Synthesis of N3- and 2-NH2-substituted 6,7-diphenylpterins and their use as intermediates for the preparation of oligonucleotide conjugates designed to target photooxidative damage on single-stranded DNA representing the bcr-abl chimeric gene

Two 17-mer oligodeoxynucleotide-5'-linked-(6,7-diphenylpterin) conjugates, 2 and 3, were prepared as photosensitisers for targeting photooxidative damage to a 34-mer DNA oligodeoxynucleotide (ODN) fragment 1 representing the chimeric bcr-abl gene that is implicated in the pathogenesis of chronic myeloid leukaemia (CML). The base sequence in the 17-mer was 3'G G T A G T T A T T C C T T C T T5'. In the first of these ODN conjugates (2) the pterin was attached at its N3 atom, via a -(CH2)3OPO(OH)- linker, to the 5'-OH group of the ODN. Conjugate 2 was prepared from 2-amino-3-(3-hydroxypropyl)-6,7-diphenyl-4(3H)-pteridinone 10, using phosphoramidite methodology. Starting material 10 was prepared from 5-amino-7-methylthiofurazano[3,4-d]pyrimidine 4 via an unusual highly resonance stabilised cation 8, incorporating the rare 2H,6H-pyrimido[6,1-b][1,3]oxazine ring system. In the characterisation of 10 two pteridine phosphazenes, 15 and 29, were obtained, as well as new products containing two uncommon tricyclic ring systems, namely pyrimido[2,1-b]pteridine (20 and 24) and pyrimido[1,2-c]pteridine (27). In the second ODN conjugate the linker was -(CH2)5CONH(CH2)6OPO(OH)- and was attached to the 2-amino group of the pterin. In the preparation of 3, the N-hydroxysuccinimide ester 37 of 2-(5-carboxypentylamino)-6,7-diphenyl-4(3H)-pteridinone was condensed with the hexylamino-modified 17-mer. Excitation of 36 with near UV light in the presence of the single-stranded target 34-mer, 5'T G A C C A T C A A T A A G14 G A A G18 A A G21 C C C T T C A G C G G C C3' 1 caused oxidative damage at guanine bases, leading to alkali-labile sites which were monitored by polyacrylamide gel electrophoresis. Cleavage was observed at all guanine sites with a marked preference for cleavage at G14. In contrast, excitation of ODN-pteridine conjugate 2 in the presence of 1 caused oxidation of the latter predominantly at G18, with a smaller extent of cleavage at G15 and G14 (in the double-stranded portion) and G21. These results contrast with our previous observation of specific cleavage at G21 with ruthenium polypyridyl sensitisers, and suggest that a different mechanism, probably one involving Type 1 photochemical electron transfer, is operative. Much lower yields were found with the ODN-pteridine conjugate 3, perhaps as a consequence of the longer linker between the ODN and the pteridine in this case.

The isolation and purification of tris-2,2'-bipyridine complexes of ruthenium(II) containing unsymmetrical ligands

Monomeric ruthenium(II) complexes [Ru(L)3]2+ containing unsymmetric bipyridine ligands [Where L = 5-methyl-2,2'-bipyridine (L1), 5-ethyl-2,2'-bipyridine (L2), 5-propyl-2,2'-bipyridine (L3), 5-(2-methylpropyl)-2,2'-bipyridine (L4), 5-(2,2-dimethylpropyl)-2,2'-bipyridine (L5) and 5-(carbomethoxy)-2,2'-bipyridine (L6)] have been studied and the meridional and facial isomers isolated by the use of cation-exchange column chromatography (SP Sephadex C-25) eluting with either sodium toluene-4-sulfonate or sodium hexanoate. The relative yield of the facial isomer was found to decrease with increasing steric bulk, preventing the isolation of fac-[Ru(L5)3]2+. The two isomeric forms were characterized by 1H NMR, with the complexes [Ru(L1-3)3]2+ demonstrating an unusually large coupling between the H6 and H4 protons. Crystals suitable for X-ray structural analysis of [Ru(L1)3]2+ were obtained as a mixture of the meridional and facial isomers, indicating that separation of this isomeric mixture could not be achieved by fractional crystallisation. The optical isomers of the complex [Ru(L3)3]2+ were chromatographically separated on SP Sephadex C-25 relying upon the inherent chirality of the support. It is apparent that chiral interactions can inhibit geometric isomer separation using this technique.

Effects of n-3 long chain polyunsaturated fatty acids on depressed mood: Systematic review of published trials.

