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Using participants’ reactions to puns (words or phrases with two or more possible meanings) embedded in hypothetical scenarios, we investigated how perceptions of punning are influenced by characteristics of both the social situation and the punster. Consistent with the reversal theory of humor, Study 1 (N=185) showed that puns are considered funnier and more appropriate in playful than serious situations and less appropriate when they interrupt conversation than when they complete a conversation sequence without causing an interruption. Consistent with age-based developmental expectations of punsters, Study 2 (N=333) indicated that obvious puns told by children are perceived more favorably than those told by adults of varying ages and levels of expertise in the subject area of the pun. Future research might benefit from using more naturalistic settings and examining the extent to which various contemporary humor frameworks (e.g. benign violations theory) apply more specifically to punning in context.

The pharmacological effects of antisense and siRNA oligonucleotides are hindered by the tendency of these molecules to become entrapped in endomembrane compartments thus failing to reach their targets in the cytosol or nucleus. We have previously used high throughput screening to identify small molecules that enhance the escape of oligonucleotides from intracellular membrane compartments and have termed such molecules OECs (oligonucleotide enhancing compounds). Here, we report on the structure–activity relationships of a family of OECs that are analogs of a hit that emerged from our original screen. These studies demonstrate key roles for the lipophilic aromatic groups, the tertiary nitrogen, and the carbamate moiety of the parent compound. We have also investigated the intracellular site of action of the OECs and have shown that activity is due to the release of oligonucleotides from intermediate endosomal compartments rather than from early endosomes or from highly acidic downstream compartments. At high concentrations of OECs toxicity occurs in a manner that is independent of caspases or of lysosomal cathepsins but instead involves increased plasma membrane permeability. Thus, in addition to describing specific characteristics of this family of OECs, the current study provides insights into basic mechanisms of oligonucleotide trafficking and their implications for oligonucleotide delivery.

Four studies examined how in-group identification in the domain of sports is associated with schadenfreude in reaction to another group’s suffering or gluckschmerz in reaction to another group’s good fortune. Schadenfreude increased as a function of in-group identification when the outgroup was a rival team rather than a non-rival team in Study 1. Study 2 showed that those who experience schadenfreude at learning of an outgroup player’s injury will also tend to feel gluckschmerz when they learn of the player’s recovery. Studies 3 and 4 replicated and extended these findings for both schadenfreude and gluckschmerz, and showed that neither the degree of severity of an injury nor the level of physical pain associated with the injury moderated the link between identification and both schadenfreude and gluckschmerz. Mediation analyses indicated that perceived in-group gain or loss, deservedness, and dislike were prime mediators of links between in-group identification and both emotions.

Dinucleoside polyphosphates act as agonists on purinergic P2Y receptors to mediate a variety of cellular processes. Symmetrical, naturally occurring purine dinucleotides are found in most living cells and their actions are generally known. Unsymmetrical purine dinucleotides and all pyrimidine containing dinucleotides, however, are not as common and therefore their actions are not well understood. To carry out a thorough examination of the activities and specificities of these dinucleotides, a robust method of synthesis was developed to allow manipulation of either nucleoside of the dinucleotide as well as the phosphate chain lengths. Adenosine containing dinucleotides exhibit some level of activity on P2Y(1) while uridine containing dinucleotides have some level of agonist response on P2Y(2) and P2Y(6). The length of the linking phosphate chain determines a different specificity; diphosphates are most accurately mimicked by dinucleoside triphosphates and triphosphates most resemble dinucleoside tetraphosphates. The pharmacological activities and relative metabolic stabilities of these dinucleotides are reported with their potential therapeutic applications being discussed.

