Investigating the Conformational Stability of Prion Strains through a Kinetic Replication Model
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{"title"=>"Investigating the conformational stability of prion strains through a kinetic replication model", "type"=>"journal", "authors"=>[{"first_name"=>"Mattia", "last_name"=>"Zampieri", "scopus_author_id"=>"24448926600"}, {"first_name"=>"Giuseppe", "last_name"=>"Legname", "scopus_author_id"=>"56962745200"}, {"first_name"=>"Claudio", "last_name"=>"Altafini", "scopus_author_id"=>"7003915919"}], "year"=>2009, "source"=>"PLoS Computational Biology", "identifiers"=>{"scopus"=>"2-s2.0-68249110632", "doi"=>"10.1371/journal.pcbi.1000420", "sgr"=>"68249110632", "isbn"=>"1553-7358 (Electronic)\\r1553-734X (Linking)", "pmid"=>"19578427", "issn"=>"1553734X", "pui"=>"355053828"}, "id"=>"83d9ab2a-4b58-3d1e-827e-adb00e31fafb", "abstract"=>"Prion 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 PrP(Sc) 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.", "link"=>"http://www.mendeley.com/research/investigating-conformational-stability-prion-strains-through-kinetic-replication-model", "reader_count"=>33, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Researcher"=>15, "Student > Ph. D. Student"=>9, "Student > Bachelor"=>2, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Researcher"=>15, "Student > Ph. D. Student"=>9, "Student > Bachelor"=>2, "Professor"=>3}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>5, "Mathematics"=>2, "Agricultural and Biological Sciences"=>19, "Physics and Astronomy"=>2, "Chemistry"=>1, "Computer Science"=>1, "Immunology and Microbiology"=>1}, "reader_count_by_subdiscipline"=>{"Chemistry"=>{"Chemistry"=>1}, "Physics and Astronomy"=>{"Physics and Astronomy"=>2}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>19}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>5}, "Mathematics"=>{"Mathematics"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>1, "Switzerland"=>1, "Spain"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/892831"], "description"=>"<p>The cartoon describes the pathways of kinetic replication of two prion strains with a different stability against denaturation: a stable one (high ) and an unstable one (low ) are drawn. These act as templates bringing the same cellular prion protein (triangle) to the two different strain conformations ( ▴→ ▪, ♦). The model assumes that the aggregation of monomers to polymers produces a very fast change of conformation and that this aggregation is unfavorable below a critical size (), which is assumed to be independent of the prion strain in our model. The experimental data suggest that stable prions are characterized by a higher and a corresponding lower . In the model, this is translated into strain-specificity of the rates of breakage and of aggregation (which are both lower for stable prions). This implies that stable fibrils are longer and prefer to proliferate while maintaining themselves as fibrils larger than the nucleus size (pathway on the left). On the contrary, unstable prions are more frangible (i.e. more sensitive to breakage), implying a shorter mean length. This means that breakage events are more likely to be associated with the formation of very short fibrils, even under the critical size. The increase in the aggregation rate is not enough to avoid an increased growth in the number of fibrils. We can therefore hypothesize that an apoptotic pathway is most likely for these last strains (pathway on the right). These conclusions are in agreement with the working hypothesis of oligomer toxicity <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000420#pcbi.1000420-Simoneau1\" target=\"_blank\">[44]</a>.</p>", "links"=>[], "tags"=>["prion"], "article_id"=>563294, "categories"=>["Medicine"], "users"=>["Mattia Zampieri", "Giuseppe Legname", "Claudio Altafini"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000420.g003", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Kinetic_model_and_prion_pathways_/563294", "title"=>"Kinetic model and prion pathways.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-07-03 00:54:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/892633"], "description"=>"<p>The reproductive ratio is plotted against the rate of growth. The downward trend is not well described by the linear model with negative angular coefficient () and an intercept () (dotted blue line). In addition, the model prediction with fixed (dashed-dot black line) fails to precisely represent the data, even if it provides a more reasonable relationship (notice that high stable prions, such as MK4985, would always be associated to positive values). Introducing one more degree of freedom (exponent ) yields a higher value (red line, ). This result corresponds to a prediction of . In addition, we tested a further simplified model version (where is considered to be much smaller than ) according to which (i.e. , shown in green). Similar conclusions could be drawn.</p>", "links"=>[], "tags"=>["empirical", "parameters"], "article_id"=>563093, "categories"=>["Medicine"], "users"=>["Mattia Zampieri", "Giuseppe Legname", "Claudio Altafini"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000420.g001", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relationships_between_the_empirical_parameters_and_/563093", "title"=>"Relationships between the empirical parameters and .", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-07-03 00:51:33"}
