Involvement of Mitochondrial Mechanisms and Cyclooxygenase-2 Activation in the Effect of Desethylamiodarone on 4T1 Triple-Negative Breast Cancer Line

Novel compounds significantly interfering with the mitochondrial energy production may have therapeutic value in triple-negative breast cancer (TNBC). This criterion is clearly fulfilled by desethylamiodarone (DEA), which is a major metabolite of amiodarone, a widely used antiarrhythmic drug, since the DEA previously demonstrated anti-neoplastic, anti-metastasizing, and direct mitochondrial effects in B16F10 melanoma cells. Additionally, the more than fifty years of clinical experience with amiodarone should answer most of the safety concerns about DEA. Accordingly, in the present study, we investigated DEA’s potential in TNBC by using a TN and a hormone receptor positive (HR+) BC cell line. DEA reduced the viability, colony formation, and invasive growth of the 4T1 cell line and led to a higher extent of the MCF-7 cell line. It lowered mitochondrial transmembrane potential and induced mitochondrial fragmentation. On the other hand, DEA failed to significantly affect various parameters of the cellular energy metabolism as determined by a Seahorse live cell respirometer. Cyclooxygenase 2 (COX-2), which was upregulated by DEA in the TNBC cell line only, accounted for most of 4T1’s DEA resistance, which was counteracted by the selective COX-2 inhibitor celecoxib. All these data indicate that DEA may have potentiality in the therapy of TNBC.     

Volatile Composition of Macedonian and Hungarian Wines Assessed by GC/MS

The volatile composition of eight varietal wines Vranec, Merlot, Cabernet Sauvignon, Temjanika and Chardonnay from the Republic of Macedonia, and Portugieser, Kékfrankos and Tokaji Aszú from Hungary has been characterized by means of gas chromatography/mass spectrometry technique. The wine volatile compounds were extracted in dichloromethane, and the extracts were concentrated under nitrogen. Forty-four volatile compounds have been identified mainly using the NIST mass spectral library and by comparison with the available standards used for quantification as well. Differences between the wines were noted for a number of compounds, such as a higher concentration of 1-pentanol and 2-phenyl ethanol in the red wines. Monoterpenes, linalool and terpineol were detected only in the white wines, Chardonnay and Tokaji. Macedonian red wines were characterized by a higher level of alcohols, while the Hungarian wines contained a higher amount of esters, fatty acids and lactones. A statistical treatment including one-way ANOVA, followed by a Tukey’s test has been performed in order to ascertain possible significant differences between the wines studied, and principal component analysis to study the possible grouping of the wines.     

Thermo-mechanical and oxidation behaviour of high temperature advanced metallic alloys

The main focus of this paper is on materials for radiant burners application. Two advanced metallic alloys, a Ni and Fe-based alloy are studied and compared to a reference ferritic stainless steel. Oxidation kinetics of such alloys at different temperatures are reported. Oxide formation mechanisms are discussed. Furthermore, thermo-mechanical resistance and eventual strengthening mechanism in temperature are studied. Finally, technical and brief tentative economical analysis of different alloys as potential candidates for the fabrication of radiant burners are given.     

Nearest multivariate system with given root multiplicities

We present a symbolic-numeric technique to find the closest multivariate polynomial system to a given one which has roots with prescribed multiplicity structure. Our method generalizes the “Weierstrass iteration”, defined by Ruatta, to the case when the input system is not exact, i.e. when it is near to a system with multiple roots, but itself might not have multiple roots. First, using interpolation techniques, we define the “generalized Weierstrass map”, a map from the set of possible roots to the set of systems which have these roots with the given multiplicity structure. Minimizing the 2-norm of this map formulates the problem as an optimization problem over all possible roots. We use Gauss–Newton iteration to compute the closest system to the input with given root multiplicity together with its roots. We give explicitly an iteration function which computes this minimum. These results extends previous results of Zhi and Wu and results of Zeng from the univariate case to the multivariate case. Finally, we give a simplified version of the iteration function analogously to the classical Weierstrass iteration, which allows a component-wise expression, and thus reduces the computational cost of each iteration. We provide numerical experiments that demonstrate the effectiveness of our method.     

