Inferring Regulatory Networks from Experimental Morphological Phenotypes: A Computational Method Reverse-Engineers Planarian Regeneration
Identifieur interne : 000117 ( Pmc/Curation ); précédent : 000116; suivant : 000118Inferring Regulatory Networks from Experimental Morphological Phenotypes: A Computational Method Reverse-Engineers Planarian Regeneration
Auteurs : Daniel Lobo ; Michael LevinSource :
- PLoS Computational Biology [ 1553-734X ] ; 2015.
Abstract
Transformative applications in biomedicine require the discovery of complex regulatory networks that explain the development and regeneration of anatomical structures, and reveal what external signals will trigger desired changes of large-scale pattern. Despite recent advances in bioinformatics, extracting mechanistic pathway models from experimental morphological data is a key open challenge that has resisted automation. The fundamental difficulty of manually predicting emergent behavior of even simple networks has limited the models invented by human scientists to pathway diagrams that show necessary subunit interactions but do not reveal the dynamics that are sufficient for complex, self-regulating pattern to emerge. To finally bridge the gap between high-resolution genetic data and the ability to understand and control patterning, it is critical to develop computational tools to efficiently extract regulatory pathways from the resultant experimental shape phenotypes. For example, planarian regeneration has been studied for over a century, but despite increasing insight into the pathways that control its stem cells, no constructive, mechanistic model has yet been found by human scientists that explains more than one or two key features of its remarkable ability to regenerate its correct anatomical pattern after drastic perturbations. We present a method to infer the molecular products, topology, and spatial and temporal non-linear dynamics of regulatory networks recapitulating
Url:
DOI: 10.1371/journal.pcbi.1004295
PubMed: 26042810
PubMed Central: 4456145
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Inferring Regulatory Networks from Experimental Morphological Phenotypes: A Computational Method Reverse-Engineers Planarian Regeneration</title>
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<front><div type="abstract" xml:lang="en"><p>Transformative applications in biomedicine require the discovery of complex regulatory networks that explain the development and regeneration of anatomical structures, and reveal what external signals will trigger desired changes of large-scale pattern. Despite recent advances in bioinformatics, extracting mechanistic pathway models from experimental morphological data is a key open challenge that has resisted automation. The fundamental difficulty of manually predicting emergent behavior of even simple networks has limited the models invented by human scientists to pathway diagrams that show necessary subunit interactions but do not reveal the dynamics that are sufficient for complex, self-regulating pattern to emerge. To finally bridge the gap between high-resolution genetic data and the ability to understand and control patterning, it is critical to develop computational tools to efficiently extract regulatory pathways from the resultant experimental shape phenotypes. For example, planarian regeneration has been studied for over a century, but despite increasing insight into the pathways that control its stem cells, no constructive, mechanistic model has yet been found by human scientists that explains more than one or two key features of its remarkable ability to regenerate its correct anatomical pattern after drastic perturbations. We present a method to infer the molecular products, topology, and spatial and temporal non-linear dynamics of regulatory networks recapitulating <italic>in silico</italic>
the rich dataset of morphological phenotypes resulting from genetic, surgical, and pharmacological experiments. We demonstrated our approach by inferring complete regulatory networks explaining the outcomes of the main functional regeneration experiments in the planarian literature; By analyzing all the datasets together, our system inferred the first systems-biology comprehensive dynamical model explaining patterning in planarian regeneration. This method provides an automated, highly generalizable framework for identifying the underlying control mechanisms responsible for the dynamic regulation of growth and form.</p>
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<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Lobo, D" uniqKey="Lobo D">D Lobo</name>
</author>
<author><name sortKey="Beane, Ws" uniqKey="Beane W">WS Beane</name>
</author>
<author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Brockes, Jp" uniqKey="Brockes J">JP Brockes</name>
</author>
<author><name sortKey="Kumar, A" uniqKey="Kumar A">A Kumar</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Farinella Ferruzza, N" uniqKey="Farinella Ferruzza N">N Farinella-Ferruzza</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Guyenot, E" uniqKey="Guyenot E">E Guyenot</name>
</author>
<author><name sortKey="Schotte, Oe" uniqKey="Schotte O">OE Schotte</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Vandenberg, Ln" uniqKey="Vandenberg L">LN Vandenberg</name>
</author>
<author><name sortKey="Adams, Ds" uniqKey="Adams D">DS Adams</name>
</author>
<author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Reddien, Pw" uniqKey="Reddien P">PW Reddien</name>
</author>
<author><name sortKey="Sanchez Alvarado, A" uniqKey="Sanchez Alvarado A">A Sánchez Alvarado</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Buetow, Kh" uniqKey="Buetow K">KH Buetow</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Oates, Ac" uniqKey="Oates A">AC Oates</name>
</author>
<author><name sortKey="Gorfinkiel, N" uniqKey="Gorfinkiel N">N Gorfinkiel</name>
</author>
<author><name sortKey="Gonzalez Gaitan, M" uniqKey="Gonzalez Gaitan M">M Gonzalez-Gaitan</name>