The main prey species in the summer (July–September) diets of harbour seals (Phoca vitulina) on the Island of Mousa (Shetland, UK), 1994–1997, were whiting (Merlangius merlangus), herring (Clupea harengus), sandeel (Ammodytidae) and garfish (Belone belone). Norway pout (Trisopterus esmarkii) was numerically important but comprised no more than 11% of prey weight in any year. There were marked between-year fluctuations in the relative importance of these prey, with whiting comprising 16–34% (by weight) of the diet, herring 12–28%, sandeels 7–18% and garfish 7–22%. Additional data on spring (April–June) diet were available for 1995–1997: sandeels were the most important prey (% weight) in all three years (51–60% of the diet), while herring (8–48%) and gadids (2–22%) varied in importance. The average size of fish eaten was larger than that reported in comparable studies from other areas. Harbour seals appear to have selected larger sandeels, whiting and Norway pout than the average size available in the area, as indicated by survey trawls, although between-year changes in the size of Norway pout in the diet did to some extent reflect availability. Interannual variation in the importance of Norway pout in the diet appeared to track trends in abundance, although the short time series precluded detection of a statistically significant correlation. Thus, some of our results are consistent with harbour seals feeding opportunistically while others point to selectivity, particularly for prey size. Estimated consumption of fish by the 500 harbour seals on Mousa during summer ranged from 152–195 tonnes.

Reductive amination of aldehydes and ketones using sodium cyanoborohydride and Rink's 4-(2′,4′-dimethoxyphenyl-aminomethyl)-phenoxymethyl-linked polystyrene resin [Rink's amine linker on copoly-(styrene-1%-divinylbenzene)]1 2 affords high yields of linker-bound, N-alkyl amines with excellent chemical selectivity. Subsequent coupling with acid derivatives gave derivatized N-substituted amides in excellent yields after cleavage from the solid-support.

Scats (N=200) of harbour seals (Phoca vitulina) were collected from haul-out sites on the Island of Mousa, south-east Shetland, during July, August and September 1994. A total of 5,531 fish otoliths were identified in scats and measured to reconstruct fish lengths and weight. Gadid fishes dominated the diet of harbour seals on Mousa during the study period, both in terms of weight and the frequency with which they occurred. There was evidence for the existence of temporal trends. Over the period July–September the importance of gadids in the diet increased while that of sandeels declined. These temporal trends are probably associated with changes in prey availability. Comparisons of the size of sandeels, herring and whiting eaten by seals with trawl catches suggest that seals were probably not size-selective, but a corollary of this is that, while otolith size is reduced during passage through seal guts, application of correction factors derived from captive feeding experiments led to over-estimates of fish size.

The development of a general strategy for the generation of molecular diversity in the form of novel, non-amide based heterocyclic structures is described. The generation of diverse peptide and peptidomimetic libraries, the automation of these strategies and computational approaches to diversity generation are also discussed. The main focus of this lecture is the the progression of these concepts into a strategy for small molecule library generation, and hence the generation of small molecule therapeutic leads.

Screening a diverse, combinatorial library of ca. 5000 synthetic dimer and trimer N-(substituted)glycine "peptides" yielded novel, high-affinity ligands for 7-transmembrane G-protein-coupled receptors. The peptoid library was efficiently assembled using readily available chemical building blocks. The choice of side chains was biased to resemble known ligands to 7-transmembrane G-protein-coupled receptors. All peptides were screened in solution-phase, competitive radioligand-binding assays. Peptoid trimer CHIR 2279 binds to the alpha 1-adrenergic receptor with a Ki of 5 nM, and trimer CHIR 4531 binds to the mu-opiate receptor with a Ki of 6 nM. This represents the first example of the discovery of high-affinity receptor ligands from a combinatorial library of non-natural chemical entities.

