A Genomics-Based Model for Prediction of Severe Bioprosthetic Mitral Valve Calcification

Severe bioprosthetic mitral valve calcification is a significant problem in cardiovascular surgery. Unfortunately, clinical markers did not demonstrate efficacy in prediction of severe bioprosthetic mitral valve calcification. Here, we examined whether a genomics-based approach is efficient in predicting the risk of severe bioprosthetic mitral valve calcification. A total of 124 consecutive Russian patients who underwent mitral valve replacement surgery were recruited. We investigated the associations of the inherited variation in innate immunity, lipid metabolism and calcium metabolism genes with severe bioprosthetic mitral valve calcification. Genotyping was conducted utilizing the TaqMan assay. Eight gene polymorphisms were significantly associated with severe bioprosthetic mitral valve calcification and were therefore included into stepwise logistic regression which identified male gender, the T/T genotype of the rs3775073 polymorphism within the TLR6 gene, the C/T genotype of the rs2229238 polymorphism within the IL6R gene, and the A/A genotype of the rs10455872 polymorphism within the LPA gene as independent predictors of severe bioprosthetic mitral valve calcification. The developed genomics-based model had fair predictive value with area under the receiver operating characteristic (ROC) curve of 0.73. In conclusion, our genomics-based approach is efficient for the prediction of severe bioprosthetic mitral valve calcification.     

Stress relaxation behavior of starch powder‐epoxy resin composites

The purpose of the present study is to investigate the quasi‐static and the viscoelastic behavior of epoxy resin reinforced with starch powder. An increase in the elastic modulus on the order of 42% was achieved; a behavior that was predicted by the modulus prediction model (MPM). Next, the composite was subjected to flexural relaxation experiments, in order to determine the relaxation modulus, at different filler‐weight fractions and flexural deflections imposed. The viscoelastic models of the standard linear solid, the power law model and the residual property model (RPM) were applied in order to simulate/predict the stress relaxation curves. Predicted values derived from the application of the above models were compared to each‐other as well as to respective experimental findings. From the above comparison it was proved the superiority of the RPM model in predicting both the linear and the nonlinear viscoelastic response of the materials investigated. © 2014 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015 , 132, 41697.     

Effects of Drying and Extraction Methods on the Quality and Antioxidant Activity of Sea Buckthorn (Hippophae rhamnoides) Berries and Leaves

Sea buckthorn is a promising source of bioactive compounds. However, there is limited information on the effect of post harvest drying and extraction of sea buckthorn on its antioxidant capacity. The effect of freeze, air, and solar dryingon the extraction yield of sea buckthorn berries and leaves was evaluated with respect to their bioactive content. Sequential extraction with solvents of different polarity and solvent-free microwave-assisted extraction were applied. Freeze-drying has better performance in the berries’ extracts, while air-drying has better performance in the leaves’ extracts. All data were analyzed by Multi Factor Analysis of Variance (ANOVA) and Duncan's post-hoc tests at a level of α = .05. Although the extraction yield in the sequential extraction of sea buckthorn berries is significantly better, the leaves’ extracts exhibit superior radical scavenging ability. Accelerated solar drying appears to preserve sea buckthorn leaves without degrading their antioxidant content. The components responsible for the high antioxidant activity of leaves’ extracts were found to be several flavonoids and polyphenols. The extract obtained by the microwave extraction of fresh berries exhibits moderate antioxidant activity compared to the polar extracts of freeze-dried berries.     

Discovery of an Acyclic Nucleoside Phosphonate that Inhibits Mycobacterium tuberculosis ThyX Based on the Binding Mode of a 5‐Alkynyl Substrate Analogue

The urgent need for new antibiotics poses a challenge to target un(der)exploited vital cellular processes. Thymidylate biosynthesis is one such process due to its crucial role in DNA replication and repair. Thymidylate synthases (TS) catalyze a crucial step in the biosynthesis of thymidine 5‐triphosphate (TTP), an elementary building block required for DNA synthesis and repair. To date, TS inhibitors have only been successfully applied in anticancer therapy due to their lack of specificity for antimicrobial versus human enzymes. However, the discovery of a new family of TS enzymes (ThyX) in a range of pathogenic bacteria that is structurally and biochemically different from the “classic” TS (ThyA) has opened the possibility to develop selective ThyX inhibitors as potent antimicrobial drugs. Here, the interaction of the known inhibitor 5‐(3‐octanamidoprop‐1yn‐1yl)‐2′‐deoxyuridine‐5′‐monophosphate ( 1 ) with Mycobacterium tuberculosis ThyX enzyme is explored using molecular modeling starting from published crystal structures, with further confirmation through NMR experiments. While the deoxyuridylate (dUMP) moiety of compound 1 occupies the cavity of the natural substrate in ThyX, the rest of the ligand (the “5‐alkynyl tail”) extends to the outside of the enzyme between two of its four subunits. The hydrophobic pocket that accommodates the alkyl part of the tail is formed by displacement of Tyr 44.C, Tyr 108.A and Lys 165.A. Changes to the resonance of the Lys 165 NH₃ group upon ligand binding were monitored in a titration experiment by 2D HISQC NMR. Guided by the results of the modeling and NMR studies, and inspired by the success of acyclic antiviral nucleosides, compounds where a 5‐alkynyl uracyl moiety is coupled to an acyclic nucleoside phosphonate (ANP) were synthesized and evaluated. Of the compounds evaluated, sodium (6‐(5‐(3‐octanamidoprop‐1‐yn‐1‐yl)‐2,4‐dioxo‐3,4‐dihydropyrimidin‐1(2H)‐yl)hexyl)phosphonate ( 3 e ) exhibited 43 % of inhibitory effect on ThyX at 50 μM . While only modest activity was achieved, this is the first example of an ANP inhibiting ThyX, and these results can be used to further guide structural modifications to this class to develop more potent compounds with potential application as antibacterial agents acting through a novel mechanism of action.     

