PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (2040340)

Clipboard (0)
None

Related Articles

1.  Structural and functional protein network analyses predict novel signaling functions for rhodopsin 
Proteomic analyses, literature mining, and structural data were combined to generate an extensive signaling network linked to the visual G protein-coupled receptor rhodopsin. Network analysis suggests novel signaling routes to cytoskeleton dynamics and vesicular trafficking.
Using a shotgun proteomic approach, we identified the protein inventory of the light sensing outer segment of the mammalian photoreceptor.These data, combined with literature mining, structural modeling, and computational analysis, offer a comprehensive view of signal transduction downstream of the visual G protein-coupled receptor rhodopsin.The network suggests novel signaling branches downstream of rhodopsin to cytoskeleton dynamics and vesicular trafficking.The network serves as a basis for elucidating physiological principles of photoreceptor function and suggests potential disease-associated proteins.
Photoreceptor cells are neurons capable of converting light into electrical signals. The rod outer segment (ROS) region of the photoreceptor cells is a cellular structure made of a stack of around 800 closed membrane disks loaded with rhodopsin (Liang et al, 2003; Nickell et al, 2007). In disc membranes, rhodopsin arranges itself into paracrystalline dimer arrays, enabling optimal association with the heterotrimeric G protein transducin as well as additional regulatory components (Ciarkowski et al, 2005). Disruption of these highly regulated structures and processes by germline mutations is the cause of severe blinding diseases such as retinitis pigmentosa, macular degeneration, or congenital stationary night blindness (Berger et al, 2010).
Traditionally, signal transduction networks have been studied by combining biochemical and genetic experiments addressing the relations among a small number of components. More recently, large throughput experiments using different techniques like two hybrid or co-immunoprecipitation coupled to mass spectrometry have added a new level of complexity (Ito et al, 2001; Gavin et al, 2002, 2006; Ho et al, 2002; Rual et al, 2005; Stelzl et al, 2005). However, in these studies, space, time, and the fact that many interactions detected for a particular protein are not compatible, are not taken into consideration. Structural information can help discriminate between direct and indirect interactions and more importantly it can determine if two or more predicted partners of any given protein or complex can simultaneously bind a target or rather compete for the same interaction surface (Kim et al, 2006).
In this work, we build a functional and dynamic interaction network centered on rhodopsin on a systems level, using six steps: In step 1, we experimentally identified the proteomic inventory of the porcine ROS, and we compared our data set with a recent proteomic study from bovine ROS (Kwok et al, 2008). The union of the two data sets was defined as the ‘initial experimental ROS proteome'. After removal of contaminants and applying filtering methods, a ‘core ROS proteome', consisting of 355 proteins, was defined.
In step 2, proteins of the core ROS proteome were assigned to six functional modules: (1) vision, signaling, transporters, and channels; (2) outer segment structure and morphogenesis; (3) housekeeping; (4) cytoskeleton and polarity; (5) vesicles formation and trafficking, and (6) metabolism.
In step 3, a protein-protein interaction network was constructed based on the literature mining. Since for most of the interactions experimental evidence was co-immunoprecipitation, or pull-down experiments, and in addition many of the edges in the network are supported by single experimental evidence, often derived from high-throughput approaches, we refer to this network, as ‘fuzzy ROS interactome'. Structural information was used to predict binary interactions, based on the finding that similar domain pairs are likely to interact in a similar way (‘nature repeats itself') (Aloy and Russell, 2002). To increase the confidence in the resulting network, edges supported by a single evidence not coming from yeast two-hybrid experiments were removed, exception being interactions where the evidence was the existence of a three-dimensional structure of the complex itself, or of a highly homologous complex. This curated static network (‘high-confidence ROS interactome') comprises 660 edges linking the majority of the nodes. By considering only edges supported by at least one evidence of direct binary interaction, we end up with a ‘high-confidence binary ROS interactome'. We next extended the published core pathway (Dell'Orco et al, 2009) using evidence from our high-confidence network. We find several new direct binary links to different cellular functional processes (Figure 4): the active rhodopsin interacts with Rac1 and the GTP form of Rho. There is also a connection between active rhodopsin and Arf4, as well as PDEδ with Rab13 and the GTP-bound form of Arl3 that links the vision cycle to vesicle trafficking and structure. We see a connection between PDEδ with prenyl-modified proteins, such as several small GTPases, as well as with rhodopsin kinase. Further, our network reveals several direct binary connections between Ca2+-regulated proteins and cytoskeleton proteins; these are CaMK2A with actinin, calmodulin with GAP43 and S1008, and PKC with 14-3-3 family members.
In step 4, part of the network was experimentally validated using three different approaches to identify physical protein associations that would occur under physiological conditions: (i) Co-segregation/co-sedimentation experiments, (ii) immunoprecipitations combined with mass spectrometry and/or subsequent immunoblotting, and (iii) utilizing the glycosylated N-terminus of rhodopsin to isolate its associated protein partners by Concanavalin A affinity purification. In total, 60 co-purification and co-elution experiments supported interactions that were already in our literature network, and new evidence from 175 co-IP experiments in this work was added. Next, we aimed to provide additional independent experimental confirmation for two of the novel networks and functional links proposed based on the network analysis: (i) the proposed complex between Rac1/RhoA/CRMP-2/tubulin/and ROCK II in ROS was investigated by culturing retinal explants in the presence of an ROCK II-specific inhibitor (Figure 6). While morphology of the retinas treated with ROCK II inhibitor appeared normal, immunohistochemistry analyses revealed several alterations on the protein level. (ii) We supported the hypothesis that PDEδ could function as a GDI for Rac1 in ROS, by demonstrating that PDEδ and Rac1 co localize in ROS and that PDEδ could dissociate Rac1 from ROS membranes in vitro.
In step 5, we use structural information to distinguish between mutually compatible (‘AND') or excluded (‘XOR') interactions. This enables breaking a network of nodes and edges into functional machines or sub-networks/modules. In the vision branch, both ‘AND' and ‘XOR' gates synergize. This may allow dynamic tuning of light and dark states. However, all connections from the vision module to other modules are ‘XOR' connections suggesting that competition, in connection with local protein concentration changes, could be important for transmitting signals from the core vision module.
In the last step, we map and functionally characterize the known mutations that produce blindness.
In summary, this represents the first comprehensive, dynamic, and integrative rhodopsin signaling network, which can be the basis for integrating and mapping newly discovered disease mutants, to guide protein or signaling branch-specific therapies.
Orchestration of signaling, photoreceptor structural integrity, and maintenance needed for mammalian vision remain enigmatic. By integrating three proteomic data sets, literature mining, computational analyses, and structural information, we have generated a multiscale signal transduction network linked to the visual G protein-coupled receptor (GPCR) rhodopsin, the major protein component of rod outer segments. This network was complemented by domain decomposition of protein–protein interactions and then qualified for mutually exclusive or mutually compatible interactions and ternary complex formation using structural data. The resulting information not only offers a comprehensive view of signal transduction induced by this GPCR but also suggests novel signaling routes to cytoskeleton dynamics and vesicular trafficking, predicting an important level of regulation through small GTPases. Further, it demonstrates a specific disease susceptibility of the core visual pathway due to the uniqueness of its components present mainly in the eye. As a comprehensive multiscale network, it can serve as a basis to elucidate the physiological principles of photoreceptor function, identify potential disease-associated genes and proteins, and guide the development of therapies that target specific branches of the signaling pathway.
