| 1. |
- Locke, Adam E, et al.
(författare)
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Genetic studies of body mass index yield new insights for obesity biology.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 2. |
- Shungin, Dmitry, et al.
(författare)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Sung, Yun Ju, et al.
(författare)
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A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure
- 2019
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 28:15, s. 2615-2633
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Tidskriftsartikel (refereegranskat)abstract
- Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.
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| 4. |
- Muncke, Jane, et al.
(författare)
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A vision for safer food contact materials: Public health concerns as drivers for improved testing
- 2023
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Ingår i: ENVIRONMENT INTERNATIONAL. - 0160-4120 .- 1873-6750. ; 180
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Tidskriftsartikel (refereegranskat)abstract
- Food contact materials (FCMs) and food contact articles are ubiquitous in today's globalized food system. Chemicals migrate from FCMs into foodstuffs, so called food contact chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health from hazardous FCCs because only individual substances used to make FCMs are tested and mostly only for genotoxicity while endocrine disruption and other hazard properties are disregarded. Indeed, FCMs are a known source of a wide range of hazardous chemicals, and they likely contribute to highly prevalent non-communicable diseases. FCMs can also include non-intentionally added substances (NIAS), which often are unknown and therefore not subject to risk assessment. To address these important shortcomings, we outline how the safety of FCMs may be improved by (1) testing the overall migrate, including (unknown) NIAS, of finished food contact articles, and (2) expanding toxicological testing beyond genotoxicity to multiple endpoints associated with non-communicable diseases relevant to human health. Toidentify mechanistic endpoints for testing, we group chronic health outcomes associated with chemical exposure into Six Clusters of Disease (SCOD) and we propose that finished food contact articles should be tested for their impacts on these SCOD. Research should focus on developing robust, relevant, and sensitive in-vitro assays based on mechanistic information linked to the SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics of Toxicants. Implementing this vision will improve prevention of chronic diseases that are associated with hazardous chemical exposures, including from FCMs.
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| 5. |
- Schug, Thaddeus T., et al.
(författare)
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Designing Endocrine Disruption Out of the Next Generation of Chemicals
- 2013
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Ingår i: Green Chemistry. - : Royal Society of Chemistry. - 1463-9262 .- 1463-9270. ; 15:1, s. 181-198
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Tidskriftsartikel (refereegranskat)abstract
- A central goal of green chemistry is to avoid hazard in the design of new chemicals. This objective is best achieved when information about a chemical's potential hazardous effects is obtained as early in the design process as feasible. Endocrine disruption is a type of hazard that to date has been inadequately addressed by both industrial and regulatory science. To aid chemists in avoiding this hazard, we propose an endocrine disruption testing protocol for use by chemists in the design of new chemicals. The Tiered Protocol for Endocrine Disruption (TiPED) has been created under the oversight of a scientific advisory committee composed of leading representatives from both green chemistry and the environmental health sciences. TiPED is conceived as a tool for new chemical design, thus it starts with a chemist theoretically at "the drawing board." It consists of five testing tiers ranging from broad in silico evaluation up through specific cell- and whole organism-based assays. To be effective at detecting endocrine disruption, a testing protocol must be able to measure potential hormone-like or hormone-inhibiting effects of chemicals, as well as the many possible interactions and signaling sequellae such chemicals may have with cell-based receptors. Accordingly, we have designed this protocol to broadly interrogate the endocrine system. The proposed protocol will not detect all possible mechanisms of endocrine disruption, because scientific understanding of these phenomena is advancing rapidly. To ensure that the protocol remains current, we have established a plan for incorporating new assays into the protocol as the science advances. In this paper we present the principles that should guide the science of testing new chemicals for endocrine disruption, as well as principles by which to evaluate individual assays for applicability, and laboratories for reliability. In a 'proof-of-principle' test, we ran 6 endocrine disrupting chemicals (EDCs) that act via different endocrinological mechanisms through the protocol using published literature. Each was identified as endocrine active by one or more tiers. We believe that this voluntary testing protocol will be a dynamic tool to facilitate efficient and early identification of potentially problematic chemicals, while ultimately reducing the risks to public health.
