Joke Reumers

An important gap in the relation between artificial evolutionary systems and their biological counterpart is the inability of artificial models to construct functional hierarchical structures in an emergent way. For composite structures to emerge and prosper in a biological hierarchical system, some form of selection is required at each level. In this paper we examine an abstract model of immune networks in terms of the selection dynamics present at the individual level and at the network level. In this context, a property of the individuals ...

... The name ARCHeMEDES was invented by the second author, in the spirit of the great inventor Archimedes, the "e" for e-learning and "arch" for architecture. 3.2. Issues in architectural design courses 1 Integrative education aims at making students aware of their learning ...

... The name ARCHeMEDES was invented by the second author, in the spirit of the great inventor Archimedes, the "e" for e-learning and "arch" for architecture. 3.2. Issues in architectural design courses 1 Integrative education aims at making students aware of their learning ...

Functional requirements shaped proteins into globular structures. Under these structural constraints, which require both regular secondary structure and a hydrophobic core, protein aggregation is an unavoidable corollary to protein structure. However, as aggregation results in reduced fitness, natural selection will tend to eliminate strongly aggregating sequences. The analysis of distribution and variation of aggregation patterns in the human proteome using the TANGO algorithm confirms the findings of a previous study on several proteomes: the flanks of aggregation-prone regions are enriched with charged residues and proline, the so-called gatekeeper-residues. Moreover, in this study, we observed a widespread redundancy in gatekeeper usage. Interestingly, aggregating regions from key proteins such as p53 or huntingtin are among the most extensive “gatekept” sequences. As a consequence, mutations that remove gatekeepers could therefore result in a strong increase in disease-susceptibility. In a set of disease-associated mutations from the UniProt database, we find a strong enrichment of mutations that disrupt gatekeeper motifs. Closer inspection of a number of case studies indicates clearly that removing gatekeepers may play a determining role in widely varying disorders, such as van der Woude syndrome (VWS), X-linked Fabry disease (FD), and limb-girdle muscular dystrophy. Hum Mutat 0, 1–7, 2009. © 2009 Wiley-Liss, Inc.

In one genetic study, the high temperature requirement A2 (HTRA2) mitochondrial protein has been associated with increased risk for sporadic Parkinson disease (PD). One missense mutation, p.Gly399Ser, in its C-terminal PDZ domain (from the initial letters of the postsynaptic density 95, PSD-95; discs large; and zonula occludens-1, ZO-1 proteins [Kennedy, 1995]) resulted in defective protease activation, and induced mitochondrial dysfunction when overexpressed in stably transfected cells. Here we examined the contribution of genetic variability in HTRA2 to PD risk in an extended series of 266 Belgian PD patients and 273 control individuals. Mutation analysis identified a novel p.Arg404Trp mutation within the PDZ domain predicted to freeze HTRA2 in an inactive form. Moreover, we identified six patient-specific variants in 5′ and 3′ regulatory regions that might affect HTRA2 expression as supported by data of luciferase reporter gene analyses. Our study confirms a role of the HTRA2 mitochondrial protein in PD susceptibility through mutations in its functional PDZ domain. In addition, it extends the HTRA2 mutation spectrum to functional variants possibly affecting transcriptional activity. The latter underpins a previously unrecognized role for altered HTRA2 expression as a risk factor relevant to parkinsonian neurodegeneration. Hum Mutat 29(6), 832–840, 2008. © 2008 Wiley-Liss, Inc.