doi:10.1038/msb.2011.83
PMCID: PMC3261702  PMID: 22108793
protein interaction network; rhodopsin signaling; structural modeling
2.  25th Annual Computational Neuroscience Meeting: CNS-2016 
Sharpee, Tatyana O. | Destexhe, Alain | Kawato, Mitsuo | Sekulić, Vladislav | Skinner, Frances K. | Wójcik, Daniel K. | Chintaluri, Chaitanya | Cserpán, Dorottya | Somogyvári, Zoltán | Kim, Jae Kyoung | Kilpatrick, Zachary P. | Bennett, Matthew R. | Josić, Kresimir | Elices, Irene | Arroyo, David | Levi, Rafael | Rodriguez, Francisco B. | Varona, Pablo | Hwang, Eunjin | Kim, Bowon | Han, Hio-Been | Kim, Tae | McKenna, James T. | Brown, Ritchie E. | McCarley, Robert W. | Choi, Jee Hyun | Rankin, James | Popp, Pamela Osborn | Rinzel, John | Tabas, Alejandro | Rupp, André | Balaguer-Ballester, Emili | Maturana, Matias I. | Grayden, David B. | Cloherty, Shaun L. | Kameneva, Tatiana | Ibbotson, Michael R. | Meffin, Hamish | Koren, Veronika | Lochmann, Timm | Dragoi, Valentin | Obermayer, Klaus | Psarrou, Maria | Schilstra, Maria | Davey, Neil | Torben-Nielsen, Benjamin | Steuber, Volker | Ju, Huiwen | Yu, Jiao | Hines, Michael L. | Chen, Liang | Yu, Yuguo | Kim, Jimin | Leahy, Will | Shlizerman, Eli | Birgiolas, Justas | Gerkin, Richard C. | Crook, Sharon M. | Viriyopase, Atthaphon | Memmesheimer, Raoul-Martin | Gielen, Stan | Dabaghian, Yuri | DeVito, Justin | Perotti, Luca | Kim, Anmo J. | Fenk, Lisa M. | Cheng, Cheng | Maimon, Gaby | Zhao, Chang | Widmer, Yves | Sprecher, Simon | Senn, Walter | Halnes, Geir | Mäki-Marttunen, Tuomo | Keller, Daniel | Pettersen, Klas H. | Andreassen, Ole A. | Einevoll, Gaute T. | Yamada, Yasunori | Steyn-Ross, Moira L. | Alistair Steyn-Ross, D. | Mejias, Jorge F. | Murray, John D. | Kennedy, Henry | Wang, Xiao-Jing | Kruscha, Alexandra | Grewe, Jan | Benda, Jan | Lindner, Benjamin | Badel, Laurent | Ohta, Kazumi | Tsuchimoto, Yoshiko | Kazama, Hokto | Kahng, B. | Tam, Nicoladie D. | Pollonini, Luca | Zouridakis, George | Soh, Jaehyun | Kim, DaeEun | Yoo, Minsu | Palmer, S. E. | Culmone, Viviana | Bojak, Ingo | Ferrario, Andrea | Merrison-Hort, Robert | Borisyuk, Roman | Kim, Chang Sub | Tezuka, Taro | Joo, Pangyu | Rho, Young-Ah | Burton, Shawn D. | Bard Ermentrout, G. | Jeong, Jaeseung | Urban, Nathaniel N. | Marsalek, Petr | Kim, Hoon-Hee | Moon, Seok-hyun | Lee, Do-won | Lee, Sung-beom | Lee, Ji-yong | Molkov, Yaroslav I. | Hamade, Khaldoun | Teka, Wondimu | Barnett, William H. | Kim, Taegyo | Markin, Sergey | Rybak, Ilya A. | Forro, Csaba | Dermutz, Harald | Demkó, László | Vörös, János | Babichev, Andrey | Huang, Haiping | Verduzco-Flores, Sergio | Dos Santos, Filipa | Andras, Peter | Metzner, Christoph | Schweikard, Achim | Zurowski, Bartosz | Roach, James P. | Sander, Leonard M. | Zochowski, Michal R. | Skilling, Quinton M. | Ognjanovski, Nicolette | Aton, Sara J. | Zochowski, Michal | Wang, Sheng-Jun | Ouyang, Guang | Guang, Jing | Zhang, Mingsha | Michael Wong, K. Y. | Zhou, Changsong | Robinson, Peter A. | Sanz-Leon, Paula | Drysdale, Peter M. | Fung, Felix | Abeysuriya, Romesh G. | Rennie, Chris J. | Zhao, Xuelong | Choe, Yoonsuck | Yang, Huei-Fang | Mi, Yuanyuan | Lin, Xiaohan | Wu, Si | Liedtke, Joscha | Schottdorf, Manuel | Wolf, Fred | Yamamura, Yoriko | Wickens, Jeffery R. | Rumbell, Timothy | Ramsey, Julia | Reyes, Amy | Draguljić, Danel | Hof, Patrick R. | Luebke, Jennifer | Weaver, Christina M. | He, Hu | Yang, Xu | Ma, Hailin | Xu, Zhiheng | Wang, Yuzhe | Baek, Kwangyeol | Morris, Laurel S. | Kundu, Prantik | Voon, Valerie | Agnes, Everton J. | Vogels, Tim P. | Podlaski, William F. | Giese, Martin | Kuravi, Pradeep | Vogels, Rufin | Seeholzer, Alexander | Podlaski, William | Ranjan, Rajnish | Vogels, Tim | Torres, Joaquin J. | Baroni, Fabiano | Latorre, Roberto | Gips, Bart | Lowet, Eric | Roberts, Mark J. | de Weerd, Peter | Jensen, Ole | van der Eerden, Jan | Goodarzinick, Abdorreza | Niry, Mohammad D. | Valizadeh, Alireza | Pariz, Aref | Parsi, Shervin S. | Warburton, Julia M. | Marucci, Lucia | Tamagnini, Francesco | Brown, Jon | Tsaneva-Atanasova, Krasimira | Kleberg, Florence I. | Triesch, Jochen | Moezzi, Bahar | Iannella, Nicolangelo | Schaworonkow, Natalie | Plogmacher, Lukas | Goldsworthy, Mitchell R. | Hordacre, Brenton | McDonnell, Mark D. | Ridding, Michael C. | Zapotocky, Martin | Smit, Daniel | Fouquet, Coralie | Trembleau, Alain | Dasgupta, Sakyasingha | Nishikawa, Isao | Aihara, Kazuyuki | Toyoizumi, Taro | Robb, Daniel T. | Mellen, Nick | Toporikova, Natalia | Tang, Rongxiang | Tang, Yi-Yuan | Liang, Guangsheng | Kiser, Seth A. | Howard, James H. | Goncharenko, Julia | Voronenko, Sergej O. | Ahamed, Tosif | Stephens, Greg | Yger, Pierre | Lefebvre, Baptiste | Spampinato, Giulia Lia Beatrice | Esposito, Elric | et Olivier Marre, Marcel Stimberg | Choi, Hansol | Song, Min-Ho | Chung, SueYeon | Lee, Dan D. | Sompolinsky, Haim | Phillips, Ryan S. | Smith, Jeffrey | Chatzikalymniou, Alexandra Pierri | Ferguson, Katie | Alex Cayco Gajic, N. | Clopath, Claudia | Angus Silver, R. | Gleeson, Padraig | Marin, Boris | Sadeh, Sadra | Quintana, Adrian | Cantarelli, Matteo | Dura-Bernal, Salvador | Lytton, William W. | Davison, Andrew | Li, Luozheng | Zhang, Wenhao | Wang, Dahui | Song, Youngjo | Park, Sol | Choi, Ilhwan | Shin, Hee-sup | Choi, Hannah | Pasupathy, Anitha | Shea-Brown, Eric | Huh, Dongsung | Sejnowski, Terrence J. | Vogt, Simon M. | Kumar, Arvind | Schmidt, Robert | Van Wert, Stephen | Schiff, Steven J. | Veale, Richard | Scheutz, Matthias | Lee, Sang Wan | Gallinaro, Júlia | Rotter, Stefan | Rubchinsky, Leonid L. | Cheung, Chung Ching | Ratnadurai-Giridharan, Shivakeshavan | Shomali, Safura Rashid | Ahmadabadi, Majid Nili | Shimazaki, Hideaki | Nader Rasuli, S. | Zhao, Xiaochen | Rasch, Malte J. | Wilting, Jens | Priesemann, Viola | Levina, Anna | Rudelt, Lucas | Lizier, Joseph T. | Spinney, Richard E. | Rubinov, Mikail | Wibral, Michael | Bak, Ji Hyun | Pillow, Jonathan | Zaho, Yuan | Park, Il Memming | Kang, Jiyoung | Park, Hae-Jeong | Jang, Jaeson | Paik, Se-Bum | Choi, Woochul | Lee, Changju | Song, Min | Lee, Hyeonsu | Park, Youngjin | Yilmaz, Ergin | Baysal, Veli | Ozer, Mahmut | Saska, Daniel | Nowotny, Thomas | Chan, Ho Ka | Diamond, Alan | Herrmann, Christoph S. | Murray, Micah M. | Ionta, Silvio | Hutt, Axel | Lefebvre, Jérémie | Weidel, Philipp | Duarte, Renato | Morrison, Abigail | Lee, Jung H. | Iyer, Ramakrishnan | Mihalas, Stefan | Koch, Christof | Petrovici, Mihai A. | Leng, Luziwei | Breitwieser, Oliver | Stöckel, David | Bytschok, Ilja | Martel, Roman | Bill, Johannes | Schemmel, Johannes | Meier, Karlheinz | Esler, Timothy B. | Burkitt, Anthony N. | Kerr, Robert R. | Tahayori, Bahman | Nolte, Max | Reimann, Michael W. | Muller, Eilif | Markram, Henry | Parziale, Antonio | Senatore, Rosa | Marcelli, Angelo | Skiker, K. | Maouene, M. | Neymotin, Samuel A. | Seidenstein, Alexandra | Lakatos, Peter | Sanger, Terence D. | Menzies, Rosemary J. | McLauchlan, Campbell | van Albada, Sacha J. | Kedziora, David J. | Neymotin, Samuel | Kerr, Cliff C. | Suter, Benjamin A. | Shepherd, Gordon M. G. | Ryu, Juhyoung | Lee, Sang-Hun | Lee, Joonwon | Lee, Hyang Jung | Lim, Daeseob | Wang, Jisung | Lee, Heonsoo | Jung, Nam | Anh Quang, Le | Maeng, Seung Eun | Lee, Tae Ho | Lee, Jae Woo | Park, Chang-hyun | Ahn, Sora | Moon, Jangsup | Choi, Yun Seo | Kim, Juhee | Jun, Sang Beom | Lee, Seungjun | Lee, Hyang Woon | Jo, Sumin | Jun, Eunji | Yu, Suin | Goetze, Felix | Lai, Pik-Yin | Kim, Seonghyun | Kwag, Jeehyun | Jang, Hyun Jae | Filipović, Marko | Reig, Ramon | Aertsen, Ad | Silberberg, Gilad | Bachmann, Claudia | Buttler, Simone | Jacobs, Heidi | Dillen, Kim | Fink, Gereon R. | Kukolja, Juraj | Kepple, Daniel | Giaffar, Hamza | Rinberg, Dima | Shea, Steven | Koulakov, Alex | Bahuguna, Jyotika | Tetzlaff, Tom | Kotaleski, Jeanette Hellgren | Kunze, Tim | Peterson, Andre | Knösche, Thomas | Kim, Minjung | Kim, Hojeong | Park, Ji Sung | Yeon, Ji Won | Kim, Sung-Phil | Kang, Jae-Hwan | Lee, Chungho | Spiegler, Andreas | Petkoski, Spase | Palva, Matias J. | Jirsa, Viktor K. | Saggio, Maria L. | Siep, Silvan F. | Stacey, William C. | Bernar, Christophe | Choung, Oh-hyeon | Jeong, Yong | Lee, Yong-il | Kim, Su Hyun | Jeong, Mir | Lee, Jeungmin | Kwon, Jaehyung | Kralik, Jerald D. | Jahng, Jaehwan | Hwang, Dong-Uk | Kwon, Jae-Hyung | Park, Sang-Min | Kim, Seongkyun | Kim, Hyoungkyu | Kim, Pyeong Soo | Yoon, Sangsup | Lim, Sewoong | Park, Choongseok | Miller, Thomas | Clements, Katie | Ahn, Sungwoo | Ji, Eoon Hye | Issa, Fadi A. | Baek, JeongHun | Oba, Shigeyuki | Yoshimoto, Junichiro | Doya, Kenji | Ishii, Shin | Mosqueiro, Thiago S. | Strube-Bloss, Martin F. | Smith, Brian | Huerta, Ramon | Hadrava, Michal | Hlinka, Jaroslav | Bos, Hannah | Helias, Moritz | Welzig, Charles M. | Harper, Zachary J. | Kim, Won Sup | Shin, In-Seob | Baek, Hyeon-Man | Han, Seung Kee | Richter, René | Vitay, Julien | Beuth, Frederick | Hamker, Fred H. | Toppin, Kelly | Guo, Yixin | Graham, Bruce P. | Kale, Penelope J. | Gollo, Leonardo L. | Stern, Merav | Abbott, L. F. | Fedorov, Leonid A. | Giese, Martin A. | Ardestani, Mohammad Hovaidi | Faraji, Mohammad Javad | Preuschoff, Kerstin | Gerstner, Wulfram | van Gendt, Margriet J. | Briaire, Jeroen J. | Kalkman, Randy K. | Frijns, Johan H. M. | Lee, Won Hee | Frangou, Sophia | Fulcher, Ben D. | Tran, Patricia H. P. | Fornito, Alex | Gliske, Stephen V. | Lim, Eugene | Holman, Katherine A. | Fink, Christian G. | Kim, Jinseop S. | Mu, Shang | Briggman, Kevin L. | Sebastian Seung, H. | Wegener, Detlef | Bohnenkamp, Lisa | Ernst, Udo A. | Devor, Anna | Dale, Anders M. | Lines, Glenn T. | Edwards, Andy | Tveito, Aslak | Hagen, Espen | Senk, Johanna | Diesmann, Markus | Schmidt, Maximilian | Bakker, Rembrandt | Shen, Kelly | Bezgin, Gleb | Hilgetag, Claus-Christian | van Albada, Sacha Jennifer | Sun, Haoqi | Sourina, Olga | Huang, Guang-Bin | Klanner, Felix | Denk, Cornelia | Glomb, Katharina | Ponce-Alvarez, Adrián | Gilson, Matthieu | Ritter, Petra | Deco, Gustavo | Witek, Maria A. G. | Clarke, Eric F. | Hansen, Mads | Wallentin, Mikkel | Kringelbach, Morten L. | Vuust, Peter | Klingbeil, Guido | De Schutter, Erik | Chen, Weiliang | Zang, Yunliang | Hong, Sungho | Takashima, Akira | Zamora, Criseida | Gallimore, Andrew R. | Goldschmidt, Dennis | Manoonpong, Poramate | Karoly, Philippa J. | Freestone, Dean R. | Soundry, Daniel | Kuhlmann, Levin | Paninski, Liam | Cook, Mark | Lee, Jaejin | Fishman, Yonatan I. | Cohen, Yale E. | Roberts, James A. | Cocchi, Luca | Sweeney, Yann | Lee, Soohyun | Jung, Woo-Sung | Kim, Youngsoo | Jung, Younginha | Song, Yoon-Kyu | Chavane, Frédéric | Soman, Karthik | Muralidharan, Vignesh | Srinivasa Chakravarthy, V. | Shivkumar, Sabyasachi | Mandali, Alekhya | Pragathi Priyadharsini, B. | Mehta, Hima | Davey, Catherine E. | Brinkman, Braden A. W. | Kekona, Tyler | Rieke, Fred | Buice, Michael | De Pittà, Maurizio | Berry, Hugues | Brunel, Nicolas | Breakspear, Michael | Marsat, Gary | Drew, Jordan | Chapman, Phillip D. | Daly, Kevin C. | Bradle, Samual P. | Seo, Sat Byul | Su, Jianzhong | Kavalali, Ege T. | Blackwell, Justin | Shiau, LieJune | Buhry, Laure | Basnayake, Kanishka | Lee, Sue-Hyun | Levy, Brandon A. | Baker, Chris I. | Leleu, Timothée | Philips, Ryan T. | Chhabria, Karishma
BMC Neuroscience  2016;17(Suppl 1):54.
Table of contents
A1 Functional advantages of cell-type heterogeneity in neural circuits
Tatyana O. Sharpee
A2 Mesoscopic modeling of propagating waves in visual cortex
Alain Destexhe
A3 Dynamics and biomarkers of mental disorders
Mitsuo Kawato
F1 Precise recruitment of spiking output at theta frequencies requires dendritic h-channels in multi-compartment models of oriens-lacunosum/moleculare hippocampal interneurons
Vladislav Sekulić, Frances K. Skinner
F2 Kernel methods in reconstruction of current sources from extracellular potentials for single cells and the whole brains
Daniel K. Wójcik, Chaitanya Chintaluri, Dorottya Cserpán, Zoltán Somogyvári
F3 The synchronized periods depend on intracellular transcriptional repression mechanisms in circadian clocks.
