01822nas a2200145   4500008004100000245009200041210006900133260002800202520132600230100002101556700002201577700001901599700002201618856003601640       2011                        en  d00aA system-level approach for deciphering the transcriptional response to prion infection0 asystemlevel approach for deciphering the transcriptional respons  bOxford University Press3 aMOTIVATION: Deciphering the response of a complex biological system to an insulting event, at the gene expression level, requires adopting theoretical models that are more sophisticated than a one-to-one comparison (i.e. t-test). Here, we investigate the ability of a novel reverse engineering approach (System Response Inference) to unveil non-obvious transcriptional signatures of the system response induced by prion infection.\\r\\nRESULTS: To this end, we analyze previously published gene expression data, from which we extrapolate a putative full-scale model of transcriptional gene-gene dependencies in the mouse central nervous system. Then, we use this nominal model to interpret the gene expression changes caused by prion replication, aiming at selecting the genes primarily influenced by this perturbation. Our method sheds light on the mode of action of prions by identifying key transcripts that are the most likely to be responsible for the overall transcriptional rearrangement from a nominal regulatory network. As a first result of our inference, we have been able to predict known targets of prions (i.e. PrP(C)) and to unveil the potential role of previously unsuspected genes.\\r\\nCONTACT: altafini@sissa.it\\r\\nSUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.1 aZampieri, Mattia1 aLegname, Giuseppe1 aSegrè, Daniel1 aAltafini, Claudio  uhttp://hdl.handle.net/1963/574501588nas a2200133   4500008004300000245010000043210006900143260000900212520113200221100002101353700002201374700002201396856003601418       2009                        en_Ud  00aInvestigating the Conformational Stability of Prion Strains through a Kinetic Replication Model0 aInvestigating the Conformational Stability of Prion Strains thro  bPLoS3 aPrion proteins are known to misfold into a range of different aggregated forms, showing different phenotypic and pathological states. Understanding strain specificities is an important problem in the field of prion disease. Little is known about which PrPSc structural properties and molecular mechanisms determine prion replication, disease progression and strain phenotype. The aim of this work is to investigate, through a mathematical model, how the structural stability of different aggregated forms can influence the kinetics of prion replication. The model-based results suggest that prion strains with different conformational stability undergoing in vivo replication are characterizable in primis by means of different rates of breakage. A further role seems to be played by the aggregation rate (i.e. the rate at which a prion fibril grows). The kinetic variability introduced in the model by these two parameters allows us to reproduce the different characteristic features of the various strains (e.g., fibrils\\\' mean length) and is coherent with all experimental observations concerning strain-specific behavior.1 aZampieri, Mattia1 aLegname, Giuseppe1 aAltafini, Claudio  uhttp://hdl.handle.net/1963/3989