Impact of Selected Small-Molecule Kinase Inhibitors on Lipid Membranes

Small-molecule protein kinase inhibitors are used for the treatment of various diseases. Although their effect(s) on the respective kinase are generally quite well understood, surprisingly, their interaction with membranes is only barely investigated; even though these drugs necessarily come into contact with the plasma and intracellular membranes. Using biophysical methods such as NMR, ESR, and fluorescence spectroscopy in combination with lipid vesicles, we studied the membrane interaction of the kinase inhibitors sunitinib, erlotinib, idelalisib, and lenvatinib; these drugs are characterized by medium log p values, a parameter reflecting the overall hydrophobicity of the molecules, which is one important parameter to predict the interaction with lipid membranes. While all four molecules tend to embed in a similar region of the lipid membrane, their presence has different impacts on membrane structure and dynamics. Most notably, sunitinib, exhibiting the lowest log p value of the four inhibitors, effectively influences membrane integrity, while the others do not. This shows that the estimation of the effect of drug molecules on lipid membranes can be rather complex. In this context, experimental studies on lipid membranes are necessary to (i) identify drugs that may disturb membranes and (ii) characterize drug–membrane interactions on a molecular level. Such knowledge is important for understanding the efficacy and potential side effects of respective drugs.Peer Reviewe

On the boundary flow off Brazil at 5-10°S and its conncetion to the interior tropical Atlantic

Within the context of the German CLIVAR program, an observational program in the western tropical Atlantic with shipboard sections, profiling floats and a moored array aims at studying the role of the shallow thermohaline subtropical cell (STC) in tropical-subtropical interactions and the cold water transports underneath. From 6 repeated shipboard profiling sections off Brazil near 5°S a northward warm water transport above 1100 m of 25.0 ± 4.4 Sv is determined, of which 13.4 ± 2.7 Sv occur in the thermocline layer supplying the Equatorial Undercurrent. Trajectories of 15 profiling floats released near the western boundary are presented that drift at shallow levels (200 m and 400 m) and delineate the different STC branches. For the southward flow of North Atlantic Deep Water (NADW) a section-mean transport of −31.7 ± 9.2 Sv was determined at 5°S. However, different from the steady NADW flow observed earlier along the topography north of the equator, the NADW currents at 5–10°S are much more variable with long periods of northward counterflow along the topography

Tracer Survey in the Cape Verde Region Traceraufnahme in der Kapverdenregion Cruise No. 10, Leg 1 October 31 – December 06, 2008 Ponta Delgada (Portugal) – Mindelo (Cape Verde Islands)

The research cruise MSM10/1 was extremely successful. All programs were able to collect high quality data and the anticipated goals of the expedition were fully met. We have been able to carry out the first comprehensive survey of a tracer release in the Guinea Upwelling region (GUTRE) roughly seven month after the tracer was released at 8°N 23°W in April 2008. We have estimated that a total of 40% of the tracer was found during this cruise. While the horizontal spreading and mixing was larger than anticipated, the vertical extent of the tracer found was small. The low vertical tracer spreading rate estimates are supported by the micro structure profile data. The extensive survey of the upper 1000m of the oxygen minimum zone (OMZ) allowed comparing our sections with several previous surveys. We found that the lowest oxygen values in the core of the OMZ have dropped at record low values below 40 μmol/kg. The preliminary findings from the trace metal work focused on Fe ligand measurements shows a slight higher excess ligand concentration in the surface (50m) for three stations. The two other stations show a slight decrease at this depth. A large number of biochemical samples were taken and were analyzed in Kiel for DNA and RNA diversity. The tracer release experiment provided an ideal environment for repeated biochemical sampling in the same water mass

Solvent effects on catalytic activity and selectivity in amine-catalyzed D-fructose isomerization