</author>
<author><name sortKey="Heisenberg, Cp" uniqKey="Heisenberg C">CP Heisenberg</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Dowell, Rd" uniqKey="Dowell R">RD Dowell</name>
</author>
<author><name sortKey="Ryan, O" uniqKey="Ryan O">O Ryan</name>
</author>
<author><name sortKey="Jansen, A" uniqKey="Jansen A">A Jansen</name>
</author>
<author><name sortKey="Cheung, D" uniqKey="Cheung D">D Cheung</name>
</author>
<author><name sortKey="Agarwala, S" uniqKey="Agarwala S">S Agarwala</name>
</author>
<author><name sortKey="Danford, T" uniqKey="Danford T">T Danford</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kicheva, A" uniqKey="Kicheva A">A Kicheva</name>
</author>
<author><name sortKey="Cohen, M" uniqKey="Cohen M">M Cohen</name>
</author>
<author><name sortKey="Briscoe, J" uniqKey="Briscoe J">J Briscoe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Barkai, N" uniqKey="Barkai N">N Barkai</name>
</author>
<author><name sortKey="Ben Zvi, D" uniqKey="Ben Zvi D">D Ben-Zvi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Niehrs, C" uniqKey="Niehrs C">C Niehrs</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Economou, Ad" uniqKey="Economou A">AD Economou</name>
</author>
<author><name sortKey="Green, Jb" uniqKey="Green J">JB Green</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Winkler, Da" uniqKey="Winkler D">DA Winkler</name>
</author>
<author><name sortKey="Burden, Fr" uniqKey="Burden F">FR Burden</name>
</author>
<author><name sortKey="Halley, Jd" uniqKey="Halley J">JD Halley</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Pohl, C" uniqKey="Pohl C">C Pohl</name>
</author>
<author><name sortKey="Bao, Z" uniqKey="Bao Z">Z Bao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fisher, J" uniqKey="Fisher J">J Fisher</name>
</author>
<author><name sortKey="Piterman, N" uniqKey="Piterman N">N Piterman</name>
</author>
<author><name sortKey="Hajnal, A" uniqKey="Hajnal A">A Hajnal</name>
</author>
<author><name sortKey="Henzinger, Ta" uniqKey="Henzinger T">TA Henzinger</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kim, Kj" uniqKey="Kim K">KJ Kim</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Salazar Ciudad, I" uniqKey="Salazar Ciudad I">I Salazar-Ciudad</name>
</author>
<author><name sortKey="Jernvall, J" uniqKey="Jernvall J">J Jernvall</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Salazar Ciudad, I" uniqKey="Salazar Ciudad I">I Salazar-Ciudad</name>
</author>
<author><name sortKey="Jernvall, J" uniqKey="Jernvall J">J Jernvall</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bodnar, J" uniqKey="Bodnar J">J Bodnar</name>
</author>
<author><name sortKey="Bradley, M" uniqKey="Bradley M">M Bradley</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bodnar, Jw" uniqKey="Bodnar J">JW Bodnar</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Slack, Jm" uniqKey="Slack J">JM Slack</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Meinhardt, H" uniqKey="Meinhardt H">H Meinhardt</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Meinhardt, H" uniqKey="Meinhardt H">H Meinhardt</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Moustakas Verho, Je" uniqKey="Moustakas Verho J">JE Moustakas-Verho</name>
</author>
<author><name sortKey="Zimm, R" uniqKey="Zimm R">R Zimm</name>
</author>
<author><name sortKey="Cebra Thomas, J" uniqKey="Cebra Thomas J">J Cebra-Thomas</name>
</author>
<author><name sortKey="Lempi Inen, Nk" uniqKey="Lempi Inen N">NK Lempiäinen</name>
</author>
<author><name sortKey="Kallonen, A" uniqKey="Kallonen A">A Kallonen</name>
</author>
<author><name sortKey="Mitchell, Kl" uniqKey="Mitchell K">KL Mitchell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hoyos, E" uniqKey="Hoyos E">E Hoyos</name>
</author>
<author><name sortKey="Kim, K" uniqKey="Kim K">K Kim</name>
</author>
<author><name sortKey="Milloz, J" uniqKey="Milloz J">J Milloz</name>
</author>
<author><name sortKey="Barkoulas, M" uniqKey="Barkoulas M">M Barkoulas</name>
</author>
<author><name sortKey="Penigault, J B" uniqKey="Penigault J">J-B Pénigault</name>
</author>
<author><name sortKey="Munro, E" uniqKey="Munro E">E Munro</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Von Dassow, G" uniqKey="Von Dassow G">G von Dassow</name>
</author>
<author><name sortKey="Meir, E" uniqKey="Meir E">E Meir</name>
</author>
<author><name sortKey="Munro, E" uniqKey="Munro E">E Munro</name>
</author>
<author><name sortKey="Odell, G" uniqKey="Odell G">G Odell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sheth, R" uniqKey="Sheth R">R Sheth</name>
</author>
<author><name sortKey="Marcon, L" uniqKey="Marcon L">L Marcon</name>
</author>
<author><name sortKey="Bastida, Mf" uniqKey="Bastida M">MF Bastida</name>
</author>
<author><name sortKey="Junco, M" uniqKey="Junco M">M Junco</name>
</author>
<author><name sortKey="Quintana, L" uniqKey="Quintana L">L Quintana</name>
</author>
<author><name sortKey="Dahn, R" uniqKey="Dahn R">R Dahn</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Raspopovic, J" uniqKey="Raspopovic J">J Raspopovic</name>
</author>
<author><name sortKey="Marcon, L" uniqKey="Marcon L">L Marcon</name>
</author>
<author><name sortKey="Russo, L" uniqKey="Russo L">L Russo</name>
</author>
<author><name sortKey="Sharpe, J" uniqKey="Sharpe J">J Sharpe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lobo, D" uniqKey="Lobo D">D Lobo</name>
</author>
<author><name sortKey="Solano, M" uniqKey="Solano M">M Solano</name>
</author>
<author><name sortKey="Bubenik, Ga" uniqKey="Bubenik G">GA Bubenik</name>
</author>
<author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yeung, Mks" uniqKey="Yeung M">MKS Yeung</name>
</author>
<author><name sortKey="Tegner, J" uniqKey="Tegner J">J Tegnér</name>
</author>
<author><name sortKey="Collins, Jj" uniqKey="Collins J">JJ Collins</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tegner, J" uniqKey="Tegner J">J Tegner</name>
</author>
