Network Harmonisation of Physical Activity Variables Through Indirect Validation

Harmonisation of data for pooled analysis relies on the principle of inferential equivalence between variables from different sources. Ideally, this is achieved using models of the direct relationship with gold standard criterion measures, but the necessary validation study data are often unavailable. This study examines an alternative method of network harmonisation using indirect models. Starting methods were self-report or accelerometry, from which we derived indirect models of relationships with doubly labelled water (DLW)-based physical activity energy expenditure (PAEE) using sets of two bridge equations via one of three intermediate measures. Coefficients and performance of indirect models were compared to corresponding direct models (linear regression of DLW-based PAEE on starting methods). Indirect model beta coefficients were attenuated compared to direct model betas (10-63%), narrowing the range of PAEE values; attenuation was greater when bridge equations were weak. Directly and indirectly harmonised models had similar error variance but most indirectly derived values were biased at group-level. Correlations with DLW-based PAEE were identical after harmonisation using continuous linear but not categorical models. Wrist acceleration harmonised to DLW-based PAEE via combined accelerometry and heart rate sensing had lowest error variance (24.5%) and non-significant mean bias 0.9 (95%CI: -1.6; 3.4) kJ•day-1•kg-1. Associations between PAEE and BMI were similar for directly and indirectly harmonised values, but most fell outside the confidence interval of the criterion PAEE-to-BMI association. Indirect models can be used for harmonisation. Performance depends on the measurement properties of original data, variance explained by available bridge equations, and similarity of population characteristics.This work was funded by UK Medical Research Council (MC_UU_12015/3) and the NIHR Biomedical Research Centre in Cambridge (IS-BRC-1215-20014). UK Biobank is acknowledged for contributing to the costs of the fieldwork. Newcastle University and MedImmune are acknowledged for contributing to the costs of the doubly labelled water measurements. The funders had no role in the design, conduct, analysis, and decision to publish results from this study

Improved Therapy for Medulloblastoma: Targeting Hedgehog and PI3K-mTOR Signaling Pathways in Combination with Chemotherapy

Aberrant activation and interactions of hedgehog (HH) and PI3K/AKT/mTOR signaling pathways are frequently associated with high-risk medulloblastoma (MB). Thus, combined targeting of the HH and PI3K/AKT/mTOR pathways could be a viable therapeutic strategy to treat high-risk patients. Therefore, we investigated the anti-MB efficacies of combined HH inhibitor Vismodegib and PI3K-mTOR dual-inhibitor BEZ235 together or combined individually with cisplatin against high-risk MB. Using non-MYC- and MYC-amplified cell lines, and a xenograft mouse model, the in vitro and in vivo efficacies of these therapies on cell growth/survival and associated molecular mechanism(s) were investigated. Results showed that combined treatment of Vismodegib and BEZ235 together, or with cisplatin, significantly decreased MB cell growth/survival in a dose-dependent-fashion. Corresponding changes in the expression of targeted molecules following therapy were observed. Results demonstrated that inhibitors not only suppressed MB cell growth/survival when combined, but also significantly enhanced cisplatin-mediated cytotoxicity. Of these combinations, BEZ235 exhibited a significantly greater efficacy in enhancing cisplatin-mediated MB cytotoxicity. Results also demonstrated that the MYC-amplified MB lines showed a higher sensitivity to combined therapies compared to non-MYC-amplified cell lines. Therefore, we tested the efficacy of combined approaches against MYC-amplified MB growing in NSG mice. In vivo results showed that combination of Vismodegib and BEZ235 or their combination with cisplatin, significantly delayed MB tumor growth and increased survival of xenografted mice by targeting HH and mTOR pathways. Thus, our studies lay a foundation for translating these combined therapeutic strategies to the clinical setting to determine their efficacies in high-risk MB patients

The WiggleZ Dark Energy Survey: Star-formation in UV-luminous galaxies from their luminosity functions

We present the ultraviolet (UV) luminosity function of galaxies from the GALEX Medium Imaging Survey with measured spectroscopic redshifts from the first data release of the WiggleZ Dark Energy Survey. This sample selects galaxies with high star formation rates: at 0.6 < z < 0.9 the median star formation rate is at the upper 95th percentile of optically-selected (r<22.5) galaxies and the sample contains about 50 per cent of all NUV < 22.8, 0.6 < z < 0.9 starburst galaxies within the volume sampled. The most luminous galaxies in our sample (-21.0>M_NUV>-22.5) evolve very rapidly with a number density declining as (1+z)^{5\pm 1} from redshift z = 0.9 to z = 0.6. These starburst galaxies (M_NUV<-21 is approximately a star formation rate of 30 \msuny) contribute about 1 per cent of cosmic star formation over the redshift range z=0.6 to z=0.9. The star formation rate density of these very luminous galaxies evolves rapidly, as (1+z)^{4\pm 1}. Such a rapid evolution implies the majority of star formation in these large galaxies must have occurred before z = 0.9. We measure the UV luminosity function in 0.05 redshift intervals spanning 0.1<z<0.9, and provide analytic fits to the results. At all redshifts greater than z=0.55 we find that the bright end of the luminosity function is not well described by a pure Schechter function due to an excess of very luminous (M_NUV<-22) galaxies. These luminosity functions can be used to create a radial selection function for the WiggleZ survey or test models of galaxy formation and evolution. Here we test the AGN feedback model in Scannapieco et al. (2005), and find that this AGN feedback model requires AGN feedback efficiency to vary with one or more of the following: stellar mass, star formation rate and redshift.Comment: 27 pages; 13 pages without appendices. 22 figures; 11 figures in the main tex

