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 Chinese bamboo leaf odorous frog (Rana (Odorrana) versabilis) and North American Rana frogs share the same families of skin antimicrobial peptides.

The Chinese bamboo leaf odorous frog (Rana (Odorrana) versabilis) and the North American pickerel frog (Rana palustris) occupy different ecological niches on two different continents with no overlap in geographical distribution. R. palustris skin secretions contain a formidable array of antimicrobial peptides including homologs of brevinin-1, esculentin-1, esculentin-2, ranatuerin-2, a temporin and a family of peptides considered of unique structural attributes when isolated, palustrins 1–3. Here we describe the structures of mature peptides and precursors of eight putative antimicrobial peptides from the skin secretion of the Chinese bamboo leaf odorous frog (Rana (Odorrana) versabilis). Each peptide represents a structural homolog of respective peptide families isolated from R. palustris, including two peptides identical in primary structure to palustrin 1c and palustrin 3b. Additionally, two peptides were found to be structural homologs of ranatuerin 2B and ranatuerin 2P from the closely-related North American species, Rana berlandieri (the Rio Grande leopard frog) and Rana pipiens (the Northern leopard frog), respectively. Both palustrins and ranatuerins have hitherto been considered unique to North American ranid frogs. The use of primary structures of amphibian skin antimicrobial peptides is thus questionable as a taxonomic device or alternatively, the micro-evolution and/or ancestry of ranid frogs is more highly complex than previously thought.

Voltammetry of oxygen in the room-temperature ionic liquids 1-ethyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)imide and hexyltriethylammonium bis((trifluoromethyl)sulfonyl)imide: One-electron reduction to form superoxide. Steady-state and transient behavior in the same cyclic voltammogram resulting from widely different diffusion coefficients of oxygen and superoxide

The electrochemical reduction of oxygen in two different room-temperature ionic liquids, 1-ethyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)imide ([EMIM][N(Tf)(2)]) and hexyltriethylammonium bis((trifluoromethyl)sulfonyl)imide ([N-6222][N(Tf)(2)]) was investigated by cyclic voltammetry at a gold microdisk electrode. Chronoamperometric measurements were made to determine the diffusion coefficient, D, and concentration, c, of the electroactive oxygen dissolved in the ionic liquid by fitting experimental transients to the Aoki model. [Aoki, K.; et al. J. Electroanal. Chem. 1981, 122, 19]. A theory and simulation designed for cyclic voltammetry at microdisk electrodes was then employed to determine the diffusion coefficient of the electrogenerated superoxide species, O-2(.-), as well as compute theoretical voltammograms to confirm the values of D and c for neutral oxygen obtained from the transients. As expected, the diffusion coefficient of the superoxide species was found to be smaller than that of the oxygen in both ionic liquids. The diffusion coefficients of O-2 and O-2(.-) in [N-6222][N(Tf)(2)], however, differ by more than a factor of 30 (D-O2 = 1.48 x 10(-10) m(2) s(-1), DO2.- = 4.66 x 10(-12) m(2) s(-1)), whereas they fall within the same order of magnitude in [EMIM][N(Tf)(2)] (D-O2 = 7.3 x 10(-10) m(2) s(-1), DO2.- = 2.7 x 10(-10) m(2) s(-1)). This difference in [N-6222][N(Tf)(2)] causes pronounced asymmetry in the concentration distributions of oxygen and superoxide, resulting in significant differences in the heights of the forward and back peaks in the cyclic voltammograms for the reduction of oxygen. This observation is most likely a result of the higher viscosity of [N-6222][N(Tf)(2)] in comparison to [EMIM][N(Tf)(2)], due to the structural differences in cationic component.

Inductive reasoning and semantic cognition: More than just different names for the same thing?

We describe evidence that certain inductive phenomena are associated with IQ, that different inductive phenomena emerge at different ages, and that the effects of causal knowledge on induction are decreased under conditions of memory load. On the basis of this evidence we argue that there is more to inductive reasoning than semantic cognition.

Do different 'magnocellular tasks' probe the same neural substrate?

The sensory abnormalities associated with disorders such as dyslexia, autism and schizophrenia have often been attributed to a generalized deficit in the visual magnocellular-dorsal stream and its auditory homologue. To probe magnocellular function, various psychophysical tasks are often employed that require the processing of rapidly changing stimuli. But is performance on these several tasks supported by a common substrate? To answer this question, we tested a cohort of 1060 individuals on four 'magnocellular tasks': detection of low-spatial-frequency gratings reversing in contrast at a high temporal frequency (so-called frequency-doubled gratings); detection of pulsed low-spatial-frequency gratings on a steady luminance pedestal; detection of coherent motion; and auditory discrimination of temporal order. Although all tasks showed test-retest reliability, only one pair shared more than 4 per cent of variance. Correlations within the set of 'magnocellular tasks' were similar to the correlations between those tasks and a 'non-magnocellular task', and there was little consistency between 'magnocellular deficit' groups comprising individuals with the lowest sensitivity for each task. Our results suggest that different 'magnocellular tasks' reflect different sources of variance, and thus are not general measures of 'magnocellular function'.