Albright hereditary osteodystrophy (AHO), an autosomal dominant disorder characterized by short stature, obesity, and skeletal defects, is associated with heterozygous inactivating mutations of GNAS1, the gene encoding the heterotrimeric G protein ␣-subunit (G s ␣) that couples multiple receptors to the stimulation of adenylyl cyclase. It has remained unclear why only some AHO patients present with multihormone resistance and why AHO patients demonstrate resistance to some hormones [e.g., parathyroid hormone (PTH)] but not to others (e.g., vasopressin), even though all activate adenylyl cyclase. We generated mice with a null allele of the mouse homolog Gnas. Homozygous G s deficiency is embryonically lethal. Heterozygotes with maternal (m؊͞؉) and paternal (؉͞p؊) inheritance of the Gnas null allele have distinct phenotypes, suggesting that Gnas is an imprinted gene. PTH resistance is present in m؊͞؉, but not ؉͞p؊, mice. G s ␣ expression in the renal cortex (the site of PTH action) is markedly reduced in m؊͞؉ but not in ؉͞p؊ mice, demonstrating that the Gnas paternal allele is imprinted in this tissue. Gnas is also imprinted in brown and white adipose tissue. The maximal physiological response to vasopressin (urinary concentrating ability) is normal in both m؊͞؉ and ؉͞p؊ mice and Gnas is not imprinted in the renal inner medulla (the site of vasopressin action). Tissue-specific imprinting of Gnas is likely the mechanism for variable and tissue-specific hormone resistance in these mice and a similar mechanism might explain the variable phenotype in AHO.

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In solving the electrical power systems economic dispatch (ED) problem, the goal is to find the optimal allocation of output power among the various generators available to serve the system load. With the continuing search for alternatives to conventional energy sources, it is necessary to include wind energy conversion system (WECS) generators in the ED problem. This paper develops a model to include the WECS in the ED problem, and in addition to the classic economic dispatch factors, factors to account for both overestimation and underestimation of available wind power are included. With the stochastic wind speed characterization based on the Weibull probability density function, the optimization problem is numerically solved for a scenario involving two conventional and two wind-powered generators. Optimal solutions are presented for various values of the input parameters, and these solutions demonstrate that the allocation of system generation capacity may be influenced by multipliers related to the risk of overestimation and to the cost of underestimation of available wind power.

The multifunctional cytokine transforming growth factor (TGF) β1 is secreted in a latent complex with its processed propeptide (latency-associated peptide [LAP]). TGFβ1 must be functionally released from this complex before it can engage TGFβ receptors. One mechanism of latent TGFβ1 activation involves interaction of the integrins αvβ6 and αvβ8 with an RGD sequence in LAP; other putative latent TGFβ1 activators include thrombospondin-1, oxidants, and various proteases. To assess the contribution of RGD-binding integrins to TGFβ1 activation in vivo, we created a mutation in Tgfb1 encoding a nonfunctional variant of the RGD sequence (RGE). Mice with this mutation (Tgfb1RGE/RGE) display the major features of Tgfb1−/− mice (vasculogenesis defects, multiorgan inflammation, and lack of Langerhans cells) despite production of normal levels of latent TGFβ1. These findings indicate that RGD-binding integrins are requisite latent TGFβ1 activators during development and in the immune system.

SummaryMice that lack activity of αvβ6-and αvβ8-integrins reproduce the abnormalities of Tgfb1-and Tgfb3-null mice