Effect of calcium supplements on risk of myocardial infarction and cardiovascular events : meta-analysis

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Roles of key active-site residues in flavocytochrome P450 BM3

Abbreviations used: P450, cytochrome P450 mono-oxygenase; ImC12, 12-(imidazolyl)dodecanoic acid; 1-PIM, 1-phenylimidazole.The effects of mutation of key active-site residues (Arg-47, Tyr-51, Phe-42 and Phe-87) in Bacillus megaterium flavocytochrome P450 BM3 were investigated. Kinetic studies on the oxidation of laurate and arachidonate showed that the side chain of Arg-47 contributes more significantly to stabilization of the fatty acid carboxylate than does that of Tyr-51 (kinetic parameters for oxidation of laurate: R47A mutant, Km 859 µM, kcat 3960 min-1; Y51F mutant, Km 432 µM, kcat 6140 min-1; wild-type, Km 288 µM, kcat 5140 min-1). A slightly increased kcat for the Y51F-catalysed oxidation of laurate is probably due to decreased activation energy (DG‡) resulting from a smaller DG of substrate binding. The side chain of Phe-42 acts as a phenyl 'cap' over the mouth of the substrate-binding channel. With mutant F42A, Km is massively increased and kcat is decreased for oxidation of both laurate (Km 2.08 mM, kcat 2450 min-1) and arachidonate (Km 34.9 µM, kcat 14620 min-1; compared with values of 4.7 µM and 17100 min-1 respectively for wild-type). Amino acid Phe-87 is critical for efficient catalysis. Mutants F87G and F87Y not only exhibit increased Km and decreased kcat values for fatty acid oxidation, but also undergo an irreversible conversion process from a 'fast' to a 'slow' rate of substrate turnover [for F87G (F87Y)-catalysed laurate oxidation: kcat 'fast', 760 (1620) min-1; kcat 'slow', 48.0 (44.6) min-1; kconv (rate of conversion from fast to slow form), 4.9 (23.8) min-1]. All mutants showed less than 10% uncoupling of NADPH oxidation from fatty acid oxidation. The rate of FMN-to-haem electron transfer was shown to become rate-limiting in all mutants analysed. For wild-type P450 BM3, the rate of FMN-to-haem electron transfer (8340 min-1) is twice the steady-state rate of oxidation (4100 min-1), indicating that other steps contribute to rate limitation. Active-site structures of the mutants were probed with the inhibitors 12-(imidazolyl)dodecanoic acid and 1-phenylimidazole. Mutant F87G binds 1-phenylimidazole > 10-fold more tightly than does the wild-type, whereas mutant Y51F binds the haem-co-ordinating fatty acid analogue 12-(imidazolyl)dodecanoic acid > 30-fold more tightly than wild-type

Structural and mechanistic mapping of a unique fumarate reductase

The 1.8 Å resolution crystal structure of the tetraheme flavocytochrome c3, Fcc3, provides the first mechanistic insight into respiratory fumarate reductases or succinate dehydrogenases. The multi-redox center, three-domain protein shows a 40 Å long ‘molecular wire’ allowing rapid conduction of electrons through a new type of cytochrome domain onto the active site flavin, driving the reduction of fumarate to succinate. In this structure a malate-like molecule is trapped in the enzyme active site. The interactions between this molecule and the enzyme suggest a clear mechanism for fumarate reduction in which the substrate is polarized and twisted, facilitating hydride transfer from the reduced flavin and subsequent proton transfer. The enzyme active site in the oxidized form is completely buried at the interface between the flavin-binding and the clamp domains. Movement of the cytochrome and clamp domains is postulated to allow release of the product

MICL controls inflammation in rheumatoid arthritis

Acknowledgments We thank G Milne, D MacCallum, S Hardison, G Wilson, C Wallace, S Hadebe and A Richmond for assistance; H. El-Gabalawy for tissues and the animal facility staff for the care of our animals. Flow cytometry was undertaken in the Iain Fraser Cytometry Centre, University of Aberdeen. Funding: GDB was funded by the Wellcome Trust and MRC (UK). AA and CDB are supported by the Arthritis Research UK Tissue Engineering Centre (grant 19429). This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk, and was funded by the Wellcome Trust (076113). MJGF was funded by The Arthritis Society and the Canadian Arthritis Network and J-ML by a scholarship from the Canadian Arthritis Network.Peer reviewedPublisher PD

