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ABSTRACTCystic fibrosis (CF) is a monogenic disease, characterized by massive chronic lung inflammation. The observed variability in clinical phenotypes in monozygotic CF twins is likely associated with the extent of inflammation. This study sought to investigate inflammation-related aberrant DNA methylation in CF twins and to determine to what extent acquired methylation changes may be associated with lung cancer.Blood-based genome-wide DNA methylation analysis was performed to compare the DNA methylomes of monozygotic twins, from the European CF Twin and Sibling Study with various degrees of disease severity. Putatively inflammation-related and differentially methylated positions were selected from a large lung cancer case-control study and investigated in blood by targeted bisulphite next-generation-sequencing. An inflammation-related locus located in the Plakophilin-3(PKP3) gene was functionally analysed regarding promoter and enhancer activity in presence and absence of methylation using luciferase reporter assays.We confirmed in a unique cohort that monozygotic twins, even if clinically discordant, have only minor differences in global DNA methylation patterns and blood cell composition. Further, we determined the most differentially methylated positions, a high proportion of which are blood cell-type-specific, whereas others may be acquired and thus have potential relevance in the context of inflammation as lung cancer risk factors. We identified a sequence in the gene body of PKP3which is hypermethylated in blood from CF twins with severe phenotype and highly variably methylated in lung cancer patients and controls, independent of known clinical parameters, and showed that this region exhibits methylation-dependent promoter activity in lung epithelial cells.

We present the assessment of the CASP4 fold recognition category. The tasks we had to execute include the splitting of multidomain targets into single domains, the classification of target domains in terms of prediction categories, the numerical evaluation of predictions, the mapping of numerical scores to quality indices, the ranking of predictors, the selection of top‐performing groups, and the analysis and critical discussion of the state of the art in this field. The 125 fold recognition groups were assessed by a total score that summarizes their performance over all targets and a quality score reflecting the average quality of the submitted models. Most of the top‐performing groups achieved respectable results on both scores simultaneously. Several groups submitted models that were much closer to the respective target structures than any of the known folds in the Protein Data Bank. The CASP4 assessment included the automated servers of the parallel CAFASP experiment. For the total score, the highest rank achieved by a fully automated server is 12. Two thirds of the predictors have rather low scores. Proteins 2001;Suppl 5:55–67. © 2002 Wiley‐Liss, Inc.

We present the assessment of the CASP4 fold recognition category. The tasks we had to execute include the splitting of multidomain targets into single domains, the classification of target domains in terms of prediction categories, the numerical evaluation of predictions, the mapping of numerical scores to quality indices, the ranking of predictors, the selection of top-performing groups, and the analysis and critical discussion of the state of the art in this field. The 125 fold recognition groups were assessed by a total score that summarizes their performance over all targets and a quality score reflecting the average quality of the submitted models. Most of the top-performing groups achieved respectable results on both scores simultaneously. Several groups submitted models that were much closer to the respective target structures than any of the known folds in the Protein Data Bank. The CASP4 assessment included the automated servers of the parallel CAFASP experiment. For the total score, the highest rank achieved by a fully automated server is 12. Two thirds of the predictors have rather low scores. Proteins 2001;Suppl 5:55–67. © 2002 Wiley-Liss, Inc.

The genome sciences face the challenge to characterize structure and function of a vast number of novel genes. Sequence search techniques are used to infer functional and structural information from similarities to experimentally characterized genes or proteins. The persistent goal is to refine these techniques and to develop alternative and complementary methods to increase the range of reliable inference.

We describe the results obtained using fold recognition techniques in our third participation in the CASP experiment. The approach relies on knowledge‐based potentials for alignment production and fold identification. As indicated by the increase in alignment quality and fold identification reliability, the predictions improved from CASP1 to CASP3. In particular, we identified structural relationships in which no known evolutionary link exists. Our predictions are based on single sequences rather than multiple sequence alignments. Additionally, we voluntarily submitted only a single model for each target because, in our view, submission of a single model is the most stringent test. We describe the methods used, the strategy adopted in the predictions, and the prediction results and discuss future work. Proteins Suppl 1999;3:112–120. © 1999 Wiley‐Liss, Inc.

We describe the results obtained using fold recognition techniques in our third participation in the CASP experiment. The approach relies on knowledge-based potentials for alignment production and fold identification. As indicated by the increase in alignment quality and fold identification reliability, the predictions improved from CASP1 to CASP3. In particular, we identified structural relationships in which no known evolutionary link exists. Our predictions are based on single sequences rather than multiple sequence alignments. Additionally, we voluntarily submitted only a single model for each target because, in our view, submission of a single model is the most stringent test. We describe the methods used, the strategy adopted in the predictions, and the prediction results and discuss future work. Proteins Suppl 1999;3:112–120. © 1999 Wiley-Liss, Inc.