inhibitor of the mitochondrial sodium calcium exchanger (CGP-37157). OM induced increases in mitochondrial oxidation in isolated cardiomyocytes, indicating that OM, an inotrope that does not increase intracellular and mitochondrial Ca2+, can induce mismatch between an increase in ATP and ROS production and unstimulated mitochondrial redox capacity. Taken together, we developed a novel setup well suitable for isometric measurements of EHTs. The effects of OM on contractility and diastolic tension are complex with concentration-, time-, species- and loading-dependent differences. Effects on mitochondrial function require further studies.

The Effect of Cobalt on the Deformation Behaviour of a Porous TiNi-Based Alloy Obtained by Sintering

This research investigates the effect of cobalt on the deformation behaviour of a porous TiNi-based alloy that was obtained by sintering. Porous TiNi-based alloys with cobalt additives, accounting for 0–2 at. % and with a pitch of 0.5, were obtained. The structural-phase state of the porous material was researched by X-ray structural analysis. The effect of different amounts of Co (used as an alloying additive) on the deformation behaviour was investigated by tensile to fracture. The fractograms of fracture of the experimental samples were analysed using scanning electron microscopy. For the first time, the present research shows a diagram of the deformation of a porous TiNi-based alloy that was obtained by sintering under tensile. The stages of deformation were described according to the physical nature of the processes taking place. The effect of the cobalt-alloying additive on the change in the critical stress of martensitic shear was investigated. It was found that the behaviour of the concentration dependency of stress at concentrations under 1.5 at. % Co was determined by an increase in the stress in the TiNi solid solution. This phenomenon is attributed to the arrangement of Co atoms on the Ti sublattice, as well as an increase in the fraction of the B19′ phase in the matrix. The steep rise of the developed forces on the concentration dependency of the martensitic shear stress at 2 at. % Co is presumably attributed to the precipitation hardening of austenite due to the precipitation of finely dispersed coherent Ti3Ni4 phase following the decrease of fraction of martensite. An analysis of fractograms showed that as more cobalt was added, areas of fracture with traces of martensite plates of the B19′ phase started to prevail. At 2 at. % Co these plates fill almost the entire area of the fracture. The research findings presented in this work are of great importance, since they can be used to achieve the set of physical and mechanical properties required for the development of biocompatible materials for implantology.

Inferring a causal relationship between ceramide levels and COVID-19 respiratory distress

A causal relationship between plasma ceramide concentration and respiratory distress symptoms in COVID-19 patients is inferred. In this study, plasma samples of 52 individuals infected with COVID-19 were utilized in a lipidomic analysis. Lipids belonging to the ceramide class exhibited a 400-fold increase in total plasma concentration in infected patients. Further analysis led to the demonstration of concentration dependency for severe COVID-19 respiratory symptoms in a subclass of ceramides. The subclasses Cer(d18:0/24:1), Cer(d18:1/24:1), and Cer(d18:1/22:0) were shown to be increased by 48-, 40-, and 33-fold, respectively, in infected plasma samples and to 116-, 91- and 50-fold, respectively, in plasma samples with respiratory distress. Hence, monitoring plasma ceramide concentration, can be a valuable tool for measuring effects of therapies on COVID-19 respiratory distress patients.

Acute Toxicity of Cu-MOF Nanoparticles (nanoHKUST-1) towards Embryos and Adult Zebrafish

Metal-organic frameworks (MOFs) demonstrate unique properties, which are prospective for drug delivery, catalysis, and gas separation, but their biomedical applications might be limited due to their obscure interactions with the environment and humans. It is important to understand their toxic effect on nature before their wide practical application. In this study, HKUST-1 nanoparticles (Cu-nanoMOF, Cu3(btc)2, btc = benzene-1,3,5-tricarboxylate) were synthesized by the microwave (MW)-assisted ionothermal method and characterized by X-ray powder diffraction (XRD) and transmission electron microscopy (TEM) techniques. The embryotoxicity and acute toxicity of HKUST-1 towards embryos and adult zebrafish were investigated. To gain a better understanding of the effects of Cu-MOF particles towards Danio rerio (D. rerio) embryos were exposed to HKUST-1 nanoparticles (NPs) and Cu2+ ions (CuSO4). Cu2+ ions showed a higher toxic effect towards fish compared with Cu-MOF NPs for D. rerio. Both forms of fish were sensitive to the presence of HKUST-1 NPs. Estimated LC50 values were 2.132 mg/L and 1.500 mg/L for zebrafish embryos and adults, respectively. During 96 h of exposure, the release of copper ions in a stock solution and accumulation of copper after 96 h were measured in the internal organs of adult fishes. Uptake examination of the major internal organs did not show any concentration dependency. An increase in the number of copper ions in the test medium was found on the first day of exposure. Toxicity was largely restricted to copper release from HKUST-1 nanomaterials structure into solution.