  • {"files"=>["https://ndownloader.figshare.com/files/893008"], "description"=>"<p>Using Eq. 9 and assuming equal to 3, the breakage rate can be estimated (second column, ) from G. In <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000420#pcbi.1000420-Masel2\" target=\"_blank\">[14]</a> the authors provide for the RML strain (bold) a lower and an upper bound for (0.98 and 3.4 prion/day) in addition to the best estimate (). The fitting obtained in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000420#pcbi-1000420-g002\" target=\"_blank\">Figure 2A</a> is used here to infer from . We can fix to the values reported in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000420#pcbi.1000420-Masel2\" target=\"_blank\">[14]</a> for different strains and estimate (as the only varying parameter) from Eq. 11. Comparing the values estimated in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000420#pcbi.1000420-Masel2\" target=\"_blank\">[14]</a> and our extrapolated values, we see contained differences (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000420#pcbi.1000420.s001\" target=\"_blank\">Figure S1</a>). This result shows that is the main parameter explaining strain kinetic variability. A remarkable advantage of this method is that it requires only a single rather simple experimental measurement (i.e. resistance to guanidine denaturation) in order to predict the replication dynamics of a particular strain.</p>", "links"=>[], "tags"=>["parameter", "prion"], "article_id"=>563471, "categories"=>["Medicine"], "users"=>["Mattia Zampieri", "Giuseppe Legname", "Claudio Altafini"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000420.t004", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Estimated_model_parameter_for_different_prion_strains_/563471", "title"=>"Estimated model parameter for different prion strains.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-07-03 00:57:51"}
  • {"files"=>["https://ndownloader.figshare.com/files/441976", "https://ndownloader.figshare.com/files/442028", "https://ndownloader.figshare.com/files/442080", "https://ndownloader.figshare.com/files/442148"], "description"=>"<div><p>Prion 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 PrP<sup>Sc</sup> 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 <em>in vivo</em> replication are characterizable <em>in primis</em> 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.</p></div>", "links"=>[], "tags"=>["investigating", "conformational", "prion", "strains", "kinetic", "replication"], "article_id"=>147129, "categories"=>["Medicine"], "users"=>["Mattia Zampieri", "Giuseppe Legname", "Claudio Altafini"], "doi"=>["https://dx.doi.org/10.1371/journal.pcbi.1000420.s001", "https://dx.doi.org/10.1371/journal.pcbi.1000420.s002", "https://dx.doi.org/10.1371/journal.pcbi.1000420.s003", "https://dx.doi.org/10.1371/journal.pcbi.1000420.s004"], "stats"=>{"downloads"=>5, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Investigating_the_Conformational_Stability_of_Prion_Strains_through_a_Kinetic_Replication_Model/147129", "title"=>"Investigating the Conformational Stability of Prion Strains through a Kinetic Replication Model", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2009-07-03 01:58:49"}
  • {"files"=>["https://ndownloader.figshare.com/files/892744"], "description"=>"<p>In (A) and (B) the stability against denaturation is plotted against the reproductive ratio and the rate of growth. A direct proportionality links to . As expected, an inverse proportionality emerges between and , reinforcing the previous results.</p>", "links"=>[], "tags"=>["computational biology/systems biology", "infectious diseases/prion diseases"], "article_id"=>563210, "categories"=>["Medicine"], "users"=>["Mattia Zampieri", "Giuseppe Legname", "Claudio Altafini"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000420.g002", "stats"=>{"downloads"=>4, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relationships_between_and_/563210", "title"=>"Relationships between , and .", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2009-07-03 00:53:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/892949"], "description"=>"<p>The linear and non linear relationships, with and without the intercept, for and are reported here. These models are fitted to the experimental measurements listed in <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000420#pcbi-1000420-t002\" target=\"_blank\">Table 2</a>. For each model the fitting parameters, and the correlation p-value are reported. When and are related to , the non linear model with a fixed intercept and a free exponent (i.e. ) is associated with the best fitting results (bold). By adding one more free parameter (i.e. ) we do not get essentially any improvement (italic). The estimated value for , without any simplification, implies , and (see <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000420#s4\" target=\"_blank\">Materials and Methods</a>). A direct proportionality is observed also for .</p>", "links"=>[], "tags"=>["curves"], "article_id"=>563414, "categories"=>["Medicine"], "users"=>["Mattia Zampieri", "Giuseppe Legname", "Claudio Altafini"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000420.t003", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fitted_values_for_the_curves_in_Figure_1_and_Figure_2_/563414", "title"=>"Fitted values for the curves in Figure 1 and Figure 2.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-07-03 00:56:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/892919"], "description"=>"<p>Description of all state variables and parameters.</p>", "links"=>[], "tags"=>["computational biology/systems biology", "infectious diseases/prion diseases"], "article_id"=>563379, "categories"=>["Medicine"], "users"=>["Mattia Zampieri", "Giuseppe Legname", "Claudio Altafini"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000420.t001", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_symbols_/563379", "title"=>"Model symbols.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-07-03 00:56:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/892980"], "description"=>"<p>The estimated values for the reproductive ratio (Eq. 11), rate of growth and stability against denaturation for different prion strains are shown. One of them (MK4985) is a synthetic prion strain that requires a high concentration of Gdn-HCL to denature 50% of the pathogenic protein. Whenever no reference is shown, <a href=\"http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1000420#pcbi.1000420-Legname1\" target=\"_blank\">[3]</a> is used.</p>", "links"=>[], "tags"=>["empirical", "parameters", "prion"], "article_id"=>563442, "categories"=>["Medicine"], "users"=>["Mattia Zampieri", "Giuseppe Legname", "Claudio Altafini"], "doi"=>"https://dx.doi.org/10.1371/journal.pcbi.1000420.t002", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Estimated_empirical_parameters_for_different_prion_strains_/563442", "title"=>"Estimated empirical parameters for different prion strains.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2009-07-03 00:57:22"}

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