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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Oxysterol-binding proteins (OSBPs) have been described in a wide range of eukaryotes, and are often found to be part of a multi-gene family. We have used bioinformatics and data mining as a starting point for identifying new family members in humans based on the presence of the OSBP signature EQVSHHPP. In addition to OSBP and the recently reported OSBP2, we have found 10 other genes encoding oxysterol-binding domains. Here, we report cDNA and deduced peptide sequences of the previously unknown OSBPs and compare the peptides and genes. All of the genes encode a pleckstrin homology domain, except OSBPL2. However, two of the peptides, OSBPL2 and OSBPL1A, consist of the OSBP domain only. A second OSBPL1 transcript (OSBPL1B) contains 15 additional upstream exons, with a deduced peptide containing a pleckstrin homology domain. Cladistic analysis divides the human OSBP genes into five groups, whose members share similarities in sequence and gene structure; RT-PCR analysis indicates that expression patterns among group members vary widely.

a b s t r a c tDetermining socially acceptable and economically viable locations for utility-scale solar projects is a costly process that depends on many technical, economic, environmental and social factors. This paper presents a GIS-based multi-criteria solar project siting study conducted in the southwestern United States with a unique social preference component. Proximity raster layers were derived from features including roads, power lines, and rivers then overlain with 10 Â 10 m raster terrain datasets including slope and potential irradiance to produce a high resolution map showing solar energy potential from "poor" to "excellent" for high potential counties across the southwestern United States. Similar maps were produced by adding social acceptance data collected from a series of surveys showing the potential public resistance to development that can be expected in areas of high solar energy suitability. Applying social preferences to the model significantly reduced the amount of suitable area in each of the selected study areas. The methods demonstrated are expected to help reduce time, money, and resources currently allocated toward finding and assessing areas of high solar power suitability.

The stimulatory guanine nucleotide-binding protein (G s ) is required for hormone-stimulated cAMP generation. Gnas, the gene encoding the G s ␣-subunit, is imprinted, and targeted disruption of this gene in mice leads to distinct phenotypes in heterozygotes depending on whether the maternal (m؊/؉) or paternal (؉/p؊) allele is mutated. Notably, m؊/؉ mice become obese, whereas ؉/p؊ mice are thinner than normal. In this study we show that despite these opposite changes in energy metabolism, both m؊/؉ and ؉/p؊ mice have greater sensitivity to insulin, with low to normal fasting glucose levels, low fasting insulin levels, improved glucose tolerance, and exaggerated hypoglycemic response to administered insulin. The combination of increased insulin sensitivity with obesity in m؊/؉ mice is unusual, because obesity is typically associated with insulin resistance. In skeletal muscles isolated from both m؊/؉ and ؉/p؊ mice, the basal rate of 2-deoxyglucose uptake was normal, whereas the rate of 2-deoxyglucose uptake in response to maximal insulin stimulation was significantly increased. The similar changes in muscle sensitivity to insulin in m؊/؉ and ؉/p؊ mice may reflect the fact that muscle G s ␣ expression is reduced by ϳ50% in both groups of mice. GLUT4 expression is unaffected in muscles from ؉/p؊ mice. Increased responsiveness to insulin is therefore the result of altered insulin signaling and/or GLUT4 translocation. This is the first direct demonstration in a genetically altered in vivo model that G s -coupled pathways negatively regulate insulin signaling.Heterotrimeric guanine nucleotide-binding proteins (G proteins) 1 transduce signals from seven transmembrane receptors to intracellular effectors. Each G protein is composed of distinct ␣, ␤, and ␥ subunits (1). The ␣-subunit binds guanine nucleotide and interacts with specific effectors, such as adenylyl cyclase, phospholipase C, and ion channels. The ␣-subunit for G s (G s ␣) is ubiquitously expressed and transmits the stimulatory signal from hormone-bound receptors to adenylyl cyclase and is therefore required for hormone-stimulated cAMP generation. Both catecholamines (whose receptors activate G s ) and cAMP have been implicated as negative regulators of insulin signaling and insulin-stimulated glucose transport in various cell types, including adipocytes and muscle cells (2-6), although this has not been found universally (7-9). In one study administration of cholera toxin (which constitutively activates G s ␣) to rats led to decreased insulin sensitivity and glucose uptake in skeletal muscle (10).Heterozygous inactivating mutations of the gene encoding G s ␣ (GNAS1 at 20q13.2-13.3; Ref. 11) cause Albright hereditary osteodystrophy, an autosomal dominant disorder characterized by obesity, short stature, and skeletal defects (12). Paternal transmission of GNAS1 mutations produces offspring with Albright hereditary osteodystrophy alone (pseudopseudohypoparathyroidism), whereas maternal transmission produces offspring who also have multihormone resistance (ter...

