An alternate model for rumor spreading over networks is suggested, in which two rumors (termed rumor 1 and rumor 2) with different probabilities of acceptance may propagate among nodes. The propagation is not symmetric in the sense that when deciding which rumor to adopt, nodes always consider rumor 1 first. The model is a natural generalization of the well-known epidemic SIS (susceptible-infective-susceptible) model and reduces to it when some of the parameters of this model are zero. We find that preferred rumor 1 is dominant in the network when the degree of nodes is high enough and/or when the network contains large clustered groups of nodes, expelling rumor 2. However, numerical simulations on synthetic networks show that it is possible for rumor 2 to occupy a nonzero fraction of the nodes in many cases as well. Specifically, in the Watts-Strogatz small-world model a moderate level of clustering supports its adoption, while increasing randomness reduces it. For Erdos-Renyi networks, a low average degree allows the coexistence of the two types of rumors. In Barabasi-Albert networks generated with a low m , where m is the number of links when a new node is added, it is also possible for rumor 2 to spread over the network.

Long-term potentiation and depression of synaptic activity in response to stimuli is a key factor in reinforcement learning. Strengthening of the corticostriatal synapses depends on the second messenger cAMP, whose synthesis is catalysed by the enzyme adenylyl cyclase 5 (AC5), which is itself regulated by the stimulatory Gαolf and inhibitory Gαi proteins. AC isoforms have been suggested to act as coincidence detectors, promoting cellular responses only when convergent regulatory signals occur close in time. However, the mechanism for this is currently unclear, and seems to lie in their diverse regulation patterns. Despite attempts to isolate the ternary complex, it is not known if Gαolf and Gαi can bind to AC5 simultaneously, nor what activity the complex would have. Using protein structure-based molecular dynamics simulations, we show that this complex is stable and inactive. These simulations, along with Brownian dynamics simulations to estimate protein association rates constants, constrain a kinetic model that shows that the presence of this ternary inactive complex is crucial for AC5's ability to detect coincident signals, producing a synergistic increase in cAMP. These results reveal some of the prerequisites for corticostriatal synaptic plasticity, and explain recent experimental data on cAMP concentrations following receptor activation. Moreover, they provide insights into the regulatory mechanisms that control signal processing by different AC isoforms. Author summaryAdenylyl cyclases (ACs) are enzymes that can translate extracellular signals into the intracellular molecule cAMP, which is thus a 2 nd messenger of extracellular events. The brain expresses nine membrane-bound AC variants, and AC5 is the dominant form in the striatum. The striatum is the input stage of the basal ganglia, a brain structure involved in reward learning, i.e. the learning of behaviors that lead to rewarding stimuli (such as food, water, sugar, etc). During reward learning, cAMP production is crucial for strengthening the synapses from cortical neurons onto the striatal principal neurons, and its formation is dependent on several neuromodulatory systems such as dopamine and acetylcholine. It is, however, not understood how AC5 is activated by transient (subsecond) changes in the neuromodulatory signals. Here we combine several computational tools, from molecular dynamics and Brownian dynamics simulations to bioinformatics approaches, to inform and constrain a kinetic model of the AC5-dependent signaling system. We use this model to show how the specific molecular properties of AC5 can detect particular combinations of cooccuring transient changes in the neuromodulatory signals which thus result in a supralinear/synergistic cAMP production. Our results also provide insights into the computational capabilities of the different AC isoforms.Recent experimental data indicates that, during the resting state, much of AC5 in the D1 MSNs could be bound to Gα i due to a tonic level of acetylcholine produced by the tonic activity of the st...

Long-term potentiation and depression of synaptic activity in response to stimuli is a key factor in reinforcement learning. Strengthening of the corticostriatal synapses depends on the second messenger cAMP, whose synthesis is catalysed by the enzyme adenylyl cyclase 5 (AC5), which is itself regulated by the stimulatory Gαolf and inhibitory Gαi proteins. AC isoforms have been suggested to act as coincidence detectors, promoting cellular responses only when convergent regulatory signals occur close in time. However, the mechanism for this is currently unclear, and seems to lie in their diverse regulation patterns. Despite attempts to isolate the ternary complex, it is not known if Gαolf and Gαi can bind to AC5 simultaneously, nor what activity the complex would have. Using protein structure-based molecular dynamics simulations, we show that this complex is stable and inactive. These simulations, along with Brownian dynamics simulations to estimate protein association rates constants, constrain a kinetic model that shows that the presence of this ternary inactive complex is crucial for AC5’s ability to detect coincident signals, producing a synergistic increase in cAMP. These results reveal some of the prerequisites for corticostriatal synaptic plasticity, and explain recent experimental data on cAMP concentrations following receptor activation. Moreover, they provide insights into the regulatory mechanisms that control signal processing by different AC isoforms.