Rational catalyst design and optimal solvent selection are key to advancing biorefining. Here, we explored the organocatalytic isomerization of D-fructose to a valuable rare monosaccharide, D-allulose, as a function of solvent. The isomerization of D-fructose to D-allulose competes with its isomerization to D-glucose and sugar degradation. In both water and DMF, the catalytic activity of amines towards D-fructose is correlated with their basicity. Solvents impact the selectivity significantly by altering the tautomeric distribution of D-fructose. Our results suggest that the furanose tautomer of D-fructose is isomerized to D-allulose, and the fractional abundance of this tautomer increases as follows: water < MeOH < DMF ≈ DMSO. Reaction rates are also higher in aprotic than in protic solvents. The best D-allulose yield, 14 %, was obtained in DMF with 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as the catalyst. The reaction kinetics and mechanism were explored using operando NMR spectroscopy

Simultaneous polydirectional transport of colloidal bipeds

Detailed control over the motion of colloidal particles is relevant in many applications in colloidal science such as lab-on-a-chip devices. Here, we use an external magnetic field to assemble paramagnetic colloidal spheres into colloidal rods of several lengths. The rods reside above a square magnetic pattern and are transported via modulation of the direction of the external magnetic field. The rods behave like bipeds walking above the pattern. Depending on their length, the bipeds perform topologically distinct classes of protected walks above the pattern. We demonstrate that it is possible to design parallel polydirectional modulation loops of the external field that command up to six classes of bipeds to walk on distinct predesigned paths. We use such parallel polydirectional loops to induce the collision of reactant bipeds, their polymerization addition reaction to larger bipeds, the separation of product bipeds from the educts, the sorting of different product bipeds, and also the parallel writing of a word consisting of several different letters

Genome-Wide Gene Amplification during Differentiation of Neural Progenitor Cells In Vitro

DNA sequence amplification is a phenomenon that occurs predictably at defined stages during normal development in some organisms. Developmental gene amplification was first described in amphibians during gametogenesis and has not yet been described in humans. To date gene amplification in humans is a hallmark of many tumors. We used array-CGH (comparative genomic hybridization) and FISH (fluorescence in situ hybridization) to discover gene amplifications during in vitro differentiation of human neural progenitor cells. Here we report a complex gene amplification pattern two and five days after induction of differentiation of human neural progenitor cells. We identified several amplified genes in neural progenitor cells that are known to be amplified in malignant tumors. There is also a striking overlap of amplified chromosomal regions between differentiating neural progenitor cells and malignant tumor cells derived from astrocytes. Gene amplifications in normal human cells as physiological process has not been reported yet and may bear resemblance to developmental gene amplifications in amphibians and insects

Acute Moraxella catarrhalis Airway Infection of Chronically Smoke-Exposed Mice Increases Mechanisms of Emphysema Development : A Pilot Study

In chronic obstructive pulmonary disease (COPD), acute exacerbations and emphysema development are characteristics for disease pathology. COPD is complicated by infectious exacerbations with acute worsening of respiratory symptoms with Moraxella catarrhalis as one of the most frequent pathogens. Although cigarette smoke (CS) is the primary risk factor, additional molecular mechanisms for emphysema development induced by bacterial infections are incompletely understood. We investigated the impact of M. catarrhalis on emphysema development in CS exposed mice and asked whether an additional infection would induce a solubilization of pro-apoptotic and proinflammatory endothelial monocyte-activating-protein-2 (EMAPII) to exert its activities in the pulmonary microvasculature and other parts of the lungs not exposed directly to CS. Mice were exposed to smoke (6 or 9 months) and/or infected with M. catarrhalis. Lungs, bronchoalveolar lavage fluid (BALF), and plasma were analyzed. CS exposure reduced ciliated area, caused rarefaction of the lungs, and induced apoptosis. EMAPII was increased independent of prior smoke exposure in BALF of infected mice. Importantly, acute M. catarrhalis infection increased release of matrixmetalloproteases-9 and -12, which are involved in emphysema development and comprise a mechanism of EMAPII release. Our data suggest that acute M. catarrhalis infection represents an independent risk factor for emphysema development in smoke-exposed mice