The WiggleZ Dark Energy Survey: improved distance measurements to z = 1 with reconstruction of the baryonic acoustic feature

We present significant improvements in cosmic distance measurements from the WiggleZ Dark Energy Survey, achieved by applying the reconstruction of the baryonic acoustic feature technique. We show using both data and simulations that the reconstruction technique can often be effective despite patchiness of the survey, significant edge effects and shot-noise. We investigate three redshift bins in the redshift range 0.2 < z < 1, and in all three find improvement after reconstruction in the detection of the baryonic acoustic feature and its usage as a standard ruler. We measure model-independent distance measures DV(rsfid/rs) of 1716 ± 83, 2221 ± 101, 2516 ± 86 Mpc (68 per cent CL) at effective redshifts z = 0.44, 0.6, 0.73, respectively, where DV is the volume-averaged distance, and rs is the sound horizon at the end of the baryon drag epoch. These significantly improved 4.8, 4.5 and 3.4 per cent accuracy measurements are equivalent to those expected from surveys with up to 2.5 times the volume of WiggleZ without reconstruction applied. These measurements are fully consistent with cosmologies allowed by the analyses of the Planck Collaboration and the Sloan Digital Sky Survey. We provide the DV(rsfid/rs) posterior probability distributions and their covariances. When combining these measurements with temperature fluctuations measurements of Planck, the polarization of Wilkinson Microwave Anisotropy Probe 9, and the 6dF Galaxy Survey baryonic acoustic feature, we do not detect deviations from a flat Λ cold dark matter (ΛCDM) model. Assuming this model, we constrain the current expansion rate to H₀ = 67.15 ± 0.98 km s⁻¹Mpc⁻¹. Allowing the equation of state of dark energy to vary, we obtain wDE = −1.080 ± 0.135. When assuming a curved ΛCDM model we obtain a curvature value of ΩK = −0.0043 ± 0.0047

Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice

Obesity is closely associated with the metabolic syndrome, a combination of disorders including insulin resistance, diabetes, dyslipidemia, and hypertension. A role for local glucocorticoid reamplification in obesity and the metabolic syndrome has been suggested. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates active cortisol from inactive 11-keto forms, and aP2-HSD1 mice with relative transgenic overexpression of this enzyme in fat cells develop visceral obesity with insulin resistance and dyslipidemia. Here we report that aP2-HSD1 mice also have high arterial blood pressure (BP). The mice have increased sensitivity to dietary salt and increased plasma levels of angiotensinogen, angiotensin II, and aldosterone. This hypertension is abolished by selective angiotensin II receptor AT-1 antagonist at a low dose that does not affect BP in non-Tg littermates. These findings suggest that activation of the circulating renin-angiotensin system (RAS) develops in aP2-HSD1 mice. The long-term hypertension is further reflected by an appreciable hypertrophy and hyperplasia of the distal tubule epithelium of the nephron, resembling salt-sensitive or angiotensin II–mediated hypertension. Taken together, our findings suggest that overexpression of 11β-HSD1 in fat is sufficient to cause salt-sensitive hypertension mediated by an activated RAS. The potential role of adipose 11β-HSD1 in mediating critical features of the metabolic syndrome extends beyond obesity and metabolic complications to include the most central cardiovascular feature of this disorder

The WiggleZ Dark Energy Survey: the growth rate of cosmic structure since redshift z=0.9

We present precise measurements of the growth rate of cosmic structure for the redshift range 0.1 < z < 0.9, using redshift-space distortions in the galaxy power spectrum of the WiggleZ Dark Energy Survey. Our results, which have a precision of around 10% in four independent redshift bins, are well-fit by a flat LCDM cosmological model with matter density parameter Omega_m = 0.27. Our analysis hence indicates that this model provides a self-consistent description of the growth of cosmic structure through large-scale perturbations and the homogeneous cosmic expansion mapped by supernovae and baryon acoustic oscillations. We achieve robust results by systematically comparing our data with several different models of the quasi-linear growth of structure including empirical models, fitting formulae calibrated to N-body simulations, and perturbation theory techniques. We extract the first measurements of the power spectrum of the velocity divergence field, P_vv(k), as a function of redshift (under the assumption that P_gv(k) = -sqrt[P_gg(k) P_vv(k)] where g is the galaxy overdensity field), and demonstrate that the WiggleZ galaxy-mass cross-correlation is consistent with a deterministic (rather than stochastic) scale-independent bias model for WiggleZ galaxies for scales k < 0.3 h/Mpc. Measurements of the cosmic growth rate from the WiggleZ Survey and other current and future observations offer a powerful test of the physical nature of dark energy that is complementary to distance-redshift measures such as supernovae and baryon acoustic oscillations.Comment: 17 pages, 11 figures, accepted for publication by MNRA

