Automated Analysis in Feature Modelling and Product Configuration

The automated analysis of feature models is one of the thriving topics of research in the software product line and variability management communities that has attracted more attention in the last years. A recent literature review reported that more than 30 analysis operations have been identi ed and di erent analysis mechanisms have been proposed. Product con guration is a well established research eld with more than 30 years of successful applications in di erent industrial domains. Our hypothesis, that is not really new, is that these two independent areas of research have interesting synergies that have not been fully explored. To try to explore the potential synergies systematically, in this paper we provide a rapid review to bring together these previously disparate streams of work. We de ne a set of research questions and give a preliminary answer to some of them. We conclude that there are many research opportunities in the synergy of these independent areas.Ministerio de Ciencia e Innovación TIN2009- 07366Junta de Andalucía TIC-590

Mutant muscle LIM protein C58G causes cardiomyopathy through protein depletion

Cysteine and glycine rich protein 3 (CSRP3) encodes Muscle LIM Protein (MLP), a well-established disease gene for Hypertrophic Cardiomyopathy (HCM). MLP, in contrast to the proteins encoded by the other recognised HCM disease genes, is non-sarcomeric, and has important signalling functions in cardiomyocytes. To gain insight into the disease mechanisms involved, we generated a knock-in mouse (KI) model, carrying the well documented HCM-causing CSRP3 mutation C58G. In vivo phenotyping of homozygous KI/KI mice revealed a robust cardiomyopathy phenotype with diastolic and systolic left ventricular dysfunction, which was supported by increased heart weight measurements. Transcriptome analysis by RNA-seq identified activation of pro-fibrotic signalling, induction of the fetal gene programme and activation of markers of hypertrophic signalling in these hearts. Further ex vivo analyses validated the activation of these pathways at transcript and protein level. Intriguingly, the abundance of MLP decreased in KI/KI mice by 80% and in KI/+ mice by 50%. Protein depletion was also observed in cellular studies for two further HCM-causing CSRP3 mutations (L44P and S54R/E55G). We show that MLP depletion is caused by proteasome action. Moreover, MLP C58G interacts with Bag3 and results in a proteotoxic response in the homozygous knock-in mice, as shown by induction of Bag3 and associated heat shock proteins. In conclusion, the newly generated mouse model provides insights into the underlying disease mechanisms of cardiomyopathy caused by mutations in the non-sarcomeric protein MLP. Furthermore, our cellular experiments suggest that protein depletion and proteasomal overload also play a role in other HCM-causing CSPR3 mutations that we investigated, indicating that reduced levels of functional MLP may be a common mechanism for HCM-causing CSPR3 mutations