Betulin Sulfonamides as Carbonic Anhydrase Inhibitors and Anticancer Agents in Breast Cancer Cells

Hypoxia-regulated protein carbonic anhydrase IX (CA IX) is up-regulated in different tumor entities and correlated with poor prognosis in breast cancer patients. Due to the radio- and chemotherapy resistance of solid hypoxic tumors, derivatives of betulinic acid (BA), a natural compound with anticancer properties, seem to be promising to benefit these cancer patients. We synthesized new betulin sulfonamides and determined their cytotoxicity in different breast cancer cell lines. Additionally, we investigated their effects on clonogenic survival, cell death, extracellular pH, HIF-1α, CA IX and CA XII protein levels and radiosensitivity. Our study revealed that cytotoxicity increased after treatment with the betulin sulfonamides compared to BA or their precursors, especially in triple-negative breast cancer (TNBC) cells. CA IX activity as well as CA IX and CA XII protein levels were reduced by the betulin sulfonamides. We observed elevated inhibitory efficiency against protumorigenic processes such as proliferation and clonogenic survival and the promotion of cell death and radiosensitivity compared to the precursor derivatives. In particular, TNBC cells showed benefit from the addition of sulfonamides onto BA and revealed that betulin sulfonamides are promising compounds to treat more aggressive breast cancers, or are at the same level against less aggressive breast cancer cells.     

A First‐Principles Investigation of the Compositional Dependent Properties of Magnetic Shape Memory Heusler Alloys

The interplay of structural and magnetic properties of magnetic shape memory alloys is closely related to their composition. In this study the influence of the valence electron concentration on the tetragonal transformation in Ni₂Mn_{1 + x}Z_{1 ? x} (Z = Ga, In, Sn, Sb) and Co₂Ni_{1 + x}Ga_{1 ? x} is investigated by means of ab initio calculations. While the type of magnetic interaction is different for the two series, the trends of the total energy changes under a tetragonal transformation are very similar. We find that tetragonal structures become energetically preferred with respect to the cubic one as the valence electron concentration e/a is increased regardless of the system under consideration. In particular, the energy difference between the austenite and martensite structures increases linearly with e/a, which is in part responsible for the linear increase of the matensite transformation temperature. The substitution of nickel by platinum increases even further the transformation temperature.     

Impacts of large amounts of wind power on design and operation of power systems,results of IEA collaboration

There are dozens of studies made and ongoing related to wind integration. However, the results are not easy to compare. IEA WIND R&D Task 25 on ‘Design and Operation of Power Systems with Large Amounts of Wind Power’ collects and shares information on wind generation impacts on power systems, with analyses and guidelines on methodologies. In the state‐of‐the‐art report (October, 2007), and the final report of the 3 years period (July, 2009) the most relevant wind power grid integration studies have been analysed especially regarding methodologies and input data. Several issues that impact on the amount of wind power that can be integrated have been identified. Large balancing areas and aggregation benefits of wide areas help in reducing the variability and forecast errors of wind power as well as help in pooling more cost effective balancing resources. System operation and functioning electricity markets at less than day‐ahead time scales help reduce forecast errors of wind power. Transmission is the key to aggregation benefits, electricity markets and larger balancing areas. Best practices in wind integration studies are described. There is also benefit when adding wind power to power systems: it reduces the total operating costs and emissions as wind replaces fossil fuels and this should be highlighted more in future studies. Copyright © 2010 John Wiley & Sons, Ltd.     

Identification of the first known inhibitors of O-acetylpeptidoglycan esterase: a potential new antibacterial target

The O‐acetylation of peptidoglycan (PG) is now known to occur in 53 species, including numerous human pathogens such as, Staphylococcus aureus, Bacillus anthracis, species of Enterococcus, Campylobacter jejuni, Helicobacter pylori, Neisseria gonorrhoeae and N. meningitidis. This modification, which occurs at the C‐6 hydroxyl of N‐acetylmuramoyl residues within PG, serves to regulate autolytic activity during PG metabolism and contributes to pathogenesis and persistence within a host. O‐Acetylpeptidoglycan esterase (Ape) was recently discovered as an enzyme responsible for the removal of O‐acetyl groups from PG, thus permitting the continued maintenance and metabolism of the sacculus. Recombinant Ape1 from N. gonorrhoeae was purified to apparent homogeneity and optimal storage conditions for the enzyme were determined. Using 4‐methylumbelliferyl acetate as substrate, a fluorogenic assay amenable for the high‐throughput screening for potential inhibitors was developed and Ape1 was screened against a subset of compounds of the Canadian Compound Collection. The overall Z′ score for the screen was 0.62, indicative of a well‐suited assay with a sufficient signal window, and the threshold was set at 65 %. After eliminating a number of false‐positives, seven compounds were identified as true inhibitors of Ape1, the first to be identified for this class of enzyme. Dose–response curves were generated leading to the identification of five of these compounds with IC₅₀ values ranging between 0.3 and 23 μM . Of these, purpurin was selected for further analysis and it was found to inhibit the growth of both Gram‐positive and Gram‐negative bacteria that produce both O‐acetylated PG and Ape.     

