A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson's disease

The dual-hit hypothesis of Parkinson's disease (PD) originally postulated that a neurotropic pathogen leads to formation of alpha-synuclein pathology in the olfactory bulb (OB) and dorsal motor nucleus of the vagus (DMV) and then invades the brain from these two entry points. Little work has been conducted to validate an important underlying premise for the dual-hit hypothesis, namely that the initial Lewy pathology does arise simultaneously in the OB and the enteric nervous system (ENS) plexuses and DMV at the earliest disease stage. We conducted a focused re-analysis of two postmortem datasets, which included large numbers of mild Lewy body disease (LBD) cases. We found that cases with alpha-synuclein pathology restricted to the peripheral autonomic nervous system and/or lower brainstem (early body-first LBD cases) very rarely had any OB pathology, suggesting that Lewy pathology commonly arises in the ENS without concomitant involvement of the OB. In contrast, cases with mild amygdala-predominant Lewy pathology (early brain-first LBD cases) nearly always showed OB pathology. This is compatible with the first pathology being triggered in the OB or amygdala followed by secondary spreading to connected structures, but without early involvement of the ENS or lower brainstem. These observations support that the pathologic process starts in either the olfactory bulb or the ENS, but rarely in the olfactory bulb and gut simultaneously. More studies on neuropathological datasets are warranted to reproduce these findings. The agreement between the revised single-hit hypothesis and the recently proposed brain-first vs. body-first model of LBD is discussed.Peer reviewe

Alpha-synuclein pathology of olfactory bulbs/peduncles in the Vantaa85+cohort exhibit two divergent patterns : a population-based study

Peer reviewe

Genotyping of human cytochrome P450 2A6 (CYP2A6), a nicotine C-oxidase

AbstractCytochrome P450 2A6 (CYP2A6) is a polymorphic enzyme responsible for the oxidation of certain precarcinogens and drugs and is the major nicotine C-oxidase. The role of CYP2A6 for nicotine elimination was emphasised recently by the finding that smokers carrying defective CYP2A6 alleles consumed fewer cigarettes [Pianezza et al. (1998) Nature 393, 750]. The method used for CYP2A6 genotyping has, however, been found to give erroneous results with respect to the coumarin hydroxylase phenotype, a probe reaction for the CYP2A6 enzyme. The present study describes an allele-specific PCR genotyping method that identifies the major defective CYP2A6 allele and accurately predicts the phenotype. An allele frequency of 1–3% was observed in Finnish, Spanish, and Swedish populations, much lower than described previously

Species and habitats in danger : estimating the relative risk posed by oil spills in the northern Baltic Sea

Large-scale oil spills can have adverse effects on biodiversity in coastal areas where maritime oil transportation is intense. In this article we conducted a spatial risk assessment to study the risk that potential tanker accidents pose to threatened habitat types and species living in the northern Baltic Sea, which has witnessed a rapid increase in maritime oil transportation within the past two decades. We applied a probabilistic method, which combines three components: a Bayesian network describing tanker accidents and uncertainties related to them, probabilistic maps showing the movement of oil, and a database of threatened species and habitats in the area. The results suggest that spatial risk posed by oil spills varies across the area, and does not correspond, for example, to the frequency of accidents in a given area. The relative risk is highest for seashore meadows, which is important to take into account when managing these habitats. Our analysis underlines the importance of a thorough risk assessment, which is not only based solely on one or two specific factors such as accident probabilities or the trajectories of spilled oil but also contains as broad a view of the consequences as possible. We believe that the probabilistic methodology applied in the study will be of high interest to people who have to cope with uncertainties typical for environmental risk assessment and management.Peer reviewe

E. coli Histidine Triad Nucleotide Binding Protein 1 (ecHinT) Is a Catalytic Regulator of D-Alanine Dehydrogenase (DadA) Activity In Vivo

Histidine triad nucleotide binding proteins (Hints) are highly conserved members of the histidine triad (HIT) protein superfamily. Hints comprise the most ancient branch of this superfamily and can be found in Archaea, Bacteria, and Eukaryota. Prokaryotic genomes, including a wide diversity of both Gram-negative and Gram-positive bacteria, typically have one Hint gene encoded by hinT (ycfF in E. coli). Despite their ubiquity, the foundational reason for the wide-spread conservation of Hints across all kingdoms of life remains a mystery. In this study, we used a combination of phenotypic screening and complementation analyses with wild-type and hinT knock-out Escherichia coli strains to show that catalytically active ecHinT is required in E. coli for growth on D-alanine as a sole carbon source. We demonstrate that the expression of catalytically active ecHinT is essential for the activity of the enzyme D-alanine dehydrogenase (DadA) (equivalent to D-amino acid oxidase in eukaryotes), a necessary component of the D-alanine catabolic pathway. Site-directed mutagenesis studies revealed that catalytically active C-terminal mutants of ecHinT are unable to activate DadA activity. In addition, we have designed and synthesized the first cell-permeable inhibitor of ecHinT and demonstrated that the wild-type E. coli treated with the inhibitor exhibited the same phenotype observed for the hinT knock-out strain. These results reveal that the catalytic activity and structure of ecHinT is essential for DadA function and therefore alanine metabolism in E. coli. Moreover, they provide the first biochemical evidence linking the catalytic activity of this ubiquitous protein to the biological function of Hints in Escherichia coli

POLICY PREFERENCE FORMATION IN LEGISLATIVE POLITICS:STRUCTURES, ACTORS, AND FOCAL POINTS

This dissertation introduces and tests a model of policy preference formation in legislative politics. Emphasizing a dynamic relationship between structure, agent, and decision-making process, it ties the question of policy choice to the dimensionality of the normative political space and the strategic actions of parliamentary agenda-setters. The model proposes that structural factors, such as ideology, shape policy preferences to the extent that legislative specialists successfully link them to specific policy proposals through the provision of informational focal points. These focal points shift attention toward particular aspects of a legislative proposal, thus shaping the dominant interpretation of its content and consequences and, in turn, individual-level policy preferences. The propositions of the focal point model are tested empirically with data from the European Parliament (EP), using both qualitative (interview data, content analyses of parliamentary debates) and quantitative methods (multinomial logit regression analyses of roll-call votes). The findings have implications for our understanding of politics and law-making in the European Union and for the study of legislative decision-making more generally