Active Site Mapping of Human Cathepsin F with Dipeptide Nitrile Inhibitors

Cleavage of the invariant chain is the key event in the trafficking pathway of major histocompatibility complex class II. Cathepsin S is the major processing enzyme of the invariant chain, but cathepsin F acts in macrophages as its functional synergist which is as potent as cathepsin S in invariant chain cleavage. Dedicated low‐molecular‐weight inhibitors for cathepsin F have not yet been developed. An active site mapping with 52 dipeptide nitriles, reacting as covalent–reversible inhibitors, was performed to draw structure–activity relationships for the non‐primed binding region of human cathepsin F. In a stepwise process, new compounds with optimized fragment combinations were designed and synthesized. These dipeptide nitriles were evaluated on human cysteine cathepsins F, B, L, K and S. Compounds 10 (N‐(4‐phenylbenzoyl)‐leucylglycine nitrile) and 12 (N‐(4‐phenylbenzoyl)leucylmethionine nitrile) were found to be potent inhibitors of human cathepsin F, with K_i values <10 nM . With all dipeptide nitriles from our study, a 3D activity landscape was generated to visualize structure–activity relationships for this series of cathepsin F inhibitors.     

Correlation of Structure and Photoelastic Response in Tin Phosphate Glass

Recently an empirical model was established to predict the photoelastic response of a glass based on its composition and the crystalline structure of its constituents. In the present work the model was tested in detail by comparing the local structure assessed by a combination of nuclear magnetic resonance and Mössbauer spectroscopy with the model predictions and the measured photoelastic response. The system investigated was (SnO)_x(P₂O₅)_1−x. It was found that while the original simple model based on data on the pure components predicted the composition of the zero stress-optic glass to within about 15 mol%, inclusion of data on mixed systems, more reflective of the true glass structure, gave substantial improvement of the prediction. This finding further confirms the relation of local bonding structure to the photoelastic response of glass.     

Modelling the effects of dam removal on migratory walleye (Sander vitreus) early life‐history stages

Many dams in the USA have outlived their intended purpose and an increasing number are being considered for removal. Yet, quantitative studies of the potential physical, biological and ecological responses are needed to assess dam removal decisions. In this paper, the responses of migratory walleye (Sander vitreus) to increased spawning habitat availability as a result of dam removal was studied by comparing scenarios with and without a high‐head dam in the Sandusky River (Ohio), a major tributary to Lake Erie. A conceptual, ecological model was proposed to define the relationship between hydrodynamics and walleye spawning, egg hatching, larval drift and survival. A mathematical, ecological model of the early life‐history stages was then developed and coupled with time series of depth and velocity predictions over the spawning grounds from a 1‐D hydrodynamic model. Model simulations were run for 1984–1993 for both the with‐ and without‐dam scenarios to assess the potential benefit of dam removal. The simulation results demonstrated that velocity, depth and water temperature are major factors influencing adult walleye spawning success. Without the dam, 10 times the amount of spawning habitat would be available for walleye to spawn. This increase in spawning habitat area resulted in up to five times the total egg deposition and seven times the larval output to the nursing grounds, based on the assumption that 5% of the walleye population of Lake Erie migrated up the Sandusky River to spawn. We concluded that the spawning habitat in the current condition (with the dam) is limiting and additional spawning habitat upstream could significantly increase the number of larval walleye drifting to Lake Erie. The model sensitivity analysis showed that the number of walleye migrating up the river in spring is the dominant factor for larval recruitment to the lake. Copyright © 2006 John Wiley & Sons, Ltd.     

Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair

Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies.     

Group awareness and self-presentation in computer-supported information exchange

A common challenge in many situations of computer-supported collaborative learning is increasing the willingness of those involved to share their knowledge with other group members. As a prototypical situation of computer-supported information exchange, a shared-database setting was chosen for the current study. This information-exchange situation represented a social dilemma: while the contribution of information to a shared database induced costs and provided no benefit for the individual, the entire group suffered when all members decided to withhold information. In order to alleviate the information-exchange dilemma, a group-awareness tool was employed. It was hypothesized that participants would use group awareness for self-presentational purposes. For the examination of this assumption, the personality variable ‘protective self-presentation’ (PSP) was measured. An interaction effect of group awareness and PSP was found: when an awareness tool provided information concerning the contribution behavior of each individual, this tool was used as a self-presentation opportunity. In order to understand this effect in more detail, single items of the PSP-scale were analyzed.     