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| 6. |
- Ellis, W. Chadwick, et al.
(författare)
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Bis phenylene flattened 13-membered tetraamide macrocyclic ligand (TAML) for square planar cobalt(III)
- 2018
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Ingår i: Journal of coordination chemistry (Print). - : TAYLOR & FRANCIS LTD. - 0095-8972 .- 1029-0389. ; 71:11-13, s. 1822-1836
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Tidskriftsartikel (refereegranskat)abstract
- The preparation, characterization, and evaluation of a cobalt(III) complex [CO{(OC)2(o,o'-NC6H4NCO)2CMe2}(OH2)]- with 13-membered tetraamide macrocyclic ligand (TAML) is described. This is a square-planar (X-ray) S=1 paramagnetic (H-1 NMR) compound, which becomes an S=0 diamagnetic octahedral species in excess d(5)-pyridine. Its one-electron oxidation at an electrode is fully reversible with the lowest E-1/2 value (0.66V vs SCE) among all investigated Co-III TAML complexes. The oxidation results in a neutral blue species which is consistent with a Co-III/radical-cation ligand. The ease of oxidation is likely due to the two benzene rings incorporated in the ligand structure (whereas there is just one in many other Co-III TAMLs). The oxidized neutral species are unexpectedly EPR silent, presumably due to the -stacking aggregation. However, they display eight-line hyperfine patterns in the presence of excess of 4-tert-butylpyridine or 4-tert-butyl isonitrile. The EPR spectra are more consistent with the Co-III/radical-cation ligand formulation rather than with a Co-IV complex. Attempts to synthesize a similar vanadium complex under the same conditions as for cobalt using [(VO)-O-V(OCHMe2)(3)] were not successful. TAML-free decavanadate was isolated instead. [GRAPHICS] .
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| 7. |
- Ellis, W. Chadwick, et al.
(författare)
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Design of More Powerful Iron-TAML Peroxidase Enzyme Mimics
- 2009
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 131:50, s. 18052-
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Tidskriftsartikel (refereegranskat)abstract
- Environmentally useful, small molecule mimics of the peroxidase enzymes must exhibit very high reactivity in water near neutral pH. Here we describe the design and structural and kinetic characterization of a second generation of iron(III)-TAML activators with unprecedented peroxidase-mimicking abilities. Iterative design has been used to remove the fluorine that led to the best performers in first-generation iron-TAMLs. The result is a superior catalyst that meets a green chemistry objective by being comprised exclusively of biochemically common elements. The rate constants for bleaching at pH 7, 9, and 11 of the model substrate, Orange 11, shows that the new Fe-III-TAML has the fastest reactivity at pH's closer to neutral of any TAML activator to date. Under appropriate conditions, the new catalyst can decolorize Orange 11 without loss of activity for at least 10 half-lives, attesting to its exceptional properties as an oxidizing enzyme mimic.
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| 8. |
- Ellis, W. Chadwick, et al.
