Isoquinolin-1-one inhibitors of the MDM2-p53 interaction

p53 has been at the centre of attention for drug design since the discovery of its growth-suppressive and pro-apoptotic activity. Herein we report the design and characterisation of a new class of isoquinolinone inhibitors of the MDM2-p53 interaction. Our identification of druglike and selective inhibitors of this protein-protein interaction included a straightforward in silico compound-selection process, a recently reported NMR spectroscopic approach for studying the MDM2-p53 interaction, and selectivity screening assays using cells with the same genetic background. The selected inhibitors were all able to induce apoptosis and the expression of p53-related genes, but only the isoquinolin-1-one-based inhibitors stabilised p53. Our NMR experiments give a persuading explanation for these results, showing that isoquinolin-1-one derivates are able to dissociate the preformed MDM2-p53 complex in vitro, releasing a folded and soluble p53. The joint application of these methods provides a framework for the discovery of protein interaction inhibitors as a promising starting point for further drug design.     

Purification of glycerol/water solutions from biodiesel synthesis by ion exchange: sodium removal Part I

BACKGROUND: In this study, equilibrium and kinetic data of the ion exchange of sodium from glycerol–water mixtures on the strong acid resin Amberlite‐252 were obtained. Basic parameters for the design of ion exchange units for the purification of the crude glycerol phase from biodiesel production have been determined. RESULTS: Equilibrium uptake of sodium ions with the strong acid ion exchanger Amberlite‐252 was studied at three temperatures. The Langmuir equation and the mass action law model were used to fit the experimental equilibrium data. Equilibrium constants and thermodynamic parameters were obtained at each temperature. Kinetic experiments were carried out to evaluate the effective diffusion coefficients of sodium on the resin Amberlite‐252 in glycerine–water media. CONCLUSIONS: Equilibrium results indicate that this process is favourable and also that its selectivity decreases with temperature increase from 303 to 333 K. Both models were able to fit the experimental equilibrium data. Kinetic experiments showed that the rate of mass transfer in this binary system is high. An Arrhenius type equation allowed the correlation of effective diffusion coefficients and temperature. The results indicate that the macroporous resin Amberlite‐252 could be useful for removal of sodium ions from glycerine/water solutions with a high salt concentration. Copyright © 2008 Society of Chemical Industry     

Immobilization of Invertase on Mesoporous Silicas to Obtain Hyper Active Biocatalysts

Comparative studies of invertase immobilized on two mesoporous cellular foams (MCF) and two supports of SBA-15 type with different pore sizes, using three highly recommended methods of protein bonding showed that activity of aminated MCF-based biocatalysts is significantly higher than that of SBA-15 counterparts, with the same textural properties. Specific activities of invertase covalently attached via GLA spacer was about 73–111% of a native enzyme. A unique microenvironment of functionalized cage-like pores of aminated MCFs is deemed to be responsible for this ultra high activity of invertase.     

Active silicas obtained by precipitation from mixtures of sodium metasilicate and ammonium chloride solutions

Studies were conducted on the production of highly dispersed silicas using the technique of precipitation from solutions of sodium metasilicate and ammonium chloride. Parameters of the precipitation process were optimised in order to obtain highly dispersed as well as uniform and stable silicas. The silicas obtained were subjected to elementary physicochemical analysis, the tendency of the silica particles to form aggregates and agglomerates was examined using scanning electron microscopy (SEM) and dynamic light scattering (DLS), and surface analysis was performed using the BET technique. The silicas obtained manifested exceptionally low bulk density and a high capacity to absorb paraffin oil. Copyright © 2003 Society of Chemical Industry     

Effect of temperature on sorption isotherms of Brussels sprout

The effect of temperature (0, 20 and 40 degrees C) on the sorptivity of freeze-dried Brussels sprout was studied. It was checked which of the sorption isotherm equations that included temperature was the best to estimate experimental data. The surface area of a monolayer and isosteric heat of sorption was calculated. From the tested equations the Guggenheim-Anderson-de Boer (GAB) and Oswin equations appeared to be the best for describing sorption isotherms of freeze-dried Brussels sprout. The Clausius-Clapeyron equation was found suitable for the calculation of pure isosteric heat of sorption.     

Barley Seeds miRNome Stability during Long-Term Storage and Aging

Seed aging is a complex biological process that has been attracting scientists’ attention for many years. High-throughput small RNA sequencing was applied to examine microRNAs contribution in barley seeds senescence. Unique samples of seeds that, despite having the same genetic makeup, differed in viability after over 45 years of storage in a dry state were investigated. In total, 61 known and 81 novel miRNA were identified in dry seeds. The highest level of expression was found in four conserved miRNA families, i.e., miR159, miR156, miR166, and miR168. However, the most astonishing result was the lack of significant differences in the level of almost all miRNAs in seed samples with significantly different viability. This result reveals that miRNAs in dry seeds are extremely stable. This is also the first identified RNA fraction that is not deteriorating along with the loss of seed viability. Moreover, the novel miRNA hvu-new41, with higher expression in seeds with the lowest viability as detected by RT-qPCR, has the potential to become an indicator of the decreasing viability of seeds during storage in a dry state.     