Characterization of the cultivable microbial community in a spinach-processing plant using MALDI-TOF MS

A better and regular control of the production chain of fresh fruits and vegetables is necessary, because a contamination of the product by human- and phyto-pathogenic microorganisms may result in high losses during storage and poses a threat to human health. Therefore, detailed knowledge about the occurrence and the diversity of microorganisms within single processing steps is required to allow target-oriented produce safety control. Recently, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was successfully used to identify bacterial colonies. Bacteria can be identified with high accuracy by comparing them with generated spectra of a reference database.     

Tetraalkynylated and Tetraalkenylated Benzenes and Pyridines: Synthesis and Photophysical Properties

Tetra(arylalkynyl)pyridines and tetra(arylalkenyl)pyridines and their benzene analogues were prepared by palladium‐catalyzed cross‐coupling reactions from the commercially available chlorinated substrates in good to excellent yields. The photophysical properties of selected compounds were investigated and compared to each other. Very good fluorescence quantum yields were observed, especially for the pyridine derivatives.     

Particle Distribution and Separation in Continuous Casting Tundish

The tundish as a part of a continuous casting machine combines the discontinuous ladle metallurgy with the continuous solidification of slabs in the mould. The tundish plays a major role in the challenging task of “clean steel” production. That means the smallest number of inclusions and high cleanliness in all steel grades after changing the conditions at the inlet of the tundish. Inclusions hinder the metal forming process and lead often to fatigue. The cleanliness of steels is important to fulfil the customer's requirements. In the present study inclusion removal was simulated in a 1:3 scaled water model of a single‐strand tundish for the production of stainless steels with a particle counter. The particle counter is capable of counting a large number of particles with a wide range of diameters. The separation rate for particle diameters from d_P = 1 ‐ 250 μm was determined with a counter for the water model tundish. With similarity conditions for the particles this deposition rate can be transformed to the melt flow in a steel tundish. The separation rate was measured for different flow rates in the water model tundish. A larger flow rate decreased the separation rate. Additionally, the separation rate for the tundish fitted with an impact pad was measured and showed a significant increase of separation for particles with a smaller diameter. Furthermore, the particle distribution in the tundish for different size groups of particles was investigated with and without an impact pad. Numerical simulations were carried out with the finite‐volume commercial code FLUENT using the realizable k‐ε turbulence model. A special boundary condition for the separation of particles at the surface was implemented.     

Transcriptome Analyses of Adipose Tissue Samples Identify EGFL6 as a Candidate Gene Involved in Obesity-Related Adipose Tissue Dysfunction in Children

Obesity develops early in childhood and is accompanied by early signs of adipose tissue (AT) dysfunction and metabolic disease in children. In order to analyse the molecular processes during obesity-related AT accumulation in children, we investigated genome-wide expression profiles in AT samples, isolated adipocytes, and stromal vascular fraction (SVF) cells and assessed their relation to obesity as well as biological and functional AT parameters. We detected alterations in gene expression associated with obesity and related parameters, i.e., BMI SDS, adipocyte size, macrophage infiltration, adiponectin, and/or leptin. While differential gene expression in AT and adipocytes shared an enrichment in metabolic pathways and pathways related to extracellular structural organisation, SVF cells showed an overrepresentation in inflammatory pathways. In adipocytes, we found the strongest positive association for epidermal growth factor-like protein 6 (EGFL6) with adipocyte hypertrophy. EGFL6 was also upregulated during in vitro adipocyte differentiation. In children, EGFL6 expression was positively correlated to parameters of AT dysfunction and metabolic disease such as macrophage infiltration into AT, hs-CRP, leptin levels, and HOMA-IR. In conclusion, we provide evidence for early alterations in AT gene expression related to AT dysfunction in children and identified EGFL6 as potentially being involved in processes underlying the pathogenesis of metabolic disease.