The Atacama Cosmology Telescope: Dynamical Masses and Scaling Relations for a Sample of Massive Sunyaev-Zel'dovich Effect Selected Galaxy Clusters

We present the first dynamical mass estimates and scaling relations for a sample of Sunyaev-Zel'dovich effect (SZE) selected galaxy clusters. The sample consists of 16 massive clusters detected with the Atacama Cosmology Telescope (ACT) over a 455 sq. deg. area of the southern sky. Deep multi-object spectroscopic observations were taken to secure intermediate-resolution (R~700-800) spectra and redshifts for ~60 member galaxies on average per cluster. The dynamical masses M_200c of the clusters have been calculated using simulation-based scaling relations between velocity dispersion and mass. The sample has a median redshift z=0.50 and a median mass M_200c~12e14 Msun/h70 with a lower limit M_200c~6e14 Msun/h70, consistent with the expectations for the ACT southern sky survey. These masses are compared to the ACT SZE properties of the sample, specifically, the match-filtered central SZE amplitude y, the central Compton parameter y0, and the integrated Compton signal Y_200c, which we use to derive SZE-Mass scaling relations. All SZE estimators correlate with dynamical mass with low intrinsic scatter (<~20%), in agreement with numerical simulations. We explore the effects of various systematic effects on these scaling relations, including the correlation between observables and the influence of dynamically disturbed clusters. Using the 3-dimensional information available, we divide the sample into relaxed and disturbed clusters and find that ~50% of the clusters are disturbed. There are hints that disturbed systems might bias the scaling relations but given the current sample sizes these differences are not significant; further studies including more clusters are required to assess the impact of these clusters on the scaling relations.Comment: 15 pages, 4 figures. Accepted for publication in The Astrophysical Journal; matches published version. Full Table 8 with complete spectroscopic member sample available in machine-readable form in the journal site and upon request to C. Sif\'o

The Atacama Cosmology Telescope: Data Characterization and Map Making

We present a description of the data reduction and mapmaking pipeline used for the 2008 observing season of the Atacama Cosmology Telescope (ACT). The data presented here at 148 GHz represent 12% of the 90 TB collected by ACT from 2007 to 2010. In 2008 we observed for 136 days, producing a total of 1423 hours of data (11 TB for the 148 GHz band only), with a daily average of 10.5 hours of observation. From these, 1085 hours were devoted to a 850 deg^2 stripe (11.2 hours by 9.1 deg) centered on a declination of -52.7 deg, while 175 hours were devoted to a 280 deg^2 stripe (4.5 hours by 4.8 deg) centered at the celestial equator. We discuss sources of statistical and systematic noise, calibration, telescope pointing, and data selection. Out of 1260 survey hours and 1024 detectors per array, 816 hours and 593 effective detectors remain after data selection for this frequency band, yielding a 38% survey efficiency. The total sensitivity in 2008, determined from the noise level between 5 Hz and 20 Hz in the time-ordered data stream (TOD), is 32 micro-Kelvin sqrt{s} in CMB units. Atmospheric brightness fluctuations constitute the main contaminant in the data and dominate the detector noise covariance at low frequencies in the TOD. The maps were made by solving the least-squares problem using the Preconditioned Conjugate Gradient method, incorporating the details of the detector and noise correlations. Cross-correlation with WMAP sky maps, as well as analysis from simulations, reveal that our maps are unbiased at multipoles ell > 300. This paper accompanies the public release of the 148 GHz southern stripe maps from 2008. The techniques described here will be applied to future maps and data releases.Comment: 20 pages, 18 figures, 6 tables, an ACT Collaboration pape

The Atacama Cosmology Telescope: Cosmological parameters from three seasons of data