<author><name sortKey="Yeung, Mk" uniqKey="Yeung M">MK Yeung</name>
</author>
<author><name sortKey="Hasty, J" uniqKey="Hasty J">J Hasty</name>
</author>
<author><name sortKey="Collins, Jj" uniqKey="Collins J">JJ Collins</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gardner, Ts" uniqKey="Gardner T">TS Gardner</name>
</author>
<author><name sortKey="Di Bernardo, D" uniqKey="Di Bernardo D">D di Bernardo</name>
</author>
<author><name sortKey="Lorenz, D" uniqKey="Lorenz D">D Lorenz</name>
</author>
<author><name sortKey="Collins, Jj" uniqKey="Collins J">JJ Collins</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Basso, K" uniqKey="Basso K">K Basso</name>
</author>
<author><name sortKey="Margolin, Aa" uniqKey="Margolin A">AA Margolin</name>
</author>
<author><name sortKey="Stolovitzky, G" uniqKey="Stolovitzky G">G Stolovitzky</name>
</author>
<author><name sortKey="Klein, U" uniqKey="Klein U">U Klein</name>
</author>
<author><name sortKey="Dalla Favera, R" uniqKey="Dalla Favera R">R Dalla-Favera</name>
</author>
<author><name sortKey="Califano, A" uniqKey="Califano A">A Califano</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bonneau, R" uniqKey="Bonneau R">R Bonneau</name>
</author>
<author><name sortKey="Reiss, Dj" uniqKey="Reiss D">DJ Reiss</name>
</author>
<author><name sortKey="Shannon, P" uniqKey="Shannon P">P Shannon</name>
</author>
<author><name sortKey="Facciotti, M" uniqKey="Facciotti M">M Facciotti</name>
</author>
<author><name sortKey="Hood, L" uniqKey="Hood L">L Hood</name>
</author>
<author><name sortKey="Baliga, Ns" uniqKey="Baliga N">NS Baliga</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Margolin, Aa" uniqKey="Margolin A">AA Margolin</name>
</author>
<author><name sortKey="Nemenman, I" uniqKey="Nemenman I">I Nemenman</name>
</author>
<author><name sortKey="Basso, K" uniqKey="Basso K">K Basso</name>
</author>
<author><name sortKey="Wiggins, C" uniqKey="Wiggins C">C Wiggins</name>
</author>
<author><name sortKey="Stolovitzky, G" uniqKey="Stolovitzky G">G Stolovitzky</name>
</author>
<author><name sortKey="Dalla Favera, R" uniqKey="Dalla Favera R">R Dalla Favera</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bonneau, R" uniqKey="Bonneau R">R Bonneau</name>
</author>
<author><name sortKey="Facciotti, Mt" uniqKey="Facciotti M">MT Facciotti</name>
</author>
<author><name sortKey="Reiss, Dj" uniqKey="Reiss D">DJ Reiss</name>
</author>
<author><name sortKey="Schmid, Ak" uniqKey="Schmid A">AK Schmid</name>
</author>
<author><name sortKey="Pan, M" uniqKey="Pan M">M Pan</name>
</author>
<author><name sortKey="Kaur, A" uniqKey="Kaur A">A Kaur</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Faith, Jj" uniqKey="Faith J">JJ Faith</name>
</author>
<author><name sortKey="Hayete, B" uniqKey="Hayete B">B Hayete</name>
</author>
<author><name sortKey="Thaden, Jt" uniqKey="Thaden J">JT Thaden</name>
</author>
<author><name sortKey="Mogno, I" uniqKey="Mogno I">I Mogno</name>
</author>
<author><name sortKey="Wierzbowski, J" uniqKey="Wierzbowski J">J Wierzbowski</name>
</author>
<author><name sortKey="Cottarel, G" uniqKey="Cottarel G">G Cottarel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Cantone, I" uniqKey="Cantone I">I Cantone</name>
</author>
<author><name sortKey="Marucci, L" uniqKey="Marucci L">L Marucci</name>
</author>
<author><name sortKey="Iorio, F" uniqKey="Iorio F">F Iorio</name>
</author>
<author><name sortKey="Ricci, Ma" uniqKey="Ricci M">MA Ricci</name>
</author>
<author><name sortKey="Belcastro, V" uniqKey="Belcastro V">V Belcastro</name>
</author>
<author><name sortKey="Bansal, M" uniqKey="Bansal M">M Bansal</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Hecker, M" uniqKey="Hecker M">M Hecker</name>
</author>
<author><name sortKey="Lambeck, S" uniqKey="Lambeck S">S Lambeck</name>
</author>
<author><name sortKey="Toepfer, S" uniqKey="Toepfer S">S Toepfer</name>
</author>
<author><name sortKey="Van Someren, E" uniqKey="Van Someren E">E Van Someren</name>
</author>
<author><name sortKey="Guthke, R" uniqKey="Guthke R">R Guthke</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Molinelli, Ej" uniqKey="Molinelli E">EJ Molinelli</name>
</author>
<author><name sortKey="Korkut, A" uniqKey="Korkut A">A Korkut</name>
</author>
<author><name sortKey="Wang, W" uniqKey="Wang W">W Wang</name>
</author>
<author><name sortKey="Miller, Ml" uniqKey="Miller M">ML Miller</name>
</author>
<author><name sortKey="Gauthier, Np" uniqKey="Gauthier N">NP Gauthier</name>
</author>
<author><name sortKey="Jing, X" uniqKey="Jing X">X Jing</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sirbu, A" uniqKey="Sirbu A">A Sirbu</name>
</author>
<author><name sortKey="Ruskin, H" uniqKey="Ruskin H">H Ruskin</name>
</author>
<author><name sortKey="Crane, M" uniqKey="Crane M">M Crane</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Botman, D" uniqKey="Botman D">D Botman</name>
</author>
<author><name sortKey="Rottinger, E" uniqKey="Rottinger E">E Röttinger</name>
</author>
<author><name sortKey="Martindale, Mq" uniqKey="Martindale M">MQ Martindale</name>
</author>
<author><name sortKey="De Jong, J" uniqKey="De Jong J">J de Jong</name>
</author>
<author><name sortKey="Kaandorp, Ja" uniqKey="Kaandorp J">JA Kaandorp</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Edwards, Js" uniqKey="Edwards J">JS Edwards</name>
</author>
<author><name sortKey="Palsson, Bo" uniqKey="Palsson B">BO Palsson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Patil, Kr" uniqKey="Patil K">KR Patil</name>
</author>
<author><name sortKey="Nielsen, J" uniqKey="Nielsen J">J Nielsen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Schmidt, Md" uniqKey="Schmidt M">MD Schmidt</name>
</author>
<author><name sortKey="Vallabhajosyula, Rr" uniqKey="Vallabhajosyula R">RR Vallabhajosyula</name>
</author>
<author><name sortKey="Jenkins, Jw" uniqKey="Jenkins J">JW Jenkins</name>
</author>
<author><name sortKey="Hood, Je" uniqKey="Hood J">JE Hood</name>
</author>
<author><name sortKey="Soni, As" uniqKey="Soni A">AS Soni</name>
