The novel mu-opioid antagonist, GSK1521498, reduces ethanol consumption in C57BL/6J mice.

RATIONALE Using the drinking-in-the-dark (DID) model, we compared the effects of a novel mu-opioid receptor antagonist, GSK1521498, with naltrexone, a licensed treatment of alcohol dependence, on ethanol consumption in mice. OBJECTIVE We test the ability of GSK1521498 to reduce alcohol consumption and compare its intrinsic efficacy to that of naltrexone by comparing the two drugs at doses matched for equivalent receptor occupancy. METHODS Thirty-six C57BL/6J mice were tested in a DID procedure. In 2-day cycles, animals experienced one baseline, injection-free session, and one test session when they received two injections, one of test drug and one placebo. All animals received GSK1521498 (0, 0.1, 1 and 3 mg/kg, i.p., 30 min pre-treatment) and naltrexone (0, 0.1, 1 and 3 mg/kg, s.c. 10 min pre-treatment) in a cross-over design. Receptor occupancies following the same doses were determined ex vivo in separate groups by autoradiography, using [3H]DAMGO. Binding in the region of interest was measured integrally by computer-assisted microdensitometry and corrected for non-specific binding. RESULTS Both GSK1521498 and naltrexone dose-dependently decreased ethanol consumption. When drug doses were matched for 70-75 % receptor occupancy, GSK1521498 3 mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1 mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1 mg/kg but not 0.1 mg/kg. In a test of conditioned taste aversion, GSK1521498 (3 mg/kg) reduced sucrose consumption 24 h following exposure to a conditioning injection. CONCLUSIONS Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone

Analysis of Polymorphisms and Haplotype Structure of the Human Thymidylate Synthase Genetic Region: A Tool for Pharmacogenetic Studies

5-fluorouracil (5FU), a widely used chemotherapeutic drug, inhibits the DNA replicative enzyme, thymidylate synthase (Tyms). Prior studies implicated a VNTR (variable numbers of tandem repeats) polymorphism in the 5′-untranslated region (5′-UTR) of the TYMS gene as a determinant of Tyms expression in tumors and normal tissues and proposed that these VNTR genotypes could help decide fluoropyrimidine dosing. Clinical associations between 5FU-related toxicity and the TYMS VNTR were reported, however, results were inconsistent, suggesting that additional genetic variation in the TYMS gene might influence Tyms expression. We thus conducted a detailed genetic analysis of this region, defining new polymorphisms in this gene including mononucleotide (poly A:T) repeats and novel single nucleotide polymorphisms (SNPs) flanking the VNTR in the TYMS genetic region. Our haplotype analysis of this region used data from both established and novel genetic variants and found nine SNP haplotypes accounting for more than 90% of the studied population. We observed non-exclusive relationships between the VNTR and adjacent SNP haplotypes, such that each type of VNTR commonly occurred on several haplotype backgrounds. Our results confirmed the expectation that the VNTR alleles exhibit homoplasy and lack the common ancestry required for a reliable marker of a linked adjacent locus that might govern toxicity. We propose that it may be necessary in a clinical trial to assay multiple types of genetic polymorphisms in the TYMS region to meaningfully model linkage of genetic markers to 5FU-related toxicity. The presence of multiple long (up to 26 nt), polymorphic monothymidine repeats in the promoter region of the sole human thymidylate synthetic enzyme is intriguing

Macrophages Homing to Metastatic Lymph Nodes Can Be Monitored with Ultrasensitive Ferromagnetic Iron-Oxide Nanocubes and a 1.5T Clinical MR Scanner

