@article {45754,
	title = {The temporal requirements for insulin signaling during development in Drosophila.},
	journal = {PLoS Biol},
	volume = {3},
	year = {2005},
	month = {2005 Sep},
	pages = {e289},
	abstract = {<p>Recent studies have indicated that the insulin-signaling pathway controls body and organ size in Drosophila, and most metazoans, by signaling nutritional conditions to the growing organs. The temporal requirements for insulin signaling during development are, however, unknown. Using a temperature-sensitive insulin receptor (Inr) mutation in Drosophila, we show that the developmental requirements for Inr activity are organ specific and vary in time. Early in development, before larvae reach the "critical size" (the size at which they commit to metamorphosis and can complete development without further feeding), Inr activity influences total development time but not final body and organ size. After critical size, Inr activity no longer affects total development time but does influence final body and organ size. Final body size is affected by Inr activity from critical size until pupariation, whereas final organ size is sensitive to Inr activity from critical size until early pupal development. In addition, different organs show different sensitivities to changes in Inr activity for different periods of development, implicating the insulin pathway in the control of organ allometry. The reduction in Inr activity is accompanied by a two-fold increase in free-sugar levels, similar to the effect of reduced insulin signaling in mammals. Finally, we find that varying the magnitude of Inr activity has different effects on cell size and cell number in the fly wing, providing a potential linkage between the mode of action of insulin signaling and the distinct downstream controls of cell size and number. We present a model that incorporates the effects of the insulin-signaling pathway into the Drosophila life cycle. We hypothesize that the insulin-signaling pathway controls such diverse effects as total developmental time, total body size and organ size through its effects on the rate of cell growth, and proliferation in different organs.</p>
},
	keywords = {Animals, Drosophila, Drosophila Proteins, Insect Hormones, Insulin, Insulin Receptor Substrate Proteins, Intracellular Signaling Peptides and Proteins, Larva, Mutation, Receptor Protein-Tyrosine Kinases, Signal Transduction, Time Factors},
	issn = {1545-7885},
	doi = {10.1371/journal.pbio.0030289},
	author = {Shingleton, Alexander W and Das, Jayatri and Vinicius, Lucio and Stern, David L}
}
@article {45760,
	title = {Comparison of diverse protein sequences of the nuclear-encoded subunits of cytochrome C oxidase suggests conservation of structure underlies evolving functional sites.},
	journal = {Mol Biol Evol},
	volume = {21},
	year = {2004},
	month = {2004 Aug},
	pages = {1572-82},
	abstract = {<p>Interspecific comparisons of protein sequences can reveal regions of evolutionary conservation that are under purifying selection because of functional constraints. Interpreting these constraints requires combining evolutionary information with structural, biochemical, and physiological data to understand the biological function of conserved regions. We take this integrative approach to investigate the evolution and function of the nuclear-encoded subunits of cytochrome c oxidase (COX). We find that the nuclear-encoded subunits evolved subsequent to the origin of mitochondria and the subunit composition of the holoenzyme varies across diverse taxa that include animals, yeasts, and plants. By mapping conserved amino acids onto the crystal structure of bovine COX, we show that conserved residues are structurally organized into functional domains. These domains correspond to some known functional sites as well as to other uncharacterized regions. We find that amino acids that are important for structural stability are conserved at frequencies higher than expected within each taxon, and groups of conserved residues cluster together at distances of less than 5 A more frequently than do randomly selected residues. We, therefore, suggest that selection is acting to maintain the structural foundation of COX across taxa, whereas active sites vary or coevolve within lineages.</p>
},
	keywords = {Animals, Catalytic Domain, Cattle, Electron Transport Complex IV, Mitochondria, Models, Molecular, Plants, Yeasts},
	issn = {0737-4038},
	doi = {10.1093/molbev/msh161},
	author = {Das, Jayatri and Miller, Stephen T and Stern, David L}
}