</author>
<author><name sortKey="Wikswo, Jp" uniqKey="Wikswo J">JP Wikswo</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lobo, D" uniqKey="Lobo D">D Lobo</name>
</author>
<author><name sortKey="Malone, Tj" uniqKey="Malone T">TJ Malone</name>
</author>
<author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kondo, S" uniqKey="Kondo S">S Kondo</name>
</author>
<author><name sortKey="Miura, T" uniqKey="Miura T">T Miura</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Francois, P" uniqKey="Francois P">P Francois</name>
</author>
<author><name sortKey="Hakim, V" uniqKey="Hakim V">V Hakim</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bongard, J" uniqKey="Bongard J">J Bongard</name>
</author>
<author><name sortKey="Lipson, H" uniqKey="Lipson H">H Lipson</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Reinitz, J" uniqKey="Reinitz J">J Reinitz</name>
</author>
<author><name sortKey="Sharp, Dh" uniqKey="Sharp D">DH Sharp</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Reinitz, J" uniqKey="Reinitz J">J Reinitz</name>
</author>
<author><name sortKey="Mjolsness, E" uniqKey="Mjolsness E">E Mjolsness</name>
</author>
<author><name sortKey="Sharp, Dh" uniqKey="Sharp D">DH Sharp</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Reinitz, J" uniqKey="Reinitz J">J Reinitz</name>
</author>
<author><name sortKey="Kosman, D" uniqKey="Kosman D">D Kosman</name>
</author>
<author><name sortKey="Vanario Alonso, Ce" uniqKey="Vanario Alonso C">CE Vanario-Alonso</name>
</author>
<author><name sortKey="Sharp, Dh" uniqKey="Sharp D">DH Sharp</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jaeger, J" uniqKey="Jaeger J">J Jaeger</name>
</author>
<author><name sortKey="Blagov, M" uniqKey="Blagov M">M Blagov</name>
</author>
<author><name sortKey="Kosman, D" uniqKey="Kosman D">D Kosman</name>
</author>
<author><name sortKey="Kozlov, Kn" uniqKey="Kozlov K">KN Kozlov</name>
</author>
<author><name sortKey="Manu" uniqKey="Manu">Manu</name>
</author>
<author><name sortKey="Myasnikova, E" uniqKey="Myasnikova E">E Myasnikova</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jaeger, J" uniqKey="Jaeger J">J Jaeger</name>
</author>
<author><name sortKey="Surkova, S" uniqKey="Surkova S">S Surkova</name>
</author>
<author><name sortKey="Blagov, M" uniqKey="Blagov M">M Blagov</name>
</author>
<author><name sortKey="Janssens, H" uniqKey="Janssens H">H Janssens</name>
</author>
<author><name sortKey="Kosman, D" uniqKey="Kosman D">D Kosman</name>
</author>
<author><name sortKey="Kozlov, Kn" uniqKey="Kozlov K">KN Kozlov</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Perkins, Tj" uniqKey="Perkins T">TJ Perkins</name>
</author>
<author><name sortKey="Jaeger, J" uniqKey="Jaeger J">J Jaeger</name>
</author>
<author><name sortKey="Reinitz, J" uniqKey="Reinitz J">J Reinitz</name>
</author>
<author><name sortKey="Glass, L" uniqKey="Glass L">L Glass</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Manu" uniqKey="Manu">Manu</name>
</author>
<author><name sortKey="Surkova, S" uniqKey="Surkova S">S Surkova</name>
</author>
<author><name sortKey="Spirov, Av" uniqKey="Spirov A">AV Spirov</name>
</author>
<author><name sortKey="Gursky, Vv" uniqKey="Gursky V">VV Gursky</name>
</author>
<author><name sortKey="Janssens, H" uniqKey="Janssens H">H Janssens</name>
</author>
<author><name sortKey="Kim, Ar" uniqKey="Kim A">AR Kim</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Manu" uniqKey="Manu">Manu</name>
</author>
<author><name sortKey="Surkova, S" uniqKey="Surkova S">S Surkova</name>
</author>
<author><name sortKey="Spirov, Av" uniqKey="Spirov A">AV Spirov</name>
</author>
<author><name sortKey="Gursky, Vv" uniqKey="Gursky V">VV Gursky</name>
</author>
<author><name sortKey="Janssens, H" uniqKey="Janssens H">H Janssens</name>
</author>
<author><name sortKey="Kim, Ar" uniqKey="Kim A">AR Kim</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gursky, Vv" uniqKey="Gursky V">VV Gursky</name>
</author>
<author><name sortKey="Panok, L" uniqKey="Panok L">L Panok</name>
</author>
<author><name sortKey="Myasnikova, Em" uniqKey="Myasnikova E">EM Myasnikova</name>
</author>
<author><name sortKey="Manu" uniqKey="Manu">Manu</name>
</author>
<author><name sortKey="Samsonova, Mg" uniqKey="Samsonova M">MG Samsonova</name>
</author>
<author><name sortKey="Reinitz, J" uniqKey="Reinitz J">J Reinitz</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Crombach, A" uniqKey="Crombach A">A Crombach</name>
</author>
<author><name sortKey="Wotton, Kr" uniqKey="Wotton K">KR Wotton</name>
</author>
<author><name sortKey="Cicin Sain, D" uniqKey="Cicin Sain D">D Cicin-Sain</name>
</author>
<author><name sortKey="Ashyraliyev, M" uniqKey="Ashyraliyev M">M Ashyraliyev</name>
</author>
<author><name sortKey="Jaeger, J" uniqKey="Jaeger J">J Jaeger</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Becker, K" uniqKey="Becker K">K Becker</name>
</author>
<author><name sortKey="Balsa Canto, E" uniqKey="Balsa Canto E">E Balsa-Canto</name>
</author>
<author><name sortKey="Cicin Sain, D" uniqKey="Cicin Sain D">D Cicin-Sain</name>
</author>
<author><name sortKey="Hoermann, A" uniqKey="Hoermann A">A Hoermann</name>
</author>
<author><name sortKey="Janssens, H" uniqKey="Janssens H">H Janssens</name>
</author>
<author><name sortKey="Banga, Jr" uniqKey="Banga J">JR Banga</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Fomekong Nanfack, Y" uniqKey="Fomekong Nanfack Y">Y Fomekong-Nanfack</name>
</author>
<author><name sortKey="Kaandorp, Ja" uniqKey="Kaandorp J">JA Kaandorp</name>
</author>
<author><name sortKey="Blom, J" uniqKey="Blom J">J Blom</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ilsley, Gr" uniqKey="Ilsley G">GR Ilsley</name>
</author>
<author><name sortKey="Fisher, J" uniqKey="Fisher J">J Fisher</name>
</author>
<author><name sortKey="Apweiler, R" uniqKey="Apweiler R">R Apweiler</name>
</author>
<author><name sortKey="Depace, Ah" uniqKey="Depace A">AH DePace</name>
</author>
