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Pain and inflammation are biologically intertwined responses that warn the body of potential danger. In this issue of the JCI, Defaye, Bradaia, and colleagues identified a functional link between inflammation and pain, demonstrating that inflammation-induced activation of stimulator of IFN genes (STING) in dorsal root ganglia nociceptors reduced pain-like behaviors in a rodent model of inflammatory pain. Utilizing mice with a gain-of-function STING mutation, Defaye, Bradaia, and colleagues identified type I IFN regulation of voltage-gated potassium channels as the mechanism of this pain relief. Further investigation into mechanisms by which proinflammatory pathways can reduce pain may reveal druggable targets and insights into new approaches for treating persistent pain., Role of the STING/IFN-I pathway in pain signaling Over the past decade, it has been demonstrated that the immune and sensory nervous systems closely collaborate to safeguard the host from [...]

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.

Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naïve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting OIH through activation of PRLR-S in female mice. Deletion of both PRLR-L and PRLR-S (total PRLR) prevented, whereas PRLR-L overexpression rescued established OIH selectively in females. Inhibition of circulating PRL with cabergoline, a dopamine D2 agonist, up-regulated PRLR-L and prevented OIH only in females. The PRLR-L isoform therefore confers protection against PRL-promoted pain in females. Limiting PRL/PRLR-S signaling pharmacologically or with gene therapies targeting the PRLR may be effective for reducing pain in a female-selective manner.

Summary: Relay selection plays a crucial role in enhancing the performance of wireless networks particularly in the context of cognitive radio (CR) systems with energy harvesters. In this paper, we propose a novel approach, namely, CGAPSO Shapley, for the best relay selection while simultaneously optimizing the parameters of signal‐to‐interference‐plus‐noise ratio (SINR), throughput, and outage probability. The CGAPSO Shapley algorithm combines the Shapley value, a cooperative game theory concept, with cellular genetic algorithm particle swarm optimization (CGAPSO) to achieve effective and efficient optimization of relay selection. The CGAPSO framework provides a hybrid structure that integrates cellular genetic algorithm (CGA) and particle swarm optimization (PSO), enabling simultaneous evolution of the population and particles within cells. The incorporation of the Shapley value and the hybrid CGAPSO framework enables effective exploration of the solution space and provides decision‐makers with comprehensive insights for relay selection. By utilizing the Shapley value, we assign weights to the relay nodes based on their contributions to the overall optimization objectives, considering their CR capabilities and energy harvesting capabilities. Some benchmark test functions are used to compare the hybrid algorithm with both the standard CGAPSO, Particle swarm optimization gravitational search algorithm (PSOGSA) and PSO algorithms in evolving best solution. The results show the hybrid algorithm possesses a better capability to escape from local optimums with faster convergence than the standard algorithms. The novel CGAPSO Shapley approach achieves an outage probability of 0.323324, marking a significant improvement of 60% over the outage probability achieved with conventional approach. [ABSTRACT FROM AUTHOR]