THE SAMI GALAXY SURVEY: GALAXY INTERACTIONS and KINEMATIC ANOMALIES IN ABELL 119

Galaxy mergers are important events that can determine the fate of a galaxy by changing its morphology, star formation activity and mass growth. Merger systems have commonly been identified from their disturbed morphologies, and we now can employ integral field spectroscopy to detect and analyze the impact of mergers on stellar kinematics as well. We visually classified galaxy morphology using deep images (μr = 28 mag arcsec- 2 ) taken by the Blanco 4 m telescope at the Cerro Tololo Inter-American Observatory. In this paper we investigate 63 bright (Mr >-19.3) spectroscopically selected galaxies in Abell 119, of which 53 are early type and 20 show a disturbed morphology by visual inspection. A misalignment between the major axes in the photometric image and the kinematic map is conspicuous in morphologically disturbed galaxies. Our sample is dominated by early-type galaxies, yet it shows a surprisingly tight TullyFisher relation except for the morphologically disturbed galaxies which show large deviations. Three out of the eight slow rotators in our sample are morphologically disturbed. The morphologically disturbed galaxies are generally more asymmetric, visually as well as kinematically. Our findings suggest that galaxy interactions, including mergers and perhaps fly-bys, play an important role in determining the orientation and magnitude of a galaxys angular momentum

The WiggleZ Dark Energy Survey: constraining galaxy bias and cosmic growth with three-point correlation functions

Higher order statistics are a useful and complementary tool for measuring the clustering of galaxies, containing information on the non-Gaussian evolution and morphology of large-scale structure in the Universe. In this work we present measurements of th

Potential for Supernova Neutrino Detection in MiniBooNE

The MiniBooNE detector at Fermilab is designed to search for $\nu_\mu \to \nu_e$ oscillation appearance at $E_\nu \sim 1 {\rm GeV}$ and to make a decisive test of the LSND signal. The main detector (inside a veto shield) is a spherical volume containing 0.680 ktons of mineral oil. This inner volume, viewed by 1280 phototubes, is primarily a \v{C}erenkov medium, as the scintillation yield is low. The entire detector is under a 3 m earth overburden. Though the detector is not optimized for low-energy (tens of MeV) events, and the cosmic-ray muon rate is high (10 kHz), we show that MiniBooNE can function as a useful supernova neutrino detector. Simple trigger-level cuts can greatly reduce the backgrounds due to cosmic-ray muons. For a canonical Galactic supernova at 10 kpc, about 190 supernova $\bar{\nu}_e + p \to e^+ + n$ events would be detected. By adding MiniBooNE to the international network of supernova detectors, the possibility of a supernova being missed would be reduced. Additionally, the paths of the supernova neutrinos through Earth will be different for MiniBooNE and other detectors, thus allowing tests of matter-affected mixing effects on the neutrino signal.Comment: Added references, version to appear in PR

<em>N</em>³-Alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides

Dimethylformamide dimethylacetal (DMFDMA) is widely used as a source of electrophilic one-carbon units at the formate oxidation level; however, electrophilic methylation with this reagent is previously unreported. Reaction of anthranilamide with DMFDMA at 150 °C for short periods gives mainly quinazolin-4-one. However, prolonged reaction with dimethylformamide di(primary-alkyl)acetals leads to subsequent alkylation at N3. 3-Substituted anthranilamides give 8-substituted 3-alkylquinazolin-4-ones. Condensation of anthranilamides with dimethylacetamide dimethylacetal provides 2,3-dimethylquinazolin-4-ones. In these reactions, the source of the N3-alkyl group is the O-alkyl group of the orthoamides. By contrast, reaction with the more sterically crowded dimethylformamide di(isopropyl)acetal diverts the alkylation to the oxygen, giving 4-isopropoxyquinazolines, along with N3-methylquinazolin-4-ones where the methyl is derived from N-Me of the orthoamides. Reaction of anthranilamide with the highly sterically demanding dimethylformamide di(t-butyl)acetal gives largely quinazolin-4-one, whereas dimethylformamide di(neopentyl)acetal forms a mixture of quinazolin-4-one and N3-methylquinazolin-4-one. The observations are rationalised in terms of formation of intermediate cationic electrophiles (alkoxymethylidene-N,N-dimethylammonium) by thermal elimination of the corresponding alkoxide from the orthoamides. These are the first observations of orthoamides as direct alkylating agents