<author><name sortKey="Luscombe, Nm" uniqKey="Luscombe N">NM Luscombe</name>
</author>
<author><name sortKey="Guigo, R" uniqKey="Guigo R">R Guigo</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Meinhardt, H" uniqKey="Meinhardt H">H Meinhardt</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wagner, De" uniqKey="Wagner D">DE Wagner</name>
</author>
<author><name sortKey="Wang, Ie" uniqKey="Wang I">IE Wang</name>
</author>
<author><name sortKey="Reddien, Pw" uniqKey="Reddien P">PW Reddien</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Reddien, Pw" uniqKey="Reddien P">PW Reddien</name>
</author>
<author><name sortKey="Oviedo, Nj" uniqKey="Oviedo N">NJ Oviedo</name>
</author>
<author><name sortKey="Jennings, Jr" uniqKey="Jennings J">JR Jennings</name>
</author>
<author><name sortKey="Jenkin, Jc" uniqKey="Jenkin J">JC Jenkin</name>
</author>
<author><name sortKey="Sanchez Alvarado, A" uniqKey="Sanchez Alvarado A">A Sanchez Alvarado</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Oviedo, Nj" uniqKey="Oviedo N">NJ Oviedo</name>
</author>
<author><name sortKey="Morokuma, J" uniqKey="Morokuma J">J Morokuma</name>
</author>
<author><name sortKey="Walentek, P" uniqKey="Walentek P">P Walentek</name>
</author>
<author><name sortKey="Kema, Ip" uniqKey="Kema I">IP Kema</name>
</author>
<author><name sortKey="Gu, Mb" uniqKey="Gu M">MB Gu</name>
</author>
<author><name sortKey="Ahn, Jm" uniqKey="Ahn J">JM Ahn</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sal, E" uniqKey="Sal E">E Saló</name>
</author>
<author><name sortKey="Abril, Jf" uniqKey="Abril J">JF Abril</name>
</author>
<author><name sortKey="Adell, T" uniqKey="Adell T">T Adell</name>
</author>
<author><name sortKey="Cebria, F" uniqKey="Cebria F">F Cebrià</name>
</author>
<author><name sortKey="Eckelt, K" uniqKey="Eckelt K">K Eckelt</name>
</author>
<author><name sortKey="Fernandez Taboada, E" uniqKey="Fernandez Taboada E">E Fernandez-Taboada</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Holland, Jh" uniqKey="Holland J">JH Holland</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lobo, D" uniqKey="Lobo D">D Lobo</name>
</author>
<author><name sortKey="Malone, Tj" uniqKey="Malone T">TJ Malone</name>
</author>
<author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Budnikova, M" uniqKey="Budnikova M">M Budnikova</name>
</author>
<author><name sortKey="Habig, J" uniqKey="Habig J">J Habig</name>
</author>
<author><name sortKey="Lobo, D" uniqKey="Lobo D">D Lobo</name>
</author>
<author><name sortKey="Cornia, N" uniqKey="Cornia N">N Cornia</name>
</author>
<author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name>
</author>
<author><name sortKey="Andersen, T" uniqKey="Andersen T">T Andersen</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gurley, Ka" uniqKey="Gurley K">KA Gurley</name>
</author>
<author><name sortKey="Rink, Jc" uniqKey="Rink J">JC Rink</name>
</author>
<author><name sortKey="Sanchez Alvarado, A" uniqKey="Sanchez Alvarado A">A Sánchez Alvarado</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Petersen, Cp" uniqKey="Petersen C">CP Petersen</name>
</author>
<author><name sortKey="Reddien, Pw" uniqKey="Reddien P">PW Reddien</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Iglesias, M" uniqKey="Iglesias M">M Iglesias</name>
</author>
<author><name sortKey="Gomez Skarmeta, Jl" uniqKey="Gomez Skarmeta J">JL Gomez-Skarmeta</name>
</author>
<author><name sortKey="Sal, E" uniqKey="Sal E">E Saló</name>
</author>
<author><name sortKey="Adell, T" uniqKey="Adell T">T Adell</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Petersen, Cp" uniqKey="Petersen C">CP Petersen</name>
</author>
<author><name sortKey="Reddien, Pw" uniqKey="Reddien P">PW Reddien</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Petersen, Cp" uniqKey="Petersen C">CP Petersen</name>
</author>
<author><name sortKey="Reddien, Pw" uniqKey="Reddien P">PW Reddien</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rink, Jc" uniqKey="Rink J">JC Rink</name>
</author>
<author><name sortKey="Gurley, Ka" uniqKey="Gurley K">KA Gurley</name>
</author>
<author><name sortKey="Elliott, Sa" uniqKey="Elliott S">SA Elliott</name>
</author>
<author><name sortKey="Sanchez Alvarado, A" uniqKey="Sanchez Alvarado A">A Sánchez Alvarado</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Oviedo, Nj" uniqKey="Oviedo N">NJ Oviedo</name>
</author>
<author><name sortKey="Morokuma, J" uniqKey="Morokuma J">J Morokuma</name>
</author>
<author><name sortKey="Walentek, P" uniqKey="Walentek P">P Walentek</name>
</author>
<author><name sortKey="Kema, I" uniqKey="Kema I">I Kema</name>
</author>
<author><name sortKey="Gu, Mb" uniqKey="Gu M">MB Gu</name>
</author>
<author><name sortKey="Ahn, J M" uniqKey="Ahn J">J-M Ahn</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Morgan, Th" uniqKey="Morgan T">TH Morgan</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gurley, Ka" uniqKey="Gurley K">KA Gurley</name>
</author>
<author><name sortKey="Elliott, Sa" uniqKey="Elliott S">SA Elliott</name>
</author>
<author><name sortKey="Simakov, O" uniqKey="Simakov O">O Simakov</name>
</author>
<author><name sortKey="Schmidt, Ha" uniqKey="Schmidt H">HA Schmidt</name>
</author>
<author><name sortKey="Holstein, Tw" uniqKey="Holstein T">TW Holstein</name>
</author>
<author><name sortKey="Sanchez Alvarado, A" uniqKey="Sanchez Alvarado A">A Sanchez Alvarado</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="King, Rd" uniqKey="King R">RD King</name>
</author>
<author><name sortKey="Rowland, J" uniqKey="Rowland J">J Rowland</name>
</author>
<author><name sortKey="Oliver, Sg" uniqKey="Oliver S">SG Oliver</name>
</author>
<author><name sortKey="Young, M" uniqKey="Young M">M Young</name>
</author>
<author><name sortKey="Aubrey, W" uniqKey="Aubrey W">W Aubrey</name>
</author>
<author><name sortKey="Byrne, E" uniqKey="Byrne E">E Byrne</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sparkes, A" uniqKey="Sparkes A">A Sparkes</name>
</author>
