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- Aad, G., et al.
(författare)
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- 2011
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swepub:Mat__t (refereegranskat)
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| 2. |
- Ahmadi, Ahmad, et al.
(författare)
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Association of a protective paraoxonase 1 (PON1) polymorphism in Parkinson's disease
- 2012
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 522:1, s. 30-35
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Tidskriftsartikel (refereegranskat)abstract
- Pesticide exposure has been suggested to increase the risk to develop Parkinson's disease (PD). The arylesterase paraoxonase 1 (PON1) is mainly expressed in the liver and hydrolyzes organophosphates such as pesticides. The polymorphism Leu54Met (rs854560) in PON1, impairing enzyme activity and leading to decreased PON1 expression levels, has been reported to be associated with Parkinson's disease (PD). PON1 is part of a cluster on chromosome 7q21.3 together with PON2 and PON3. We investigated the occurrence of four additional polymorphisms in PON1 and two in PON2 in a Swedish PD case-control material. We found a significant association (p = 0.007) with a PON1 promoter polymorphism, rs854571. The minor allele was more common among controls than PD cases which suggest a protective effect. This is strengthened by the fact that rs854571 is in strong linkage disequilibrium with another PON1 promoter polymorphism, rs854572, reported to increase PON1 gene expression. Our findings support the hypothesis that PON1 is involved in the etiology of PD and that higher PON1 levels are reducing the risk for PD. (C) 2012 Elsevier Ireland Ltd. All rights reserved.
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| 6. |
- Karlsson, Björn C. G., et al.
(författare)
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How warfarin’s structural diversity influences its phospholipid bilayer membrane permeation
- 2013
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Ingår i: Journal of Physical Chemistry B. - : American Chemical Society (ACS). - 1520-6106 .- 1520-5207. ; 117:8, s. 2384-2395
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Tidskriftsartikel (refereegranskat)abstract
- The role of the structural diversity of the widely used anticoagulant drug warfarin on its distribution in 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) bilayer membranes was investigated using a series of both restrained (umbrella sampling) and unrestrained molecular dynamics simulations. Data collected from unrestrained simulations revealed favorable positions for neutral isomers of warfarin, the open side chain form (OCO), and the cyclic hemiketal (CCO), along the bilayer normal close to the polar headgroup region and even in the relatively distant nonpolar lipid tails. The deprotonated open side chain form (DCO) was found to have lower affinity for the DOPC bilayer membrane relative to the neutral forms, with only a small fraction interacting with the membrane, typically within the polar headgroup region. The conformation of OCO inside the lipid bilayer was found to be stabilized by intramolecular hydrogen bonding thereby mimicking the structure of CCO. Differences in free energies, for positions of OCO and CCO inside the bilayer membrane, as compared to positions in the aqueous phase, were −97 and −146 kJ·mol–1. Kinetic analysis based on the computed free energy barriers reveal that warfarin will diffuse through the membranes within hours, in agreement with experimental results on warfarin’s accumulation in the plasma, thus suggesting a passive diffusion mechanism. We propose that this membrane transport may be an isomerization-driven process where warfarin adapts to the various local molecular environments encountered under its journey through the membrane. Collectively, these results improve our understanding of the influence of warfarin’s structural diversity on the drug’s distribution and bioavailability, which in turn may provide insights for developing new formulations of this important pharmaceutical to better address its narrow therapeutic window.
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| 7. |
- Quax, Tessa E. F., et al.
(författare)
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Differential Translation Tunes Uneven Production of Operon-Encoded Proteins
- 2013
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 4:5, s. 938-944
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Tidskriftsartikel (refereegranskat)abstract
- Clustering of functionally related genes in operons allows for coregulated gene expression in prokaryotes. This is advantageous when equal amounts of gene products are required. Production of protein complexes with an uneven stoichiometry, however, requires tuning mechanisms to generate subunits in appropriate relative quantities. Using comparative genomic analysis, we show that differential translation is a key determinant of modulated expression of genes clustered in operons and that codon bias generally is the best in silico indicator of unequal protein production. Variable ribosome density profiles of polycistronic transcripts correlate strongly with differential translation patterns. In addition, we provide experimental evidence that de novo initiation of translation can occur at intercistronic sites, allowing for differential translation of any gene irrespective of its position on a polycistronic messenger. Thus, modulation of translation efficiency appears to be a universal mode of control in bacteria and archaea that allows for differential production of operon-encoded proteins.
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| 10. |
- Zhao, Liyun, et al.
(författare)
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Glacier volume and area change by 2050 in high mountain Asia
- 2014
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Ingår i: Global and Planetary Change. - : Elsevier BV. - 0921-8181 .- 1872-6364. ; 122, s. 197-207
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Tidskriftsartikel (refereegranskat)abstract
- We estimate individual area and volume change by 2050 of all 67,028 glaciers, with a total area of 122,969 km(2), delineated in the Randolph Glacier Inventory 2.0 of high mountain Asia (HMA). We used the 25 km resolution regional climate model RegCM 3.0 temperature and precipitation change projections forced by the IPCC A1B scenario. Glacier simulations were based on a novel surface mass balance-altitude parameterization fitted to observational data, and various volume-area scaling approaches using Shuttle Radar Topography Mission surface topography of each individual glacier. We generate mass balance-altitude relations for all the glaciers by region using nearest available glacier measurements. Equilibrium line altitude (ELA) sensitivities to temperature and precipitation change vary by region based on the relative importance of sublimation and melting processes. We also made simulations with mass balance tuned to match satellite observations of glacier thickness changes in HMA from 2003 to 2009. Net mass loss is half as much using the tuned model than using just glaciological calibration data, suggesting the representativity of benchmark glaciers is a larger source of uncertainty in future HIM contributions to sea level rise than errors in glacier inventories or volume-area scaling. Both models predict that about 35% of the glaciers in Karakoram and the northwestern Himalaya are advancing, which is consistent with the observed slight mass gain of glaciers in these regions in recent years. However, we find that 76% of all the glaciers will retreat, most of which are of the maritime type. We project total glacier area loss in high mountain Asia in 2050 to be 22% (in the tuned model) or 35% (un-tuned) of their extent in 2000, and they will contribute 5 mm (tuned model) to global sea level rise.
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