New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

Water Oxidation Catalysis Beginning with 2.5 μM [Co₄(H₂O)₂(PW₉O₃₄)₂]^10–: Investigation of the True Electrochemically Driven Catalyst at ≥600 mV Overpotential at a Glassy Carbon Electrode

Evidence for the true water oxidation catalyst (WOC) when beginning with the cobalt polyoxometalate [Co₄(H₂O)₂(PW₉O₃₄)₂]^10– (Co₄–POM) is investigated at deliberately chosen low polyoxometalate concentrations (2.5 μM) and high electrochemical potentials (≥1.3 V vs Ag/AgCl) in pH 5.8 and 8.0 sodium phosphate electrolyte at a glassy carbon working electrodeconditions which ostensibly favor Co₄–POM catalysis if present. Multiple experiments argue against the dominant catalyst being CoO_<i>x</i> formed exclusively from Co²⁺ dissociated from the parent POM. Measurement of [Co²⁺] in the Co₄–POM solution and catalytic controls with the corresponding amount of Co­(NO₃)₂ cannot account for the O₂ generated from 2.5 μM [Co₄(H₂O)₂(PW₉O₃₄)₂]^10– solutions. This result contrasts with our prior investigation of Co₄–POM under higher concentration and lower potential conditions (i.e., 500 μM [Co₄(H₂O)₂(PW₉O₃₄)₂]^10–, 1.1 V vs Ag/AgCl, as described in Stracke, J. J.; Finke, R. G. <i>J. Am. Chem. Soc.</i> <b>2011</b>, <i>133</i>, 14872) and <i>highlights the importance of</i> <i>reaction</i> <i>conditions in governing the identity of the true, active WOC.</i> Although electrochemical studies are consistent with Co₄–POM being oxidized at the glassy carbon electrode, it is not yet possible to distinguish a Co₄–POM catalyst from a CoO_<i>x</i> catalyst formed via decomposition of Co₄–POM. Controls with authentic CoO_<i>x</i> indicate conversion of only 3.4% or 8.3% (at pH 8.0 and 5.8) of Co₄–POM into a CoO_<i>x</i> catalyst could account for the O₂-generating activity, and HPLC quantification of the Co₄–POM stability shows the postreaction Co₄–POM concentration decreases by 2.7 ± 7.6% and 9.4 ± 5.1% at pH 8.0 and 5.8. Additionally, the [Co²⁺] in a 2.5 μM Co₄–POM solution increases by 0.55 μM during 3 min of electrolysisfurther evidence of the <i>Co</i>_<i>4</i><i>-POM instability under oxidizing conditions</i>. Overall, this study demonstrates the challenges of identifying the true WOC when examining micromolar amounts of a partially stable material and when <i>nanomolar</i> heterogeneous metal-oxide will account for the observed O₂-generating activity

Water Oxidation Catalysis Beginning with Co₄(H₂O)₂(PW₉O₃₄)₂^10– When Driven by the Chemical Oxidant Ruthenium(III)tris(2,2′-bipyridine): Stoichiometry, Kinetic, and Mechanistic Studies en Route to Identifying the True Catalyst

Stoichiometry and kinetics are reported for catalytic water oxidation to O₂ beginning with the cobalt polyoxometalate Co₄(H₂O)₂(PW₉O₃₄)₂^10– (Co₄POM) and the chemical oxidant ruthenium­(III)­tris­(2,2′-bipyridine) (Ru­(III)­(bpy)₃³⁺). This specific water oxidation system was first reported in a 2010 <i>Science</i> paper (Yin et al. <i>Science</i> <b>2010</b>, <i>328</i>, 342). Under standard conditions employed herein of 1.0 μM Co₄POM, 500 μM Ru­(III)­(bpy)₃³⁺, 100 μM Ru­(II)­(bpy)₃²⁺, pH 7.2, and 0.03 M sodium phosphate buffer, the highest O₂ yields of 22% observed herein are seen when Ru­(II)­(bpy)₃²⁺ is added prior to the Ru­(III)­(bpy)₃³⁺ oxidant; hence, those conditions are employed in the present study. Measurement of the initial O₂ evolution and Ru­(III)­(bpy)₃³⁺ reduction rates while varying the initial pH, [Ru­(III)­(bpy)₃³⁺], [Ru­(II)­(bpy)₃²⁺], and [Co₄POM] indicate that the reaction follows the empirical rate law: −d­[Ru­(III)­(bpy)₃³⁺]/d<i>t</i> = (<i>k</i>₁ + <i>k</i>₂)­[Co₄POM]_soluble[Ru­(III)­(bpy)₃³⁺]/[H⁺], where the rate constants <i>k</i>₁ ∼ 0.0014 s^–1 and <i>k</i>₂ ∼ 0.0044 s^–1 correspond to the water oxidation and ligand oxidation reactions, and for O₂ evolution, d­[O₂]/d<i>t</i> = (<i>k</i>₁/4)­[Co₄POM]_soluble[Ru­(III)­(bpy)₃³⁺]/[H⁺]. Overall, at least seven important insights result from the present studies: (i) Parallel WOC and Ru­(III)­(bpy)₃³⁺ self-oxidation reactions well documented in the prior literature limit the desired WOC and selectivity to O₂ in the present system to ≤28%. (ii) The formation of a precipitate from ∼2 Ru­(II)­(bpy)₃²⁺/3 Co₄(H₂O)₂(PW₉O₃₄)₂^10– with a <i>K</i>_sp = (8 ± 7) × 10^–25 (M⁵) greatly complicates the reaction and interpretation of the observed kinetics, but (iii) the best O₂ yields are still when Ru­(II)­(bpy)₃²⁺ is preadded. (iv) CoO_<i>x</i> is 2–11 times more active than Co₄POM under the reaction conditions, but (v) Co₄POM is still the dominant WOC under the Co₄POM/Ru­(III)­(bpy)₃³⁺ and other reaction conditions employed. The present studies also (vi) confirm that the specific conditions matter greatly in determining the true WOC and (vii) allow one to begin to construct a plausible WOC mechanism for the Co₄POM/Ru­(III)­(bpy)₃³⁺ system

