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Insulin-like peptides (ILPs) play highly conserved roles in development and physiology. Most animal genomes encode multiple ILPs. Here we identify mechanisms for how the forty Caenorhabditis elegans ILPs coordinate diverse processes, including development, reproduction, longevity and several specific stress responses. Our systematic studies identify an ILP-based combinatorial code for these phenotypes characterized by substantial functional specificity and diversity rather than global redundancy. Notably, we show that ILPs regulate each other transcriptionally, uncovering an ILP-to-ILP regulatory network that underlies the combinatorial phenotypic coding by the ILP family. Extensive analyses of genetic interactions among ILPs reveal how their signals are integrated. A combined analysis of these functional and regulatory ILP interactions identifies local genetic circuits that act in parallel and interact by crosstalk, feedback and compensation. This organization provides emergent mechanisms for phenotypic specificity and graded regulation for the combinatorial phenotypic coding we observe. Our findings also provide insights into how large hormonal networks regulate diverse traits.

The type of food source has previously been shown to be as important as the level of food intake in influencing lifespan. Here we report that different Escherichia coli food sources alter Caenorhabditis elegans lifespan. These effects are modulated by different subsets of sensory neurons, which act with nmur-1, a homolog of mammalian neuromedin U receptors. Wild-type nmur-1, which is expressed in the somatic gonad, sensory neurons, and interneurons, shortens lifespan only on specific E. coli food sources-an effect that is dependent on the type of E. coli lipopolysaccharide structure. Moreover, the food type-dependent effect of nmur-1 on lifespan is different from that of food-level restriction. Together our data suggest that nmur-1 processes information from specific food cues to influence lifespan and other aspects of physiology., Competing Interests: We would like to disclose that the role of nmur-1 in modulating lifespan is the subject matter of a patent application (PCT/EP2008/061541).

Flagellin, the main building block of the bacterial flagellum, acts as a pathogen-associated molecular pattern triggering the innate immune response in animals and plants. In Arabidopsis thaliana, the Leu-rich repeat transmembrane receptor kinase FLAGELLIN SENSITIVE2 (FLS2) is essential for flagellin perception. Here, we demonstrate the specific interaction of the elicitor-active epitope flg22 with the FLS2 protein by chemical cross-linking and immunoprecipitation. The functionality of this receptor was further tested by heterologous expression of the Arabidopsis FLS2 gene in tomato (Lycopersicon esculentum) cells. The perception of flg22 in tomato differs characteristically from that in Arabidopsis. Expression of Arabidopsis FLS2 conferred an additional flg22-perception system on the cells of tomato, which showed all of the properties characteristic of the perception of this elicitor in Arabidopsis. In summary, these results show that FLS2 constitutes the pattern-recognition receptor that determines the specificity of flagellin perception.

The induction of ethylene biosynthesis by an elicitor partially purified from yeast extract was studied in suspension-cultured tomato (Lycopersicon esculentum Mill.) cells. Unstimulated cells produced little ethylene during exponential growth and even less in stationary phase. Treatment with elicitor stimulated ethylene biosynthesis 10-fold to 20-fold in the exponentially growing cells and more than 100-fold in stationary cells. Activities of both 1-aminocyclopropane-1-carboxylate (ACC) synthase, measured in vitro, and ethylene-forming enzyme (EFE), measured in vivo, increased strongly in response to elicitor treatments. During exponential growth, cells contained large pools of ACC, and the elicitor stimulated ethylene biosynthesis primarily through induction of EFE. In the stationary phase, cells contained almost no ACC, and the elicitor stimulated ethylene biosynthesis primarily through its effect on ACC synthase activity. Cordycepin did not affect the increase in activity of ACC synthase but blocked that of EFE, indicating that the former was posttranscriptionally regulated, the latter transcriptionally regulated. Removal of elicitor by washing or inactivation of a biotinylated derivative of the elicitor by complexation with avidin caused a rapid cessation of the increase in ACC synthase activity, suggesting that continuous presence of stimulus is necessary for the response. Using induction of ethylene production to measure amounts of elicitor, it was found that the elicitor disappeared from the incubation medium during the course of the treatment.

Platelet shape change and aggregation as well as serotonin (5-hydroxytryptamine; 5HT) content in platelets, spontaneous release of 5HT, 5HT plasma levels, urinary excretion of 5-hydroxyindoleacetic acid (5HIAA) and plasma beta-thromboglobulin (beta-TG) were investigated in 45 healthy subjects (27 men, 18 women). Platelets from women were more susceptible to aggregation (both by 5HT and ADP) than platelets from men. However, in men, 5HT-induced shape change and aggregation as well as plasma beta-TG concentration increased with age. In men, 5HT-induced platelet aggregation correlated positively with 5HT plasma levels. An inverse relationship was found in men between platelet number on the one hand and platelet 5HT content, 5HT release, 5HT plasma levels and urinary 5HIAA excretion rates on the other hand. In all subjects 5HT-induced platelet aggregation correlated negatively with platelet number. These results indicate that age and gender must be considered in designing clinical studies on 5HT and in evaluating human platelet 5HT kinetics. The platelet number seems to be related to 5HT kinetics of platelets and their reaction to 5HT in men. An age-dependent change in the reactivity of platelets to 5HT (rather than their absolute 5HT sensitivity) may contribute to the enhanced platelet turnover and higher incidence of cardiac events in older men.