Jae Kyoung Kim, Zachary P. Kilpatrick, Matthew R. Bennett, Kresimir Josić
O1 Assessing irregularity and coordination of spiking-bursting rhythms in central pattern generators
Irene Elices, David Arroyo, Rafael Levi, Francisco B. Rodriguez, Pablo Varona
O2 Regulation of top-down processing by cortically-projecting parvalbumin positive neurons in basal forebrain
Eunjin Hwang, Bowon Kim, Hio-Been Han, Tae Kim, James T. McKenna, Ritchie E. Brown, Robert W. McCarley, Jee Hyun Choi
O3 Modeling auditory stream segregation, build-up and bistability
James Rankin, Pamela Osborn Popp, John Rinzel
O4 Strong competition between tonotopic neural ensembles explains pitch-related dynamics of auditory cortex evoked fields
Alejandro Tabas, André Rupp, Emili Balaguer-Ballester
O5 A simple model of retinal response to multi-electrode stimulation
Matias I. Maturana, David B. Grayden, Shaun L. Cloherty, Tatiana Kameneva, Michael R. Ibbotson, Hamish Meffin
O6 Noise correlations in V4 area correlate with behavioral performance in visual discrimination task
Veronika Koren, Timm Lochmann, Valentin Dragoi, Klaus Obermayer
O7 Input-location dependent gain modulation in cerebellar nucleus neurons
Maria Psarrou, Maria Schilstra, Neil Davey, Benjamin Torben-Nielsen, Volker Steuber
O8 Analytic solution of cable energy function for cortical axons and dendrites
Huiwen Ju, Jiao Yu, Michael L. Hines, Liang Chen, Yuguo Yu
O9 C. elegans interactome: interactive visualization of Caenorhabditis elegans worm neuronal network
Jimin Kim, Will Leahy, Eli Shlizerman
O10 Is the model any good? Objective criteria for computational neuroscience model selection
Justas Birgiolas, Richard C. Gerkin, Sharon M. Crook
O11 Cooperation and competition of gamma oscillation mechanisms
Atthaphon Viriyopase, Raoul-Martin Memmesheimer, Stan Gielen
O12 A discrete structure of the brain waves
Yuri Dabaghian, Justin DeVito, Luca Perotti
O13 Direction-specific silencing of the Drosophila gaze stabilization system
Anmo J. Kim, Lisa M. Fenk, Cheng Lyu, Gaby Maimon
O14 What does the fruit fly think about values? A model of olfactory associative learning
Chang Zhao, Yves Widmer, Simon Sprecher,Walter Senn
O15 Effects of ionic diffusion on power spectra of local field potentials (LFP)
Geir Halnes, Tuomo Mäki-Marttunen, Daniel Keller, Klas H. Pettersen,Ole A. Andreassen, Gaute T. Einevoll
O16 Large-scale cortical models towards understanding relationship between brain structure abnormalities and cognitive deficits
Yasunori Yamada
O17 Spatial coarse-graining the brain: origin of minicolumns
Moira L. Steyn-Ross, D. Alistair Steyn-Ross
O18 Modeling large-scale cortical networks with laminar structure
Jorge F. Mejias, John D. Murray, Henry Kennedy, Xiao-Jing Wang
O19 Information filtering by partial synchronous spikes in a neural population
Alexandra Kruscha, Jan Grewe, Jan Benda, Benjamin Lindner
O20 Decoding context-dependent olfactory valence in Drosophila
Laurent Badel, Kazumi Ohta, Yoshiko Tsuchimoto, Hokto Kazama
P1 Neural network as a scale-free network: the role of a hub
B. Kahng
P2 Hemodynamic responses to emotions and decisions using near-infrared spectroscopy optical imaging
Nicoladie D. Tam
P3 Phase space analysis of hemodynamic responses to intentional movement directions using functional near-infrared spectroscopy (fNIRS) optical imaging technique
Nicoladie D.Tam, Luca Pollonini, George Zouridakis
P4 Modeling jamming avoidance of weakly electric fish
Jaehyun Soh, DaeEun Kim
P5 Synergy and redundancy of retinal ganglion cells in prediction
Minsu Yoo, S. E. Palmer
P6 A neural field model with a third dimension representing cortical depth
Viviana Culmone, Ingo Bojak
P7 Network analysis of a probabilistic connectivity model of the Xenopus tadpole spinal cord
Andrea Ferrario, Robert Merrison-Hort, Roman Borisyuk
P8 The recognition dynamics in the brain
Chang Sub Kim
P9 Multivariate spike train analysis using a positive definite kernel
Taro Tezuka
P10 Synchronization of burst periods may govern slow brain dynamics during general anesthesia
Pangyu Joo
P11 The ionic basis of heterogeneity affects stochastic synchrony
Young-Ah Rho, Shawn D. Burton, G. Bard Ermentrout, Jaeseung Jeong, Nathaniel N. Urban
P12 Circular statistics of noise in spike trains with a periodic component
Petr Marsalek
P14 Representations of directions in EEG-BCI using Gaussian readouts
Hoon-Hee Kim, Seok-hyun Moon, Do-won Lee, Sung-beom Lee, Ji-yong Lee, Jaeseung Jeong
P15 Action selection and reinforcement learning in basal ganglia during reaching movements
Yaroslav I. Molkov, Khaldoun Hamade, Wondimu Teka, William H. Barnett, Taegyo Kim, Sergey Markin, Ilya A. Rybak
P17 Axon guidance: modeling axonal growth in T-Junction assay
Csaba Forro, Harald Dermutz, László Demkó, János Vörös
P19 Transient cell assembly networks encode persistent spatial memories
Yuri Dabaghian, Andrey Babichev
P20 Theory of population coupling and applications to describe high order correlations in large populations of interacting neurons
Haiping Huang
P21 Design of biologically-realistic simulations for motor control
Sergio Verduzco-Flores
P22 Towards understanding the functional impact of the behavioural variability of neurons
Filipa Dos Santos, Peter Andras
P23 Different oscillatory dynamics underlying gamma entrainment deficits in schizophrenia
Christoph Metzner, Achim Schweikard, Bartosz Zurowski
P24 Memory recall and spike frequency adaptation
James P. Roach, Leonard M. Sander, Michal R. Zochowski
P25 Stability of neural networks and memory consolidation preferentially occur near criticality
Quinton M. Skilling, Nicolette Ognjanovski, Sara J. Aton, Michal Zochowski
P26 Stochastic Oscillation in Self-Organized Critical States of Small Systems: Sensitive Resting State in Neural Systems
Sheng-Jun Wang, Guang Ouyang, Jing Guang, Mingsha Zhang, K. Y. Michael Wong, Changsong Zhou
P27 Neurofield: a C++ library for fast simulation of 2D neural field models
Peter A. Robinson, Paula Sanz-Leon, Peter M. Drysdale, Felix Fung, Romesh G. Abeysuriya, Chris J. Rennie, Xuelong Zhao
P28 Action-based grounding: Beyond encoding/decoding in neural code
Yoonsuck Choe, Huei-Fang Yang
P29 Neural computation in a dynamical system with multiple time scales
Yuanyuan Mi, Xiaohan Lin, Si Wu
P30 Maximum entropy models for 3D layouts of orientation selectivity
Joscha Liedtke, Manuel Schottdorf, Fred Wolf
P31 A behavioral assay for probing computations underlying curiosity in rodents
Yoriko Yamamura, Jeffery R. Wickens
P32 Using statistical sampling to balance error function contributions to optimization of conductance-based models
Timothy Rumbell, Julia Ramsey, Amy Reyes, Danel Draguljić, Patrick R. Hof, Jennifer Luebke, Christina M. Weaver
P33 Exploration and implementation of a self-growing and self-organizing neuron network building algorithm
Hu He, Xu Yang, Hailin Ma, Zhiheng Xu, Yuzhe Wang
P34 Disrupted resting state brain network in obese subjects: a data-driven graph theory analysis
Kwangyeol Baek, Laurel S. Morris, Prantik Kundu, Valerie Voon
P35 Dynamics of cooperative excitatory and inhibitory plasticity
Everton J. Agnes, Tim P. Vogels
P36 Frequency-dependent oscillatory signal gating in feed-forward networks of integrate-and-fire neurons
William F. Podlaski, Tim P. Vogels
P37 Phenomenological neural model for adaptation of neurons in area IT
Martin Giese, Pradeep Kuravi, Rufin Vogels
P38 ICGenealogy: towards a common topology of neuronal ion channel function and genealogy in model and experiment
Alexander Seeholzer, William Podlaski, Rajnish Ranjan, Tim Vogels
P39 Temporal input discrimination from the interaction between dynamic synapses and neural subthreshold oscillations
Joaquin J. Torres, Fabiano Baroni, Roberto Latorre, Pablo Varona
P40 Different roles for transient and sustained activity during active visual processing
Bart Gips, Eric Lowet, Mark J. Roberts, Peter de Weerd, Ole Jensen, Jan van der Eerden
P41 Scale-free functional networks of 2D Ising model are highly robust against structural defects: neuroscience implications
