451 research outputs found
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 3Â mg/kg, i.p., 30Â min pre-treatment) and naltrexone (0, 0.1, 1 and 3Â mg/kg, s.c. 10Â 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 70-75Â % receptor occupancy, GSK1521498 3Â mg/kg, i.p., caused a 2.5-fold greater reduction in alcohol consumption than naltrexone 0.1Â mg/kg, s.c. Both GSK1521498 and naltrexone significantly reduced sucrose consumption at a dose of 1Â mg/kg but not 0.1Â mg/kg. In a test of conditioned taste aversion, GSK1521498 (3Â mg/kg) reduced sucrose consumption 24Â h following exposure to a conditioning injection.
CONCLUSIONS
Both opioid receptor antagonists reduced alcohol consumption but GK1521498 has higher intrinsic efficacy than naltrexone
The Impact of Covariance Misspecification in Multivariate Gaussian Mixtures on Estimation and Inference: An Application to Longitudinal Modeling
Multivariate Gaussian mixtures are a class of models that provide a flexible parametric approach for the representation of heterogeneous multivariate outcomes. When the outcome is a vector of repeated measurements taken on the same subject, there is often inherent dependence between observations. However, a common covariance assumption is conditional independence---that is, given the mixture component label, the outcomes for subjects are independent. In this paper, we study, through asymptotic bias calculations and simulation, the impact of covariance misspecification in multivariate Gaussian mixtures. Although maximum likelihood estimators of regression and mixing probability parameters are not consistent under misspecification, they have little asymptotic bias when mixture components are well-separated or if the assumed correlation is close to the truth even when the covariance is misspecified. We also present a robust standard error estimator and show that it outperforms conventional estimators in simulations and can indicate the model is misspecified. Body mass index data from a national longitudinal study is used to demonstrate the effects of misspecification on potential inferences made in practice
The protein structure initiative structural genomics knowledgebase
The Protein Structure Initiative Structural Genomics Knowledgebase (PSI SGKB, http://kb.psi-structuralgenomics.org) has been created to turn the products of the PSI structural genomics effort into knowledge that can be used by the biological research community to understand living systems and disease. This resource provides central access to structures in the Protein Data Bank (PDB), along with functional annotations, associated homology models, worldwide protein target tracking information, available protocols and the potential to obtain DNA materials for many of the targets. It also offers the ability to search all of the structural and methodological publications and the innovative technologies that were catalyzed by the PSI's high-throughput research efforts. In collaboration with the Nature Publishing Group, the PSI SGKB provides a research library, editorials about new research advances, news and an events calendar to present a broader view of structural biology and structural genomics. By making these resources freely available, the PSI SGKB serves as a bridge to connect the structural biology and the greater biomedical communitie
Shakespeare and the Other Virgil: Pity and Imperium in Titus Andronicus
The influence of Virgilâs Aeneid in Shakespeareâs Titus Andronicus is more extensive than has been recognized to date, largely because Shakespeare studies, surprisingly, still has not entirely acknowledged or addressed the more ambiguous reading of the Aeneid put forward in recent decades by the so-called âHarvard Schoolâ of Virgil criticism. This interpretation of the Aeneid draws attention to Virgilâs sympathy for human suffering, especially his pity for the fallen enemies of Rome. Revisionary critics such as Adam Parry, Wendell Clausen and Michael Putnam argue that the âmelancholyâ tone of the poem, resigned, mournful and at times finely ironic, arises from a sense of sorrow at the human cost of establishing the Roman Empire, undermining its ostensible purpose as Augustan propaganda. Virgilâs âprivate voiceâ of compassion undercuts his âpublic voiceâ of praise for Augustusâs pax Romana. Although associated today with criticism that emerged in America in the wake of the Vietnam War, as Craig Kallendorf has shown, this âpessimisticâ reading of the Aeneid, what he calls âthe other Virgilâ, was available in England in the Renaissance, and arguably dates back to antiquity.1 As apparent from his allusions to Virgil in Titus Andronicus, Shakespeareâs reading of the Aeneid is in keeping with this vision. Virgilâs epic is the touchstone and the model for his own critique of Romanitas
The Echinococcus canadensis (G7) genome: A key knowledge of parasitic platyhelminth human diseases
Background: The parasite Echinococcus canadensis (G7) (phylum Platyhelminthes, class Cestoda) is one of the causative agents of echinococcosis. Echinococcosis is a worldwide chronic zoonosis affecting humans as well as domestic and wild mammals, which has been reported as a prioritized neglected disease by the World Health Organisation. No genomic data, comparative genomic analyses or efficient therapeutic and diagnostic tools are available for this severe disease. The information presented in this study will help to understand the peculiar biological characters and to design species-specific control tools. Results: We sequenced, assembled and annotated the 115-Mb genome of E. canadensis (G7). Comparative genomic analyses using whole genome data of three Echinococcus species not only confirmed the status of E. canadensis (G7) as a separate species but also demonstrated a high nucleotide sequences divergence in relation to E. granulosus (G1). The E. canadensis (G7) genome contains 11,449 genes with a core set of 881 orthologs shared among five cestode species. Comparative genomics revealed that there are more single nucleotide polymorphisms (SNPs) between E. canadensis (G7) and E. granulosus (G1) than between E. canadensis (G7) and E. multilocularis. This result was unexpected since E. canadensis (G7) and E. granulosus (G1) were considered to belong to the species complex E. granulosus sensu lato. We described SNPs in known drug targets and metabolism genes in the E. canadensis (G7) genome. Regarding gene regulation, we analysed three particular features: CpG island distribution along the three Echinococcus