Improved homology-driven computational validation of protein-protein interactions motivated by the evolutionary gene duplication and divergence hypothesis

<p>Abstract</p> <p>Background</p> <p>Protein-protein interaction (PPI) data sets generated by high-throughput experiments are contaminated by large numbers of erroneous PPIs. Therefore, computational methods for PPI validation are necessary to improve the quality of such data sets. Against the background of the theory that most extant PPIs arose as a consequence of gene duplication, the sensitive search for homologous PPIs, i.e. for PPIs descending from a common ancestral PPI, should be a successful strategy for PPI validation.</p> <p>Results</p> <p>To validate an experimentally observed PPI, we combine FASTA and PSI-BLAST to perform a sensitive sequence-based search for pairs of interacting homologous proteins within a large, integrated PPI database. A novel scoring scheme that incorporates both quality and quantity of all observed matches allows us (1) to consider also tentative paralogs and orthologs in this analysis and (2) to combine search results from more than one homology detection method. ROC curves illustrate the high efficacy of this approach and its improvement over other homology-based validation methods.</p> <p>Conclusion</p> <p>New PPIs are primarily derived from preexisting PPIs and not invented <it>de novo</it>. Thus, the hallmark of true PPIs is the existence of homologous PPIs. The sensitive search for homologous PPIs within a large body of known PPIs is an efficient strategy to separate biologically relevant PPIs from the many spurious PPIs reported by high-throughput experiments.</p

Identification of regulatory variants associated with genetic susceptibility to meningococcal disease

Non-coding genetic variants play an important role in driving susceptibility to complex diseases but their characterization remains challenging. Here, we employed a novel approach to interrogate the genetic risk of such polymorphisms in a more systematic way by targeting specific regulatory regions relevant for the phenotype studied. We applied this method to meningococcal disease susceptibility, using the DNA binding pattern of RELA - a NF-kB subunit, master regulator of the response to infection - under bacterial stimuli in nasopharyngeal epithelial cells. We designed a custom panel to cover these RELA binding sites and used it for targeted sequencing in cases and controls. Variant calling and association analysis were performed followed by validation of candidate polymorphisms by genotyping in three independent cohorts. We identified two new polymorphisms, rs4823231 and rs11913168, showing signs of association with meningococcal disease susceptibility. In addition, using our genomic data as well as publicly available resources, we found evidences for these SNPs to have potential regulatory effects on ATXN10 and LIF genes respectively. The variants and related candidate genes are relevant for infectious diseases and may have important contribution for meningococcal disease pathology. Finally, we described a novel genetic association approach that could be applied to other phenotypes

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Revid. und bearb. von C. D. Fleischhauer; A. ElkerIn Fraktur. - Hinten angebunden: Selbstgesammelte Koch-Rezepte: [18] leere Bl.; Werbeanzeigen: XII, 52 S

Formal Models of Scientific Inquiry in a Social Context: An Introduction

Formal models of scientific inquiry, aimed at capturing socio-epistemic aspects underlying the process of scientific research, have become an important method in formal social epistemology and philosophy of science. In this introduction to the special issue we provide a historical overview of the development of formal models of this kind and analyze their methodological contributions to discussions in philosophy of science. In particular, we show that their significance consists in different forms of ‘methodological iteration’ (Elliott 2012) whereby the models initiate new lines of inquiry, isolate and clarify problems with existing knowledge claims, and stimulate further research

A Generalized Proof-Theoretic Approach to Logical Argumentation Based on Hypersequents

In this paper we introduce hypersequent-based frameworks for the modelling of defeasible reasoning by means of logic-based argumentation and the induced entailment relations. These structures are an extension of sequent-based argumentation frameworks, in which arguments and the attack relations among them are expressed not only by Gentzen-style sequents, but by more general expressions, called hypersequents. This generalization allows us to overcome some of the known weaknesses of logical argumentation frameworks and to prove several desirable properties of the entailments that are induced by the extended (hypersequent-based) frameworks. It also allows us to incorporate as the deductive base of our formalism some well-known logics (like the intermediate logic LC, the modal logic S5, and the relevance logic RM), which lack cut-free sequent calculi, and so are not adequate for standard sequent-based argumentation. We show that hypersequent-based argumentation yields robust defeasible variants of these logics, with many desirable properties

Tuning Logical Argumentation Frameworks: A Postulate-Derived Approach

Logical argumentation is a well-known approach to modelling nonmonotonic reasoning with conflicting information. In this paper we provide a proof-theoretic study of properties of logical argumentation frameworks. Given some desiderata in terms of rationality postulates, we consider the conditions that an argumentation framework should fulfill for the desiderata to hold. The rationality behind this approach is to assist designers to “plug-in” pre-defined formalisms according to actual needs. This work extends related research on the subject in several ways: more postulates are characterized, a more abstract notion of arguments is considered, and it is shown how the nature of the attack rules (subset attacks versus direct attacks) affects the properties of the whole setting