Abdorreza Goodarzinick, Mohammad D. Niry, Alireza Valizadeh
P42 High frequency neuron can facilitate propagation of signal in neural networks
Aref Pariz, Shervin S. Parsi, Alireza Valizadeh
P43 Investigating the effect of Alzheimer’s disease related amyloidopathy on gamma oscillations in the CA1 region of the hippocampus
Julia M. Warburton, Lucia Marucci, Francesco Tamagnini, Jon Brown, Krasimira Tsaneva-Atanasova
P44 Long-tailed distributions of inhibitory and excitatory weights in a balanced network with eSTDP and iSTDP
Florence I. Kleberg, Jochen Triesch
P45 Simulation of EMG recording from hand muscle due to TMS of motor cortex
Bahar Moezzi, Nicolangelo Iannella, Natalie Schaworonkow, Lukas Plogmacher, Mitchell R. Goldsworthy, Brenton Hordacre, Mark D. McDonnell, Michael C. Ridding, Jochen Triesch
P46 Structure and dynamics of axon network formed in primary cell culture
Martin Zapotocky, Daniel Smit, Coralie Fouquet, Alain Trembleau
P47 Efficient signal processing and sampling in random networks that generate variability
Sakyasingha Dasgupta, Isao Nishikawa, Kazuyuki Aihara, Taro Toyoizumi
P48 Modeling the effect of riluzole on bursting in respiratory neural networks
Daniel T. Robb, Nick Mellen, Natalia Toporikova
P49 Mapping relaxation training using effective connectivity analysis
Rongxiang Tang, Yi-Yuan Tang
P50 Modeling neuron oscillation of implicit sequence learning
Guangsheng Liang, Seth A. Kiser, James H. Howard, Jr., Yi-Yuan Tang
P51 The role of cerebellar short-term synaptic plasticity in the pathology and medication of downbeat nystagmus
Julia Goncharenko, Neil Davey, Maria Schilstra, Volker Steuber
P52 Nonlinear response of noisy neurons
Sergej O. Voronenko, Benjamin Lindner
P53 Behavioral embedding suggests multiple chaotic dimensions underlie C. elegans locomotion
Tosif Ahamed, Greg Stephens
P54 Fast and scalable spike sorting for large and dense multi-electrodes recordings
Pierre Yger, Baptiste Lefebvre, Giulia Lia Beatrice Spampinato, Elric Esposito, Marcel Stimberg et Olivier Marre
P55 Sufficient sampling rates for fast hand motion tracking
Hansol Choi, Min-Ho Song
P56 Linear readout of object manifolds
SueYeon Chung, Dan D. Lee, Haim Sompolinsky
P57 Differentiating models of intrinsic bursting and rhythm generation of the respiratory pre-Bötzinger complex using phase response curves
Ryan S. Phillips, Jeffrey Smith
P58 The effect of inhibitory cell network interactions during theta rhythms on extracellular field potentials in CA1 hippocampus
Alexandra Pierri Chatzikalymniou, Katie Ferguson, Frances K. Skinner
P59 Expansion recoding through sparse sampling in the cerebellar input layer speeds learning
N. Alex Cayco Gajic, Claudia Clopath, R. Angus Silver
P60 A set of curated cortical models at multiple scales on Open Source Brain
Padraig Gleeson, Boris Marin, Sadra Sadeh, Adrian Quintana, Matteo Cantarelli, Salvador Dura-Bernal, William W. Lytton, Andrew Davison, R. Angus Silver
P61 A synaptic story of dynamical information encoding in neural adaptation
Luozheng Li, Wenhao Zhang, Yuanyuan Mi, Dahui Wang, Si Wu
P62 Physical modeling of rule-observant rodent behavior
Youngjo Song, Sol Park, Ilhwan Choi, Jaeseung Jeong, Hee-sup Shin
P64 Predictive coding in area V4 and prefrontal cortex explains dynamic discrimination of partially occluded shapes
Hannah Choi, Anitha Pasupathy, Eric Shea-Brown
P65 Stability of FORCE learning on spiking and rate-based networks
Dongsung Huh, Terrence J. Sejnowski
P66 Stabilising STDP in striatal neurons for reliable fast state recognition in noisy environments
Simon M. Vogt, Arvind Kumar, Robert Schmidt
P67 Electrodiffusion in one- and two-compartment neuron models for characterizing cellular effects of electrical stimulation
Stephen Van Wert, Steven J. Schiff
P68 STDP improves speech recognition capabilities in spiking recurrent circuits parameterized via differential evolution Markov Chain Monte Carlo
Richard Veale, Matthias Scheutz
P69 Bidirectional transformation between dominant cortical neural activities and phase difference distributions
Sang Wan Lee
P70 Maturation of sensory networks through homeostatic structural plasticity
Júlia Gallinaro, Stefan Rotter
P71 Corticothalamic dynamics: structure, number of solutions and stability of steady-state solutions in the space of synaptic couplings
Paula Sanz-Leon, Peter A. Robinson
P72 Optogenetic versus electrical stimulation of the parkinsonian basal ganglia. Computational study
Leonid L. Rubchinsky, Chung Ching Cheung, Shivakeshavan Ratnadurai-Giridharan
P73 Exact spike-timing distribution reveals higher-order interactions of neurons
Safura Rashid Shomali, Majid Nili Ahmadabadi, Hideaki Shimazaki, S. Nader Rasuli
P74 Neural mechanism of visual perceptual learning using a multi-layered neural network
Xiaochen Zhao, Malte J. Rasch
P75 Inferring collective spiking dynamics from mostly unobserved systems
Jens Wilting, Viola Priesemann
P76 How to infer distributions in the brain from subsampled observations
Anna Levina, Viola Priesemann
P77 Influences of embedding and estimation strategies on the inferred memory of single spiking neurons
Lucas Rudelt, Joseph T. Lizier, Viola Priesemann
P78 A nearest-neighbours based estimator for transfer entropy between spike trains
Joseph T. Lizier, Richard E. Spinney, Mikail Rubinov, Michael Wibral, Viola Priesemann
P79 Active learning of psychometric functions with multinomial logistic models
Ji Hyun Bak, Jonathan Pillow
P81 Inferring low-dimensional network dynamics with variational latent Gaussian process
Yuan Zaho, Il Memming Park
P82 Computational investigation of energy landscapes in the resting state subcortical brain network
Jiyoung Kang, Hae-Jeong Park
P83 Local repulsive interaction between retinal ganglion cells can generate a consistent spatial periodicity of orientation map
Jaeson Jang, Se-Bum Paik
P84 Phase duration of bistable perception reveals intrinsic time scale of perceptual decision under noisy condition
Woochul Choi, Se-Bum Paik
P85 Feedforward convergence between retina and primary visual cortex can determine the structure of orientation map
Changju Lee, Jaeson Jang, Se-Bum Paik
P86 Computational method classifying neural network activity patterns for imaging data
Min Song, Hyeonsu Lee, Se-Bum Paik
P87 Symmetry of spike-timing-dependent-plasticity kernels regulates volatility of memory
Youngjin Park, Woochul Choi, Se-Bum Paik
P88 Effects of time-periodic coupling strength on the first-spike latency dynamics of a scale-free network of stochastic Hodgkin-Huxley neurons
Ergin Yilmaz, Veli Baysal, Mahmut Ozer
P89 Spectral properties of spiking responses in V1 and V4 change within the trial and are highly relevant for behavioral performance
Veronika Koren, Klaus Obermayer
P90 Methods for building accurate models of individual neurons
Daniel Saska, Thomas Nowotny
P91 A full size mathematical model of the early olfactory system of honeybees
Ho Ka Chan, Alan Diamond, Thomas Nowotny
P92 Stimulation-induced tuning of ongoing oscillations in spiking neural networks
Christoph S. Herrmann, Micah M. Murray, Silvio Ionta, Axel Hutt, Jérémie Lefebvre
P93 Decision-specific sequences of neural activity in balanced random networks driven by structured sensory input
Philipp Weidel, Renato Duarte, Abigail Morrison
P94 Modulation of tuning induced by abrupt reduction of SST cell activity
Jung H. Lee, Ramakrishnan Iyer, Stefan Mihalas
P95 The functional role of VIP cell activation during locomotion
Jung H. Lee, Ramakrishnan Iyer, Christof Koch, Stefan Mihalas
P96 Stochastic inference with spiking neural networks
Mihai A. Petrovici, Luziwei Leng, Oliver Breitwieser, David Stöckel, Ilja Bytschok, Roman Martel, Johannes Bill, Johannes Schemmel, Karlheinz Meier
P97 Modeling orientation-selective electrical stimulation with retinal prostheses
Timothy B. Esler, Anthony N. Burkitt, David B. Grayden, Robert R. Kerr, Bahman Tahayori, Hamish Meffin
P98 Ion channel noise can explain firing correlation in auditory nerves
