Phytanic acid impairs mitochondrial respiration through protonophoric action

Refsum disease is a rare, inherited neurodegenerative disorder characterized by accumulation of the dietary branched-chain fatty acid phytanic acid in plasma and tissues caused by a defect in the alphaoxidation pathway. The accumulation of phytanic acid is believed to be the main pathophysiological cause of the disease. However, the exact mechanism(s) by which phytanic acid exerts its toxicity have not been resolved. In this study, the effect of phytanic acid on mitochondrial respiration was investigated. The results show that in digitonin-permeabilized fibroblasts, phytanic acid decreases ATP synthesis, whereas substrate oxidation per se is not affected. Importantly, studies in intact fibroblasts revealed that phytanic acid decreases both the mitochondrial membrane potential and NAD(P)H autofluorescence. Taken together, the results described here show that unesterified phytanic acid exerts its toxic effect mainly through its protonophoric action, at least in human skin fibroblasts. Received 4 August 2007; received after revision 26 September 2007; accepted 10 October 2007 J. C. Komen, F. Distelmaier: These authors contributed equally to this work.     

Influence of Microstructure and Sintering Routes on Transport Properties of Apatite Materials for Fuel Cells

1 Results Oxy-apatite materials are thought as zirconia-substitutes in Solid Oxide Fuel Cells due to their fast ionic conduction. However, the well known difficulties related to their densification prevent them from being used as such. This study presents strategies to obtain oxy-apatite dense materials and the influence of elaboration route on transport properties. Particular emphasis is put on the microstructure effect on ion conduction. By the combined use of freeze-drying and conventional or spark p...     

The serini reaction

Zusammenfassung Der Mechanismus der Serini-Reaktion wird kurz erörtert und ein 17, 20-Oxyd als Zwischenprodukt vorgeschlagen. Das stereochemische Ergebnis der Reaktion soll von zwei Faktoren abhängig sein, und zwar: 1. von der Geometrie des « transition state » und 2. von der Konfiguration des Oxydrings. Ausgehend von diesen Überlegungen, kann vorausgesagt werden, daßReichsteins Substanz 0-Diacetat durch die Serini-Reaktion in ein 17-Iso-20-keton und nicht in ein 17-Normal-20-keton umgewandelt werden soll. Tatsächlich ist das 17-Isoallopregnanol-(3)-on-20 als einziges Produkt experimentell aufgefunden worden.     

Solving Non-Uniqueness in Agglomerative Hierarchical Clustering Using Multidendrograms

In agglomerative hierarchical clustering, pair-group methods suffer from a problem of non-uniqueness when two or more distances between different clusters coincide during the amalgamation process. The traditional approach for solving this drawback has been to take any arbitrary criterion in order to break ties between distances, which results in different hierarchical classifications depending on the criterion followed. In this article we propose a variable-group algorithm that consists in grouping more than two clusters at the same time when ties occur. We give a tree representation for the results of the algorithm, which we call a multidendrogram, as well as a generalization of the Lance andWilliams’ formula which enables the implementation of the algorithm in a recursive way. The authors thank A. Arenas for discussion and helpful comments. This work was partially supported by DGES of the Spanish Government Project No. FIS2006–13321–C02–02 and by a grant of Universitat Rovira i Virgili.     

A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 x 10(-7)) was in the KIAA1109-TENR-IL2-IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5' of IL21; meta-analysis P = 1.3 x 10(-14), odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.     

The human genome and understanding of common disease: present and future technologies

The study of candidate genes over the past three decades has yielded notable successes in common-disease genetics. During this time, however, interpretation of genetic association studies has been hampered by the use of clinical cohorts of inadequate power and insufficient information on genetic variation in candidate genes. The unavailability of highthroughput and low-cost genotyping technologies has also limited the scope of complex-disease genetic studies. More recently, however, the sequencing and characterization of variation within the human genome has revolutionized genetic studies and enabled full genome-wide scans for genes associated with disease. The identification of disease-associated (causative) genes has illuminated disease mechanisms. The translation of this knowledge into direct clinical benefit in diagnosis, prognosis and therapy for an individual’s disease still remains a challenge. Received 11 September 2006; received after revision 17 December 2006; accepted 18 January 2007     

Genetic studies of diseases

Pancreatitis is usually inflammation of the pancreas without infection. Our understanding of pancreatitis has been built on autopsy studies, surgical biopsies and surrogate markers of inflammation and fibroses, including abdominal imaging techniques and pancreatic functional studies. However, the discovery that a number of different environmental factors and various genetic abnormalities are seen in patients with similar appearing pancreatitis phenotypes teaches us that end-stage pathology is not the disorder. Understanding complex associations and interactions requires that the components and their interactions be organized, stratified and functionally defined. Systems biology, in the broad sense, provides the approach and tools to define the complex mechanisms driving pathology. As the mathematics behind these pathways and mechanisms are defined and calibrated, the potential pathology of patients with early signs of disease can be predicted, and a number of patient-specific targets for intervention can be defined.