TLR4 mutations are associated with endotoxin hyporesponsiveness in humans

There is much variability between individuals in the response to inhaled toxins, but it is not known why certain people develop disease when challenged with environmental agents and others remain healthy. To address this, we investigated whether TLR4 (encoding the toll-like receptor-4), which has been shown to affect lipopolysaccharide (LPS) responsiveness in mice, underlies the variability in airway responsiveness to inhaled LPS in humans. Here we show that common, co-segregating missense mutations (Asp299Gly and Thr399Ile) affecting the extracellular domain of the TLR4 receptor are associated with a blunted response to inhaled LPS in humans. Transfection of THP-1 cells demonstrates that the Asp299Gly mutation (but not the Thr399Ile mutation) interrupts TLR4-mediated LPS signalling. Moreover, the wild-type allele of TLR4 rescues the LPS hyporesponsive phenotype in either primary airway epithelial cells or alveolar macrophages obtained from individuals with the TLR4 mutations. Our findings provide the first genetic evidence that common mutations in TLR4 are associated with differences in LPS responsiveness in humans, and demonstrate that gene-sequence changes can alter the ability of the host to respond to environmental stress.     

arrow encodes an LDL-receptor-related protein essential for Wingless signalling

The Wnt family of secreted molecules functions in cell-fate determination and morphogenesis during development in both vertebrates and invertebrates (reviewed in ref. 1). Drosophila Wingless is a founding member of this family, and many components of its signal transduction cascade have been identified, including the Frizzled class of receptor. But the mechanism by which the Wingless signal is received and transduced across the membrane is not completely understood. Here we describe a gene that is necessary for all Wingless signalling events in Drosophila. We show that arrow gene function is essential in cells receiving Wingless input and that it acts upstream of Dishevelled. arrow encodes a single-pass transmembrane protein, indicating that it may be part of a receptor complex with Frizzled class proteins. Arrow is a low-density lipoprotein (LDL)-receptor-related protein (LRP), strikingly homologous to murine and human LRP5 and LRP6. Thus, our data suggests a new and conserved function for this LRP subfamily in Wingless/Wnt signal reception.     

Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski-/- mice.

Experiments involving overexpression of Ski have suggested that this gene is involved in neural tube development and muscle differentiation. In agreement with these findings, Ski-/- mice display a cranial neural tube defect that results in exencephaly and a marked reduction in skeletal muscle mass. Here we show that the penetrance and expressivity of the phenotype changes when the null mutation is backcrossed into the C57BL6/J background, with the principal change involving a switch from a neural tube defect to midline facial clefting. Other defects, including depressed nasal bridge, eye abnormalities, skeletal muscle defects and digit abnormalities, show increased penetrance in the C57BL6/J background. These phenotypes are interesting because they resemble some of the features observed in individuals diagnosed with 1p36 deletion syndrome, a disorder caused by monosomy of the short arm of human chromosome 1p (refs. 6-9). These similarities prompted us to re-examine the chromosomal location of human SKI and to determine whether SKI is included in the deletions of 1p36. We found that human SKI is located at distal 1p36.3 and is deleted in all of the individuals tested so far who have this syndrome. Thus, SKI may contribute to some of the phenotypes common in 1p36 deletion syndrome, and particularly to facial clefting.     

Water balance and fluid consumption in the southern grasshopper mouse, Onychomys torridus

Weight loss was rapid and fluid consumption decreased sharply when Onychomys torridus were exposed to salinities greater than 0.3 Molar. The southern grasshopper mouse is physiologically unspecialized for maintaining water balance in its xeric habitat. The southern grasshopper mouse is capable of weight maintenance on smaller daily water rations than is the northern grasshopper mouse ( Onychomys leucogaster ) . Differences in the water balance of O. torridus and O. leucogaster may influence their local distributions in areas of sympatry.     

Diffusion of new products in risk-sensitive markets

Diffusion of new products may be deterred by consumers' uncertainties about how they will perform. This paper introduces a decision-theoretic framework for modeling the diffusion of consumables, in which consumers choose between a current and new product so as to maximize expected utility. Consumers that are sufficiently risk-averse delay adoption, and change their prior uncertainties in a Bayesian fashion using information generated by early adopters. Under certain assumptions about the underlying consumer choice process and the market dynamics, the result is logistic growth in the share of consumers that choose the new product. The model can be generalized by allowing for consumer heterogeneity with respect to performance of the new product. The paper concludes with a discussion of applications for market forecasting, design of market trials and other extensions.     

Two methods of catecholamine depletion in kitten visual cortex yield different effects on plasticity

As first clearly demonstrated by the experiments of Wiesel and Hubel, the developing visual cortex is exquisitely sensitive to sensory deprivation. Temporary closure of one eye of a kitten during a critical period that extends from 3 weeks to 3 months of age results in a dramatic cortical reorganization such that most neurones, originally binocularly driven, are dominated exclusively by the open eye. Recently, attention has been directed to chemical factors which may influence the degree of plasticity during the critical period. The work of Kasamatsu and pettigrew suggests that cortical catecholamines, especially noradrenaline (NA), are essential for the normal plastic response to visual deprivation. In an effort to clarify the role of NA in visual cortical plasticity, we have monocularly deprived kittens whose cortex had been depleted of catecholamines by the neurotoxin 6-hydroxydopamine (6-OHDA). We used two strategies to deplete cortical NA: the first, pioneered by Kasamatsu el al., utilized osmotic minipumps to deliver 6-OHDA to visual cortex; the second involved systemic neonatal injections of 6-OHDA, a technique which has proved effective in rodents. We found, using high-pressure liquid chromatography (HPLC), that both techniques produced a substantial reduction in the level of cortical NA. However, single unit recording in area 17 revealed that the plastic response to monocular deprivation (MD) was only diminished in the kittens depleted by minipump.