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MOTIVATION: The genome projects produce a wealth of protein sequences. Theoretical methods to predict possible structures and functions are needed for screening purposes, large-scale comparisons and in-depth analysis to identify worthwhile targets for further experimental research. Sequence-structure alignment is a basic tool for the identification of model folds for protein sequences and the construction of crude structural models. Empirical contact potentials (potentials of mean force) are used to optimize and evaluate such alignments. RESULTS: We propose new scoring schemes based on a contact definition derived from Voronoi decompositions of the three-dimensional coordinates of protein structures. We demonstrate that Voronoi potentials are superior to pure distance-based contact potentials with respect to recognition rate and significance for native folds. Moreover, the scoring scheme has the potential to provide a reasonable balance of detail and ion such that it is also useful for the recognition of distantly related (both homologous and non-homologous) proteins. This is demonstrated here on a set of structural alignments showing much better correspondence of native and model scores for the Voronoi potentials as compared to conventional distance-based potentials.
We propose a new alignment procedure that is capable of aligning protein sequences and structures in a unified manner. Recursive dynamic programming (RDP) is a hierarchical method which, on each level of the hierarchy, identifies locally optimal solutions and assembles them into partial alignments of sequences and/or structures. In contrast to classical dynamic programming, RDP can also handle alignment problems that use objective functions not obeying the principle of prefix optimality, e.g.\ scoring schemes derived from energy potentials of mean force. For such alignment problems, RDP aims at computing solutions that are near-optimal with respect to the involved cost function and biologically meaningful at the same time. Towards this goal, RDP maintains a dynamic balance between different factors governing alignment fitness such as evolutionary relationships and structural preferences. As in the RDP method gaps are not scored explicitly, the problematic assignment of gap cost parameters is circumvented. In order to evaluate the RDP approach we analyse whether known and accepted multiple alignments based on structural information can be reproduced with the RDP method. For this purpose, we consider the family of ferredoxins as our prime example. Our experiments show that, if properly tuned, the RDP method can outperform methods based on classical sequence alignment algorithms as well as methods that take purely structural information into account.
Autoimmune lymphoproliferative syndrome is frequently caused by mutations in genes involved in the Fas death receptor pathway, but for 20–30% of patients the genetic defect is unknown. We observed that treatment of healthy T cells with interleukin-12 induces upregulation of Fas ligand and Fas ligand-dependent apoptosis. Consistently, interleukin-12 could not induce apoptosis in Fas ligand-deficient T cells from patients with autoimmune lymphoproliferative syndrome. We hypothesized that defects in the interleukin-12 signaling pathway may cause a similar phenotype as that caused by mutations of the Fas ligand gene. To test this, we analyzed 20 patients with autoimmune lymphoproliferative syndrome of unknown cause by whole-exome sequencing. We identified a homozygous nonsense mutation (c.698G>A, p.R212*) in the interleukin-12/interleukin-23 receptor-component IL12RB1 in one of these patients. The mutation led to IL12RB1 protein truncation and loss of cell surface expression. Interleukin-12 and -23 signaling was completely abrogated as demonstrated by deficient STAT4 phosphorylation and interferon γ production. Interleukin-12-mediated expression of membrane-bound and soluble Fas ligand was lacking and basal expression was much lower than in healthy controls. The patient presented with the classical symptoms of autoimmune lymphoproliferative syndrome: chronic non-malignant, non-infectious lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10. Sanger sequencing and whole-exome sequencing excluded the presence of germline or somatic mutations in genes known to be associated with the autoimmune lymphoproliferative syndrome. Our data suggest that deficient regulation of Fas ligand expression by regulators such as the interleukin-12 signaling pathway may be an alternative cause of autoimmune lymphoproliferative syndrome-like disease.