The sialyl Lewis X (SLe{sup x}) determinant (NeuAc-{alpha}-2,3-Gal-{beta}-1,4-[Fuc-{alpha}-1,3]-GlcNAc), compound 1, is a ligand for E-selectin (endothelial leucocyte adhesion molecule 1, or ELAM-1), a member of the selectin family of cell adhesion molecules. Interactions between E-selectin and leucocyte-bound SLe{sup x} or closely related oligosaccharides are thought to be important early events in the inflammation process. Binding analysis has shown that the sialic acid (NeuAc) and the fucose (Fuc) moieties are essential for high affinity. The related desialylated trisaccharide Le{sup x} (Gas-{beta}-1,4-[Fuc-{alpha}-1,3]-GlcNAc), for example, is not a high-affinity ligand for E-selectin. In this communication, the authors describe the syntheses of SLe{sup x} 1 and the {beta}-O-allyl glycoside of Le{sup x} 2 using a cloned fucosyltransferase and their complete NMR spectral assignments including ROESY and NOESY experiments in order to investigate the conformation of these compounds in solution. 25 refs., 2 figs.

The development of a general strategy for the generation of molecular diversity in the form of novel, non-amide based heterocyclic structures is described. The generation of diverse peptide and peptidomimetic libraries, the automation of these strategies and computational approaches to diversity generation are also discussed. The main focus of this lecture is the the progression of these concepts into a strategy for small molecule library generation, and hence the generation of small molecule therapeutic leads.

The sialyl Lewis X (SLe{sup x}) determinant (NeuAc-{alpha}-2,3-Gal-{beta}-1,4-[Fuc-{alpha}-1,3]-GlcNAc), compound 1, is a ligand for E-selectin (endothelial leucocyte adhesion molecule 1, or ELAM-1), a member of the selectin family of cell adhesion molecules. Interactions between E-selectin and leucocyte-bound SLe{sup x} or closely related oligosaccharides are thought to be important early events in the inflammation process. Binding analysis has shown that the sialic acid (NeuAc) and the fucose (Fuc) moieties are essential for high affinity. The related desialylated trisaccharide Le{sup x} (Gas-{beta}-1,4-[Fuc-{alpha}-1,3]-GlcNAc), for example, is not a high-affinity ligand for E-selectin. In this communication, the authors describe the syntheses of SLe{sup x} 1 and the {beta}-O-allyl glycoside of Le{sup x} 2 using a cloned fucosyltransferase and their complete NMR spectral assignments including ROESY and NOESY experiments in order to investigate the conformation of these compounds in solution. 25 refs., 2 figs.

Protection de la fonction alcool du cholesterol par un groupement allyl puis deprotection en utilisant (Ph 3 P) 4 RhH/TFA comme catalyseur

The synthesis of 5,10-dideazaaminopterin by two independent routes is described. Condensation of the piperidine enamine of 4-p-carbomethoxyphenylbutyraldehyde (4) with ethoxymethylenemalononitrile followed by treatment of the resultant arylethylenaminomalononitrile (5) with methanolic ammonia produced 2-amino-3-cyano-5-p-carbomethoxyphenethylpyridine (6). Cyclization of the aminocyanopyridine with guanidine afforded 4-amino-4-deoxy-5,10-dideazapteroic acid (8). Coupling of the pteroate intermediate with glutamate yielded the target 5,10-dideazaaminopterin (10). Alternatively, reduction of 2,4-diamino-6-formyl-5-deazapteridine (11) with sodium borohydride gave the 6-hydroxymethyl compound 12. Conversion to the bromide was followed by alkylation of dimethyl homoterephthalate to afford methyl 4-amino-4-deoxy-10-carbomethoxy-5,10-dideazapteroate (14). Decarboxylation with ester cleavage (sodium cyanide in dimethyl sulfoxide at 180°) also gave the diaminopteroic acid (8). 5,10-dideazaaminopterin (10) was an effective growth inhibitorof folate dependent bacteria, S. faecium and L. casei.

Electronic control, as a consequence of differential olefin substitution, and a comparison of conformational versus electronic control in the iodolactonization of 1,6-heptadien-4-carboxylic acid derivatives are reported.

THE photograph of the “Leaning” Tower of Pisa in NATURE of August 4 shows clearly that the top tier is not square with the rest. From a rough alignment with the edge of a postcard, the photograph appears as if the tower was of the order of 25 mm./metre out of plumb when the top tier was put on presumably plumb.