Antibacterial Activity of Copper Nanoparticles against Xanthomonas campestris pv. vesicatoria in Tomato Plants

Copper-based bactericides have appeared as a new tool in crop protection and offer an effective solution to combat bacterial resistance. In this work, two copper nanoparticle products that were previously synthesized and evaluated against major bacterial and fungal pathogens were tested on their ability to control the bacterial spot disease of tomato. Growth of Xanthomonas campestris pv. vesicatoria, the causal agent of the disease, was significantly suppressed by both nanoparticles, which had superior function compared to conventional commercial formulations of copper. X-ray fluorescence spectrometry measurements in tomato leaves revealed that bioavailability of copper is superior in the case of nanoparticles compared to conventional formulations and is dependent on synthesis rather than size. This is the first report correlating bioavailability of copper to nanoparticle efficacy.     

Mechanistic Insight in the Ethane Dehydrogenation Reaction over Cr/Al2O3 Catalysts

A Cr/Al₂O₃ alkane dehydrogenation catalyst exhibits a maximum in ethylene yield during an ethane dehydrogenation cycle. Isotopic labelling experiments with monolabelled ¹³C-ethane and deuterium were used to elucidate whether the initial activity increase could be due to formation of an active, larger hydrocarbon intermediate on the surface. The results strongly indicate that this is not the case, and instead point to a traditional reaction cycle involving adsorption of ethane to form an ethyl species, followed by desorption of ethene and hydrogen. Transient kinetic data suggest that ethane adsorption is the rate-determining step of reaction.     

GPR55 Receptor Activation by the N-Acyl Dopamine Family Lipids Induces Apoptosis in Cancer Cells via the Nitric Oxide Synthase (nNOS) Over-Stimulation

GPR55 is a GPCR of the non-CB1/CB2 cannabinoid receptor family, which is activated by lysophosphatidylinositol (LPI) and stimulates the proliferation of cancer cells. Anandamide, a bioactive lipid endocannabinoid, acts as a biased agonist of GPR55 and induces cancer cell death, but is unstable and psychoactive. We hypothesized that other endocannabinoids and structurally similar compounds, which are more hydrolytically stable, could also induce cancer cell death via GPR55 activation. We chemically synthesized and tested a set of fatty acid amides and esters for cell death induction via GPR55 activation. The most active compounds appeared to be N-acyl dopamines, especially N-docosahexaenoyl dopamine (DHA-DA). Using a panel of cancer cell lines and a set of receptor and intracellular signal transduction machinery inhibitors together with cell viability, Ca²⁺, NO, ROS (reactive oxygen species) and gene expression measurement, we showed for the first time that for these compounds, the mechanism of cell death induction differed from that published for anandamide and included neuronal nitric oxide synthase (nNOS) overstimulation with concomitant oxidative stress induction. The combination of DHA-DA with LPI, which normally stimulates cancer proliferation and is increased in cancer setting, had an increased cytotoxicity for the cancer cells indicating a therapeutic potential.     

Some Molecular and Cellular Stress Mechanisms Associated with Neurodegenerative Diseases and Atherosclerosis

Chronic stress is a combination of nonspecific adaptive reactions of the body to the influence of various adverse stress factors which disrupt its homeostasis, and it is also a corresponding state of the organism’s nervous system (or the body in general). We hypothesized that chronic stress may be one of the causes occurence of several molecular and cellular types of stress. We analyzed literary sources and considered most of these types of stress in our review article. We examined genes and mutations of nuclear and mitochondrial genomes and also molecular variants which lead to various types of stress. The end result of chronic stress can be metabolic disturbance in humans and animals, leading to accumulation of reactive oxygen species (ROS), oxidative stress, energy deficiency in cells (due to a decrease in ATP synthesis) and mitochondrial dysfunction. These changes can last for the lifetime and lead to severe pathologies, including neurodegenerative diseases and atherosclerosis. The analysis of literature allowed us to conclude that under the influence of chronic stress, metabolism in the human body can be disrupted, mutations of the mitochondrial and nuclear genome and dysfunction of cells and their compartments can occur. As a result of these processes, oxidative, genotoxic, and cellular stress can occur. Therefore, chronic stress can be one of the causes forthe occurrence and development of neurodegenerative diseases and atherosclerosis. In particular, chronic stress can play a large role in the occurrence and development of oxidative, genotoxic, and cellular types of stress.     

Pre-Senescence Induction in Hepatoma Cells Favors Hepatitis C Virus Replication and Can Be Used in Exploring Antiviral Potential of Histone Deacetylase Inhibitors

Recent evidence suggests that fibrotic liver injury in patients with chronic hepatitis C correlates with cellular senescence in damaged liver tissue. However, it is still unclear how senescence can affect replication of the hepatitis C virus (HCV). In this work, we report that an inhibitor of cyclin-dependent kinases 4/6, palbociclib, not only induced in hepatoma cells a pre-senescent cellular phenotype, including G1 arrest in the cell cycle, but also accelerated viral replicon multiplication. Importantly, suppression of HCV replication by direct acting antivirals (DAAs) was barely affected by pre-senescence induction, and vice versa, the antiviral activities of host-targeting agents (HTAs), such as inhibitors of human histone deacetylases (HDACi), produced a wide range of reactions—from a dramatic reduction to a noticeable increase. It is very likely that under conditions of the G1 arrest in the cell cycle, HDACi exhibit their actual antiviral potency, since their inherent anticancer activity that complicates the interpretation of test results is minimized.