Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp³ hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC₅₀ value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling.     

Experimental and numerical analysis of the influence of cable tray arrangements on the resulting mass loss rate and fire spreading

In the context of industrial buildings and power plants, electrical installations and cable trays represent a main fuel load and a potential initial fire source due to possible short circuits or comparable malfunction. Furthermore, a fire can spread from one tray to additional trays mounted above and/or horizontally on one tray. Because of the high significance of cable fires, several research projects have been carried out, investigating the fire behaviour of cables from small‐scale tests, eg, the cone calorimeter, up to large‐scale tests, analysing complete cable tray constructions. The goal of the work presented in this paper is the extension of the knowledge regarding the influence of geometrical parameters like the packing density and tray distance on the burning behaviour and fire spread of cable tray installations. The results are considered, together with test results from the literature, to quantify the main physical parameters describing the burning behaviour. In a next step, the general applicability of these parameters as input data for the parametrization of the source term of numerical simulations is shown. The test results show that the burning behaviour and the fire spreading highly depend on the cable arrangement of the cables on the cable tray, in combination with other boundary conditions. By applying the results as input for a fire simulation, the mass loss rate is considered appropriately.     

Dielectric relaxation of vegetable-based polyurethane

Vegetable-based polyurethane (PU) was prepared in the thin film form by spin coating. This polymer is synthesised from castor oil, which can be extracted from the seeds of a native plant in Brazil called mamona. This polymer is biocompatible and is being used as material for artificial bone. The PU was characterised by dielectric spectroscopy in a wide range of frequency (10^–5 Hz to 10⁵ Hz) and by thermally stimulated discharge current (TSDC) measurements. The glass transition temperature (T _g = 39°C) was determined and using the initial rise method the activation energy was found to be 1.58 eV.     

Experimental evidence of a relationship between monomer plasma residence time and carboxyl group retention in acrylic acid plasma polymers

Decreasing carboxyl retention in deposits from the glow region of an acrylic acid plasma was measured by X-ray photoelectron spectroscopy and chemical derivatisation as the collection distance from the monomer vapour inlet was increased. Volatilisation of plasma polymerised acrylic acid was detected after trifluoroethanol derivatisation; this is correlated with evaporation of low molecular weight components observed previously.     

Parameters affecting the use of the lac repressor system in eukaryotic cells and transgenic animals

Elements of the lactose operon were used to study parameters affecting gene expression in cultured cells and transgenic animals. A Lac repressor protein containing a nuclear transport signal was shown to inhibit expression of a reporter gene by interacting with lac operator sequences. In cultured cells, operator sequence, operator placement and induction parameters were all shown to be important for obtaining tight repression of a reporter gene followed by high level expression upon induction. Induction levels were also dependent on the reporter gene, with the luciferase gene yielding higher induction levels than the chloramphenicol acetyltransferase gene. In transgenic animals, the lacI mRNA was not detected in the C57BL/6 mouse strain until the animal was exposed to a demethylating agent. After 5-azacytidine treatment, expression of lacI mRNA was detected in the brain, heart, kidney, lung and ovary. In the FVB transgenic mouse strain, expression of lacI mRNA was detected without 5-azacytidine treatment in the kidney, liver, lung, and testes. Preliminary experiments with double transgenic animals containing both lacI and operator/luciferase transgenes showed a decrease in luciferase expression compared to the luciferase-only animals in both tissue extracts and transgenic fetal primary cultures, although IPTG induction was not achieved in these animals or primary cultures. The applicability and challenges of the system for regulation of gene expression are discussed.     

Clarification of a wheat straw‐derived medium with ion‐exchange resins for xylitol crystallization

BACKGROUND: Xylitol bioproduction from lignocellulosic residues comprises hydrolysis of the hemicellulose, detoxification of the hydrolysate, bioconversion of the xylose, and recovery of xylitol from the fermented hydrolysate. There are relatively few reports on xylitol recovery from fermented media. In the present study, ion‐exchange resins were used to clarify a fermented wheat straw hemicellulosic hydrolysate, which was then vacuum‐concentrated and submitted to cooling in the presence of ethanol for xylitol crystallization. RESULTS: Sequential adsorption into two anion‐exchange resins (A‐860S and A‐500PS) promoted considerable reductions in the content of soluble by‐products (up to 97.5%) and in medium coloration (99.5%). Vacuum concentration led to a dark‐colored viscous solution that inhibited xylitol crystallization. This inhibition could be overcome by mixing the concentrated medium with a commercial xylitol solution. Such a strategy led to xylitol crystals with up to 95.9% purity. The crystallization yield (43.5%) was close to that observed when using commercial xylitol solution (51.4%). CONCLUSION: The experimental data demonstrate the feasibility of using ion‐exchange resins followed by cooling in the presence of ethanol as a strategy to promote the fast recovery and purification of xylitol from hemicellulose‐derived fermentation media. Copyright © 2008 Society of Chemical Industry     

,,Rich Internet Applications“ – Eine perfekte Kombination benutzerfreundlicher Schnittstellen mit Webtechnologie

Zusammenfassung  ,,Rich Internet Applications“ (RIA) sind Webapplikationen, die mit einer wesentlich interaktiveren Benutzerschnittstelle ausgestattet sind, als wir das bisher von den auf HTML basierten ,,poor ugly web applications“ (PUWA) gewohnt waren.     

Premature introduction of progestin-only contraceptive methods during lactation

INTRODUCTIONS: Cochlear implants are used for the rehabilitation of bilaterally deaf patients. Due to the improvements in speech processing they might be also useful for patients with residual hearing and some speech understanding. METHODS: Pre- and postoperative speech understanding scores in 26 patients receiving implants were evaluated in a retrospective study. RESULTS: The preoperative pure-tone threshold in the implanted ear was between 80 and 115 dB in the frequency range of 500 to 2000 Hz. On the contralateral side the mean threshold was 10 dB better. The mean score for the number test was 11.3%, for the monosyllables below 5%. Postoperatively speech understanding improved significantly up to 97% for numbers and 48% for monosyllables (tested with the Freiburger Speech Test). Cochlear implantation also benefits patients with residual hearing and some speech understanding with hearing aids under optimum conditions. The speech understanding scores must be below certain limits. General selection criteria cannot yet be specified. The individual decision must be based upon several criteria, especially the speech understanding scores in quiet and noise under optimum conditions. A prospective study is needed to develop generally applicable criteria.     

Wave propagation by the passage of two high-speed trains in a tunnel

A numerical simulation of unsteady compressible flow induced by two high-speed trains in oncoming traffic within a tunnel is presented. The computations were carried out by means of a second-order accurate Harten-Yee type upwind TVD scheme. In order to take the effect of friction into account, a source term is included in the governing flow equations. In the computation, moving boundary configurations were used to simulate the two trains passing through the tunnel. As geometrical configuration, the Einmalberg tunnel, where experimental data are available, was selected. The computational results agree reasonably well with their experimental counter-part. The waves interaction and the waves propagation process at the tunnel entrance and exit as well as within the tunnel are addressed. Finally, the influence on the transmitted waves at the tunnel exit portal and the variation of the negative pressure drop during the passage of the two trains are discussed.     

Systemised serendipity for producing computer art

Serendipity applied to Newton's method, and its derivative the Secant Method, produces unusual and beautiful fractal patterns. Serendipity may be systemised, for example, by the introduction of a perturbation parameter P1, [1] to facilitate searches for interesting pattern variations.