Nova proteins are neuron-specific antigens targeted in paraneoplastic opsoclonus myoclonus ataxia (POMA), an autoimmune neurologic disease characterized by abnormal motor inhibition. Nova proteins regulate neuronal pre-messenger RNA splicing by directly binding to RNA. To identify Nova RNA targets, we developed a method to purify protein-RNA complexes from mouse brain with the use of ultraviolet cross-linking and immunoprecipitation (CLIP).Thirty-four transcripts were identified multiple times by Nova CLIP.Three-quarters of these encode proteins that function at the neuronal synapse, and one-third are involved in neuronal inhibition.Splicing targets confirmed in Nova-/- mice include c-Jun N-terminal kinase 2, neogenin, and gephyrin; the latter encodes a protein that clusters inhibitory gamma-aminobutyric acid and glycine receptors, two previously identified Nova splicing targets.Thus, CLIP reveals that Nova coordinately regulates a biologically coherent set of RNAs encoding multiple components of the inhibitory synapse, an observation that may relate to the cause of abnormal motor inhibition in POMA.

Alternative RNA splicing greatly increases proteome diversity and may thereby contribute to tissue-specific functions. We carried out genome-wide quantitative analysis of alternative splicing using a custom Affymetrix microarray to assess the role of the neuronal splicing factor Nova in the brain. We used a stringent algorithm to identify 591 exons that were differentially spliced in the brain relative to immune tissues, and 6.6% of these showed major splicing defects in the neocortex of Nova2-/- mice. We tested 49 exons with the largest predicted Nova-dependent splicing changes and validated all 49 by RT-PCR. We analyzed the encoded proteins and found that all those with defined brain functions acted in the synapse (34 of 40, including neurotransmitter receptors, cation channels, adhesion and scaffold proteins) or in axon guidance (8 of 40). Moreover, of the 35 proteins with known interaction partners, 74% (26) interact with each other. Validating a large set of Nova RNA targets has led us to identify a multi-tiered network in which Nova regulates the exon content of RNAs encoding proteins that interact in the synapse.

Cheaper Cooperation In the context of public goods games in which optimal benefit is achieved when all participants contribute, bad behavior cannot always be deterred by direct punishment, and has the added disadvantage that the punisher may suffer a cost. Alternatively, instead of punishment, rewarding those who contribute can be effective in encouraging and maintaining widespread cooperation, with the added plus that group benefits are not diminished by the costs of punishment. But Ule et al. (p. 1701 ) discovered experimentally that if someone is treated depending on how they have behaved in previous interactions, retaining the option to occasionally apply punishment shifts the payouts to favor cooperators more than defectors.

Human cooperation in large groups can emerge when help is channeled towards individuals with a good reputation of helping others. Evolutionary models suggest that, for reputation-based cooperation to be stable, the recipient's reputation should be based not only on his past behavior (1st-order information) but also on the past behavior of the recipient's recipient (2nd-order information). Second-order information reflects the context of others' actions, and allows people to distinguish whether or not giving (or denying) help was justified. Little is known yet about how people actually condition their cooperation on 2nd-order information. With a behavioral experiment, we show that people actively seek 2nd-order information and take this into account in their own helping decisions. In an anonymous iterated helping game, donors learned if their recipients helped others in the past and could obtain 2nd-order information about these actions. Donors often requested this 2nd-order information and were especially interested to know why help was denied (i.e., defection). Justified defection was rewarded: help was generally directed towards those who defected against the selfish, and away from those who defected against helpful individuals. A detailed analysis of individual strategies reveals that many subjects based their decisions solely on 1st-order information about their recipients' past behavior. However, a substantial fraction of subjects consistently considered also the 2nd-order information about their recipients' behavior. Our results provide strong empirical support for the mechanisms that theoretically underpin reputation-based cooperation, and highlight pronounced individual variation in human cooperative strategies.

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Abstract

Networks, Cooperation, Non-cooperative games, Experiments, Simulations,

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