An endocannabinoid mechanism for stress-induced analgesia

Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stress-induced analgesia, is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB(1) receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol (2-AG) and anandamide. A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase, selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase, which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.     

An 84-microG magnetic field in a galaxy at redshift z = 0.692

The magnetic field pervading our Galaxy is a crucial constituent of the interstellar medium: it mediates the dynamics of interstellar clouds, the energy density of cosmic rays, and the formation of stars. The field associated with ionized interstellar gas has been determined through observations of pulsars in our Galaxy. Radio-frequency measurements of pulse dispersion and the rotation of the plane of linear polarization, that is, Faraday rotation, yield an average value for the magnetic field of B approximately 3 microG (ref. 2). The possible detection of Faraday rotation of linearly polarized photons emitted by high-redshift quasars suggests similar magnetic fields are present in foreground galaxies with redshifts z > 1. As Faraday rotation alone, however, determines neither the magnitude nor the redshift of the magnetic field, the strength of galactic magnetic fields at redshifts z > 0 remains uncertain. Here we report a measurement of a magnetic field of B approximately 84 microG in a galaxy at z = 0.692, using the same Zeeman-splitting technique that revealed an average value of B = 6 microG in the neutral interstellar gas of our Galaxy. This is unexpected, as the leading theory of magnetic field generation, the mean-field dynamo model, predicts large-scale magnetic fields to be weaker in the past rather than stronger.     

Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population

Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 × 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 × 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 × 10(-12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 × 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis.     

A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer

We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.     

Short‐term forecasting of industrial electricity consumption in Brazil

This paper presents short‐term forecasting methods applied to electricity consumption in Brazil. The focus is on comparing the results obtained after using two distinct approaches: dynamic non‐linear models and econometric models. The first method, that we propose, is based on structural statistical models for multiple time series analysis and forecasting. It involves non‐observable components of locally linear trends for each individual series and a shared multiplicative seasonal component described by dynamic harmonics. The second method, adopted by the electricity power utilities in Brazil, consists of extrapolation of the past data and is based on statistical relations of simple or multiple regression type. To illustrate the proposed methodology, a numerical application is considered with real data. The data represents the monthly industrial electricity consumption in Brazil from the three main power utilities: Eletropaulo, Cemig and Light, situated at the major energy‐consuming states, Sao Paulo, Rio de Janeiro and Minas Gerais, respectively, in the Brazilian Southeast region. The chosen time period, January 1990 to September 1994, corresponds to an economically unstable period just before the beginning of the Brazilian Privatization Program. Implementation of the algorithms considered in this work was made via the statistical software S‐PLUS. Copyright © 1999 John Wiley & Sons, Ltd.     

Discovery of a short-necked sauropod dinosaur from the Late Jurassic period of Patagonia

Sauropod dinosaurs are one of the most conspicuous groups of Mesozoic terrestrial vertebrates. They show general trends towards an overall increase in size and elongation of the neck, by means of considerable elongation of the length of individual vertebrae and a cervical vertebra count that, in some cases, increases to 19 (ref. 1). The long neck is a particular hallmark of sauropod dinosaurs and is usually regarded as a key feeding adaptation. Here we describe a new dicraeosaurid sauropod, from the latest Jurassic period of Patagonia, that has a particularly short neck. With a neck that is about 40% shorter than in other known dicraeosaurs, this taxon demonstrates a trend opposite to that seen in most sauropods and indicates that the ecology of dicraeosaurids might have differed considerably from that of other sauropods. The new taxon indicates that there was a rapid radiation and dispersal of dicraeosaurids in the Late Jurassic of the Southern Hemisphere, after the separation of Gondwana from the northern continents by the late Middle Jurassic.     

Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome

Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.     

A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism

Submicroscopic genomic copy number changes have been identified only recently as an important cause of mental retardation. We describe the detection of three interstitial, overlapping 17q21.31 microdeletions in a cohort of 1,200 mentally retarded individuals associated with a clearly recognizable clinical phenotype of mental retardation, hypotonia and a characteristic face. The deletions encompass the MAPT and CRHR1 genes and are associated with a common inversion polymorphism.     

Computationally driven deletion of broadly distributed T cell epitopes in a biotherapeutic candidate

Biotherapeutics are subject to immune surveillance within the body, and anti-biotherapeutic immune responses can compromise drug efficacy and patient safety. Initial development of targeted antidrug immune memory is coordinated by T cell recognition of immunogenic subsequences, termed “T cell epitopes.” Biotherapeutics may therefore be deimmunized by mutating key residues within cognate epitopes, but there exist complex trade-offs between immunogenicity, mutational load, and protein structure–function. Here, a protein deimmunization algorithm has been applied to P99 beta-lactamase, a component of antibody-directed enzyme prodrug therapies. The algorithm, integer programming for immunogenic proteins, seamlessly integrates computational prediction of T cell epitopes with both 1- and 2-body sequence potentials that assess protein tolerance to epitope-deleting mutations. Compared to previously deimmunized P99 variants, which bore only one or two mutations, the enzymes designed here contain 4–5 widely distributed substitutions. As a result, they exhibit broad reductions in major histocompatibility complex recognition. Despite their high mutational loads and markedly reduced immunoreactivity, all eight engineered variants possessed wild-type or better catalytic activity. Thus, the protein design algorithm is able to disrupt broadly distributed epitopes while maintaining protein function. As a result, this computational tool may prove useful in expanding the repertoire of next-generation biotherapeutics.