The activating mutation R201C in GNAS promotes intestinal tumourigenesis in Apc(Min/+) mice through activation of Wnt and ERK1/2 MAPK pathways.

Somatically acquired, activating mutations of GNAS, the gene encoding the stimulatory G-protein Gsalpha subunit, have been identified in kidney, thyroid, pituitary, leydig cell, adrenocortical and, more recently, in colorectal tumours, suggesting that mutations such as R201C may be oncogenic in these tissues. To study the role of GNAS in intestinal tumourigenesis, we placed GNAS R201C under the control of the A33-antigen promoter (Gpa33), which is almost exclusively expressed in the intestines. The GNAS R201C mutation has been shown to result in the constitutive activation of Gsalpha and adenylate cyclase and to lead to the autonomous synthesis of cyclic adenosine monophosphate (cAMP). Gpa33(tm1(GnasR201C)Wtsi/+) mice showed significantly elevated cAMP levels and a compensatory upregulation of cAMP-specific phosphodiesterases in the intestinal epithelium. GNAS R201C alone was not sufficient to induce tumourigenesis by 12 months, but there was a significant increase in adenoma formation when Gpa33(tm1(GnasR201C)Wtsi/+) mice were bred onto an Apc(Min/+) background. GNAS R201C expression was associated with elevated expression of Wnt and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (ERK1/2 MAPK) pathway target genes, increased phosphorylation of ERK1/2 MAPK and increased immunostaining for the proliferation marker Ki67. Furthermore, the effects of GNAS R201C on the Wnt pathway were additive to the inactivation of Apc. Our data strongly suggest that activating mutations of GNAS cooperate with inactivation of APC and are likely to contribute to colorectal tumourigenesis

Human rights, non-refoulement and the protection of refugees in Hong Kong

Although the 1951 Convention relating to the Status of Refugees and its 1967 Protocol do not apply to Hong Kong, asylum seekers have challenged Hong Kong's lack of an adequate refugee policy in a series of judicial review actions grounded in human rights and common law principles. This article focuses on two cases in particular in which the applicants have attempted to rely, in part, on a right to non-refoulement, derived from international and domestic law, to compel the Government to establish procedures to determine the status of refugees and other similar categories of claimants. The first, Secretary for Security v. Sakthevel Prabakar, led to the creation of a 'torture screening' mechanism based on article 3 of the Convention against Torture and other Cruel, Inhuman, or Degrading Treatment or Punishment. In the second, C v. Director of Immigration, the court considered whether a rule of non-refoulement has emerged in customary international law and, if so, whether it applies to Hong Kong and requires government-administered refugee status determination. Although the applicants failed at first instance,1 an analysis of the judgment with reference to Hong Kong's human rights obligations reveals gaps in the court's reasoning and demonstrates the potential for greater reliance on these standards as the basis for developing a more comprehensive protection framework. This examination of the Hong Kong experience may have broader comparative value, especially in the Asian region and in jurisdictions not bound by the Refugee Convention or its Protocol. © The Author (2010). Published by Oxford University Press. All rights reserved.postprin

Conductivity and quasinormal modes in holographic theories

We show that in field theories with a holographic dual the retarded Green's function of a conserved current can be represented as a convergent sum over the quasinormal modes. We find that the zero-frequency conductivity is related to the sum over quasinormal modes and their high-frequency asymptotics via a sum rule. We derive the asymptotics of the quasinormal mode frequencies and their residues using the phase-integral (WKB) approach and provide analytic insight into the existing numerical observations concerning the asymptotic behavior of the spectral densities.Comment: 24 pages, 3 figure

Equity effects of children’s physical activity interventions: a systematic scoping review