Simplified Mantle Architecture and Distribution of Radiogenic Power

The mantle components that represent the source region of ocean island basalts (OIB) and feed hotspot volcanism are predicted to contain 160 +/- 20 (2(sub m)) ng/g Th, a heatproducing element. This critical model composition indicates that the OIB source region (OSR) comprises a significant amount of recycled oceanic crust and constitutes 19(sup +3)(sub 2) (2(sub m))% of the mantle by mass. The mass fraction of this reservoir supports a mantle architecture with a basal thermochemical layering at an average depth of 2000 +/- 100 (2(sub m)) km or two thermochemical piles that extend up to midmantle levels. The hotspot source described here generates 10 pW/kg of radiogenic heat and supplies 7.3 TW to the planet's total surface heat flux. Given that the silicate portion of the Earth produces some 20.4 TW of radiogenic power, with 7.2 TW derived from the continental crust, the mantle source responsible for midocean ridge volcanism provides only 5.9 TW of radiogenic power (or <2 pW/kg). As a result, the source of hotspots generates >5x more radiogenic heat than the source of midocean ridges, thus contributing to the energetics that drive mantle convection and potentially the formation of longlived plumes via bottom heating of the modern mantle. The potential for a sequestered or unsampled mantle reservoir would impact the relative mass fractions of the source regions of OIB and midocean ridge volcanism but not the compositional model of the OSR presented here

The Mesoproterozoic zig-zag dal basalts and associated intrusions of eastern north Greenland : mantle plume-lithosphere interaction

The lavas of the Zig-Zag Dal Formation of eastern North Greenland constitute a Mesoproterozoic tholeiitic flood basalt succession up to 1,350 m thick, extending >10,000 km2, and underlain by a sill complex. U–Pb dating on baddeleyite from one of the sills thought to be contemporaneous with the lava extrusion, gives an age of 1,382±2 Ma. The lavas, subdivided from oldest to youngest into Basal, Aphyric and Porphyritic units, are dominantly basaltic (>6 wt.% MgO), with more evolved lavas occurring within the Aphyric unit. The most magnesian lavas occur in the Basal unit and the basaltic lavas exhibit a generalised upward decrease in Mg number (MgO/(MgO + Fe2O3T)) through the succession. All of the lavas are regarded as products of variable degrees of olivine, augite and plagioclase fractionation and to be residual after generation of cumulates in the deep crust. The basaltic lavas display an up-section fall in the ratio of light to heavy rare-earth elements (LREE/HREE) but an up-section rise in Zr/Nb, Sc, Y and HREE. The older lavas (Basal and Aphyric units) are characterised by low Nd and Hf in contrast to higher values in the younger (Porphyritic unit) lavas. The Porphyritic Unit basalts are characterised by a notable enrichment in Fe and Ti. The Zig-Zag Dal succession is inferred to reflect an increase in melt fraction in the sub-lithospheric mantle, with melting commencing in garnet–lherzolite facies peridotites and subsequently involving spinel-facies mantle at increasingly shallow depths. Melting is deduced to have occurred beneath an attenuating continental lithosphere in conjunction with ascent of a mantle plume. Lithospheric contamination of primitive melts is inferred to have diminished with time with the Porphyritic unit basalts being products of essentially uncontaminated plume-source magmas. The high iron signature may reflect a relatively iron-rich plume source

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