Abstract. We present a novel and relatively simple method for magnifying forces perceived by an operator using a tool. A sensor measures the force between the tip of a tool and its handle held by the operator's fingers. These measurements are used to create a proportionally greater force between the handle and a brace attached to the operator's hand, providing an enhanced perception of forces between the tip of the tool and a target. We have designed and tested a prototype that is completely hand-held and thus can be easily manipulated to a wide variety of locations and orientations. Preliminary psychophysical evaluation demonstrates that the device improves the ability to detect and differentiate between small forces at the tip of the tool. Magnifying forces in this manner may provide an improved ability to perform delicate surgical procedures, while preserving the flexibility of a hand-held instrument.

Mitochondria are the main bioenergetic organelles of cells. Exposure to chemicals targeting mitochondria therefore generally results in the development of toxicity. The cellular response to perturbations in cellular energy production is a balance between adaptation, by reorganisation and organelle biogenesis, and sacrifice, in the form of cell death. In homeostatic conditions, aerobic mitochondrial energy production requires the maintenance of a mitochondrial membrane potential (MMP). Chemicals can perturb this MMP, and the extent of this perturbation depends both on the pharmacokinetics of the chemicals and on downstream MMP dynamics. Here we obtain a quantitative understanding of mitochondrial adaptation upon exposure to various mitochondrial respiration inhibitors by applying mathematical modeling to partially published high-content imaging time-lapse confocal imaging data, focusing on MMP dynamics in HepG2 cells over a period of 24 h. The MMP was perturbed using a set of 24 compounds, either acting as uncoupler or as mitochondrial complex inhibitor targeting complex I, II, III or V. To characterize the effect of chemical exposure on MMP dynamics, we adapted an existing differential equation model and fitted this model to the observed MMP dynamics. Complex III inhibitor data were better described by the model than complex I data. Incorporation of pharmacokinetic decay into the model was required to obtain a proper fit for the uncoupler FCCP. Furthermore, oligomycin (complex V inhibitor) model fits were improved by either combining pharmacokinetic (PK) decay and ion leakage or a concentration-dependent decay. Subsequent mass spectrometry measurements showed that FCCP had a significant decay in its PK profile as predicted by the model. Moreover, the measured oligomycin PK profile exhibited only a limited decay at high concentration, whereas at low concentrations the compound remained below the detection limit within cells. This is consistent with the hypothesis that oligomycin exhibits a concentration-dependent decay, yet awaits further experimental verification with more sensitive detection methods. Overall, we show that there is a complex interplay between PK and MMP dynamics within mitochondria and that data-driven modeling is a powerful combination to unravel such complexity.

Conventional research on gratitude has focused on the benefits of expressing or experiencing gratitude for the individual. However, recent theory and research have highlighted that there may too be benefits associated with receiving others' gratitude. Grounded in the Work-Home Resources model, we develop a conceptual model to understand whether, how, and for whom service providers (i.e., healthcare professionals) benefit from receiving service beneficiaries' (i.e., patients) gratitude in their daily work. We hypothesize that perceived gratitude from service beneficiaries enhances service providers' relational energy at work, which spills over to benefit their family lives later in the day. In addition, we hypothesize that the effect of gratitude on relational energy and its subsequent spillover effect to the family are contingent on employees' occupational identity. Two experience sampling studies with data collected from healthcare professionals and their spouses for two consecutive weeks (each) provided support for our hypothesized model. We conclude by discussing the theoretical and practical implications of our work.