Manganese Is a Strong Specific Activator of the RNA Synthetic Activity of Human Polη

DNA polymerase η (Polη) is a translesion synthesis polymerase that can bypass different DNA lesions with varying efficiency and fidelity. Its most well-known function is the error-free bypass of ultraviolet light-induced cyclobutane pyrimidine dimers. The lack of this unique ability in humans leads to the development of a cancer-predisposing disease, the variant form of xeroderma pigmentosum. Human Polη can insert rNTPs during DNA synthesis, though with much lower efficiency than dNTPs, and it can even extend an RNA chain with ribonucleotides. We have previously shown that Mn²⁺ is a specific activator of the RNA synthetic activity of yeast Polη that increases the efficiency of the reaction by several thousand-fold over Mg²⁺. In this study, our goal was to investigate the metal cofactor dependence of RNA synthesis by human Polη. We found that out of the investigated metal cations, only Mn²⁺ supported robust RNA synthesis. Steady state kinetic analysis showed that Mn²⁺ activated the reaction a thousand-fold compared to Mg²⁺, even during DNA damage bypass opposite 8-oxoG and TT dimer. Our results revealed a two order of magnitude higher affinity of human Polη towards ribonucleotides in the presence of Mn²⁺ compared to Mg²⁺. It is noteworthy that activation occurred without lowering the base selectivity of the enzyme on undamaged templates, whereas the fidelity decreased across a TT dimer. In summary, our data strongly suggest that, like with its yeast homolog, Mn²⁺ is the proper metal cofactor of hPolη during RNA chain extension, and selective metal cofactor utilization contributes to switching between its DNA and RNA synthetic activities.     

Solving over-determined systems by the subresultant method (with an appendix by Marc Chardin)

A general subresultant method is introduced to compute elements of a given ideal with few terms and bounded coefficients. This subresultant method is applied to solve over-determined polynomial systems by either finding a triangular representation of the solution set or by reducing the problem to eigenvalue computation. One of the ingredients of the subresultant method is the computation of a matrix that satisfies certain requirements, called the subresultant properties  . Our general framework allows us to use matrices of significantly smaller size than previous methods. We prove that certain previously known matrix constructions, in particular, Macaulay’s, Chardin’s and Jouanolou’s resultant and subresultant matrices possess the subresultant properties. However, these results rely on some assumptions about the regularity of the over-determined system to be solved. The appendix, written by Marc Chardin, contains relevant results on the regularity of n$n$ homogeneous forms in n$n$ variables.     

Preparation and Structural Characterization of Rapidly Solidified AI-Cu Alloys

Rapidly solidified Al_(100-x)—Cu_x alloys(x = 5,10,1 5,25,35 wt%) were prepared and analyzed.High cooling rate increased the Cu solubility in 9.-AI matrix.The influence of the cooling rate on Cu solubility extension in Al was experimentally simulated.Thus the pouring was performed in metallic die and by melt spinning-low pressure(MSLP) technique.Melt processing by liquid quenching was performed using a self-designed melt spinning set-up which combined the cooling technology of a melt jet on the spinning disc with the principle of the mold feeding from low pressure casting technology.The thickness of the melt-spun ribbons was in the range of30—70 μm.The cooling rate provided by MS-LP was within 10~5—10~6 K/s after the device calibration.The obtained alloys were characterized from structural,thermal and mechanical point of view.Optical microscopy and scanning electron microscopy were employed for the microstructural characterization which was followed by X-ray analysis.The thermal properties were evaluated by dilatometric and differential scanning calorimetric measurements.Vickers microhardness measurements were performed in the study.In the case of the hypereutectic alloy with 35 wt%Cu obtained by MS-LP method,the microhardness value increased by 45%compared to the same alloy obtained by gravity casting method.This was due to the extended solubility of the alloying element in the α-AI solid solution.