BACKGROUND: Differential effects of physical activity (PA) interventions across population sub-groups may contribute to inequalities in health. This systematic scoping review explored the state of the evidence on equity effects in response to interventions targeting children’s PA promotion. The aims were to assess and summarise the availability of evidence on differential intervention effects of children’s PA interventions across gender, body mass index, socioeconomic status, ethnicity, place of residence and religion. METHODS: Using a pre-piloted search strategy, six electronic databases were searched for controlled intervention trials, aiming to increase PA in children (6–18 years of age), that used objective forms of measurement. Screening and data extraction were conducted in duplicate. Reporting of analyses of differential effects were summarized for each equity characteristic and logistic regression analyses run to investigate intervention characteristics associated with the reporting of equity analyses. RESULTS: The literature search identified 13,052 publications and 7963 unique records. Following a duplicate screening process 125 publications representing 113 unique intervention trials were included. Although the majority of trials collected equity characteristics at baseline, few reported differential effects analyses across the equity factors of interest. All 113 included interventions reported gender at baseline with 46% of non-gender targeted interventions reporting differential effect analyses by gender. Respective figures were considerably smaller for body mass index, socioeconomic status, ethnicity, place of residence and religion. There was an increased likelihood of studying differential effects in school based interventions (OR: 2.9 [1.2–7.2]) in comparison to interventions in other settings, larger studies (per increase in 100 participants; 1.2 [1.0 – 1.4]); and where a main intervention effect on objectively measured PA was reported (3.0 [1.3–6.8]). CONCLUSIONS: Despite regularly collecting relevant information at baseline, most controlled trials of PA interventions in children do not report analyses of differences in intervention effect across outlined equity characteristics. Consequently, there is a scarcity of evidence concerning the equity effects of these interventions, particularly beyond gender, and a lack of understanding of subgroups that may benefit from, or be disadvantaged by, current intervention efforts. Further evidence synthesis and primary research is needed to effectively understand the impact of PA interventions on existing behavioural inequalities within population subgroups of children.Funding for this study and the work of all authors was supported, wholly or in part, by the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence (RES-590-28-0002). Funding from the British Heart Foundation, Department of Health, Economic and Social Research Council, Medical Research Council, and the Wellcome Trust, under the auspices of the UK Clinical Research Collaboration, is gratefully acknowledged. Rebecca Love is funded by a Gates Cambridge Scholarship. The work of Esther M F van Sluijs was supported by the Medical Research Council (MC_UU_12015/7)

Lyman Alpha Blobs as an Observational Signature of Cold Accretion Streams into Galaxies

Recent hydrodynamic simulations of galaxy formation reveal streams of cold (T ~ 1e4 K) gas flowing into the centers of dark matter halos as massive as 1e12-1e13.5 M_sun at redshifts z~1-3. In this paper we show that if > 20% of the gravitational binding energy of the gas is radiated away, then the simulated cold flows are spatially extended Lyman Alpha (Lya) sources with luminosities, Lya line widths, and number densities that are comparable to those of observed Lya blobs. Furthermore, the filamentary structure of the cold flows can explain the wide range of observed Lya blob morphologies. Since the most massive halos form in dense environments, the association of Lya blobs with overdense regions arise naturally. We argue that Lya blobs - even those which are clearly associated with starburst galaxies or quasars - provide direct observational support for the cold accretion mode of galaxies. We discuss various testable predictions of this association.Comment: MNRAS in press. 13 pages, 6 figures. Discussion + references added. Main conclusions unaffecte

The LacI–family transcription factor, RbsR, is a pleiotropic regulator of motility, virulence, siderophore and antibiotic production, gas vesicle morphogenesis and flotation in Serratia

Gas vesicles (GVs) are proteinaceous, gas-filled organelles used by some bacteria to enable upward movement into favorable air/liquid interfaces in aquatic environments. Serratia sp. ATCC39006 (S39006) was the first enterobacterium discovered to produce GVs naturally. The regulation of GV assembly in this host is complex and part of a wider regulatory network affecting various phenotypes, including antibiotic biosynthesis. To identify new regulators of GVs, a comprehensive mutant library containing 71,000 insertion mutants was generated by random transposon mutagenesis and 311 putative GV-defective mutants identified. Three of these mutants were found to have a transposon inserted in a LacI family transcription regulator gene (rbsR) of the putative ribose operon. Each of these rbsR mutants was GV-defective; no GVs were visible by phase contrast microscopy (PCM) or transmission electron microscopy (TEM). GV deficiency was caused by the reduction of gvpA1 and gvrA transcription (the first genes of the two contiguous operons in the GV gene locus). Our results also showed that a mutation in rbsR was highly pleiotropic; the production of two secondary metabolites (carbapenem and prodigiosin antibiotics) was abolished. Interestingly, the intrinsic resistance to the carbapenem antibiotic was not affected by the rbsR mutation. In addition, the production of a siderophore, cellulase and plant virulence was reduced in the mutant, whereas it exhibited increased swimming and swarming motility. The RbsR protein was predicted to bind to regions upstream of at least18 genes in S39006 including rbsD (the first gene of the ribose operon) and gvrA. Electrophoretic mobility shift assays (EMSA) confirmed that RbsR bound to DNA sequences upstream of rbsD, but not gvrA. The results of this study indicate that RbsR is a global regulator that affects the modulation of GV biogenesis, but also with complex pleiotropic physiological impacts in S39006.CL was sponsored under the Academic Staff Training Scheme from the Malaysian Ministry of Education. Work in the Salmond lab is funded by the Biotechnology and Biological Sciences Research Council (BBSRC)—UK

Neuropsychological Deficits Are Correlated with Frontal Hypometabolism in Positron Emission Tomography Studies of Older Alcoholic Patients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66315/1/j.1530-0277.1993.tb00750.x.pd