p53 Transactivation and the Impact of Mutations, Cofactors and Small Molecules Using a Simplified Yeast-Based Screening System

The p53 tumor suppressor, which is altered in most cancers, is a sequence-specific transcription factor that is able to modulate the expression of many target genes and influence a variety of cellular pathways. Inactivation of the p53 pathway in cancer frequently occurs through the expression of mutant p53 protein. In tumors that retain wild type p53, the pathway can be altered by upstream modulators, particularly the p53 negative regulators MDM2 and MDM4. promoter, ii) single copy, chromosomally located p53-responsive and control luminescence reporters, iii) enhanced chemical uptake using modified ABC-transporters, iv) small-volume formats for treatment and dual-luciferase assays, and v) opportunities to co-express p53 with other cofactor proteins. This robust system can distinguish different levels of expression of WT and mutant p53 as well as interactions with MDM2 or 53BP1.We found that the small molecules Nutlin and RITA could both relieve the MDM2-dependent inhibition of WT p53 transactivation function, while only RITA could impact p53/53BP1 functional interactions. PRIMA-1 was ineffective in modifying the transactivation capacity of WT p53 and missense p53 mutations. This dual-luciferase assay can, therefore, provide a high-throughput assessment tool for investigating a matrix of factors that can influence the p53 network, including the effectiveness of newly developed small molecules, on WT and tumor-associated p53 mutants as well as interacting proteins

Supernova remnants: the X-ray perspective

Supernova remnants are beautiful astronomical objects that are also of high scientific interest, because they provide insights into supernova explosion mechanisms, and because they are the likely sources of Galactic cosmic rays. X-ray observations are an important means to study these objects.And in particular the advances made in X-ray imaging spectroscopy over the last two decades has greatly increased our knowledge about supernova remnants. It has made it possible to map the products of fresh nucleosynthesis, and resulted in the identification of regions near shock fronts that emit X-ray synchrotron radiation. In this text all the relevant aspects of X-ray emission from supernova remnants are reviewed and put into the context of supernova explosion properties and the physics and evolution of supernova remnants. The first half of this review has a more tutorial style and discusses the basics of supernova remnant physics and thermal and non-thermal X-ray emission. The second half offers a review of the recent advances.The topics addressed there are core collapse and thermonuclear supernova remnants, SN 1987A, mature supernova remnants, mixed-morphology remnants, including a discussion of the recent finding of overionization in some of them, and finally X-ray synchrotron radiation and its consequences for particle acceleration and magnetic fields.Comment: Published in Astronomy and Astrophysics Reviews. This version has 2 column-layout. 78 pages, 42 figures. This replaced version has some minor language edits and several references have been correcte

Effects on thrombocytic hemostasis of a new derivate indolinone

Objective. Specific activity of an antiplatelet drug of indolinone series (codenamed DI) was studied in vitro in a model of ADP-induced platelet aggregation in vitro and in vivo in a model of streptozotocininduced diabetes mellitus in rats.&#x0D; Material and Methods. Acetylsalicylic acid and dipyridamole were used as reference drugs. In vitro tests have demonstrated that DI exhibits antiplatelet activity in a wide range of concentrations (0,75×10-6 – 1.5×10-5 М, р&lt;0,05), being comparable to acetylsalicylic acid and dipyridamole. In vivo tests have demonstrated dose-dependent antiplatelet activity of DI in doses of 2,5 – 20 mg/kg (21-14 %).&#x0D; Results and Discussion.Increasing the dose of DI above 10 mg/kg doesn’t increase its antiplatelet activity. After multiple oral administration to rats with streptozotocin-induced diabetes mellitus in 10 mg/kg dose, DI has exhibited antiplatelet activity, reducing the platelet aggregation rate to that of the control group (р&lt;0,05).&#x0D; Conclusion. Thus, DI isapromisingcompound for furtherdevelopmentof an antiplatelet drug with new mechanism of action&#x0D; Bangladesh Journal of Medical Science Vol.18(3) 2019 p.574-576</jats:p

Additive Manufacturing of Ceramic Products Based on Millimeter-Wave Heating

Abstract Additive manufacturing of ceramic articles making use of concentrated energy flows attracts the research interest worldwide. While the application of laser beams faces serious problems associated with high temperature of sintering and low thermal conductivity of ceramics, layer-by-layer sintering by focused millimeter-wave radiation appears to be a promising method of additive manufacturing. This paper describes the studies of fast millimeter-wave sintering of yttria-stabilized zirconia and hydroxyapatite ceramics. Coefficients of the millimeter-wave absorption have been determined in broad frequency and temperature ranges. Rapid sintering of compacted ceramics samples was accomplished using volumetric microwave heating in a work chamber of a 24 GHz / 5 kW gyrotron system. In addition, using a 263 GHz / 1 kW cwgyrotron millimeter-wave source and a purposely designed electrodynamic focusing structure, radiation intensities of up to 20 kW/cm2could be achieved, which was sufficient for fast localized heating of ceramic layers to the solidification temperature. The results of a study of the microstructure and mechanical properties of the sintered ceramics are presented.</jats:p

Light-induced defects in KTaO3

Photoconductivity (PC), thermally stimulated conductivity (TSC), photoluminescence (PL), thermoluminescence (TL), and electron spin resonance (ESR) measurements have been made on single crystals of potassium tantalate over the temperature range 4.2–290 K. We revealed two sorts of O− shallow hole centers which are responsible for the two temperature regions of PL and PC enhancement: T<70 K and 100–150 K. Both O− centers were identified by their ESR spectra. While at low temperatures PL and PC have a rather intrinsic origin, i.e., they do not depend essentially on the sort or quality of crystals, at 100–150 K both quantities strongly depend on the defect content and vanish in well-oxidized crystals. We show that O− centers serve as radiative electron–hole recombination centers. Their energy levels are situated at 0.08 and 0.16 eV above the top of the valence band. Measurements of TSC and TL after UV irradiation revealed several glow peaks at temperatures 18–30 K and 65–70 K. There is a good correlation between TSC and TL intensity in different samples as well as after annealing in O2 and H2 atmospheres. Because electrons are mobile species in KTaO3, we attribute both TSC and TL to the thermal ionization of the same shallow donor centers related with isolated oxygen vacancies. The experimental data were treated in a one-trap/one-recombination center model, which takes into account the presence of “thermally disconnected” deep electron traps