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2005 was particularly notable for the range and scope of exciting advances in cell signaling research. Nominations from leading scientists ranged from plant signaling, neurobiology, and immunology to systems biology and structural biology. In plant biology, a new piece added to a long-standing puzzle in auxin signaling was discovered. The exploitation and regulation of RNA in cell signaling was also in the limelight. Intriguing new twists were highlighted in relation to functional and dysfunctional signaling in the brain, calcium-mediated signals, and the innate immune response. Finally, mathematical and statistical analysis of biochemical networks provided new insights into the circuitry of cell signaling pathways.