Multiple solution conformations of the integrin-binding cyclic pentapeptide cyclo(-Ser-D-Leu-Asp-Val-Pro-). Analysis of the (phi, psi) space available to cyclic pentapeptides

The aqueous solution structure of the cyclic pentapeptide cyclo(-Ser-D-Leu-Asp-Val-Pro-) has been determined by two-dimensional 1H-NMR spectroscopy, combined with a conformational search and distance-geometry calculations. As many as five conformers in slow exchange were observed, and the rate of interconversion between components was measured from the build-up rates of exchange peaks. NMR data allowed the structures of the two predominant conformers to be determined. The major component (66%) contained a cis-proline as part of a type-VIa2 beta-turn encompassing residues Asp-Val-cis-Pro-Ser. The second component (16%) contained only trans-amide bonds, and a type-VIII beta-turn formed by residues Val-Pro-Ser-D-Leu. These structures are discussed in relation to the (phi, psi), space available to the cyclic pentapeptide, determined by a conformational search, and in relation to previously published cyclic-pentapeptide structures. The molecule exhibits activity in a scintillation-proximity assay for the inhibition of the interaction between the integrin very-late antigen-4 (VLA-4; alpha 4 beta 1) and vascular-cell-adhesion molecule-1 (VCAM-1). The structure/activity relationship of the LDV sequence is discussed and related to the recently published X-ray structure of VCAM-1. The relevance of the work to the design of anti-inflammatory drugs is discussed.     

A lower bound for structuring element decompositions

A theoretical lower bound on the number of points required in the decomposition of morphological structuring elements is described. It is shown that the decomposition of an arbitrary N-point structuring element will require at least [3 ln N/ln 3]points. Using this lower bound it is possible to find the optimal decompositions (in terms of the minimum number of unions or the minimum number of points) for all one-dimensional connected line segments. L-dimensional rectangles may be decomposed by optimally decomposing the L one-dimensional line segments that describe the rectangle     

Fibre Bragg grating compression-tuned over 110 nm

A fibre Bragg grating with a tuning range covering beyond the C- and L-bands has been realised, which represents the broadest tuning range reported of any Bragg grating. The device exhibits constant spectral response and polarisation mode dispersion within these bands.     

A study into the effects of protein binding on nucleotide conformation

In this study, we examine the effects of binding to protein upon nucleotide conformation, by the comparison of X-ray crystal structures of free and protein-bound nucleotides. A dataset of structurally non-homologous protein-nucleotide complexes was derived from the Brookhaven Protein Data Bank by a novel protocol of dual sequential and structural alignments, and a dataset of native nucleotide structures was obtained from the Cambridge Structural Database. The nucleotide torsion angles and sugar puckers, which describe nucleotide conformation, were analysed in both datasets and compared. Differences between them are described and discussed. Overall, the nucleotides were found to bind in low energy conformations, not significantly different from their 'free' conformations except that they adopted an extended conformation in preference to the 'closed' structure predominantly observed by free nucleotide. The archetypal conformation of a protein-bound nucleotide is derived from these observations.     

The novel inotropic agent CGP 48506 alters force primarily by Ca(2+)-independent mechanisms in porcine skinned trabeculae

OBJECTIVES: The aim was to determine whether, and by what mechanism(s), a novel inotropic agent 5-methyl-6-phenyl-1,3,5,6-tetrahydro-3, 6-methano-1,5-benzodiazocine-2,4-dione (BA 41899) and its enantiomers directly alter the Ca2+ sensitivity of cardiac myofilaments. METHODS: Porcine ventricular trabeculae were permeabilised with Triton X-100. The relationship between force and pCa (-log[Ca2+]) was determined in the presence and absence of ATP. Troponin I was extracted, using vanadate, to produce unregulated maximally activated myofilaments. Force and actomyosin ATPase activity were measured simultaneously to determine tension cost (ATPase activity/tension). The effects of the (+) enantiomer (CGP 48506) on the twitch of intact muscle were demonstrated using rat papillary muscle. RESULTS: 100 microM BA 41899 had a pronounced Ca2+ sensitising effect on force production by porcine skinned cardiac fibres, increasing the pCa required for 50% maximal activation by 0.64 units, while suppressing maximum force by 18.3%. Resting tension was unaffected. These actions were primarily caused by CGP 48506 and were concentration dependent. At concentrations less than 100 microM, CGP 48506 also increased twitch amplitude in intact papillary muscles with no effect on resting tension, whereas 100 microM CGP 48506 increased resting force due to a slowing of relaxation. 100 microM CGP 48506 potentiated Ca(2+)-independent rigor tension in skinned trabeculae, indicating a Ca2+ sensitising mechanism unrelated to Ca2+ binding to troponin C. Tension cost was unaffected by 100 microM CGP 48506 over the entire range of activating Ca2+ concentrations. Suppression of maximum force by CGP 48506 was independent of both Ca2+ concentration and the regulatory troponin complex. CONCLUSIONS: Both the increase in Ca2+ sensitivity during submaximal activation and the depression of maximum force which are induced by CGP 48506 in skinned trabeculae occur at least partly through Ca(2+)-independent mechanisms.     

Lysis of human monocytic leukemia cells by extracellular adenosine triphosphate: mechanism and characterization of the adenosine triphosphate receptor

The present study shows that extracellular adenosine triphosphate (ATP) has the capacity to mediate dose-dependent lysis of the monocytic leukemia cell line THP-1. The lysis, assessed by 51Cr release, was found to be selective for ATP, because adenosine diphosphate (ADP) or other nucleotides were less effective in their ability to lyse the cells. The amount of 51Cr released was particularly enhanced by the stimulation of the cells with 1,000 U/mL of interferon gamma (IFN-gamma) for 3 days, and the sensitivity was time and dose dependent. Analysis of the mechanism of lysis indicated that the fully ionized form, ATP4-, mediated the lysis, because the addition of cation chelators or the absence of the divalent cations, Ca2+ and Mg2+, in the culture medium of a 6-hour 51Cr release assay increased the percent specific lysis. Therefore, the ATP receptors on THP-1 cells were classified as P2Z purinoceptors. Moreover, it is shown here that the Ca2+/calmodulin complex plays a role in the regulation of the lysis by extracellular ATP of THP-1 cells, because antagonists of this complex, such as trifluoperazine or KN-62, were found to inhibit the ATP-mediated cell lysis.     

Wind energy systems

Wind energy has matured to a level of development where it is ready to become a generally accepted utility generation technology. A brief discussion of this development is presented, and the operating and design principles are discussed. Alternative designs for wind turbines and the tradeoffs that must be considered are briefly compared. Development of a wind energy system and the impacts on the utility network including frequency stability, voltage stability, and power quality are discussed. The assessment of wind power station economics and the key economic factors that determine the economic viability of a wind power plant are presented     

Validation of a specific selection criterion for dental periapical radiography

We report three children with hemidystonia in whom anti-cardiolipin (aCL) antibodies were demonstrated. Systemic lupus erythematosus was excluded on the basis of both clinical and serological criteria, and the diagnosis of primary antiphospholipid syndrome (PAPS) was made. In two cases, aCL antibodies could be causally related to a presumed immune-mediated thrombotic event involving the basal ganglia as shown by magnetic resonance imaging (MRI). In the remaining patient the finding of white matter alteration on NMR might be due to cross-reactivity of anti-phospholipid (aPL) antibodies with cerebral phospholipids, resulting in demyelination. We suggest that PAPS must always be considered when isolated or recurrent focal cerebral ischaemia, and particularly hemidystonia, occur in childhood.