genomes, DNA methylation system and small RNA pathway. The results suggest the occurrence of yet unknown gene regulation mechanisms in Echinococcus. Conclusions: This is the first work that addresses Echinococcus comparative genomics. The resources presented here will promote the study of mechanisms of parasite development as well as new tools for drug discovery. The availability of a high-quality genome assembly is critical for fully exploring the biology of a pathogenic organism. The E. canadensis (G7) genome presented in this study provides a unique opportunity to address the genetic diversity among the genus Echinococcus and its particular developmental features. At present, there is no unequivocal taxonomic classification of Echinococcus species; however, the genome-wide SNPs analysis performed here revealed the phylogenetic distance among these three Echinococcus species. Additional cestode genomes need to be sequenced to be able to resolve their phylogeny.Fil: Maldonado, Lucas Luciano. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica; ArgentinaFil: Assis, Juliana. FundaciĂłn Oswaldo Cruz; BrasilFil: Gomes AraĂșjo, FlĂĄvio M.. FundaciĂłn Oswaldo Cruz; BrasilFil: Salim, Anna C. M.. FundaciĂłn Oswaldo Cruz; BrasilFil: Macchiaroli, Natalia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica; ArgentinaFil: Cucher, Marcela Alejandra. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica; ArgentinaFil: Camicia, Federico. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica; ArgentinaFil: Fox, Adolfo. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica; ArgentinaFil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica; ArgentinaFil: Oliveira, Guilherme. Instituto TecnolĂłgico Vale; Brasil. FundaciĂłn Oswaldo Cruz; BrasilFil: Kamenetzky, Laura. Consejo Nacional de Investigaciones CientĂficas y TĂ©cnicas. Oficina de CoordinaciĂłn Administrativa Houssay. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en MicrobiologĂa y ParasitologĂa MĂ©dica; Argentin
Hamiltonian dynamics and Noether symmetries in Extended Gravity Cosmology
We discuss the Hamiltonian dynamics for cosmologies coming from Extended
Theories of Gravity. In particular, minisuperspace models are taken into
account searching for Noether symmetries. The existence of conserved quantities
gives selection rule to recover classical behaviors in cosmic evolution
according to the so called Hartle criterion, that allows to select correlated
regions in the configuration space of dynamical variables. We show that such a
statement works for general classes of Extended Theories of Gravity and is
conformally preserved. Furthermore, the presence of Noether symmetries allows a
straightforward classification of singularities that represent the points where
the symmetry is broken. Examples of nonminimally coupled and higher-order
models are discussed.Comment: 20 pages, Review paper to appear in EPJ
Debris Disks: Probing Planet Formation
Debris disks are the dust disks found around ~20% of nearby main sequence
stars in far-IR surveys. They can be considered as descendants of
protoplanetary disks or components of planetary systems, providing valuable
information on circumstellar disk evolution and the outcome of planet
formation. The debris disk population can be explained by the steady
collisional erosion of planetesimal belts; population models constrain where
(10-100au) and in what quantity (>1Mearth) planetesimals (>10km in size)
typically form in protoplanetary disks. Gas is now seen long into the debris
disk phase. Some of this is secondary implying planetesimals have a Solar
System comet-like composition, but some systems may retain primordial gas.
Ongoing planet formation processes are invoked for some debris disks, such as
the continued growth of dwarf planets in an unstirred disk, or the growth of
terrestrial planets through giant impacts. Planets imprint structure on debris
disks in many ways; images of gaps, clumps, warps, eccentricities and other
disk asymmetries, are readily explained by planets at >>5au. Hot dust in the
region planets are commonly found (<5au) is seen for a growing number of stars.
This dust usually originates in an outer belt (e.g., from exocomets), although
an asteroid belt or recent collision is sometimes inferred.Comment: Invited review, accepted for publication in the 'Handbook of
Exoplanets', eds. H.J. Deeg and J.A. Belmonte, Springer (2018
Childhood febrile illness and the risk of myopia in UK Biobank participants
Purpose Historical reports suggest febrile illness during childhood is a risk factor for myopia. The establishment of the UK Biobank provided a unique opportunity to investigate this relationship.
Patients and methods We studied a sample of UK Biobank participants of White ethnicity aged 40â69 years old who underwent autorefraction (N=91â592) and were classified as myopic (â€â0.75 Dioptres (D)), highly myopic (â€â6.00âD), or non-myopic (>â0.75âD). Self-reported age at diagnosis of past medical conditions was ascertained during an interview with a nurse at a Biobank assessment centre. Logistic regression analysis was used to calculate the odds ratio (OR) for myopia or high myopia associated with a diagnosis before age 17 years of each of nine febrile illnesses, after adjusting for potential confounders (age, sex, highest educational qualification, and birth order).
Results Rubella, mumps, and pertussis were associated with myopia: rubella, OR=1.38, 95% CI: 1.03â1.85, P=0.030; mumps, OR=1.32, 95% CI: 1.07â1.64, P=0.010; and pertussis, OR=1.39, 95% CI 1.03â1.87, P=0.029. Measles, rubella, and pertussis were associated with high myopia: measles, OR=1.48, 95% CI: 1.07â2.07, P=0.019; rubella, OR=1.94, 95% CI: 1.12â3.35, P=0.017; and pertussis, OR=2.15, 95% CI: 1.24â3.71, P=0.006. The evidence did not support an interaction between education and febrile illness in explaining the above risks.
Conclusion A history of childhood measles, rubella, or pertussis was associated with high myopia, whereas a history of childhood rubella, mumps, or pertussis was associated with any myopia. The reasons for these associations are unclear
Effects of insular cortex lesions on conditioned taste aversion and latent inhibition in the rat
State of the art review: the data revolution in critical care
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2015 and co-published as a series in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annualupdate2015. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901
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