| 1. |
- Horvath, Istvan, et al.
(författare)
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Modulation of α-synuclein fibrillization by ring-fused 2-pyridones : templation and inhibition involve oligomers with different structure
- 2013
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Ingår i: Archives of Biochemistry and Biophysics. - : Elsevier. - 0003-9861 .- 1096-0384. ; 532:2, s. 84-90
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Tidskriftsartikel (refereegranskat)abstract
- In a recent study we discovered that a ring-fused 2-pyridone compound triggered fibrillization of a key protein in Parkinson's disease, α-synuclein. To reveal how variations in compound structure affect protein aggregation, we now prepared a number of strategic analogs and tested their effects on α-synuclein amyloid fiber formation in vitro. We find that, in contrast to the earlier templating effect, some analogs inhibit α-synuclein fibrillization. For both templating and inhibiting compounds, the key species formed in the reactions are α-synuclein oligomers that contain compound. Despite similar macroscopic appearance, the templating and inhibiting oligomers are distinctly different in secondary structure content. When the inhibitory oligomers are added in seed amounts, they inhibit fresh α-synuclein aggregation reactions. Our study demonstrates that small chemical changes to the same central fragment can result in opposite effects on protein aggregation.
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| 2. |
- Pocock, Stuart, et al.
(författare)
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International differences in treatment effect : do they really exist and why?
- 2013
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 34:24, s. 1846-1852
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Tidskriftsartikel (refereegranskat)abstract
- With the increasing globalization of clinical trials, the opportunity exists to explore potential geographic differences in treatment effect within any major trial. Such geographic differences may arise because of international differences in patient selection, medical practice, or evaluation of outcomes, and such international variations need better documentation in trial reports. Appropriate pre-defined statistical analyses, including statistical tests of interaction regarding geographic heterogeneity in treatment effect, are important. Geographic variations are a particularly tricky form of subgroup analysis: they lack statistical power, are at best hypothesis-generating and can generate more confusion than insight. Referring to key examples, e.g. the PLATO and MERIT-HF, we emphasize the need for caution in interpreting evidence of potential geographic inconsistencies in treatment effect. Although it is appropriate to explore any biological or practical reasons for apparent geographic anomalies in treatment effect, the play of chance is often the most plausible and wise interpretation.
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| 3. |
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| 4. |
- Sellstedt, Magnus, et al.
(författare)
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Four-Component Assembly of Natural-Product-Like Ring-Fused Isoquinuclidines
- 2013
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Ingår i: European Journal of Organic Chemistry. - : John Wiley & Sons. - 1434-193X .- 1099-0690. ; 2013:33, s. 7476-7479
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Tidskriftsartikel (refereegranskat)abstract
- A four-component reaction between formyl-substituted 2-pyridones, aldehydes, amines, and activated alkenes has been developed. The resulting products are ring-fused natural-product-like isoquinuclidines. Three carbon–carbon bonds, two carbon–nitrogen bonds, and four or five stereocentres are formed in the reaction with overall product yields in the range 23–67 %. In most cases a single diastereomer was obtained. An intramolecular version of the reaction yielded analogues of the multi-ring-fused natural product catharanthine in a single step.
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