Synthesis and SAR of Tetracyclic Inhibitors of Protein Kinase CK2 Derived from Furocarbazole W16

The serine/threonine kinase CK2 modulates the activity of more than 300 proteins and thus plays a crucial role in various physiological and pathophysiological processes including neurodegenerative disorders of the central nervous system and cancer. The enzymatic activity of CK2 is controlled by the equilibrium between the heterotetrameric holoenzyme CK2α₂β₂ and its monomeric subunits CK2α and CK2β. A series of analogues of W16 ((3aR,4S,10S,10aS)-4-{[(S)-4-benzyl-2-oxo-1,3-oxazolidin-3-yl]carbonyl}-10-(3,4,5-trimethoxyphenyl)-4,5,10,10a-tetrahydrofuro[3,4-b]carbazole-1,3(3aH)-dione ((+)- 3 a )) was prepared in an one-pot, three-component Levy reaction. The stereochemistry of the tetracyclic compounds was analyzed. Additionally, the chemically labile anhydride structure of the furocarbazoles 3 was replaced by a more stable imide ( 9 ) and N-methylimide ( 10 ) substructure. The enantiomer (−)- 3 a (K_i=4.9 μM) of the lead compound (+)- 3 a (K_i=31 μM) showed a more than sixfold increased inhibition of the CK2α/CK2β interaction (protein-protein interaction inhibition, PPII) in a microscale thermophoresis (MST) assay. However, (−)- 3 a did not show an increased enzyme inhibition of the CK2α₂β₂ holoenzyme, the CK2α subunit or the mutated CK2α′ ^C336S subunit in the capillary electrophoresis assay. In the pyrrolocarbazole series, the imide (−)- 9 a (K_i=3.6 μM) and the N-methylimide (+)- 10 a (K_i=2.8 μM) represent the most promising inhibitors of the CK2α/CK2β interaction. However, neither compound could inhibit enzymatic activity. Unexpectedly, the racemic tetracyclic pyrrolocarbazole (±)- 12 , with a carboxy moiety in the 4-position, displays the highest CK2α/CK2β interaction inhibition (K_i=1.8 μM) of this series of compounds.     

Lipoxygenase Products in the Urine Correlate with Renal Function and Body Temperature but not with Acute Transplant Rejection

Acute transplant rejection is the leading cause of graft loss in the first months after kidney transplantation. Lipoxygenase products mediate pro- and anti-inflammatory actions and thus we aimed to correlate the histological reports of renal transplant biopsies with urinary lipoxygenase products concentrations to evaluate their role as a diagnostic marker. This study included a total of 34 kidney transplant recipients: 17 with an acute transplant rejection and 17 controls. LTE4, LTB4, 12-HETE and 15-HETE concentrations were measured by enzyme immunoassay. Urinary lipoxygenase product concentrations were not significantly changed during an acute allograft rejection. Nevertheless, LTB4 concentrations correlated significantly with the body temperature (P ≤ 0.05) 3 months after transplantation, and 12- and 15-HETE concentrations correlated significantly with renal function (P ≤ 0.05) 2 weeks after transplantation. In conclusion, our data show a correlation for LTB4 with the body temperature 3 months after transplantation and urinary 12- and 15-HETE concentrations correlate positively with elevated serum creatinine concentrations but do not predict acute allograft rejection.     

Inactivation of staphylococcal enterotoxins by heat and reactivation by high pH treatment

Inactivation of staphylococcal enterotoxins (SE) added to different media upon heat treatment (80 degrees C or 100 degrees C for 10 min) and reactivation of inactivated SE was studied. In gelatin (pH 4.0), lettuce extract, peas and beans extracts and ovalbumin (pH 5.0) the immunological activity of SE was lost almost completely upon heating. The loss of immunological activity of SEA was accompanied by a concomitant loss of biological activity of this toxin (monkey feeding test). A high pH treatment (pH 11) of the different preparations restored both the immunological and biological activity in most samples tested. Heating at 80 degrees C or 100 degrees C for 10 min of SE containing gelatin (pH 7.0), cauliflower extract (pH 4.0 or pH 7.0), milk (pH 4.0), casein (pH 6.0), rice extract (pH 7.0), noodles extract (pH 4.0) and oat-flakes extract (pH 7.0) had a much lower effect on the immunological activity of the SE (activity greater than or equal to 25%).     

Dissolution,Transport and Reaction at a DICY/DGEBA Interface

The curing of an epoxy consisting of the solid hardener dicyandiamide (DICY) and the resin diglycidyl ether of bisphenol A (DGEBA) is studied in a system consisting of a tablet of DICY embedded in liquid DGEBA. Dissolution of DICY within the liquid DGEBA in combination with the transport of dissolved DICY from the tablet border into DGEBA and the chemical reaction of both reactants is studied by scanning Brillouin microscopy and infrared spectroscopy. Scanning Brillouin microscopy demonstrates the spatial and temporal evolution of the static and dynamic hypersonic properties in the course of curing in the vicinity of the DICY tablet. Infrared spectroscopy performed on epoxy pieces extracted from the final sample at different distances from the tablet surface give information about the spatial evolution of the curing process. The results achieved by both techniques are finally combined to yield a better understanding of the curing of DICY-based epoxies, which transform upon curing from strongly heterogeneous systems towards increasingly homogeneous systems.     

