Interferon-γ links ultraviolet radiation to melanomagenesis in mice

Cutaneous malignant melanoma is a highly aggressive and frequently chemoresistant cancer, the incidence of which continues to rise. Epidemiological studies show that the major aetiological melanoma risk factor is ultraviolet (UV) solar radiation, with the highest risk associated with intermittent burning doses, especially during childhood. We have experimentally validated these epidemiological findings using the hepatocyte growth factor/scatter factor transgenic mouse model, which develops lesions in stages highly reminiscent of human melanoma with respect to biological, genetic and aetiological criteria, but only when irradiated as neonatal pups with UVB, not UVA. However, the mechanisms underlying UVB-initiated, neonatal-specific melanomagenesis remain largely unknown. Here we introduce a mouse model permitting fluorescence-aided melanocyte imaging and isolation following in vivo UV irradiation. We use expression profiling to show that activated neonatal skin melanocytes isolated following a melanomagenic UVB dose bear a distinct, persistent interferon response signature, including genes associated with immunoevasion. UVB-induced melanocyte activation, characterized by aberrant growth and migration, was abolished by antibody-mediated systemic blockade of interferon-γ (IFN-γ), but not type-I interferons. IFN-γ was produced by macrophages recruited to neonatal skin by UVB-induced ligands to the chemokine receptor Ccr2. Admixed recruited skin macrophages enhanced transplanted melanoma growth by inhibiting apoptosis; notably, IFN-γ blockade abolished macrophage-enhanced melanoma growth and survival. IFN-γ-producing macrophages were also identified in 70% of human melanomas examined. Our data reveal an unanticipated role for IFN-γ in promoting melanocytic cell survival/immunoevasion, identifying a novel candidate therapeutic target for a subset of melanoma patients.     

Room-temperature ferroelectricity in strained SrTiO3

Systems with a ferroelectric to paraelectric transition in the vicinity of room temperature are useful for devices. Adjusting the ferroelectric transition temperature (T(c)) is traditionally accomplished by chemical substitution-as in Ba(x)Sr(1-x)TiO(3), the material widely investigated for microwave devices in which the dielectric constant (epsilon(r)) at GHz frequencies is tuned by applying a quasi-static electric field. Heterogeneity associated with chemical substitution in such films, however, can broaden this phase transition by hundreds of degrees, which is detrimental to tunability and microwave device performance. An alternative way to adjust T(c) in ferroelectric films is strain. Here we show that epitaxial strain from a newly developed substrate can be harnessed to increase T(c) by hundreds of degrees and produce room-temperature ferroelectricity in strontium titanate, a material that is not normally ferroelectric at any temperature. This strain-induced enhancement in T(c) is the largest ever reported. Spatially resolved images of the local polarization state reveal a uniformity that far exceeds films tailored by chemical substitution. The high epsilon(r) at room temperature in these films (nearly 7,000 at 10 GHz) and its sharp dependence on electric field are promising for device applications.     

A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands

A genomic sequence close to the cystic fibrosis locus with the characteristics of an HTF island has been selectively cloned and characterized. Two markers flanking this sequence, which is conserved throughout mammalian evolution, show a very much greater disequilibrium than that found with any existing marker. A single mutational event accounts for most cases of cystic fibrosis. The sequence is expressed, and is a candidate for the cystic fibrosis gene.     

Testimony and knowing how

Much of what we learn from talking and listening does not qualify as testimonial knowledge: we can learn a great deal from other people without simply accepting what they say as being true. In this article, I examine the ways in which we acquire skills or knowledge how from our interactions with other people, and I discuss whether there is a useful notion of testimonial knowledge how.     

Transfer of a cloned immunoglobulin light-chain gene to mutant hybridoma cells restores specific antibody production

The expression of immunoglobulin (Ig) genes is regulated at several levels. For example, although kappa-chain production requires a DNA rearrangement that juxtaposes variable and joining segments, this rearrangement is not sufficient for kappa-chain gene expression; that is, some cell types do not permit immunoglobulin production. The mechanisms responsible for the regulation of the expression of rearranged immunoglobulin genes are poorly understood. The technique of modifying cloned genes in vitro and transferring the modified genes to cells in culture provides a tool for identifying the structural features required for gene expression. To analyse immunoglobulin genes in this manner, however, it is first necessary to use, as recipients, cells that normally permit immunoglobulin production. We report here that a cloned kappa-chain gene is expressed in immunoglobulin-producing hybridoma cells. Furthermore, the product of the transferred kappa-chain gene is capable of restoring specific antibody production to the transformed cells.     

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.     

Rat navigation guided by remote control

Free animals can be 'virtually' trained by microstimulating key areas of their brains.