A phosphatase cascade by which rewarding stimuli control nucleosomal response

Dopamine orchestrates motor behaviour and reward-driven learning. Perturbations of dopamine signalling have been implicated in several neurological and psychiatric disorders, and in drug addiction. The actions of dopamine are mediated in part by the regulation of gene expression in the striatum, through mechanisms that are not fully understood. Here we show that drugs of abuse, as well as food reinforcement learning, promote the nuclear accumulation of 32-kDa dopamine-regulated and cyclic-AMP-regulated phosphoprotein (DARPP-32). This accumulation is mediated through a signalling cascade involving dopamine D1 receptors, cAMP-dependent activation of protein phosphatase-2A, dephosphorylation of DARPP-32 at Ser 97 and inhibition of its nuclear export. The nuclear accumulation of DARPP-32, a potent inhibitor of protein phosphatase-1, increases the phosphorylation of histone H3, an important component of nucleosomal response. Mutation of Ser 97 profoundly alters behavioural effects of drugs of abuse and decreases motivation for food, underlining the functional importance of this signalling cascade.     

The Eyes Absent proteins in development and disease

The Eyes Absent (EYA) proteins, first described in the context of fly eye development, are now implicated in processes as disparate as organ development, innate immunity, DNA damage repair, photoperiodism, angiogenesis, and cancer metastasis. These functions are associated with an unusual combination of biochemical activities: tyrosine phosphatase and threonine phosphatase activities in separate domains, and transactivation potential when associated with a DNA-binding partner. EYA mutations are linked to multiorgan developmental disorders, as well as to adult diseases ranging from dilated cardiomyopathy to late-onset sensorineural hearing loss. With the growing understanding of EYA biochemical and cellular activity, biological function, and association with disease, comes the possibility that the EYA proteins are amenable to the design of targeted therapeutics. The availability of structural information, direct links to disease states, available animal models, and the fact that they utilize unconventional reaction mechanisms that could allow specificity, suggest that EYAs are well-positioned for drug discovery efforts. This review provides a summary of EYA structure, activity, and function, as they relate to development and disease, with particular emphasis on recent findings.     

Astrocladistics: A Phylogenetic Analysis of Galaxy Evolution I. Character Evolutions and Galaxy Histories

This series of papers is intended to present astrocladistics in some detail and evaluate this methodology in reconstructing phylogenies of galaxies. Being based on the evolution of all the characters describing galaxies, it is an objective way of understanding galaxy diversity through evolutionary relationships. In this first paper, we present the basic steps of a cladistic analysis and show both theoretically and practically that it can be applied to galaxies. For illustration, we use a sample of 50 simulated galaxies taken from the GALICS database, which are described by 91 observables (dynamics, masses and luminosities). These 50 simulated galaxies are indeed 10 different galaxies taken at 5 cosmological epochs, and they are free of merger events. The astrocladistic analysis easily reconstructs the true chronology of evolution relationships within this sample. It also demonstrates that burst characters are not relevant for galaxy evolution as a whole. A companion paper is devoted to the formalization of the concepts of formation and diversification in galaxy evolution.     

Variant between CPT1B and CHKB associated with susceptibility to narcolepsy

Narcolepsy (hypocretin deficiency), a sleep disorder characterized by sleepiness, cataplexy and rapid eye movement (REM) sleep abnormalities, is tightly associated with HLA-DRB1*1501 (M17378) and HLA-DQB1*0602 (M20432). Susceptibility genes other than those in the HLA region are also likely involved. We conducted a genome-wide association study using 500K SNP microarrays in 222 Japanese individuals with narcolepsy and 389 Japanese controls, with replication of top hits in 159 Japanese individuals with narcolepsy and 190 Japanese controls, followed by the testing of 424 Koreans, 785 individuals of European descent and 184 African Americans. rs5770917, a SNP located between CPT1B and CHKB, was associated with narcolepsy in Japanese (rs5770917[C], odds ratio (OR) = 1.79, combined P = 4.4 x 10(-7)) and other ancestry groups (OR = 1.40, P = 0.02). Real-time quantitative PCR assays in white blood cells indicated decreased CPT1B and CHKB expression in subjects with the C allele, suggesting that a genetic variant regulating CPT1B or CHKB expression is associated with narcolepsy. Either of these genes is a plausible candidate, as CPT1B regulates beta-oxidation, a pathway involved in regulating theta frequency during REM sleep, and CHKB is an enzyme involved in the metabolism of choline, a precursor of the REM- and wake-regulating neurotransmitter acetylcholine.     

Revealing forecaster's preferences: A Bayesian multivariate loss function approach

Revealing the underlying preferences of a forecaster has always been at the core of much controversy. Herein, we build on the multivariate loss function concept and propose a flexible and multivariate family of likelihoods. This allows examining whether a vector of forecast errors, along with control variables, shapes a forecaster's preferences and, therefore, the underlying multivariate, nonseparable, loss function. We estimate the likelihood function using Bayesian exponentially tilted empirical likelihood, which reveals the shape of the parameter and the power of the multivariate loss function. In the empirical section, the reported evidence reveals that the EU Commission forecasts are predominantly asymmetric, leaning towards optimism in the year ahead, while a correction towards pessimism occurs in the current year forecast. There is some variability of this asymmetry across member states, with forecasts, i.e. gross domestic product growth, for large Member States exhibiting more optimism     

Aspects of natural history in a sand boa,Eryx muelleri (Erycidae) from arid savannahs in Burkina Faso,Togo, and Nigeria (West Africa)

The ecology of West African arid savannah snakes is still poorly known, especially in regard to the fossorial species. Here, field data on distribution, morphometrics, habitat use and diet are reported for the sand boa Eryx muelleri (Erycidae) from three different countries, i.e. Burkina Faso, Togo and Nigeria. This snake was observed in 21 distinct localities, and a total of 39 individuals was recorded. The species is likely fairly common and locally abundant. Mean body length of snakes was similar among countries and between sexes, but males had proportionately longer tails than females. Body length was significantly positively correlated with both tail length and head length. Adult sex ratio was close to parity. Most of the specimens were found in well-vegetated spots with low percentage of bare soil. There were apparently both ontogenetic and intersexual dietary variations: (1) a single analysed juvenile fed upon a small-sized lizard, whereas adults fed considerably upon young rodents; and (2) females fed exclusively upon young rodents and males upon both lizards and young rodents. In conservation terms, the species is actively exported from Togo for the pet trade, and additional individuals may also be illegally collected in other countries.     

A Systems Study for a European Community Program on Inspection and Accreditation of Blood Collection Establishments

This paper reports on an action research study for the development of a common program on inspection and accreditation of blood collection establishments in the European Union member states. Using soft systems methodology to guide the study, we have developed the systems required and arrived at the actions that are necessary to realize and maintain them.