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Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88x10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10x10(-57)). After a correction for multiple comparisons (P-value

MOTIVATION: Structural alignments of proteins are important for identification of structural similarities, homology detection and functional annotation. The structural alignment problem is well studied and computationally difficult. Many different scoring schemes for structural similarity as well as many algorithms for finding high-scoring alignments have been proposed. Algorithms using contact map overlap (CMO) as scoring function are currently the only practical algorithms able to compute provably optimal alignments. RESULTS: We propose a new mathematical model for the alignment of inter-residue distance matrices, building upon previous work on maximum CMO. Our model includes all elements needed to emulate various scoring schemes for the alignment of protein distance matrices. The algorithm that we use to compute alignments is practical only for sparse distance matrices. Therefore, we propose a more effective scoring function, which uses a distance threshold and only positive structural scores. We show that even under these restrictions our approach is in terms of alignment accuracy competitive with state-of-the-art structural alignment algorithms, whereas it additionally either proves the optimality of an alignment or returns bounds on the optimal score. Our novel method is freely available and constitutes an important promising step towards truly provably optimal structural alignments of proteins. AVAILABILITY: An executable of our program PAUL is available at http://planet-lisa.net/.

Inflammatory bowel disease (IBD) typically manifests as either ulcerative colitis (UC) or Crohn's disease (CD). Systematic identification of susceptibility genes for IBD has thus far focused mainly on CD, and little is known about the genetic architecture of UC. Here we report a genome-wide association study with 440,794 SNPs genotyped in 1,167 individuals with UC and 777 healthy controls. Twenty of the most significantly associated SNPs were tested for replication in three independent European case-control panels comprising a total of 1,855 individuals with UC and 3,091 controls. Among the four consistently replicated markers, SNP rs3024505 immediately flanking the IL10 (interleukin 10) gene on chromosome 1q32.1 showed the most significant association in the combined verification samples (P = 1.35 × 10 -12; OR = 1.46 (1.31-1.62)). The other markers were located in ARPC2 and in the HLA-BTNL2 region. Association between rs3024505 and CD (1,848 cases, 1,804 controls) was weak (P = 0.013; OR = 1.17 (1.01-1.34)). IL10 is an immunosuppressive cytokine that has long been proposed to influence IBD pathophysiology. Our findings strongly suggest that defective IL10 function is central to the pathogenesis of the UC subtype of IBD. © 2008 Nature Publishing Group.