Bahar Moezzi, Nicolangelo Iannella, Mark D. McDonnell
P99 Limits of temporal encoding of thalamocortical inputs in a neocortical microcircuit
Max Nolte, Michael W. Reimann, Eilif Muller, Henry Markram
P100 On the representation of arm reaching movements: a computational model
Antonio Parziale, Rosa Senatore, Angelo Marcelli
P101 A computational model for investigating the role of cerebellum in acquisition and retention of motor behavior
Rosa Senatore, Antonio Parziale, Angelo Marcelli
P102 The emergence of semantic categories from a large-scale brain network of semantic knowledge
K. Skiker, M. Maouene
P103 Multiscale modeling of M1 multitarget pharmacotherapy for dystonia
Samuel A. Neymotin, Salvador Dura-Bernal, Alexandra Seidenstein, Peter Lakatos, Terence D. Sanger, William W. Lytton
P104 Effect of network size on computational capacity
Salvador Dura-Bernal, Rosemary J. Menzies, Campbell McLauchlan, Sacha J. van Albada, David J. Kedziora, Samuel Neymotin, William W. Lytton, Cliff C. Kerr
P105 NetPyNE: a Python package for NEURON to facilitate development and parallel simulation of biological neuronal networks
Salvador Dura-Bernal, Benjamin A. Suter, Samuel A. Neymotin, Cliff C. Kerr, Adrian Quintana, Padraig Gleeson, Gordon M. G. Shepherd, William W. Lytton
P107 Inter-areal and inter-regional inhomogeneity in co-axial anisotropy of Cortical Point Spread in human visual areas
Juhyoung Ryu, Sang-Hun Lee
P108 Two bayesian quanta of uncertainty explain the temporal dynamics of cortical activity in the non-sensory areas during bistable perception
Joonwon Lee, Sang-Hun Lee
P109 Optimal and suboptimal integration of sensory and value information in perceptual decision making
Hyang Jung Lee, Sang-Hun Lee
P110 A Bayesian algorithm for phoneme Perception and its neural implementation
Daeseob Lim, Sang-Hun Lee
P111 Complexity of EEG signals is reduced during unconsciousness induced by ketamine and propofol
Jisung Wang, Heonsoo Lee
P112 Self-organized criticality of neural avalanche in a neural model on complex networks
Nam Jung, Le Anh Quang, Seung Eun Maeng, Tae Ho Lee, Jae Woo Lee
P113 Dynamic alterations in connection topology of the hippocampal network during ictal-like epileptiform activity in an in vitro rat model
Chang-hyun Park, Sora Ahn, Jangsup Moon, Yun Seo Choi, Juhee Kim, Sang Beom Jun, Seungjun Lee, Hyang Woon Lee
P114 Computational model to replicate seizure suppression effect by electrical stimulation
Sora Ahn, Sumin Jo, Eunji Jun, Suin Yu, Hyang Woon Lee, Sang Beom Jun, Seungjun Lee
P115 Identifying excitatory and inhibitory synapses in neuronal networks from spike trains using sorted local transfer entropy
Felix Goetze, Pik-Yin Lai
P116 Neural network model for obstacle avoidance based on neuromorphic computational model of boundary vector cell and head direction cell
Seonghyun Kim, Jeehyun Kwag
P117 Dynamic gating of spike pattern propagation by Hebbian and anti-Hebbian spike timing-dependent plasticity in excitatory feedforward network model
Hyun Jae Jang, Jeehyun Kwag
P118 Inferring characteristics of input correlations of cells exhibiting up-down state transitions in the rat striatum
Marko Filipović, Ramon Reig, Ad Aertsen, Gilad Silberberg, Arvind Kumar
P119 Graph properties of the functional connected brain under the influence of Alzheimer’s disease
Claudia Bachmann, Simone Buttler, Heidi Jacobs, Kim Dillen, Gereon R. Fink, Juraj Kukolja, Abigail Morrison
P120 Learning sparse representations in the olfactory bulb
Daniel Kepple, Hamza Giaffar, Dima Rinberg, Steven Shea, Alex Koulakov
P121 Functional classification of homologous basal-ganglia networks
Jyotika Bahuguna,Tom Tetzlaff, Abigail Morrison, Arvind Kumar, Jeanette Hellgren Kotaleski
P122 Short term memory based on multistability
Tim Kunze, Andre Peterson, Thomas Knösche
P123 A physiologically plausible, computationally efficient model and simulation software for mammalian motor units
Minjung Kim, Hojeong Kim
P125 Decoding laser-induced somatosensory information from EEG
Ji Sung Park, Ji Won Yeon, Sung-Phil Kim
P126 Phase synchronization of alpha activity for EEG-based personal authentication
Jae-Hwan Kang, Chungho Lee, Sung-Phil Kim
P129 Investigating phase-lags in sEEG data using spatially distributed time delays in a large-scale brain network model
Andreas Spiegler, Spase Petkoski, Matias J. Palva, Viktor K. Jirsa
P130 Epileptic seizures in the unfolding of a codimension-3 singularity
Maria L. Saggio, Silvan F. Siep, Andreas Spiegler, William C. Stacey, Christophe Bernard, Viktor K. Jirsa
P131 Incremental dimensional exploratory reasoning under multi-dimensional environment
Oh-hyeon Choung, Yong Jeong
P132 A low-cost model of eye movements and memory in personal visual cognition
Yong-il Lee, Jaeseung Jeong
P133 Complex network analysis of structural connectome of autism spectrum disorder patients
Su Hyun Kim, Mir Jeong, Jaeseung Jeong
P134 Cognitive motives and the neural correlates underlying human social information transmission, gossip
Jeungmin Lee, Jaehyung Kwon, Jerald D. Kralik, Jaeseung Jeong
P135 EEG hyperscanning detects neural oscillation for the social interaction during the economic decision-making
Jaehwan Jahng, Dong-Uk Hwang, Jaeseung Jeong
P136 Detecting purchase decision based on hyperfrontality of the EEG
Jae-Hyung Kwon, Sang-Min Park, Jaeseung Jeong
P137 Vulnerability-based critical neurons, synapses, and pathways in the Caenorhabditis elegans connectome
Seongkyun Kim, Hyoungkyu Kim, Jerald D. Kralik, Jaeseung Jeong
P138 Motif analysis reveals functionally asymmetrical neurons in C. elegans
Pyeong Soo Kim, Seongkyun Kim, Hyoungkyu Kim, Jaeseung Jeong
P139 Computational approach to preference-based serial decision dynamics: do temporal discounting and working memory affect it?
Sangsup Yoon, Jaehyung Kwon, Sewoong Lim, Jaeseung Jeong
P141 Social stress induced neural network reconfiguration affects decision making and learning in zebrafish
Choongseok Park, Thomas Miller, Katie Clements, Sungwoo Ahn, Eoon Hye Ji, Fadi A. Issa
P142 Descriptive, generative, and hybrid approaches for neural connectivity inference from neural activity data
JeongHun Baek, Shigeyuki Oba, Junichiro Yoshimoto, Kenji Doya, Shin Ishii
P145 Divergent-convergent synaptic connectivities accelerate coding in multilayered sensory systems
Thiago S. Mosqueiro, Martin F. Strube-Bloss, Brian Smith, Ramon Huerta
P146 Swinging networks
Michal Hadrava, Jaroslav Hlinka
P147 Inferring dynamically relevant motifs from oscillatory stimuli: challenges, pitfalls, and solutions
Hannah Bos, Moritz Helias
P148 Spatiotemporal mapping of brain network dynamics during cognitive tasks using magnetoencephalography and deep learning
Charles M. Welzig, Zachary J. Harper
P149 Multiscale complexity analysis for the segmentation of MRI images
Won Sup Kim, In-Seob Shin, Hyeon-Man Baek, Seung Kee Han
P150 A neuro-computational model of emotional attention
René Richter, Julien Vitay, Frederick Beuth, Fred H. Hamker
P151 Multi-site delayed feedback stimulation in parkinsonian networks
Kelly Toppin, Yixin Guo
P152 Bistability in Hodgkin–Huxley-type equations
Tatiana Kameneva, Hamish Meffin, Anthony N. Burkitt, David B. Grayden
P153 Phase changes in postsynaptic spiking due to synaptic connectivity and short term plasticity: mathematical analysis of frequency dependency
Mark D. McDonnell, Bruce P. Graham
P154 Quantifying resilience patterns in brain networks: the importance of directionality
Penelope J. Kale, Leonardo L. Gollo
P155 Dynamics of rate-model networks with separate excitatory and inhibitory populations
Merav Stern, L. F. Abbott
P156 A model for multi-stable dynamics in action recognition modulated by integration of silhouette and shading cues
Leonid A. Fedorov, Martin A. Giese
P157 Spiking model for the interaction between action recognition and action execution
Mohammad Hovaidi Ardestani, Martin Giese
P158 Surprise-modulated belief update: how to learn within changing environments?