<author><name sortKey="Aubrey, W" uniqKey="Aubrey W">W Aubrey</name>
</author>
<author><name sortKey="Byrne, E" uniqKey="Byrne E">E Byrne</name>
</author>
<author><name sortKey="Clare, A" uniqKey="Clare A">A Clare</name>
</author>
<author><name sortKey="Khan, Mn" uniqKey="Khan M">MN Khan</name>
</author>
<author><name sortKey="Liakata, M" uniqKey="Liakata M">M Liakata</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gil, Y" uniqKey="Gil Y">Y Gil</name>
</author>
<author><name sortKey="Greaves, M" uniqKey="Greaves M">M Greaves</name>
</author>
<author><name sortKey="Hendler, J" uniqKey="Hendler J">J Hendler</name>
</author>
<author><name sortKey="Hirsh, H" uniqKey="Hirsh H">H Hirsh</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tarcea, Vg" uniqKey="Tarcea V">VG Tarcea</name>
</author>
<author><name sortKey="Weymouth, T" uniqKey="Weymouth T">T Weymouth</name>
</author>
<author><name sortKey="Ade, A" uniqKey="Ade A">A Ade</name>
</author>
<author><name sortKey="Bookvich, A" uniqKey="Bookvich A">A Bookvich</name>
</author>
<author><name sortKey="Gao, J" uniqKey="Gao J">J Gao</name>
</author>
<author><name sortKey="Mahavisno, V" uniqKey="Mahavisno V">V Mahavisno</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jayapandian, M" uniqKey="Jayapandian M">M Jayapandian</name>
</author>
<author><name sortKey="Chapman, A" uniqKey="Chapman A">A Chapman</name>
</author>
<author><name sortKey="Tarcea, Vg" uniqKey="Tarcea V">VG Tarcea</name>
</author>
<author><name sortKey="Yu, C" uniqKey="Yu C">C Yu</name>
</author>
<author><name sortKey="Elkiss, A" uniqKey="Elkiss A">A Elkiss</name>
</author>
<author><name sortKey="Ianni, A" uniqKey="Ianni A">A Ianni</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wagner, De" uniqKey="Wagner D">DE Wagner</name>
</author>
<author><name sortKey="Wang, Ie" uniqKey="Wang I">IE Wang</name>
</author>
<author><name sortKey="Reddien, Pw" uniqKey="Reddien P">PW Reddien</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Franceschini, A" uniqKey="Franceschini A">A Franceschini</name>
</author>
<author><name sortKey="Szklarczyk, D" uniqKey="Szklarczyk D">D Szklarczyk</name>
</author>
<author><name sortKey="Frankild, S" uniqKey="Frankild S">S Frankild</name>
</author>
<author><name sortKey="Kuhn, M" uniqKey="Kuhn M">M Kuhn</name>
</author>
<author><name sortKey="Simonovic, M" uniqKey="Simonovic M">M Simonovic</name>
</author>
<author><name sortKey="Roth, A" uniqKey="Roth A">A Roth</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="De Jong, H" uniqKey="De Jong H">H de Jong</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Davidson, Eh" uniqKey="Davidson E">EH Davidson</name>
</author>
<author><name sortKey="Rast, Jp" uniqKey="Rast J">JP Rast</name>
</author>
<author><name sortKey="Oliveri, P" uniqKey="Oliveri P">P Oliveri</name>
</author>
<author><name sortKey="Ransick, A" uniqKey="Ransick A">A Ransick</name>
</author>
<author><name sortKey="Calestani, C" uniqKey="Calestani C">C Calestani</name>
</author>
<author><name sortKey="Yuh, Ch" uniqKey="Yuh C">CH Yuh</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Di Ventura, B" uniqKey="Di Ventura B">B Di Ventura</name>
</author>
<author><name sortKey="Lemerle, C" uniqKey="Lemerle C">C Lemerle</name>
</author>
<author><name sortKey="Michalodimitrakis, K" uniqKey="Michalodimitrakis K">K Michalodimitrakis</name>
</author>
<author><name sortKey="Serrano, L" uniqKey="Serrano L">L Serrano</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Iber, D" uniqKey="Iber D">D Iber</name>
</author>
<author><name sortKey="Zeller, R" uniqKey="Zeller R">R Zeller</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Umesono, Y" uniqKey="Umesono Y">Y Umesono</name>
</author>
<author><name sortKey="Tasaki, J" uniqKey="Tasaki J">J Tasaki</name>
</author>
<author><name sortKey="Nishimura, Y" uniqKey="Nishimura Y">Y Nishimura</name>
</author>
<author><name sortKey="Hrouda, M" uniqKey="Hrouda M">M Hrouda</name>
</author>
<author><name sortKey="Kawaguchi, E" uniqKey="Kawaguchi E">E Kawaguchi</name>
</author>
<author><name sortKey="Yazawa, S" uniqKey="Yazawa S">S Yazawa</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rink, Jc" uniqKey="Rink J">JC Rink</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="King, Rs" uniqKey="King R">RS King</name>
</author>
<author><name sortKey="Newmark, Pa" uniqKey="Newmark P">PA Newmark</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Adell, T" uniqKey="Adell T">T Adell</name>
</author>
<author><name sortKey="Cebria, F" uniqKey="Cebria F">F Cebrià</name>
</author>
<author><name sortKey="Sal, E" uniqKey="Sal E">E Saló</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Brockes, Jr" uniqKey="Brockes J">JR Brockes</name>
</author>
<author><name sortKey="Kumar, A" uniqKey="Kumar A">A Kumar</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Meinhardt, H" uniqKey="Meinhardt H">H Meinhardt</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Meinhardt, H" uniqKey="Meinhardt H">H Meinhardt</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kakugawa, S" uniqKey="Kakugawa S">S Kakugawa</name>
</author>
<author><name sortKey="Langton, Pf" uniqKey="Langton P">PF Langton</name>
</author>
<author><name sortKey="Zebisch, M" uniqKey="Zebisch M">M Zebisch</name>
</author>
<author><name sortKey="Howell, Sa" uniqKey="Howell S">SA Howell</name>
</author>
<author><name sortKey="Chang, T H" uniqKey="Chang T">T-H Chang</name>
</author>
<author><name sortKey="Liu, Y" uniqKey="Liu Y">Y Liu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Molina, Md" uniqKey="Molina M">MD Molina</name>
</author>
<author><name sortKey="Sal, E" uniqKey="Sal E">E Saló</name>
</author>
<author><name sortKey="Cebria, F" uniqKey="Cebria F">F Cebrià</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Orii, H" uniqKey="Orii H">H Orii</name>
</author>
<author><name sortKey="Watanabe, K" uniqKey="Watanabe K">K Watanabe</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Gavi O, Ma" uniqKey="Gavi O M">MA Gaviño</name>