Background: Due to the ability of macrophages to specifically home to tumors, their potential use as a delivery vehicle for cancer therapeutics has been suggested. Tracking the delivery and engraftment of macrophages into human tumors with a 1.5T clinical MR scanner requires the development of sensitive contrast agents for cell labeling. Therefore, this study aimed to determine whether intravenously injected macrophages could target a primary tumor as well as metastatic LNs, and whether these cells could be detected in vivo by MRI. Methodology: Peritoneal macrophages were obtained from BALB/c nude mice. The viability, phagocytotic capacity and migratory activity of the macrophages were assessed. MR imaging was performed using a clinical 1.5 T MR scanner and we estimated the T2 * of the labeled macrophages. Metastatic lymph nodes were produced in BALB/c nude mice. We administrated 2610 6 macrophages labeled with 50 mg Fe/mL FIONs intravenously into the mice. In the 3D T2 * GRE MR images obtained one day after the injection of the labeled macrophages or FION solution, the percentages of pixels in the tumors or LNs below the minimum normalized SI (signal intensity) threshold were summated and reported as the black pixel count (%) for the FION hypointensity. Tumors in the main tumor model as well as the brachial, axillary and inguinal lymph nodes in the metastatic LN models were removed and stained. For all statistical analyses, single-group data were assessed using t test or the Mann-Whitney test. Repeated measurements analysis of variance (ANOVA) with Tukey–Krame

Holographic c-theorems in arbitrary dimensions

We re-examine holographic versions of the c-theorem and entanglement entropy in the context of higher curvature gravity and the AdS/CFT correspondence. We select the gravity theories by tuning the gravitational couplings to eliminate non-unitary operators in the boundary theory and demonstrate that all of these theories obey a holographic c-theorem. In cases where the dual CFT is even-dimensional, we show that the quantity that flows is the central charge associated with the A-type trace anomaly. Here, unlike in conventional holographic constructions with Einstein gravity, we are able to distinguish this quantity from other central charges or the leading coefficient in the entropy density of a thermal bath. In general, we are also able to identify this quantity with the coefficient of a universal contribution to the entanglement entropy in a particular construction. Our results suggest that these coefficients appearing in entanglement entropy play the role of central charges in odd-dimensional CFT's. We conjecture a new c-theorem on the space of odd-dimensional field theories, which extends Cardy's proposal for even dimensions. Beyond holography, we were able to show that for any even-dimensional CFT, the universal coefficient appearing the entanglement entropy which we calculate is precisely the A-type central charge.Comment: 62 pages, 4 figures, few typo's correcte

Application of Homozygosity Haplotype Analysis to Genetic Mapping with High-Density SNP Genotype Data

BACKGROUND: In families segregating a monogenic genetic disorder with a single disease gene introduction, patients share a mutation-carrying chromosomal interval with identity-by-descent (IBD). Such a shared chromosomal interval or haplotype, surrounding the actual pathogenic mutation, is typically detected and defined by multipoint linkage and phased haplotype analysis using microsatellite or SNP genotype data. High-density SNP genotype data presents a computational challenge for conventional genetic analyses. A novel non-parametric method termed Homozygosity Haplotype (HH) was recently proposed for the genome-wide search of the autosomal segments shared among patients using high density SNP genotype data. METHODOLOGY/PRINCIPAL FINDINGS: The applicability and the effectiveness of HH in identifying the potential linkage of disease causative gene with high-density SNP genotype data were studied with a series of monogenic disorders ascertained in eastern Canadian populations. The HH approach was validated using the genotypes of patients from a family affected with a rare autosomal dominant disease Schnyder crystalline corneal dystrophy. HH accurately detected the approximately 1 Mb genomic interval encompassing the causative gene UBIAD1 using the genotypes of only four affected subjects. The successful application of HH to identify the potential linkage for a family with pericentral retinal disorder indicates that HH can be applied to perform family-based association analysis by treating affected and unaffected family members as cases and controls respectively. A new strategy for the genome-wide screening of known causative genes or loci with HH was proposed, as shown the applications to a myoclonus dystonia and a renal failure cohort. CONCLUSIONS/SIGNIFICANCE: Our study of the HH approach demonstrates that HH is very efficient and effective in identifying potential disease linked region. HH has the potential to be used as an efficient alternative approach to sequencing or microsatellite-based fine mapping for screening the known causative genes in genetic disease study

Landscape determinants of European roller foraging habitat: implications for the definition of agri-environmental measures for species conservation