Improved signal-to-noise ratio in EPI sequences with highly asymmetric spin echo and highly asymmetric STEAM preparations (HASE-EPI and HASTEAM-EPI)

Magnetic Resonance Materials in Physics, Biology and Medicine - Alternative versions of echo-planar imaging (EPI) sequences with standard spin echo (SE) or stimulated echo acquisition mode (STEAM)...     

Optimizing substrate surface and catalyst conditions for high yield chemical vapor deposition grown epitaxially aligned single-walled carbon nanotubes

Single-crystal stable-temperature (ST)-cut quartz substrates, which have a (0 1 1 1) crystallographic plane with their surface normal lying close to 38° from the y axis ([0 1 0]), were annealed in air prior to use as a support for aligned carbon nanotube growth by chemical vapor deposition. Very smooth substrate surfaces were obtained with annealing times in the vicinity of 15 h at a temperature of 750 °C. These smooth surfaces are ideal for the growth of horizontally aligned SWCNTs with high spatial density, while less dense SWCNTs were obtained with less smooth surfaces. Under optimized growth conditions, only SWCNT are observed and they can grow to lengths in excess of 100 μm. Our findings suggest structural defects interfere with the growth process. A binary Fe/Co catalyst was employed to grow the nanotubes. No obvious dependence on the Fe:Co ratio is observed.     

Activation of Polycyclic Aromatic Compounds by cDNA-Expressed Phase I and Phase II Enzymes

A large number of human and other mammalian xenobiotic-metabolizing enzymes have been expressed in target cells of standard mutagenicity tests, such as Ames's Salmonella typhimurium strains and Chinese hamster V79 cells. These recombinant cells are useful for determining the ability of individual enzymes to activate (or inactivate) a given compound. In contrast to standard S9-mediated test systems, they also allow the detection of mutagenic metabolites that do not penetrate cell membranes--a situation often found with reactive phase II metabolites. We present mutagenicity data for benzo[ a ]pyrene and dibenzo[ a,l ]pyrene in V79-derived cells expressing human cytochrome P450 (CYP) 1A1, 1A2, and 1B1, and for 1-hydroxymethylpyrene, R - and S -1-( f -hydroxyethyl) pyrene, 4-hydroxycyclopenta[ def ]chrysene and N -hydroxy-2-acetylaminofluorene in V79-derived cells and/or Salmonella strains expressing the 11 human sulfotransferases (SULTs) identified. In some cases, allelic variants and orthologous enzymes from other mammalian species were also investigated. The data indicate that mutagenicity of many compounds is detected in the appropriate recombinant systems at extremely low substrate concentrations, that the activation of various promutagens is mediated with high specificity by only one or few enzyme forms, and that substantial differences may occur between alloenzymes from the same species and orthologous enzymes from different species. Such information could be important for understanding differences in susceptibility between tissues, species, individual genetic traits, and physiological states.     

Fiber scaffolds of polysialic acid via electrospinning for peripheral nerve regeneration

Fiber scaffolds of bioactive polysialic acid have been prepared via electrospinning for peripheral nerve regeneration. The diameter, morphology and alignment of fibers in scaffolds were adjusted by variation of electrospinning parameters, which are decisive for the cell-scaffold interaction. Due to the high water solubility of polysialic acid (poly-α-2,8-N-acetylneuraminic acid) a photoactive derivative (poly-α-2,8-N-pentenoylneuraminic acid) was used to obtain stable fiber scaffolds in water by photochemical crosslinking. At the optimized fiber scaffolds good cell viability and directed cell proliferation along the fibers was achieved by cell tests with immortalized Schwann cells.