Ceramide Levels and COVID-19 Respiratory Distress, a Causal Relationship

A causal relationship between plasma ceramide concentration and respiratory distress symptoms in COVID-19 patients is presented. In this study, plasma samples of 52 individuals infected with COVID-19 were utilized in a lipidomic analysis. Lipids belonging to the ceramide class exhibited a 400-fold increase in total plasma concentration in infected patients. Further analysis led to the demonstration of concentration dependency for severe COVID-19 respiratory symptoms in a subclass of ceramides. The subclasses Cer(d18:0/24:1), Cer(d18:1/24:1), and Cer(d18:1/22:0) were shown to be increased by 48-, 40-, and 33-fold, respectively, in infected plasma samples and to 116-, 91- and 50-fold, respectively, in plasma samples with respiratory distress. Hence, monitoring plasma ceramide concentration, targeting ceramide synthesis, its salvage and its regulatory mechanisms are validated approaches towards enhancing survival from COVID-19 respiratory distress.

Ceramide Levels and Covid-19 Respiratory Distress, a Causal Relationship

A causal relationship between plasma ceramide concentration and Covid-19 patients with respiratory distress symptoms is presented. In this study, plasma samples of 52 individuals infected with Covid-19 were utilized in a lipidomic analysis. Lipids belonging to ceramide class exhibited a 400-fold increase in total plasma concentration in infected patients. Further analysis lead to demonstration of concentration dependency, for severe Covid-19 respiratory symptoms, in a subclass of ceramides. The subclasses Cer(d18:0/24:1), Cer(d18:1/24:1), and Cer(d18:1/22:0) are shown to be increased by 48, 40, and 33–folds respectively in infected plasma samples, and to 116, 91 and 50-folds in plasma samples with respiratory distress. Hence, monitoring of plasma ceramide concentration, targeting ceramide synthesis, its salvage and its regulatory mechanisms, are validated approach towards enhancing survival from Covid-19 respiratory distress.

Ceramide Levels and Covid-19 Respiratory Distress, a Causal Relationship

A causal relationship between plasma ceramide concentration and Covid-19 patients with respiratory distress symptoms is presented. Hence, monitoring of plasma ceramide concentration, targeting ceramide synthesis, its salvage and its regulatory mechanisms, are validated approach towards enhancing survival from Covid-19 respiratory distress. In this study, plasma samples of 52 individuals infected with Covid-19 were utilized in a lipidomic analysis. Lipids belonging to ceramide class exhibited a 400-fold increase in total plasma concentration in infected patients. Further analysis lead to demonstration of concentration dependency, for severe Covid-19 respiratory symptoms, in a subclass of ceramides. The subclasses Cer(d18:0/24:1), Cer(d18:1/24:1), and Cer(d18:1/22:0) are shown to be increased by 48, 40, and 33–folds respectively in infected plasma samples, and to 116, 91 and 50-folds in plasma samples with respiratory distress.

Gummy candies production with natural sugar source: Effect of molasses types and gelatin ratios

Nowadays, attention has been dedicated towards the development of foodstuffs whose constituents are from natural sources. In this study, grape, mulberry, and carob molasses containing natural sugars were evaluated in order to replace the use of sugar syrup and artificial additives in the production of gummy candy which was prepared by varied gelatin ratios. The molasses which have similar °Brix values (78–79) presented different types and amounts of sugar components. High invert sugar with low sucrose was observed in grape and mulberry but high sucrose with low fructose and glucose appeared in carob molasses. Unlike grape and mulberry, carob based jellies had a whitish appearance possibly as a result of the crystallization due to its high sucrose/invert sugar ratio. For all parameters of TPA, carob candy with 5 g/100 g gelatin and grape candy with 10 g/100g gelatin had the lowest and highest values, respectively. Gelatin concentration dependency trend of hardness, gumminess, chewiness and resilience was determined as grape > mulberry > carob. No significant effect ( p > 0.05) on gelling temperatures (21–29 °C) but significant effect (p < 0.05) on melting points (33–39 °C) of molasses types were observed for candies. The properties of grape based candy having higher thermal stability and lower temperature sensitivity were attributed to its higher total sugar contents than other samples. The sensorial acceptability score for molasses gummy candies obtained more than 3.0 on a 5-point hedonic scale. These results illustrate the potential for the use of molasses in a healthier confectionery product development instead of commonly used sugars.