(författare)
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Designing Green Oxidation Catalysts for Purifying Environmental Waters
- 2010
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 132:28, s. 9774-9781
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Tidskriftsartikel (refereegranskat)abstract
- We describe the synthesis, characterization, aqueous behavior, and catalytic activity of a new generation of Fe-III-TAML (tetraamido macrocycle ligand) activators of peroxides (2), variants of [Fe{(OC)(2)(o,o'-NC6H4NCO)(2)CMe2}(OH2)(-)] (2d), which have been designed to be especially suitable for purifying water of recalcitrant oxidizable pollutants. Activation of H2O2 by 2 (k(I)) as a function of pH was analyzed via kinetic studies of Orange II bleaching. This was compared with the known behavior of the first generation of Fe-III-TAMLs (1). Novel reactivity features impact the potential for oxidant activation for water purification by 2d and its aromatic ring-substituted dinitro (2e) and tetrachloro (2f) derivatives. Thus, the maximum activity for 2e occurs at pH 9, the closest yet to the EPA guidelines for drinking water (6.5-8.5), allowing 2e to rapidly activate H2O2 at pH 7.7. In water, 2e has two axial water ligands with pK(a)'s of 8.4 and 10.0 (25 degrees C). The former is the lowest for all Fe-III-TAMLs developed to date and is key to 2e's exceptional catalytic activity in neutral and slightly basic solutions. Below pH 7, 2d was found to be quite sensitive to demetalation in phosphate buffers. This was overcome by iterative design to give 2e (hydrolysis rate 2d > 100 x 2e). Mechanistic studies highlight 2e's increased stability by establishing that to demetalate 2e at a comparable rate to which H2PO4- demetalates 2d, H3PO4 is required. A critical criterion for green catalysts for water purification is the avoidance of endocrine disruptors, which can impair aquatic life. Fe-III-TAMLs do not alter transcription mediated by mammalian thyroid, androgen, or estrogen hormone receptors, suggesting that 2 do not bind to the receptors and reducing concerns that the catalysts might have endocrine disrupting activity.
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| 9. |
- Polshin, Victor, et al.
(författare)
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Attaining control by design over the hydrolytic stability of Fe-TAML oxidation catalysts
- 2008
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 130:13, s. 4497-4506
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Tidskriftsartikel (refereegranskat)abstract
- The iron(III) complexes of tetra amidato macrocyclic ligands (TAMLs) ([Fe{1-X-1-2-X2C6H2-4,5-(NCOCMe2NCO)(2)CR2}(OH2)](-), 1: X-1 = X-2 = H, R-2 = Me-2 (a), R-2 = (CH2)(2) (b); X-1 = X-2 = Cl, R-2 = F-2, (c), etc.), which the proton is known to demetalate at pH < 3, are also subject to catalyzed demetalation by Bronsted acid buffer components at pH 4-9 such as H2PO4-, HSO3-, and CH3- CO2H, HO2CCH2CO2-. Buffers based on pyridine (py) and tris(hydroxymethyl)aminomethane (TRIS) are catalytically inactive. Where reactions proceed, the products are demetalated TAMLs and iron species of variable composition. Pseudo-first-order rate constants for the demetalation (k(obs)) are linear functions of the acid concentrations, and the effective second-order rate constants k(1),(eff) have a hyperbolic dependence on [H+] (k(1),eff = a(1)[H+]/(b(1)+[H+]). The rate of demetalation of 1a in H2PO4-/HPO42- buffer is appreciable, but the k(obs) values for 1b and 1c are immeasurably low, showing that the rates are strongly affected by the CR2 or "tail" fragments, which are known to potently affect the TAML basicity. The reactivities of 1 depend insignificantly on the aromatic ring or "head" group of 1. The proposed mechanism involves precoordination of the acidic buffer species followed by hydrolysis. The demetalating abilities of buffer species depend on their structures and acidities. Thus, although pyridine-2-carboxylic (picolinic) acid catalyzes the demetalation, its 3- and 4-isomers (nicotinic and isonicotininc acids) are inactive. The difference is rationalized to result from the ability that only coordinated picolinic acid has to deliver a proton to an amidato nitrogen in an intramolecular manner. The reaction order in picolinic acid equals one for la and two for 1a. For 1b, "inactive" pyridine and nicotinic acid speed up the demetalation in the presence of picolinic acid, suggesting that the second order arises from the axial binding of two pyridine molecules, one of which must be picolinic acid. The binding of pyridine- and imidazole-type ligands was confirmed by UV/vis equilibrium measurements and X-ray crystallography. The implications of these mechanistic findings for designing superior Fe-TAML oxidation catalysts and catalyst formulations are discussed using the results of DFT calculations.
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| 10. |
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