Background: Greater dietary intakes of n–3 long-chain polyunsaturated fatty acids (n–3 PUFAs) may be beneficial for depressed mood. Objective: This study aimed to systematically review all published randomized controlled trials investigating the effects of n–3 PUFAs on depressed mood. Design: Eight medical and health databases were searched over all years of records until June 2006 for trials that exposed participants to n–3 PUFAs or fish, measured depressed mood, were conducted on human participants, and included a comparison group. Results: Eighteen randomized controlled trials were identified; 12 were included in a meta-analysis. The pooled standardized difference in mean outcome (fixed-effects model) was 0.13 SDs (95% CI: 0.01, 0.25) in those receiving n–3 PUFAs compared with placebo, with strong evidence of heterogeneity (I2 = 79%, P <0.001). The presence of funnel plot asymmetry suggested that publication bias was the likely source of heterogeneity. Sensitivity analyses that excluded one large trial increased the effect size estimates but did not reduce heterogeneity. Metaregression provided some evidence that the effect was stronger in trials involving populations with major depression—the difference in the effect size estimates was 0.73 (95% CI: 0.05, 1.41; P = 0.04), but there was still considerable heterogeneity when trials that involved populations with major depression were pooled separately (I2 = 72%, P <0.001). Conclusions: Trial evidence that examines the effects of n–3 PUFAs on depressed mood is limited and is difficult to summarize and evaluate because of considerable heterogeneity. The evidence available provides little support for the use of n–3 PUFAs to improve depressed mood. Larger trials with adequate power to detect clinically important benefits are required.

A new approach for the detection of ethylene using silica-supported palladium complexes

The coordination of olefins to square-planar Pd(II) and Pt(II) complexes containing 2,9-dimethylphenanthroline (L1) often involves a change of color associated with a change of geometry at the metal center. In order to obtain suitable colorimetric detectors for ethylene gas, a series of new Pd(II) and Pt(II) compounds with a range of 2,9-disubstituted phenanthroline ligands [2,9-di-n-butyl-1,10-phenanthroline (L-2), 2,9-di-s-butyl-1,10-phenanthroline (L3), 2,9-diphenyl-1,10-phenanthroline (L4), and 2,9-dimethyl-4,7-diphenyl-1,10-phenanthroline (bathocuproine, L5)] have been prepared and their reactivity toward ethylene investigated both in solution and after depositing the detector compounds on a variety of solid supports. The Pd(II) complex [PdCl2(L2)] supported on silica undergoes a clear color change upon exposure to ethylene, while remaining stable toward air and water, and forms the basis for new simple colorimetric detectors with potential applications in ethylene pipe-leak detection and the monitoring of fruit ripening. Encouragingly, the detector is able to discriminate between fruit at different stages of ripening. The response of the detector to other volatiles was also examined, and specific color changes were also observed upon exposure to aromatic acetylenes. The crystal structures of four new derivatives, including the ethylene-Pt(II) complex [PtCl2(C2H4)(L2)], are also described.

Is there a role for n-3 long-chain polyunsaturated fatty acids in the regulation of mood and behaviour? A review of the evidence to date from epidemiological studies, clinical studies and intervention trials

Selected biochemical evidence suggests a potential role for n-3 long-chain PUFA (n-3PUFA) in the regulation of mood and behaviour. The present paper reviews the relevant evidence, to date, from epidemiological studies, clinical studies and intervention trials. Most evidence is available investigating a role for n-3PUFA in depression, depressive illness and suicidal behaviour, but work is also available on anxiety and anxiety-related disorders, fatigue and fatigue-related disorders, aggression, hostility and anti-social behaviour, inattention, impulsivity and attention deficit hyperactivity disorder and schizophrenic disorders. For all these aspects of mood and behaviour, the evidence available is currently limited and highly inconsistent, both in terms of study methodology and study findings. There is a clear need for further work in this area.

