Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Part 1: identification of dipeptide derived leads

Dipeptide derivatives bearing various P2 residues and pyrrolidine derivatives as P1 mimics were evaluated in order to identify lead structures for the development of DPP8 and DPP9 inhibitors. Structure–activity-relationship data obtained in this way led to the preparation of a series of α-aminoacyl ((2S, 4S)-4-azido-2-cyanopyrrolidines). These compounds were shown to be nanomolar DPP8/9 inhibitors with modest overall selectivity toward DPP IV and DPP II.     

Exploration of the hydrogen producing potential of Rhodobacter capsulatus chemostat cultures: The application of deceleration‐stat and gradient‐stat methodology

In this work, the dependency of the volumetric hydrogen production rate of ammonium‐limited Rhodobacter capsulatus chemostat cultures on their imposed biomass concentration and dilution rate was investigated. A deceleration‐stat experiment was performed by lowering the dilution rate from 1.0 d^?1 to zero aimed at a constant biomass concentration of 4.0 g L^?1 at constant incident light intensity. The results displayed a maximal volumetric hydrogen production rate of 0.6 mmol m^?3 s^?1, well below model predictions. Possibly the high cell density limited the average light availability, resulting in a sub‐optimal specific hydrogen production rate. To investigate this hypothesis, a gradient‐stat experiment was conducted at constant dilution rate of 0.4 d^?1 at constant incident light intensity. The biomass concentration was increased from 0.7 to 4.0 g L^?1 by increasing the influent ammonium concentration. Up to a biomass concentration of 1.5 g L^?1, the volumetric hydrogen production rate of the system increased according to model predictions, after which it started to decline. The results obtained provide strong evidence that the observed decline in volumetric hydrogen production rate at higher biomass concentrations was at least partly caused by a decrease in light availability. © 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2009     

The Pupillary Light Response Reveals the Focus of Covert Visual Attention

The pupillary light response is often assumed to be a reflex that is not susceptible to cognitive influences. In line with recent converging evidence, we show that this reflexive view is incomplete, and that the pupillary light response is modulated by covert visual attention: Covertly attending to a bright area causes a pupillary constriction, relative to attending to a dark area under identical visual input. This attention-related modulation of the pupillary light response predicts cuing effects in behavior, and can be used as an index of how strongly participants attend to a particular location. Therefore, we suggest that pupil size may offer a new way to continuously track the focus of covert visual attention, without requiring a manual response from the participant. The theoretical implication of this finding is that the pupillary light response is neither fully reflexive, nor under complete voluntary control, but is instead best characterized as a stereotyped response to a voluntarily selected target. In this sense, the pupillary light response is similar to saccadic and smooth pursuit eye movements. Together, eye movements and the pupillary light response maximize visual acuity, stabilize visual input, and selectively filter visual information as it enters the eye.     

Effect of Abscisic Acid on Uptake and Metabolism of [H]Gibberellin A(1) and [H]Pseudogibberellin A(1) by Barley Half-seeds

Uptake and metabolism of 1,2-[³H]gibberellin A₁ ([³H]GA₁, I) and its 3-hydroxy epimer ([³H]pseudoGA₁, II) by barley (Hordeum vulgare L.) half-seeds were measured after 24 hours of incubation, in the presence or absence of abscisic acid in the media. Uptake of both compounds was enhanced by abscisic acid, and abscisic acid enhanced the extent of metabolism of [³H]GA₁. However, [³H]pseudoGA₁ was not metabolized, even in the presence of abscisic acid. The significance of the stereo-chemistry of the 3-hydroxyl position is discussed.     

Interactions between Bdellovibrio and its host cell.

The bdellovibrios are extremely small bacteria with the unique property of being parasites of other (gram-negative) bacteria. In the presence of viable and susceptible bacteria a Bdellovibrio cell physically 'attacks' an individual host cell, attaches to its surface, penetrates the cell wall, and multiples within the periplasmic (intramural) space of its prey. The invading Bdellovibrio and its progeny degrade and consume the cellular constituents of the invaded host bacterium. This process finally results in complete lysis of the host cell and release of the Bdellovibrio progeny. From a population of parasitic bdellovibrios, derivatives can be selected that grow on complex nutrient media. Currently, none of the different nutritional types can be propagated in a fully defined synthetic medium. By degradation of the cellular constituents of the host the Bdellovibrio cell in its periplasmic space has available all the monomeric subunits needed to synthesis of the macromolecules. Peculiarities of Bdellovibrio metabolism with respect to uptake of preformed molecules and energy efficiency are discussed.     