</author>
<author><name sortKey="Reddien, Pw" uniqKey="Reddien P">PW Reddien</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Molina, Md" uniqKey="Molina M">MD Molina</name>
</author>
<author><name sortKey="Neto, A" uniqKey="Neto A">A Neto</name>
</author>
<author><name sortKey="Maeso, I" uniqKey="Maeso I">I Maeso</name>
</author>
<author><name sortKey="Gomez Skarmeta, Jl" uniqKey="Gomez Skarmeta J">JL Gomez-Skarmeta</name>
</author>
<author><name sortKey="Sal, E" uniqKey="Sal E">E Saló</name>
</author>
<author><name sortKey="Cebria, F" uniqKey="Cebria F">F Cebrià</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lobo, D" uniqKey="Lobo D">D Lobo</name>
</author>
<author><name sortKey="Feldman, Eb" uniqKey="Feldman E">EB Feldman</name>
</author>
<author><name sortKey="Shah, M" uniqKey="Shah M">M Shah</name>
</author>
<author><name sortKey="Malone, Tj" uniqKey="Malone T">TJ Malone</name>
</author>
<author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lobo, D" uniqKey="Lobo D">D Lobo</name>
</author>
<author><name sortKey="Feldman, Eb" uniqKey="Feldman E">EB Feldman</name>
</author>
<author><name sortKey="Shah, M" uniqKey="Shah M">M Shah</name>
</author>
<author><name sortKey="Malone, Tj" uniqKey="Malone T">TJ Malone</name>
</author>
<author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mustard, J" uniqKey="Mustard J">J Mustard</name>
</author>
<author><name sortKey="Levin, M" uniqKey="Levin M">M Levin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Doursat, R" uniqKey="Doursat R">R Doursat</name>
</author>
<author><name sortKey="Sayama, H" uniqKey="Sayama H">H Sayama</name>
</author>
<author><name sortKey="Michel, O" uniqKey="Michel O">O Michel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lobo, D" uniqKey="Lobo D">D Lobo</name>
</author>
<author><name sortKey="Fernandez, Jd" uniqKey="Fernandez J">JD Fernández</name>
</author>
<author><name sortKey="Vico, Fj" uniqKey="Vico F">FJ Vico</name>
</author>
<author><name sortKey="Doursat, R" uniqKey="Doursat R">R Doursat</name>
</author>
<author><name sortKey="Sayama, H" uniqKey="Sayama H">H Sayama</name>
</author>
<author><name sortKey="Michel, O" uniqKey="Michel O">O Michel</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Diestel, R" uniqKey="Diestel R">R Diestel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Legewie, S" uniqKey="Legewie S">S Legewie</name>
</author>
<author><name sortKey="Bluthgen, N" uniqKey="Bluthgen N">N Bluthgen</name>
</author>
<author><name sortKey="Herzel, H" uniqKey="Herzel H">H Herzel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Press, Wh" uniqKey="Press W">WH Press</name>
</author>
<author><name sortKey="Flannery, Bp" uniqKey="Flannery B">BP Flannery</name>
</author>
<author><name sortKey="Teukolsky, Sa" uniqKey="Teukolsky S">SA Teukolsky</name>
</author>
<author><name sortKey="Vetterling, Wt" uniqKey="Vetterling W">WT Vetterling</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Oviedo, Nj" uniqKey="Oviedo N">NJ Oviedo</name>
</author>
<author><name sortKey="Newmark, Pa" uniqKey="Newmark P">PA Newmark</name>
</author>
<author><name sortKey="Sanchez Alvarado, A" uniqKey="Sanchez Alvarado A">A Sánchez Alvarado</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Forrest, S" uniqKey="Forrest S">S Forrest</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Luke, S" uniqKey="Luke S">S Luke</name>
</author>
<author><name sortKey="Partait, L" uniqKey="Partait L">L Partait</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Whitley, D" uniqKey="Whitley D">D Whitley</name>
</author>
<author><name sortKey="Rana, S" uniqKey="Rana S">S Rana</name>
</author>
<author><name sortKey="Heckendorn, Rb" uniqKey="Heckendorn R">RB Heckendorn</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mahfoud, Sw" uniqKey="Mahfoud S">SW Mahfoud</name>
</author>
<author><name sortKey="Manner, R" uniqKey="Manner R">R Manner</name>
</author>
<author><name sortKey="Manderick, B" uniqKey="Manderick B">B Manderick</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Comput Biol</journal-id>
<journal-id journal-id-type="iso-abbrev">PLoS Comput. Biol</journal-id>
<journal-id journal-id-type="publisher-id">plos</journal-id>
<journal-id journal-id-type="pmc">ploscomp</journal-id>
<journal-title-group><journal-title>PLoS Computational Biology</journal-title>
</journal-title-group>
<issn pub-type="ppub">1553-734X</issn>
<issn pub-type="epub">1553-7358</issn>
<publisher><publisher-name>Public Library of Science</publisher-name>
<publisher-loc>San Francisco, CA USA</publisher-loc>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">26042810</article-id>
<article-id pub-id-type="pmc">4456145</article-id>
<article-id pub-id-type="doi">10.1371/journal.pcbi.1004295</article-id>
<article-id pub-id-type="publisher-id">PCOMPBIOL-D-14-02114</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>Inferring Regulatory Networks from Experimental Morphological Phenotypes: A Computational Method Reverse-Engineers Planarian Regeneration</article-title>
<alt-title alt-title-type="running-head">Inferring Regulatory Networks from Experimental Phenotypic Data</alt-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Lobo</surname>
<given-names>Daniel</given-names>
</name>
<xref ref-type="aff" rid="aff001"></xref>
</contrib>
<contrib contrib-type="author"><name><surname>Levin</surname>
<given-names>Michael</given-names>
</name>
<xref rid="cor001" ref-type="corresp">*</xref>
<xref ref-type="aff" rid="aff001"></xref>
</contrib>
</contrib-group>
<aff id="aff001"><addr-line>Center for Regenerative and Developmental Biology, Department of Biology, Tufts University, Medford, Massachusetts, United States of America</addr-line>
</aff>
<contrib-group><contrib contrib-type="editor"><name><surname>Saucerman</surname>
<given-names>Jeffrey J.</given-names>
</name>
<role>Editor</role>
<xref ref-type="aff" rid="edit1"></xref>
</contrib>
</contrib-group>
<aff id="edit1"><addr-line>University of Virginia, UNITED STATES</addr-line>