The impact of Al2O3 amount on the synthesis of CASH samples and their influence on the early stage hydration of calcium aluminate cement

In this work the impact of Al₂O₃ amount on the synthesis (200?°C; 4–8?h) of calcium aluminium silicate hydrates (CSAH) samples and their influence on the early stage hydration of calcium aluminate cement (CAC) was examined. It was found that the amount of Al₂O₃ plays an important role in the formation of calcium aluminate hydrates (CAH) because in the mixtures with 2.7% Al₂O₃ only calcium silicate hydrates (CSH) intercalated with Al³⁺ ions were formed. While in the mixtures with a higher amount of Al₂O₃ (5.3–15.4%), calcium aluminate hydrate – C₃AH₆, is formed under all experimental conditions. It is worth noting that the largest quantity of mentioned compound was obtained after 4?h of hydrothermal treatment, in the mixtures with 15.4% of Al₂O₃. It was proved that synthesized C₃AH₆ remain stable up to 300?°C and at higher temperature (945?°C) recrystallized to mayenite (Ca₁₂Al₁₄O₃₃), which reacted with the rest part of CaO and amorphous structure compound, resulting in the formation of gehlenite (Ca₂Al₂SiO₇). Moreover, the synthesized C₃AH₆ addition induced the early stage of CAC hydration. Besides, in the samples with an addition, the induction period was effectively shortened: in a case of pure CAC (G70) paste, hydration takes about 6–6.5?h, while with addition – only 2–2.5?h. The synthesized and calcinated compounds was characterized by using XRD and STA analysis.     

Effect of production season on protein fraction content in milk of various breeds of goats in Poland

Milk of various goat breeds was analysed to assess the effect of production season on content of basic chemical components, with regard to whey proteins. Milk of goats in the productive herds (white and coloured coat) contained significantly (P < 0.01) more total protein, casein, fat, dry matter and functional whey proteins. The production season significantly determined the content of total protein (P < 0.01), casein (P < 0.01) and whey proteins (P < 0.05), including α‐lactalbumin (P < 0.01) and lactoferrin (P < 0.01). A higher content of total protein and casein was found in the autumn–winter season and the content of whey proteins was higher in the spring–summer period.     

The rs2516839 Polymorphism of the USF1 Gene May Modulate Serum Triglyceride Levels in Response to Cigarette Smoking

Single nucleotide polymorphisms (SNPs) of the USF1 gene (upstream stimulatory factor 1) influence plasma lipid levels. This study aims to determine whether USF1 SNPs interact with traditional risk factors of atherosclerosis to increase coronary artery disease (CAD) risk. In the present study serum lipid levels and USF1 gene polymorphisms (rs2516839 and rs3737787) were determined in 470 subjects: 235 patients with premature CAD and 235 controls. A trend of increasing triglycerides (TG) levels in relation to the C allele dose of rs2516839 SNP was observed. The synergistic effect of cigarette smoking and C allele carrier state on CAD risk was also found (SIM = 2.69, p = 0.015). TG levels differentiated significantly particular genotypes in smokers (1.53 mmol/L for TT, 1.80 mmol/L for CT and 2.27 mmol/L for CC subjects). In contrast, these differences were not observed in the non-smokers subgroup (1.57 mmol/L for TT, 1.46 mmol/L for CT and 1.49 mmol/L for CC subjects). In conclusion, the rs2516839 polymorphism may modulate serum triglyceride levels in response to cigarette smoking. Carriers of the C allele seem to be particularly at risk of CAD, when exposed to cigarette smoking.     

Influence of different recultivation methods on durability of nitrogen compounds changes in the waters of an urban lake

The study was conducted on D?ugie Lake, which was fed with raw domestic sewage for 20 years. After preliminary conservation operations, the lake was restored by the artificial circulation and phosphorus inactivation methods. Before the restoration of lake, average amount of ammonia in the bottom water layer achieved a value of 20.71 mg/L, and Total nitrogen (TN) 22.89 mg/L. Start up of artificial aeration caused a distinct change in the concentration of nitrogen compounds in the lake. The intensive nitrification processes occurred due to improving oxygenation of the lower layer and increasing the temperature. It resulted in an increase of nitrate nitrogen concentration to about 1.30 mg/L. A tenfold decrease in ammonia and TN concentration has been achieved as a result of the artificial aeration. Concentrations of nitrogen compounds which were noted 8 years after termination of the lake recultivation were typical for reservoirs with moderate trophic status.