Across much of Europe, farmland birds are declining more than those in other habitats. From a conservation perspective, identifying the primary preferred habitats could help improve the foraging conditions of target species and, consequently, enhance their breeding success and survival. Here, we investigated the ranging behaviour and foraging habitat selection of the European roller (Coracias garrulus) during the breeding season in an agricultural landscape of South Iberia. The occurrence of foraging rollers was predicted to gradually increase with decreasing distance from the nest and increasing availability of perches, such as fences and electric wires. Traditional olive groves and stubble fields were positively and negatively associated with the occurrence of rollers, respectively. Additionally, analysis of hunting strikes showed that rollers highly prefer foraging in fallows rather than cereal or stubble fields. Prey surveys revealed that fallows had the highest abundance of grasshoppers, rollers’ preferred prey during chick-rearing. Pair home-ranges, obtained from 95% fixed Kernel estimators averaged 70.9 ha (range = 34–118 ha) and most foraging trips (80%) occurred in the close vicinity of the nest (<500 m). Number of chicks fledged was not affected by mean foraging distances travelled during the chick-rearing period. Overall, our results suggest that traditional extensive practices of cereal cultivation, with large areas of low-intensity grazed fallows, represent a high-quality foraging habitat for rollers and should be promoted through agri-environmental schemes within at least 1-km radius from the nest. These recommendations are targeted at the roller, but have been shown to apply broadly to several other steppe-bird species

A Measurement of Rb using a Double Tagging Method

The fraction of Z to bbbar events in hadronic Z decays has been measured by the OPAL experiment using the data collected at LEP between 1992 and 1995. The Z to bbbar decays were tagged using displaced secondary vertices, and high momentum electrons and muons. Systematic uncertainties were reduced by measuring the b-tagging efficiency using a double tagging technique. Efficiency correlations between opposite hemispheres of an event are small, and are well understood through comparisons between real and simulated data samples. A value of Rb = 0.2178 +- 0.0011 +- 0.0013 was obtained, where the first error is statistical and the second systematic. The uncertainty on Rc, the fraction of Z to ccbar events in hadronic Z decays, is not included in the errors. The dependence on Rc is Delta(Rb)/Rb = -0.056*Delta(Rc)/Rc where Delta(Rc) is the deviation of Rc from the value 0.172 predicted by the Standard Model. The result for Rb agrees with the value of 0.2155 +- 0.0003 predicted by the Standard Model.Comment: 42 pages, LaTeX, 14 eps figures included, submitted to European Physical Journal

Measurement of the B+ and B-0 lifetimes and search for CP(T) violation using reconstructed secondary vertices

The lifetimes of the B+ and B-0 mesons, and their ratio, have been measured in the OPAL experiment using 2.4 million hadronic Z(0) decays recorded at LEP. Z(0) --> b (b) over bar decays were tagged using displaced secondary vertices and high momentum electrons and muons. The lifetimes were then measured using well-reconstructed charged and neutral secondary vertices selected in this tagged data sample. The results aretau(B+) = 1.643 +/- 0.037 +/- 0.025 pstau(Bo) = 1.523 +/- 0.057 +/- 0.053 pstau(B+)/tau(Bo) = 1.079 +/- 0.064 +/- 0.041,where in each case the first error is statistical and the second systematic.A larger data sample of 3.1 million hadronic Z(o) decays has been used to search for CP and CPT violating effects by comparison of inclusive b and (b) over bar hadron decays, No evidence fur such effects is seen. The CP violation parameter Re(epsilon(B)) is measured to be Re(epsilon(B)) = 0.001 +/- 0.014 +/- 0.003and the fractional difference between b and (b) over bar hadron lifetimes is measured to(Delta tau/tau)(b) = tau(b hadron) - tau((b) over bar hadron)/tau(average) = -0.001 +/- 0.012 +/- 0.008

The dipolar endofullerene HF@C60

The cavity inside fullerenes provides a unique environment for the study of isolated atoms and molecules. We report encapsulation of hydrogen fluoride inside C60 using molecular surgery to give the endohedral fullerene HF@C60. The key synthetic step is the closure of the open fullerene cage while minimizing escape of HF. The encapsulated HF molecule moves freely inside the cage and exhibits quantization of its translational and rotational degrees of freedom, as revealed by inelastic neutron scattering and infrared spectroscopy. The rotational and vibrational constants of the encapsulated HF molecules were found to be redshifted relative to free HF. The NMR spectra display a large 1H-19F J coupling typical of an isolated species. The dipole moment of HF@C60 was estimated from the temperature-dependence of the dielectric constant at cryogenic temperatures and showed that the cage shields around 75% of the HF dipole