</aff>
<author-notes><fn fn-type="conflict" id="coi001"><p>The authors have declared that no competing interests exist.</p>
</fn>
<fn fn-type="con" id="contrib001"><p>Conceived and designed the experiments: DL ML. Performed the experiments: DL. Analyzed the data: DL. Contributed reagents/materials/analysis tools: DL ML. Wrote the paper: DL ML.</p>
</fn>
<corresp id="cor001">* E-mail: <email>michael.levin@tufts.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="epub"><day>4</day>
<month>6</month>
<year>2015</year>
</pub-date>
<pub-date pub-type="collection"><month>6</month>
<year>2015</year>
</pub-date>
<volume>11</volume>
<issue>6</issue>
<elocation-id>e1004295</elocation-id>
<history><date date-type="received"><day>24</day>
<month>11</month>
<year>2014</year>
</date>
<date date-type="accepted"><day>21</day>
<month>4</month>
<year>2015</year>
</date>
</history>
<permissions><copyright-statement>© 2015 Lobo, Levin</copyright-statement>
<copyright-year>2015</copyright-year>
<copyright-holder>Lobo, Levin</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.</license-p>
</license>
</permissions>
<self-uri content-type="pdf" xlink:type="simple" xlink:href="pcbi.1004295.pdf"></self-uri>
<abstract><p>Transformative applications in biomedicine require the discovery of complex regulatory networks that explain the development and regeneration of anatomical structures, and reveal what external signals will trigger desired changes of large-scale pattern. Despite recent advances in bioinformatics, extracting mechanistic pathway models from experimental morphological data is a key open challenge that has resisted automation. The fundamental difficulty of manually predicting emergent behavior of even simple networks has limited the models invented by human scientists to pathway diagrams that show necessary subunit interactions but do not reveal the dynamics that are sufficient for complex, self-regulating pattern to emerge. To finally bridge the gap between high-resolution genetic data and the ability to understand and control patterning, it is critical to develop computational tools to efficiently extract regulatory pathways from the resultant experimental shape phenotypes. For example, planarian regeneration has been studied for over a century, but despite increasing insight into the pathways that control its stem cells, no constructive, mechanistic model has yet been found by human scientists that explains more than one or two key features of its remarkable ability to regenerate its correct anatomical pattern after drastic perturbations. We present a method to infer the molecular products, topology, and spatial and temporal non-linear dynamics of regulatory networks recapitulating <italic>in silico</italic>
the rich dataset of morphological phenotypes resulting from genetic, surgical, and pharmacological experiments. We demonstrated our approach by inferring complete regulatory networks explaining the outcomes of the main functional regeneration experiments in the planarian literature; By analyzing all the datasets together, our system inferred the first systems-biology comprehensive dynamical model explaining patterning in planarian regeneration. This method provides an automated, highly generalizable framework for identifying the underlying control mechanisms responsible for the dynamic regulation of growth and form.</p>
</abstract>
<abstract abstract-type="summary"><title>Author Summary</title>
<p>Developmental and regenerative biology experiments are producing a huge number of morphological phenotypes from functional perturbation experiments. However, existing pathway models do not generally explain the dynamic regulation of anatomical shape due to the difficulty of inferring and testing non-linear regulatory networks responsible for appropriate form, shape, and pattern. We present a method that automates the discovery and testing of regulatory networks explaining morphological outcomes directly from the resultant phenotypes, producing network models as testable hypotheses explaining regeneration data. Our system integrates a formalization of the published results in planarian regeneration, an <italic>in silico</italic>
simulator in which the patterning properties of regulatory networks can be quantitatively tested in a regeneration assay, and a machine learning module that evolves networks whose behavior in this assay optimally matches the database of planarian results. We applied our method to explain the key experiments in planarian regeneration, and discovered the first comprehensive model of anterior-posterior patterning in planaria under surgical, pharmacological, and genetic manipulations. Beyond the planarian data, our approach is readily generalizable to facilitate the discovery of testable regulatory networks in developmental biology and biomedicine, and represents the first developmental model discovered <italic>de novo</italic>
from morphological outcomes by an automated system.</p>
</abstract>
<funding-group><funding-statement>This work was supported by NSF grant EF-1124651, NIH grant GM078484, USAMRMC grant W81XWH-10-2-0058, and the Mathers Foundation. Computation used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by NSF grant OCI-1053575, and a cluster computer awarded by Silicon Mechanics. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.</funding-statement>
</funding-group>
<counts><fig-count count="10"></fig-count>
<table-count count="0"></table-count>
<page-count count="28"></page-count>
</counts>
<custom-meta-group><custom-meta id="data-availability"><meta-name>Data Availability</meta-name>
<meta-value>All relevant data are within the paper and its Supporting Information files.</meta-value>
</custom-meta>
</custom-meta-group>
</article-meta>
<notes><title>Data Availability</title>
<p>All relevant data are within the paper and its Supporting Information files.</p>
</notes>
</front>
</pmc>
</record>
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