| 1. |
- Zhou, XP, et al.
(author)
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Non-coding variability at the APOE locus contributes to the Alzheimer's risk
- 2019
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3310-
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Journal article (peer-reviewed)abstract
- Alzheimer’s disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood. High-throughput genome-wide chromosome conformation capture analysis further supports the roles of these risk haplotypes in modulating chromatin states and gene expression in the brain. Our findings provide compelling evidence for additional risk factors in the APOE locus that contribute to AD pathogenesis.
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| 2. |
- Covarrubias, Yesenia, et al.
(author)
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Pilot study on longitudinal change in pancreatic proton density fat fraction during a weight-loss surgery program in adults with obesity
- 2019
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In: Journal of Magnetic Resonance Imaging. - : WILEY. - 1053-1807 .- 1522-2586. ; 50:4, s. 1092-1102
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Journal article (peer-reviewed)abstract
- Background Quantitative-chemical-shift-encoded (CSE)-MRI methods have been applied to the liver. The feasibility and potential utility CSE-MRI in monitoring changes in pancreatic proton density fat fraction (PDFF) have not yet been demonstrated. Purpose To use quantitative CSE-MRI to estimate pancreatic fat changes during a weight-loss program in adults with severe obesity and nonalcoholic fatty liver disease (NAFLD). To explore the relationship of reduction in pancreatic PDFF with reductions in anthropometric indices. Study Type Prospective/longitudinal. Population Nine adults with severe obesity and NAFLD enrolled in a weight-loss program. Field Strength/Sequence CSE-MRI fat quantification techniques and multistation-volumetric fat/water separation techniques were performed at 3 T. Assessment PDFF values were recorded from parametric maps colocalized across timepoints. Statistical Tests Rates of change of log-transformed variables across time were determined (linear-regression), and their significance assessed compared with no change (Wilcoxon test). Rates of change were correlated pairwise (Spearmans correlation). Results Mean pancreatic PDFF decreased by 5.7% (range 0.7-17.7%) from 14.3 to 8.6%, hepatic PDFF by 11.4% (2.6-22.0%) from 14.8 to 3.4%, weight by 30.9 kg (17.3-64.2 kg) from 119.0 to 88.1 kg, body mass index by 11.0 kg/m(2) (6.3-19.1 kg/m(2)) from 44.1 to 32.9 kg/m(2), waist circumference (WC) by 25.2 cm (4.0-41.0 cm) from 133.1 to 107.9 cm, HC by 23.5 cm (4.5-47.0 cm) from 135.8 to 112.3 cm, visceral adipose tissue (VAT) by 2.9 L (1.7-5.7 L) from 7.1 to 4.2 L, subcutaneous adipose tissue (SCAT) by 4.0 L (2.9-7.4 L) from 15.0 to 11.0 L. Log-transformed rate of change for pancreatic PDFF was moderately correlated with log-transformed rates for hepatic PDFF, VAT, SCAT, and WC (rho = 0.5, 0.47, 0.45, and 0.48, respectively), although not statistically significant. Data Conclusion Changes in pancreatic PDFF can be estimated by quantitative CSE-MRI in adults undergoing a weight-loss surgery program. Pancreatic and hepatic PDFF and anthropometric indices decreased significantly. Technical Efficacy Stage: 1 J. Magn. Reson. Imaging 2019;50:1092-1102.
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| 3. |
- Silkstone, R S, et al.
(author)
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The βLys66Tyr Variant of Human Hemoglobin as a Component of a Blood Substitute.
- 2016
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In: Advances in Experimental Medicine and Biology. - New York, NY : Springer New York. - 0065-2598. ; 876, s. 455-460
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Journal article (peer-reviewed)abstract
- It has been proposed that introducing tyrosine residues into human hemoglobin (e.g. βPhe41Tyr) may be able to reduce the toxicity of the ferryl heme species in extracellular hemoglobin-based oxygen carriers (HBOC) by facilitating long-range electron transfer from endogenous and exogenous antioxidants. Surface-exposed residues lying close to the solvent exposed heme edge may be good candidates for mutations. We therefore studied the properties of the βLys66Tyr mutation. Hydrogen peroxide (H2O2) was added to generate the ferryl protein. The ferryl state in βLys66Tyr was more rapidly reduced to ferric (met) by ascorbate than recombinant wild type ((r)wt) or βPhe41Tyr. However, βLys66Tyr suffered more heme and globin damage following H2O2 addition as measured by UV/visible spectroscopy and HPLC analysis. βLys66Tyr differed notably from the (r)wt protein in other ways. In the ferrous state the βLys66Tyr forms oxy, CO, and NO bound heme complexes similar to (r)wt. However, the kinetics of CO binding to the mutant was faster than (r)wt, suggesting a more open heme crevice. In the ferric (met) form the typical met Hb acid-alkaline transition (H2O to (-)OH) appeared absent in the mutant protein. A biphasicity of cyanide binding was also evident. Expression in E. coli of the βLys66Tyr mutant was lower than the (r)wt protein, and purification included significant protein heterogeneity. Whilst, βLys66Tyr and (r)wt autoxidised (oxy to met) at similar rates, the oxygen p50 for βLys66Tyr was very low. Therefore, despite the apparent introduction of a new electron transfer pathway in the βLys66Tyr mutant, the heterogeneity, and susceptibility to oxidative damage argue against this mutant as a suitable starting material for a HBOC.
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| 5. |
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| 6. |
- Simons, Michelle, et al.
(author)
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Comparison of the oxidative reactivity of recombinant fetal and adult human hemoglobin : implications for the design of hemoglobin-based oxygen carriers
- 2018
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In: Bioscience Reports. - 0144-8463. ; 38:4
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Journal article (peer-reviewed)abstract
- Hemoglobin (Hb)-based oxygen carriers (HBOCs) have been engineered to replace or augment the oxygen carrying capacity of erythrocytes. However, clinical results have generally been disappointing, in part due to the intrinsic oxidative toxicity of Hb. The most common HBOC starting material is adult human or bovine Hb. However, it has been suggested that fetal Hb may offer advantages due to decreased oxidative reactivity. Large-scale manufacturing of HBOC will likely and ultimately require recombinant sources of human proteins. We, therefore, directly compared the functional properties and oxidative reactivity of recombinant fetal (rHbF) and recombinant adult (rHbA) Hb. rHbA and rHbF produced similar yields of purified functional protein. No differences were seen in the two proteins in: autoxidation rate; the rate of hydrogen peroxide reaction; NO scavenging dioxygenase activity; and the NO producing nitrite reductase activity. The rHbF protein was: less damaged by low levels of hydrogen peroxide; less damaging when added to human umbilical vein endothelial cells (HUVEC) in the ferric form; and had a slower rate of intrinsic heme loss. The rHbA protein was: more readily reducible by plasma antioxidants such as ascorbate in both the reactive ferryl and ferric states; less readily damaged by lipid peroxides; and less damaging to phosphatidylcholine liposomes. In conclusion in terms of oxidative reactivity, there are advantages and disadvantages to the use of rHbA or rHbF as the basis for an effective HBOC.
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