Mohammad Javad Faraji, Kerstin Preuschoff, Wulfram Gerstner
P159 A fast, stochastic and adaptive model of auditory nerve responses to cochlear implant stimulation
Margriet J. van Gendt, Jeroen J. Briaire, Randy K. Kalkman, Johan H. M. Frijns
P160 Quantitative comparison of graph theoretical measures of simulated and empirical functional brain networks
Won Hee Lee, Sophia Frangou
P161 Determining discriminative properties of fMRI signals in schizophrenia using highly comparative time-series analysis
Ben D. Fulcher, Patricia H. P. Tran, Alex Fornito
P162 Emergence of narrowband LFP oscillations from completely asynchronous activity during seizures and high-frequency oscillations
Stephen V. Gliske, William C. Stacey, Eugene Lim, Katherine A. Holman, Christian G. Fink
P163 Neuronal diversity in structure and function: cross-validation of anatomical and physiological classification of retinal ganglion cells in the mouse
Jinseop S. Kim, Shang Mu, Kevin L. Briggman, H. Sebastian Seung, the EyeWirers
P164 Analysis and modelling of transient firing rate changes in area MT in response to rapid stimulus feature changes
Detlef Wegener, Lisa Bohnenkamp, Udo A. Ernst
P165 Step-wise model fitting accounting for high-resolution spatial measurements: construction of a layer V pyramidal cell model with reduced morphology
Tuomo Mäki-Marttunen, Geir Halnes, Anna Devor, Christoph Metzner, Anders M. Dale, Ole A. Andreassen, Gaute T. Einevoll
P166 Contributions of schizophrenia-associated genes to neuron firing and cardiac pacemaking: a polygenic modeling approach
Tuomo Mäki-Marttunen, Glenn T. Lines, Andy Edwards, Aslak Tveito, Anders M. Dale, Gaute T. Einevoll, Ole A. Andreassen
P167 Local field potentials in a 4 × 4 mm2 multi-layered network model
Espen Hagen, Johanna Senk, Sacha J. van Albada, Markus Diesmann
P168 A spiking network model explains multi-scale properties of cortical dynamics
Maximilian Schmidt, Rembrandt Bakker, Kelly Shen, Gleb Bezgin, Claus-Christian Hilgetag, Markus Diesmann, Sacha Jennifer van Albada
P169 Using joint weight-delay spike-timing dependent plasticity to find polychronous neuronal groups
Haoqi Sun, Olga Sourina, Guang-Bin Huang, Felix Klanner, Cornelia Denk
P170 Tensor decomposition reveals RSNs in simulated resting state fMRI
Katharina Glomb, Adrián Ponce-Alvarez, Matthieu Gilson, Petra Ritter, Gustavo Deco
P171 Getting in the groove: testing a new model-based method for comparing task-evoked vs resting-state activity in fMRI data on music listening
Matthieu Gilson, Maria AG Witek, Eric F. Clarke, Mads Hansen, Mikkel Wallentin, Gustavo Deco, Morten L. Kringelbach, Peter Vuust
P172 STochastic engine for pathway simulation (STEPS) on massively parallel processors
Guido Klingbeil, Erik De Schutter
P173 Toolkit support for complex parallel spatial stochastic reaction–diffusion simulation in STEPS
Weiliang Chen, Erik De Schutter
P174 Modeling the generation and propagation of Purkinje cell dendritic spikes caused by parallel fiber synaptic input
Yunliang Zang, Erik De Schutter
P175 Dendritic morphology determines how dendrites are organized into functional subunits
Sungho Hong, Akira Takashima, Erik De Schutter
P176 A model of Ca2+/calmodulin-dependent protein kinase II activity in long term depression at Purkinje cells
Criseida Zamora, Andrew R. Gallimore, Erik De Schutter
P177 Reward-modulated learning of population-encoded vectors for insect-like navigation in embodied agents
Dennis Goldschmidt, Poramate Manoonpong, Sakyasingha Dasgupta
P178 Data-driven neural models part II: connectivity patterns of human seizures
Philippa J. Karoly, Dean R. Freestone, Daniel Soundry, Levin Kuhlmann, Liam Paninski, Mark Cook
P179 Data-driven neural models part I: state and parameter estimation
Dean R. Freestone, Philippa J. Karoly, Daniel Soundry, Levin Kuhlmann, Mark Cook
P180 Spectral and spatial information processing in human auditory streaming
Jaejin Lee, Yonatan I. Fishman, Yale E. Cohen
P181 A tuning curve for the global effects of local perturbations in neural activity: Mapping the systems-level susceptibility of the brain
Leonardo L. Gollo, James A. Roberts, Luca Cocchi
P182 Diverse homeostatic responses to visual deprivation mediated by neural ensembles
Yann Sweeney, Claudia Clopath
P183 Opto-EEG: a novel method for investigating functional connectome in mouse brain based on optogenetics and high density electroencephalography
Soohyun Lee, Woo-Sung Jung, Jee Hyun Choi
P184 Biphasic responses of frontal gamma network to repetitive sleep deprivation during REM sleep
Bowon Kim, Youngsoo Kim, Eunjin Hwang, Jee Hyun Choi
P185 Brain-state correlate and cortical connectivity for frontal gamma oscillations in top-down fashion assessed by auditory steady-state response
Younginha Jung, Eunjin Hwang, Yoon-Kyu Song, Jee Hyun Choi
P186 Neural field model of localized orientation selective activation in V1
James Rankin, Frédéric Chavane
P187 An oscillatory network model of Head direction and Grid cells using locomotor inputs
Karthik Soman, Vignesh Muralidharan, V. Srinivasa Chakravarthy
P188 A computational model of hippocampus inspired by the functional architecture of basal ganglia
Karthik Soman, Vignesh Muralidharan, V. Srinivasa Chakravarthy
P189 A computational architecture to model the microanatomy of the striatum and its functional properties
Sabyasachi Shivkumar, Vignesh Muralidharan, V. Srinivasa Chakravarthy
P190 A scalable cortico-basal ganglia model to understand the neural dynamics of targeted reaching
Vignesh Muralidharan, Alekhya Mandali, B. Pragathi Priyadharsini, Hima Mehta, V. Srinivasa Chakravarthy
P191 Emergence of radial orientation selectivity from synaptic plasticity
Catherine E. Davey, David B. Grayden, Anthony N. Burkitt
P192 How do hidden units shape effective connections between neurons?
Braden A. W. Brinkman, Tyler Kekona, Fred Rieke, Eric Shea-Brown, Michael Buice
P193 Characterization of neural firing in the presence of astrocyte-synapse signaling
Maurizio De Pittà, Hugues Berry, Nicolas Brunel
P194 Metastability of spatiotemporal patterns in a large-scale network model of brain dynamics
James A. Roberts, Leonardo L. Gollo, Michael Breakspear
P195 Comparison of three methods to quantify detection and discrimination capacity estimated from neural population recordings
Gary Marsat, Jordan Drew, Phillip D. Chapman, Kevin C. Daly, Samual P. Bradley
P196 Quantifying the constraints for independent evoked and spontaneous NMDA receptor mediated synaptic transmission at individual synapses
Sat Byul Seo, Jianzhong Su, Ege T. Kavalali, Justin Blackwell
P199 Gamma oscillation via adaptive exponential integrate-and-fire neurons
LieJune Shiau, Laure Buhry, Kanishka Basnayake
P200 Visual face representations during memory retrieval compared to perception
Sue-Hyun Lee, Brandon A. Levy, Chris I. Baker
P201 Top-down modulation of sequential activity within packets modeled using avalanche dynamics
Timothée Leleu, Kazuyuki Aihara
Q28 An auto-encoder network realizes sparse features under the influence of desynchronized vascular dynamics
Ryan T. Philips, Karishma Chhabria, V. Srinivasa Chakravarthy
doi:10.1186/s12868-016-0283-6
PMCID: PMC5001212  PMID: 27534393
3.  Information Flow Analysis of Interactome Networks 
PLoS Computational Biology  2009;5(4):e1000350.
Recent studies of cellular networks have revealed modular organizations of genes and proteins. For example, in interactome networks, a module refers to a group of interacting proteins that form molecular complexes and/or biochemical pathways and together mediate a biological process. However, it is still poorly understood how biological information is transmitted between different modules. We have developed information flow analysis, a new computational approach that identifies proteins central to the transmission of biological information throughout the network. In the information flow analysis, we represent an interactome network as an electrical circuit, where interactions are modeled as resistors and proteins as interconnecting junctions. Construing the propagation of biological signals as flow of electrical current, our method calculates an information flow score for every protein. Unlike previous metrics of network centrality such as degree or betweenness that only consider topological features, our approach incorporates confidence scores of protein–protein interactions and automatically considers all possible paths in a network when evaluating the importance of each protein. We apply our method to the interactome networks of Saccharomyces cerevisiae and Caenorhabditis elegans. We find that the likelihood of observing lethality and pleiotropy when a protein is eliminated is positively correlated with the protein's information flow score. Even among proteins of low degree or low betweenness, high information scores serve as a strong predictor of loss-of-function lethality or pleiotropy. The correlation between information flow scores and phenotypes supports our hypothesis that the proteins of high information flow reside in central positions in interactome networks. We also show that the ranks of information flow scores are more consistent than that of betweenness when a large amount of noisy data is added to an interactome. Finally, we combine gene expression data with interaction data in C. elegans and construct an interactome network for muscle-specific genes. We find that genes that rank high in terms of information flow in the muscle interactome network but not in the entire network tend to play important roles in muscle function. This framework for studying tissue-specific networks by the information flow model can be applied to other tissues and other organisms as well.
