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| 62. |
- Nicoletti, Paola, et al.
(författare)
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Shared Genetic Risk Factors Across Carbamazepine-Induced Hypersensitivity Reactions
- 2019
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Ingår i: Clinical Pharmacology and Therapeutics. - : John Wiley & Sons. - 0009-9236 .- 1532-6535. ; 106:5, s. 1028-1036
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Tidskriftsartikel (refereegranskat)abstract
- Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 x 10(-9)) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 x 10(-9)) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.
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| 63. |
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| 64. |
- Patel, Jayendra Z., et al.
(författare)
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Chiral 1,3,4-Oxadiazol-2-ones as Highly Selective FAAH Inhibitors
- 2013
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 56:21, s. 8484-8496
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Tidskriftsartikel (refereegranskat)abstract
- In the present study, identification of chiral 1,3,4-oxadiazol-2-ones as potent and selective FAAH inhibitors has been described. The separated enantiomers showed clear differences in the potency and selectivity toward both FAAH and MAGL. Additionally, the importance of the chirality on the inhibitory activity and selectivity was proven by the simplification approach by removing a methyl group at the 3-position of the 1,3,4-oxadiazol-2-one ring. The most potent compound of the series, the S-enantiomer of 3-(1-(4-isobutylphenyl)ethyl)-5-methoxy-1,3,4-oxadiazol-2(3H)-one (JZP-327A, Si), inhibited human recombinant FAAH (hrFAAH) in the low nanomolar range (IC50 = 11 mu M), whereas its corresponding R-enantiomer 52 showed only moderate inhibition toward hrFAAH (IC50 = 0.24 mu M). In contrast to hrFAAH, R-enantiomer 52 was more potent in inhibiting the activity of hrMAGL compared to S-enantiomer 51 (IC50 = 4.0 mu M and 16% inhibition at 10 mu M, respectively). The FAAH selectivity of the compound Si over the supposed main off-targets, MAGL and COX, was found to be >900-fold. In addition, activity-based protein profiling (ABPP) indicated high selectivity over other serine hydrolases. Finally, the selected Senantiomers 51, 53, and 55 were shown to be tight binding, slowly reversible inhibitors of the hrFAAH.
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| 65. |
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| 66. |
- Pulkkinen, T. I., et al.
(författare)
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Magnetospheric modes and solar wind energy coupling efficiency
- 2010
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Ingår i: Journal of Geophysical Research. - 0148-0227 .- 2156-2202. ; 115:3, s. A03207-
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Tidskriftsartikel (refereegranskat)abstract
- Using observations and two different global MHD simulations, we demonstrate that the solar wind speed controls the magnetospheric response such that the higher the speed, the more dynamic and irregular is the magnetospheric response. For similar level of driving solar wind electric field, the magnetospheric modes can be organized in terms of speed: Low speed produces steady convection events, intermediate speeds result in periodic sawtooth oscillations, and high speeds drive large geomagnetic storms. We show that the control parameter of energy transfer and coupling is the electric field along the large-scale X line. We demonstrate using global MHD simulations that for slowly varying interplanetary magnetic field (IMF), the reconnection line is tilted approximately by an angle theta/2, where theta is the IMF clock angle. Then, for clock angles away from northward, the magnetospheric energy entry and response scale with the electric field along the reconnection line (E-PAR), rather than the traditionally used E-Y. If we define the energy coupling efficiency as response/E-PAR, we can show it to be independent of the IMF clock angle and only weakly dependent on the solar wind dynamic pressure. These results demonstrate the ability of the localized reconnection line to control the energy input through the entire magnetopause.
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| 67. |
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| 68. |
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| 69. |
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| 70. |
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