High hyperdiploid acute lymphoblastic leukemia (HeH-ALL) is characterized by 51-67 chromosomes and nonrandom gains of specific chromosomes (X, 4, 6, 10, 14, 17, 18, and 21). It presents the most frequent numerical cytogenetic alteration in childhood pre B-cell ALL occurring in 25-30% of cases. Recurrent disease will affect 15-20%. Pre-leukemic HeH clones are generated in utero, but cooperating oncogenic lesions are necessary for overt leukemia and remain to be determined. Recently, a phenomenon termed chromothripsis has been described in which massive structural variations occur in a single aberrant mitosis. Whole or partial chromosomes are shattered and some fragments are lost in the process of rejoining. Thus, characteristically, chromosomal copy numbers oscillate between two copy number states. Chromothripsis has been suggested to be a tumor-driving alteration that may be present in 2-3% of all human cancers. Its role as a potential cooperating or initiating lesion in HeH-ALL has not been determined.
The authors point out that, in order to perform the design of printed circuit boards as time- and cost-efficiently as possible, electromagnetic compatability (EMC) phenomena have to be taken into account during layout synthesis. The EMC router HERO offers a robust framework for incorporating EMC constraints and cost criteria into routing. Using HERO, it will not be possible to obtain a completely failsafe layout, in general. However, experimental results for typical boards prove that a great number of EMC problems can be avoided during layout synthesis and that the effects of EMC phenomena can be reduced substantially. Detailed reports of EMC design rule violations provide effective input to the succeeding EMC verification phase. Violations of EMC design rules are mainly caused by an inappropriate placement. Therefore, it seems to be of great promise to combine hierarchical placement methods with this approach for hierarchical routing.
TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.
Dysregulation of IL12 Signaling As a Novel Cause of an Autoimmune Lymphoproliferative like Syndrome
(2014)
Survival of patients with pediatric acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-SCT) is mainly compromised by leukemia relapse, carrying dismal prognosis. As novel individualized therapeutic approaches are urgently needed, we performed whole-exome sequencing of leukemic blasts of 10 children with post–allo-SCT relapses with the aim of thoroughly characterizing the mutational landscape and identifying druggable mutations. We found that post–allo-SCT ALL relapses display highly diverse and mostly patient-individual genetic lesions. Moreover, mutational cluster analysis showed substantial clonal dynamics during leukemia progression from initial diagnosis to relapse after allo-SCT. Only very few alterations stayed constant over time. This dynamic clonality was exemplified by the detection of thiopurine resistance-mediating mutations in the nucleotidase NT5C2 in 3 patients’ first relapses, which disappeared in the post–allo-SCT relapses on relief of selective pressure of maintenance chemotherapy. Moreover, we identified TP53 mutations in 4 of 10 patients after allo-SCT, reflecting acquired chemoresistance associated with selective pressure of prior antineoplastic treatment. Finally, in 9 of 10 children’s post–allo-SCT relapse, we found alterations in genes for which targeted therapies with novel agents are readily available. We could show efficient targeting of leukemic blasts by APR-246 in 2 patients carrying TP53 mutations. Our findings shed light on the genetic basis of post–allo-SCT relapse and may pave the way for unraveling novel therapeutic strategies in this challenging situation.
The automated annotation of data from high throughput sequencing and genomics experiments is a significant challenge for bioinformatics. Most current approaches rely on sequential pipelines of gene finding and gene function prediction methods that annotate a gene with information from different reference data sources. Each function prediction method contributes evidence supporting a functional assignment. Such approaches generally ignore the links between the information in the reference datasets. These links, however, are valuable for assessing the plausibility of a function assignment and can be used to evaluate the confidence in a prediction. We are working towards a novel annotation system that uses the network of information supporting the function assignment to enrich the annotation process for use by expert curators and predicting the function of previously unannotated genes. In this paper we describe our success in the first stages of this development. We present the data integration steps that are needed to create the core database of integrated reference databases (UniProt, PFAM, PDB, GO and the pathway database Ara-Cyc) which has been established in the ONDEX data integration system. We also present a comparison between different methods for integration of GO terms as part of the function assignment pipeline and discuss the consequences of this analysis for improving the accuracy of gene function annotation. The methods and algorithms presented in this publication are an integral part of the ONDEX system which is freely available from http://ondex.sf.net/.