We present constraints on cosmological and astrophysical parameters from high-resolution microwave background maps at 148 GHz and 218 GHz made by the Atacama Cosmology Telescope (ACT) in three seasons of observations from 2008 to 2010. A model of primary cosmological and secondary foreground parameters is fit to the map power spectra and lensing deflection power spectrum, including contributions from both the thermal Sunyaev-Zeldovich (tSZ) effect and the kinematic Sunyaev-Zeldovich (kSZ) effect, Poisson and correlated anisotropy from unresolved infrared sources, radio sources, and the correlation between the tSZ effect and infrared sources. The power ell^2 C_ell/2pi of the thermal SZ power spectrum at 148 GHz is measured to be 3.4 +\- 1.4 muK^2 at ell=3000, while the corresponding amplitude of the kinematic SZ power spectrum has a 95% confidence level upper limit of 8.6 muK^2. Combining ACT power spectra with the WMAP 7-year temperature and polarization power spectra, we find excellent consistency with the LCDM model. We constrain the number of effective relativistic degrees of freedom in the early universe to be Neff=2.79 +\- 0.56, in agreement with the canonical value of Neff=3.046 for three massless neutrinos. We constrain the sum of the neutrino masses to be Sigma m_nu < 0.39 eV at 95% confidence when combining ACT and WMAP 7-year data with BAO and Hubble constant measurements. We constrain the amount of primordial helium to be Yp = 0.225 +\- 0.034, and measure no variation in the fine structure constant alpha since recombination, with alpha/alpha0 = 1.004 +/- 0.005. We also find no evidence for any running of the scalar spectral index, dns/dlnk = -0.004 +\- 0.012.Comment: 26 pages, 22 figures. This paper is a companion to Das et al. (2013) and Dunkley et al. (2013). Matches published JCAP versio

Genome-Wide Association Study Using Extreme Truncate Selection Identifies Novel Genes Affecting Bone Mineral Density and Fracture Risk

Osteoporotic fracture is a major cause of morbidity and mortality worldwide. Low bone mineral density (BMD) is a major predisposing factor to fracture and is known to be highly heritable. Site-, gender-, and age-specific genetic effects on BMD are thought to be significant, but have largely not been considered in the design of genome-wide association studies (GWAS) of BMD to date. We report here a GWAS using a novel study design focusing on women of a specific age (postmenopausal women, age 55–85 years), with either extreme high or low hip BMD (age- and gender-adjusted BMD z-scores of +1.5 to +4.0, n = 1055, or −4.0 to −1.5, n = 900), with replication in cohorts of women drawn from the general population (n = 20,898). The study replicates 21 of 26 known BMD–associated genes. Additionally, we report suggestive association of a further six new genetic associations in or around the genes CLCN7, GALNT3, IBSP, LTBP3, RSPO3, and SOX4, with replication in two independent datasets. A novel mouse model with a loss-of-function mutation in GALNT3 is also reported, which has high bone mass, supporting the involvement of this gene in BMD determination. In addition to identifying further genes associated with BMD, this study confirms the efficiency of extreme-truncate selection designs for quantitative trait association studies

Further Defining Spectral Type "Y" and Exploring the Low-mass End of the Field Brown Dwarf Mass Function

We present the discovery of another seven Y dwarfs from the Wide-field Infrared Survey Explorer (WISE). Using these objects, as well as the first six WISE Y dwarf discoveries from Cushing et al., we further explore the transition between spectral types T and Y. We find that the T/Y boundary roughly coincides with the spot where the J-H colors of brown dwarfs, as predicted by models, turn back to the red. Moreover, we use preliminary trigonometric parallax measurements to show that the T/Y boundary may also correspond to the point at which the absolute H (1.6 um) and W2 (4.6 um) magnitudes plummet. We use these discoveries and their preliminary distances to place them in the larger context of the Solar Neighborhood. We present a table that updates the entire stellar and substellar constituency within 8 parsecs of the Sun, and we show that the current census has hydrogen-burning stars outnumbering brown dwarfs by roughly a factor of six. This factor will decrease with time as more brown dwarfs are identified within this volume, but unless there is a vast reservoir of cold brown dwarfs invisible to WISE, the final space density of brown dwarfs is still expected to fall well below that of stars. We also use these new Y dwarf discoveries, along with newly discovered T dwarfs from WISE, to investigate the field substellar mass function. We find that the overall space density of late-T and early-Y dwarfs matches that from simulations describing the mass function as a power law with slope -0.5 < alpha < 0.0; however, a power-law may provide a poor fit to the observed object counts as a function of spectral type because there are tantalizing hints that the number of brown dwarfs continues to rise from late-T to early-Y. More detailed monitoring and characterization of these Y dwarfs, along with dedicated searches aimed at identifying more examples, are certainly required.Comment: 91 pages, 15 figures, accepted for publication in The Astrophysical Journa