Manufacture and measurement of combinatorial libraries of dielectric ceramics: Part II. Dielectric measurements of Ba1−xSrxTiO3 libraries

Applying combinatorial methods to materials science offers the opportunity to accelerate the discovery of more efficient dielectric ceramics. High-throughput methods have the potential to investigate the effects of a wide range of dopants on the dielectric properties, and to optimise existing systems, encouraging the short innovation cycles that the communications technology industry requires. The London University Search Instrument (LUSI) is a fully automated, high-throughput combinatorial robot that has the potential capability to produce large numbers of sintered bulk ceramic samples with varying composition in 1 day, as combinatorial libraries on alumina substrates. Ba_1−xSr_xTiO₃ (BST) libraries were produced by LUSI as a proof-of-principle, with x = 0–1 in steps of 0.1, and fired to 1350 and 1400 °C for 1 h. Part I of this paper described the manufacture and physical characterisation of BST libraries, showing a regular change in composition with x across the libraries. In this second part, the dielectric properties of BST libraries produced by LUSI are assessed at frequencies between 100 Hz and 1 MHz, and at temperatures between 150 and 500 K. Local piezoelectric properties were also characterised by scanning probe microscope (SPM). All measurements showed evidence of a clear functional gradient varying with x across the library, with measured _r corresponding to expected values for BST.     

Performance of a bioreactor with submerged membranes for aerobic treatment of municipal waste water

Aerobic treatment of municipal waste water in a membrane bioreactor was studied for 535 d. Apart from sampling, sludge was retained completely by a submerged hollow fibre membrane with a pore-size of 0.2 microm. The pilot plant comprised an anoxic zone to enable denitrification. The maximum liquid hold-up of the plant was 3.9 m3. In this study the reactor performance and the stability of the process and the membrane capacity were investigated. A stable flux of 181 m(-2)h(-1) could be realised with a mean transmembrane pressure difference of 0.3bar with air-bubbling and backflushing the membrane and cleaning it in place every two months for one or two hours. For about 140d, a flux of 271 m(-2)h(-1) was achieved, but cleaning became necessary more often. The hydraulic retention time (HRT) varied between 10.4 and 15.6h. Accordingly the volumetric loading rate was between 1.1 and 1.7kg CODm(-3)d(-1). No inoculum was used. The mixed liquor suspended solids (MLSS) concentration gradually increased to 18-20g MLSSl(-1). The feed to microorganism (F/M) ratio varied according to the operation conditions but decreased against a value of 0.07 kg COD kg(-1) MLSSd(-1). Treatment performance was very stable and on a high level. The COD was reduced by 95%. Nitrification was complete and up to 82% of the total nitrogen could be denitrified.     

The live cell irradiation and observation setup at SNAKE

We describe a new setup at the ion microprobe SNAKE (Superconducting Nanoscope for Applied nuclear (Kern-) physics Experiments) at the Munich 14 MV Tandem accelerator that facilitates both living cell irradiation with sub micrometer resolution and online optical imaging of the cells before and after irradiation by state of the art phase contrast and fluorescence microscopy. The cells are kept at standard cell growth conditions at 37 °C in cell culture medium. After irradiation it is possible to switch from single ion irradiation conditions to cell observation within 0.5 s. First experiments were performed targeting substructures of a cell nucleus that were tagged by TexasRed labeled nucleotides incorporated in the cellular DNA by 55 MeV single carbon ion irradiation. In addition we show first online sequences of short time kinetics of Mdc1 protein accumulation in the vicinity of double strand breaks after carbon ion irradiation.     

Efficient data association for view based SLAM using connected dominating sets

Loop closing in vision based SLAM applications is a difficult task. Comparing new image data with all previously acquired image data is practically impossible because of the high computational costs. Most approaches therefore compare new data with only a subset of the old data, for example by sampling the data over time or over space by using a position estimate. In this paper, we propose a more natural approach, which dynamically determines a subset of images that best describes the complete image data in the space of all previously seen images. The actual problem of finding such a subset is called the “Connected Dominating Set” (CDS) problem, which is well studied in the field of graph theory. Application on large indoor datasets results in approximately the same map using only 13% of the computational resources with respect to comparing with all previous images. Also, it outperforms other sampling approaches. The proposed method is particularly beneficial for realistic mapping scenarios including moving objects and persons, motion blur and changing light conditions.¹     

The calculation of the heat release rate by oxygen consumption in a controlled‐atmosphere cone calorimeter

The standard cone calorimeter according to ASTM E 1354 and ISO 5660 enables reaction‐to‐fire tests to be performed in ambient atmospheric conditions. A controlled‐atmosphere chamber modifies the standard apparatus in a way that allows tests to be performed in nonambient conditions as well. The enclosed chamber is placed underneath the standard exhaust hood and does not have a closed connection to the hood. With this open arrangement, the exhaust gases are diluted by excess air drawn in from the laboratory surroundings. Heat‐induced changes in the consequential dilution ratio affect the calculation of fire quantities and, when neglected, lead to deviations of up to 30% in heat release rate. The paper introduces a test protocol and equations to calculate the heat release rate taking dilution effects into account. A mathematical correction is shown that compensates for the dilution effects while avoiding extensive mechanical changes in the equipment. Copyright © 2013 John Wiley & Sons, Ltd.     

Pain, depression, and physical functioning following burn injury.

Objective: Little is known about how pain and depression after burn injury may influence long-term outcomes such as physical functioning. This prospective study examined associations between pain, depression, and physical functioning in a sample of burn injury survivors. Design and Participants: Questionnaires assessing pain, depression, and physical functioning were completed by 64 (52% of original sample) adult burn survivors shortly after discharge from burn care and at 1- and 2-year follow-ups. Results: Pain and physical functioning improved over the 2 years of the study, whereas depression levels were stable. Pain and depression were associated with poorer physical functioning over time, but associations varied according to the time span under consideration. Also, the association between pain and physical functioning was strongest among persons with higher depression scores. Conclusions: Pain and depression may contribute independently to compromises in physical functioning. The co-occurrence of pain and depression represents even greater risk for reduced physical functioning over time among burn survivors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)