D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A(2) (IIa) with antiinflammatory activity

Few reported inhibitors of secretory phospholipase A(2) enzymes inhibit the IIa human isoform (hnpsPLA(2)-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivastised to give a series of potent new inhibitors of hnpsPLA(2)-IIa. A 2.2-Angstrom crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca2+ ion through carboxylate and amide oxygen atoms, H bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group-His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.

Macrocyclic systems containing 2,6,9-trioxabicyclo[3.3.1]-nona-3,7-dienes as chiral spacer groups: Synthesis, stereochemical features and preliminary complexation properties

Novel 2:2-macrocycles bearing bridged concave 2,6,9-trioxabicyclo[3.3.1]nona-3,7-dienes as chiral spacer units were obtained by cyclocondensation reaction of the chiral bisacid chloride and the corresponding diols, while use of methylene diamines instead of diols afforded 1:1 macrocycles only. Applying the same, but now template-assisted, experimental procedure to the reaction of the bisacid chloride with triethylene glycol brought about a significant increase in yield as well as a suitable simplification of the work-up during preparation and separation of the corresponding 1:1 as well as 2:2 macrocycles, when compared to results reported previously. HPLC separation on chiral columns revealed the presence of diastereoisomers [RR(S,S)- and RS-(meso)-forms] for all 2:2 macrocycles, which was further evidenced by the CD spectrum of one of those species as an example. Preliminary ESI-MS experiments indicated strong complexation abilities of the sulphur-containing ligand towards Ag(I), Cu(II) and Au(III) ions.

Unidirectional inversion of ibuprofen in Caco-2 cells: Developing a suitable model for presystemic chiral inversion study

Intestinal chiral inversion of ibuprofen is still lacking direct evidence. In a preliminary experiment, ibuprofen was found to undergo inversion in Caco-2 cells. This investigation was thus conducted to determine the characteristics and influence of some biochemical factors on the chiral inversion of ibuprofen in Caco-2 cells. The effects of substrate concentration (2.5-40 mu g/ml), cell density (0.5-2 x 10(6) cells/ well), content of serum (0-20%), coexistence of S ibuprofen (corresponding doses), sodium azide (10mm), exogenous Coenzyme A (CoA) (0.1 - 0.4 mm),. and palmitic acid (5-25 mu m) on inversion were examined. A stereoselective HPLC method based on the Chromasil-CHI-TBB column was developed for quantitative analysis of the drug in cell culture medium. The inversion ratio (F-i) and elimination rate constant were calculated as the indexes of inversion extent. Inversion of ibuprofen in Caeo-2 cells was found to be both dose and cell density dependent, indicating saturable characteristics. Addition of serum significantly inhibited the inversion, to an extent of 2.7 fold decrease at 20% content. Preexistence of S enantiomer exerted a significant inhibitory effect (p < 0.01 for all tests). Sodium azide decreased the inversion ratio from 0.43 to 0.32 (p < 0.01). Exogenous CoA and palmitic acid significantly promoted the inversion at all tested doses (p < 0.01 for all tests). This research provided strong evidence to the capacity and capability of intestinal chiral inversion. Although long incubation times up to 120 h were required, Caco-2 cells should be a suitable model for chiral inversion research of 2-APAs considering the human-resourced and well-defined characteristics from the present study.

Axial Anomaly for Eguchi-Hanson Metrics with Nonzero Total Mass

We compute the Dirac indexes for. the two spin structures kappa(0) and kappa(1) for Eguchi-Hanson metrics with nonzero total mass. It shows that the Dirac indexes do not vanish in general, and axial anomaly exists. When the metric has zero total mass, the Dirac index vanishes for the spin structure no, and no axial anomaly exists in this case.

Increased DNA Methylation at the AXIN1 Gene in a Monozygotic Twin from a Pair Discordant for a Caudal Duplication Anomaly

The AXIN1 gene has been implicated in caudal duplication anomalies. Its coding region was sequenced in both members of a monozygotic ( MZ) twin pair discordant for a caudal duplication anomaly, but no mutation was found. Using bisulfite sequencing, we examined methylation at the promoter region of the AXIN1 gene in these twins and in twin and age-matched singleton controls. Methylation of the promoter region in peripheral blood mononucleated cells was variable among individuals, including MZ pairs. In the MZ pair discordant for the caudal duplication, this region of the affected twin was significantly more methylated than that of the unaffected twin (), which was significantly more P < .0001 methylated than those of the controls (). We have confirmed that this CpG island does function as a promoter P = .02 in vitro and that its activity is inversely proportional to the extent of methylation. This finding raises the possibility that hypermethylation of the AXIN1 promoter, by mechanisms as yet undetermined, is associated with the malformation. This case may be paradigmatic for some cases of MZ discordance.

A total electron content space weather study of the Nighttime Weddell Sea Anomaly of 1996/97 southern summer with TOPEX/Poseidon radar altimetry

This paper reports on a total electron content space weather study of the nighttime Weddell Sea Anomaly, overlooked by previously published TOPEX/Poseidon climate studies, and of the nighttime ionosphere during the 1996/1997 southern summer. To ascertain the morphology of spatial TEC distribution over the oceans in terms of hourly, geomagnetic, longitudinal and summer-winter variations, the TOPEX TEC, magnetic, and published neutral wind velocity data are utilized. To understand the underlying physical processes, the TEC results are combined with inclination and declination data plus global magnetic field-line maps. To investigate spatial and temporal TEC variations, geographic/magnetic latitudes and local times are computed. As results show, the nighttime Weddell Sea Anomaly is a large (∼1,600(°)2; ∼22 million km2 estimated for a steady ionosphere) space weather feature. Extending between 200°E and 300°E (geographic), it is an ionization enhancement peaking at 50°S–60°S/250°E–270°E and continuing beyond 66°S. It develops where the spacing between the magnetic field lines is wide/medium, easterly declination is large-medium (20°–50°), and inclination is optimum (∼55°S). Its development and hourly variations are closely correlated with wind speed variations. There is a noticeable (∼43%) reduction in its average area during the high magnetic activity period investigated. Southern summer nighttime TECs follow closely the variations of declination and field-line configuration and therefore introduce a longitudinal division of four (Indian, western/eastern Pacific, Atlantic). Northern winter nighttime TECs measured over a limited area are rather uniform longitudinally because of the small declination variation. TOPEX maps depict the expected strong asymmetry in TEC distribution about the magnetic dip equator.

The knowledge transfer anomaly

Knowledge transfer between units within MNC’s and between independent organisations involved in international business is an important element of performance. Researchers have shown that generally cultural differences place difficulties in the way of both information and knowledge transfer across national borders, both within MNC’s and across organisations. This study examines the knowledge transfer process between different cultural groups in a particular setting and concludes that in this situation cultural differences do not hinder knowledge transfer. Explanations are provided for this anomaly and implications for international business managers are drawn.