No clear evidence of an association between plasma concentrations of n-3 long-chain polyunsaturated fatty acids and depressed mood in a non-clinical population

Previous research suggests that low n-3 long-chain polyunsaturated fatty acid (n-3PUFA) status is associated with higher levels of depression in clinical populations. This analysis aimed to investigate the relationship between depressed mood and n-3PUFA status in a non-clinical population. The analysis was conducted on data collected as part of a large randomized controlled trial investigating the impact of n-3PUFA supplementation on depressed mood in a community-based population. On entry into the trial, data on depressed mood were collected using the Depression, Anxiety and Stress Scales (DASS) and the Beck Depression Inventory (BDI). Plasma concentrations of various n-3PUFAs and n-6 long-chain polyunsaturated fatty acids (n-6PUFAs) were obtained from fasting venous blood samples, and various demographics were also measured. Using regression, there was no evidence of an association between either measure of depressed mood and any of the measures of n-3PUFA status or of n-6PUFA: n-3PUFA ratios. Clear associations were also not found when demographic factors were included in the analyses. These findings suggest that n-3PUFAs may not have a role in the aetiology of minor depression. This is also consistent with the results of other studies that have not demonstrated an association between depressed mood and n-3PUFA status in non-clinical populations and epidemiological studies that have not demonstrated an association between depressed mood and n-3PUFA intake in these populations. (C) 2008 Elsevier Ltd. All rights reserved.

Does the level of graphical detail of a virtual handball thrower influence a goal-keeper's motor response?

The authors investigated how different levels of detail (LODs) of a virtual throwing action can influence a handball goalkeeper's motor response. Goalkeepers attempted to stop a virtual ball emanating from five different graphical LODs of the same virtual throwing action. The five levels of detail were: a textured reference level (L0), a non-textured level (L1), a wire-frame level (L2), a point-light-display (PLD) representation (L3) and a PLD level with reduced ball size (L4). For each motor response made by the goalkeeper we measured and analyzed the time to respond (TTR), the percentage of successful motor responses, the distance between the ball and the closest limb (when the stopping motion was incorrect) and the kinematics of the motion. Results showed that TTR, percentage of successful motor responses and distance with the closest limb were not significantly different for any of the five different graphical LODs. However the kinematics of the motion revealed that the trajectory of the stopping limb was significantly different when comparing the L1 and L3 levels, and when comparing the L1 and L4 levels. These differences in the control of the goalkeeper's actions suggests that the different level of information available in the PLD representations ( L3 and L4) are causing the goalkeeper to adopt different motor strategies to control the approach of their limb to stop the ball.

Influence of the Graphical Levels of Detail of a Virtual Thrower on the Perception of the Movement

Virtual reality has a number of advantages for analyzing sports interactions such as the standardization of experimental conditions, stereoscopic vision, and complete control of animated humanoid movement. Nevertheless, in order to be useful for sports applications, accurate perception of simulated movement in the virtual sports environment is essential. This perception depends on parameters of the synthetic character such as the number of degrees of freedom of its skeleton or the levels of detail (LOD) of its graphical representation. This study focuses on the influence of this latter parameter on the perception of the movement. In order to evaluate it, this study analyzes the judgments of immersed handball goalkeepers that play against a graphically modified virtual thrower. Five graphical representations of the throwing action were defined: a textured reference level (L0), a nontextured level (L1), a wire-frame level (L2), a moving point light display (MLD) level with a normal-sized ball (L3), and a MLD level where the ball is represented by a point of light (L4). The results show that judgments made by goalkeepers in the L4 condition are significantly less accurate than in all the other conditions (p

Red meat from animals offered a grass diet increases plasma and platelet n-3 PUFA in healthy consumers

Red meat from grass-fed animals, compared with concentrate-fed animals, contains increased concentrations of long-chain (LC) n-3 PUPA. However, the effects of red meat consumption from grass-fed animals on consumer blood concentrations of LC n-3 PUFA are unknown. The aim of the present study was to compare the effects on plasma and platelet LC n-3 PUFA status of consuming red meat produced from either grass-fed animals or concentrate-fed animals. A randomised, double-blinded, dietary intervention study was carried out for 4 weeks on healthy subjects who replaced their habitual red meat intake with three portions per week of red meat (beef and lamb) from animals offered a finishing diet of either grass or concentrate (n 20 consumers). Plasma and platelet fatty acid composition, dietary intake, blood pressure, and serum lipids and lipoproteins were analysed at baseline and post-intervention. Dietary intakes of total n-3 PUFA, as well as plasma and platelet concentrations of LC n-3 PUFA, were significantly higher in those subjects who consumed red meat from grass-fed animals compared with those who consumed red meat from concentrate-fed animals (P<0.05). No significant differences in concentrations of serum cholesterol, TAG or blood pressure were observed between groups. Consuming red meat from grass-fed animals compared with concentrate-fed animals as part of the habitual diet can significantly increase consumer plasma and platelet LC n-3 PUFA status. As a result, red meat from grass-fed animals may contribute to dietary intakes of LC n-3 PUFA in populations where red meat is habitually consumed.