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  • Castillo Abel posted an update 18 days ago

    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. learn more All generated iPSCs maintained pluripotency, normal karyotype, and spontaneous in vivo and in vitro differentiation capacity.Arrhythmogenic cardiomyopathy (ACM) is characterized by fibro-fatty replacement of the myocardium, heart failure and life-threatening ventricular arrhythmias. Causal mutations were identified in genes encoding for proteins of the desmosomes, predominantly plakophilin-2 (PKP2) and desmoglein-2 (DSG2). We generated gene-edited knock-out iPSC lines for PKP2 (JMUi001-A-2) and DSG2 (JMUi001-A-3) using the CRISPR/Cas9 system in a healthy control iPSC background (JMUi001-A). Stem cell-like morphology, robust expression of pluripotency markers, embryoid body formation and normal karyotypes confirmed the generation of high quality iPSCs to provide a novel isogenic human in vitro model system mimicking ACM when differentiated into cardiomyocytes.Ruxolitinib is a Janus Kinase inhibitor currently approved for the treatment of myelofibrosis. It is also a promising drug for the treatment of skin and infectious diseases. In terms of pharmaceutical stability, although ruxolitinib has been established as being sensitive to light, no data on photodegradation processes are available to date, while these may be useful for quality risk management and any potential development of other pharmaceutical forms for other routes of administration. One way to partially fill this gap was to carry out a study that combines a consistent determination of the most sensitive sites of the molecule to photolysis through theoretical calculations based on functional density, with the identification of the main photodegradation products obtained after forced degradation. This integrated approach has shown converging results describing the mechanisms based on photo-oxidation that can lead to the opening of the pyrrole ring. Having access to the structure of the degradation products and intermediates then made it possible to carry out an in silico evaluation of their potential mutagenicity and it appears that some of them feature alert structures.This study aims to investigate the chemical constituents of sponges Dysidea avara (D. avara) and Axinella sinoxea (A. sinoxea), grown up in the Persian Gulf, as well as dehydrodeoxycholic acid (DHCA) content in methanolic extracts of the selected sponges. The chromatography-mass spectrometry (GC-MS) fingerprint of bioactive compounds from methanolic extracts of the selected marine sponge samples was investigated. Based on molecular docking results, among chemical compounds found in marine sponges, DHCA has anti-inflammatory and antipsoriatic properties. They also indicated that DHCA generated stable complexes with 1w81, 3bqm, and 3k8o receptors (psoriasis-related targets) with a binding energy (BE) of -9.26, -10.62, and -7.59 kcal mol-1, respectively. DHCA is isolated from the methanolic extracts of marine sponge samples on chromatographic plates was quantified after derivatization with anisaldehyde reagent by the validated HPTLC method. In-situ HPTLC-DPPH was also calculated to evaluate the free radical-scavenging activity (FRSA) of DHCA. In-silico ADME (Absorption, Distribution, Metabolism, Excretion) predictions revealed that the compound had minimum toxicity and acceptable human intestinal absorption (HIA), as well as low skin permeability. These can potentially be employed as lead compounds to develop a novel antipsoriatic drug.Natural products have been a primary source of medicines throughout the history of human existence. It is estimated that close to 70 % of small molecule pharmaceuticals on the market are derived from natural products. With increasing antibiotic resistance, natural products remain an important source for the discovery of novel antimicrobial compounds. The plant rosemary (Rosmarinus officinalis), has been widely and commonly used as a food preservative due to its antimicrobial potential. To evaluate the antimicrobial profile of this plant, we used bioassay-guided fractionation and bioinformatics approaches. Through bioassay-guided fractionation, we tested in vitro activities of a R. officinalis extract and fractions thereof, as well as pure compounds micromeric acid (1), oleanolic acid (2), and ursolic acid (3) against methicillin-resistant Staphylococcus aureus (MRSA). Compounds 1 and 3 showed complete inhibition of MRSA (with MIC values of 32 μg/mL and 8 μg/mL, respectively) while compound 2 displayed only parison with its commercial standard by employed ultra-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS), while 4, 5a-b and 7 were putatively identified based on MS data and in comparison with the literature. This is the first reported antimicrobial activity of micromeric acid (1) against MRSA.This review reflects different aspects of wide current studies of the phenomena related to the shear-induced structure transformation in various complex liquids. Experimental data, being the basis of this discussion, were obtained for polymeric liquids (melts, blends, solutions) and different dispersions (colloidal solutions, suspensions, emulsions). The general initial input of shearing is the creation of inhomogeneities which can continue to remain as separate domains, become the nuclei of new phases, or become diffuse, leading to phase separation. The following effects are discussed diffusion-induced phase separation, phase transitions occurring mainly due to the deformation-driven orientation of polymer chains and worm-like micelles that results in the formation of a liquid-crystal state, as well as self-assembly effects. It can be stressed that the appearance of regular structures takes place in systems that can coexist in different concentrations or phase states at the same stress or shear rate. This is linked with the existence of two-value points on flow curves (part of a flow curve with negative slope) or transient regimes of deformation that lead to instability of the flow.

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