Development of a novel cytochrome p450 bioaffinity detection system coupled online to gradient reversed-phase high-performance liquid chromatography

A high-resolution screening platform, coupling online affinity detection for mammalian cytochrome P450s (Cyt P450s) to gradient reversed-phase high-performance liquid chromatography (HPLC), is described. To this end, the online Cyt P450 enzyme affinity detection (EAD) system was optimized for enzyme (beta-NF-induced rat liver microsomes), probe substrate (ethoxyresorufine), and organic modifier (methanol or acetonitrile). The optimized Cyt P450 EAD system has first been evaluated in a flow injection analysis (FIA) mode with 7 known ligands of Cyt P450 1A1/1A2 (alpha-naphthoflavone, beta-naphthoflavone, ellipticine, 9-hydroxy-ellipticine, fluvoxamine, caffein, and phenacetin). Subsequently, IC50 values were online in FIA-mode determined and compared with those obtained with standardmicrosomal assay conditions. The IC50 values obtained with the online Cyt P450 EAD system agreed well with the IC50 values obtained in the standard assays. For high affinity ligands of Cyt P450 1A1/1A2, detection limits of 1 to 3 pmol injected (n=3; signal to noise [S/N]=3) were obtained. The individual inhibitory properties of ligands in mixtures of the ligands were subsequently investigated using an optimized Cyt P450 EAD system online coupled to gradient HPLC. Using the integrated online gradient HPLC Cyt P450 EAD platform, detection limits of 10 to 25 pmol injected (n=1; S/N=3) were obtained for high-affinity ligands. It is concluded that this novel screening technology offers new perspectives for rapid and sensitive screening of individual compounds in mixtures exhibiting affinity for liver microsomal Cyt P450s.     

When do mixotrophs specialize? Adaptive dynamics theory applied to a dynamic energy budget model

In evolutionary history, several events have occurred at which mixotrophs specialized into pure autotrophs and heterotrophs. We studied the conditions under which such events take place, using the Dynamic Energy Budget (DEB) theory for physiological rules of the organisms' metabolism and Adaptive Dynamics (AD) theory for evolutionary behavior of parameter values. We modeled a population of mixotrophs that can take up dissolved inorganic nutrients by autotrophic assimilation and detritus by heterotrophic assimilation. The organisms have a certain affinity for both pathways; mutations that occur in the affinities enable the population to evolve. One of the possible evolutionary outcomes is a branching point which provides an opportunity for the mixotrophic population to split up and specialize into separate autotrophs and heterotrophs. Evolutionary branching is not a common feature of the studied system, but is found to occur only under specific conditions. These conditions depend on intrinsic properties such as the cost function, the level of the costs and the boundaries of the trait space: only at intermediate cost levels and when an explicit advantage exists to pure strategies over mixed ones may evolutionary branching occur. Usually, such an advantage (and hence evolutionary branching) can be induced by interference between the two affinities, but this result changes due to the constraints on the affinities. Now, only some of the more complicated cost functions give rise to a branching point. In contrast to the intrinsic properties, extrinsic properties such as the total nutrient content or light intensity were found to have no effect on the evolutionary outcomes at all.     

A First-in-Human,Phase I Study of Neural Stem Cell Transplantation for Chronic Spinal Cord Injury

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Life-history traits are correlated with geographical distribution patterns of western European forest herb species

Aim To investigate whether six plant life‐history traits that have been related to colonization ability at local scales are also related to the geographical range characteristics of 273 forest plant species. Location Continental western Europe, five countries in particular: France, Luxemburg, Belgium, the Netherlands and Germany. The region is situated between 42° and 55°N and 5°W and 15°E and has a summed total area of 971,404 km². Methods Distribution data were compiled from five national data bases and converted to a 10′ grid. Life‐history traits were taken from existing compilations of autecological information of European species. The spatial arrangement of occupied grid cells was investigated using Ripley's K. Cross‐species correlations and phylogenetically independent contrasts were used to investigate the relationships between plant life‐history traits and three range characteristics: area of occupancy, latitudinal extent and centroid latitude. Results For herbaceous species, seed dispersal mode, seed production and seed bank longevity exhibited significant associations with geographical range characteristics, including area of occupancy. Woody plant species exhibited fewer significant associations, although maximum height was positively associated with range centroid latitude within the study area. Furthermore, the ranges of species with limited dispersal ability were found to be more clustered than the ranges of species with morphological adaptations for long‐distance seed dispersal. Main conclusions For western European forest plant species, life‐history traits that are related to colonization ability at local scales are associated with variation in large‐scale geographical range characteristics. This finding implies that the distributions of some forest plant species in the study area may be limited by seed dispersal and colonization capacity rather than climate or other environmental factors.