Author Summary
Protein–protein interactions mediate numerous biological processes. In the last decade, there have been efforts to comprehensively map protein–protein interactions occurring in an organism. The interaction data generated from these high-throughput projects can be represented as interconnected networks. It has been found that knockouts of proteins residing in topologically central positions in the networks more likely result in lethality of the organism than knockouts of peripheral proteins. However, it is difficult to accurately define topologically central proteins because high-throughput data is error-prone and some interactions are not as reliable as others. In addition, the architecture of interaction networks varies in different tissues for multi-cellular organisms. To this end, we present a novel computational approach to identify central proteins while considering the confidence of data and gene expression in tissues. Moreover, our approach takes into account multiple alternative paths in interaction networks. We apply our method to yeast and nematode interaction networks. We find that the likelihood of observing lethality and pleiotropy when a given protein is eliminated correlates better with our centrality score for that protein than with its scores based on traditional centrality metrics. Finally, we set up a framework to identify central proteins in tissue-specific interaction networks.
doi:10.1371/journal.pcbi.1000350
PMCID: PMC2685719  PMID: 19503817
4.  Dynamic Changes in Protein Functional Linkage Networks Revealed by Integration with Gene Expression Data 
PLoS Computational Biology  2008;4(11):e1000237.
Response of cells to changing environmental conditions is governed by the dynamics of intricate biomolecular interactions. It may be reasonable to assume, proteins being the dominant macromolecules that carry out routine cellular functions, that understanding the dynamics of protein∶protein interactions might yield useful insights into the cellular responses. The large-scale protein interaction data sets are, however, unable to capture the changes in the profile of protein∶protein interactions. In order to understand how these interactions change dynamically, we have constructed conditional protein linkages for Escherichia coli by integrating functional linkages and gene expression information. As a case study, we have chosen to analyze UV exposure in wild-type and SOS deficient E. coli at 20 minutes post irradiation. The conditional networks exhibit similar topological properties. Although the global topological properties of the networks are similar, many subtle local changes are observed, which are suggestive of the cellular response to the perturbations. Some such changes correspond to differences in the path lengths among the nodes of carbohydrate metabolism correlating with its loss in efficiency in the UV treated cells. Similarly, expression of hubs under unique conditions reflects the importance of these genes. Various centrality measures applied to the networks indicate increased importance for replication, repair, and other stress proteins for the cells under UV treatment, as anticipated. We thus propose a novel approach for studying an organism at the systems level by integrating genome-wide functional linkages and the gene expression data.
Author Summary
Many cellular processes and the response of cells to environmental cues are determined by the intricate protein∶protein interactions. These cellular protein interactions can be represented in the form of a graph, where the nodes represent the proteins and the edges signify the interactions between them. However, the available protein functional linkage maps do not incorporate the dynamics of gene expression and thus do not portray the dynamics of true protein∶protein interactions in vivo. We have used gene expression data as well as the available protein functional interaction information for Escherichia coli to build the protein interaction networks for expressed genes in a given condition. These networks, named conditional networks, capture the differences in the protein interaction networks and hence the cell physiology. Thus, by exploring the dynamics of protein interaction profiles, we hope to understand the response of cells to environmental changes.
doi:10.1371/journal.pcbi.1000237
PMCID: PMC2580820  PMID: 19043542
5.  Human Cancer Protein-Protein Interaction Network: A Structural Perspective 
PLoS Computational Biology  2009;5(12):e1000601.
Protein-protein interaction networks provide a global picture of cellular function and biological processes. Some proteins act as hub proteins, highly connected to others, whereas some others have few interactions. The dysfunction of some interactions causes many diseases, including cancer. Proteins interact through their interfaces. Therefore, studying the interface properties of cancer-related proteins will help explain their role in the interaction networks. Similar or overlapping binding sites should be used repeatedly in single interface hub proteins, making them promiscuous. Alternatively, multi-interface hub proteins make use of several distinct binding sites to bind to different partners. We propose a methodology to integrate protein interfaces into cancer interaction networks (ciSPIN, cancer structural protein interface network). The interactions in the human protein interaction network are replaced by interfaces, coming from either known or predicted complexes. We provide a detailed analysis of cancer related human protein-protein interfaces and the topological properties of the cancer network. The results reveal that cancer-related proteins have smaller, more planar, more charged and less hydrophobic binding sites than non-cancer proteins, which may indicate low affinity and high specificity of the cancer-related interactions. We also classified the genes in ciSPIN according to phenotypes. Within phenotypes, for breast cancer, colorectal cancer and leukemia, interface properties were found to be discriminating from non-cancer interfaces with an accuracy of 71%, 67%, 61%, respectively. In addition, cancer-related proteins tend to interact with their partners through distinct interfaces, corresponding mostly to multi-interface hubs, which comprise 56% of cancer-related proteins, and constituting the nodes with higher essentiality in the network (76%). We illustrate the interface related affinity properties of two cancer-related hub proteins: Erbb3, a multi interface, and Raf1, a single interface hub. The results reveal that affinity of interactions of the multi-interface hub tends to be higher than that of the single-interface hub. These findings might be important in obtaining new targets in cancer as well as finding the details of specific binding regions of putative cancer drug candidates.
Author Summary
Protein-protein interaction networks provide a global picture of cellular function and biological processes. The dysfunction of some interactions causes many diseases, including cancer. Proteins interact through their interfaces. Therefore, studying the interface properties of cancer-related proteins will help explain their role in the interaction networks. The structural details of interfaces are immensely useful in efforts to answer some fundamental questions such as: (i) what features of cancer-related protein interfaces make them act as hubs; (ii) how hub protein interfaces can interact with tens of other proteins with varying affinities; and (iii) which interactions can occur simultaneously and which are mutually exclusive. Addressing these questions, we propose a method to characterize interactions in a human protein-protein interaction network using three-dimensional protein structures and interfaces. Protein interface analysis shows that the strength and specificity of the interactions of hub proteins and cancer proteins are different than the interactions of non-hub and non-cancer proteins, respectively. In addition, distinguishing overlapping from non-overlapping interfaces, we illustrate how a fourth dimension, that of the sequence of processes, is integrated into the network with case studies. We believe that such an approach should be useful in structural systems biology.
doi:10.1371/journal.pcbi.1000601
PMCID: PMC2785480  PMID: 20011507
6.  HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology 
We present HepatoNet1, a manually curated large-scale metabolic network of the human hepatocyte that encompasses >2500 reactions in six intracellular and two extracellular compartments.Using constraint-based modeling techniques, the network has been validated to replicate numerous metabolic functions of hepatocytes corresponding to a reference set of diverse physiological liver functions.Taking the detoxification of ammonia and the formation of bile acids as examples, we show how these liver-specific metabolic objectives can be achieved by the variable interplay of various metabolic pathways under varying conditions of nutrients and oxygen availability.
The liver has a pivotal function in metabolic homeostasis of the human body. Hepatocytes are the principal site of the metabolic conversions that underlie diverse physiological functions of the liver. These functions include provision and homeostasis of carbohydrates, amino acids, lipids and lipoproteins in the systemic blood circulation, biotransformation, plasma protein synthesis and bile formation, to name a few. Accordingly, hepatocyte metabolism integrates a vast array of differentially regulated biochemical activities and is highly responsive to environmental perturbations such as changes in portal blood composition (Dardevet et al, 2006). The complexity of this metabolic network and the numerous physiological functions to be achieved within a highly variable physiological environment necessitate an integrated approach with the aim of understanding liver metabolism at a systems level. To this end, we present HepatoNet1, a stoichiometric network of human hepatocyte metabolism characterized by (i) comprehensive coverage of known biochemical activities of hepatocytes and (ii) due representation of the biochemical and physiological functions of hepatocytes as functional network states. The network comprises 777 metabolites in six intracellular (cytosol, endoplasmic reticulum and Golgi apparatus, lysosome, mitochondria, nucleus, and peroxisome) and two extracellular compartments (bile canaliculus and sinusoidal space) and 2539 reactions, including 1466 transport reactions. It is based on the manual evaluation of >1500 original scientific research publications to warrant a high-quality evidence-based model. The final network is the result of an iterative process of data compilation and rigorous computational testing of network functionality by means of constraint-based modeling techniques. We performed flux-balance analyses to validate whether for >300 different metabolic objectives a non-zero stationary flux distribution could be established in the network. Figure 1 shows one such functional flux mode associated with the synthesis of the bile acid glycochenodeoxycholate, one important hepatocyte-specific physiological liver function. Besides those pathways directly linked to the synthesis of the bile acid, the mevalonate pathway and the de novo synthesis of cholesterol, the flux mode comprises additional pathways such as gluconeogenesis, the pentose phosphate pathway or the ornithine cycle because the calculations were routinely performed on a minimal set of exchangeable metabolites, that is all reactants were forced to be balanced and all exportable intermediates had to be catabolized into non-degradable end products. This example shows how HepatoNet1 under the challenges of limited exchange across the network boundary can reveal numerous cross-links between metabolic pathways traditionally perceived as separate entities. For example, alanine is used as gluconeogenic substrate to form glucose-6-phosphate, which is used in the pentose phosphate pathway to generate NADPH. The glycine moiety for bile acid conjugation is derived from serine. Conversion of ammonia into non-toxic nitrogen compounds is one central homeostatic function of hepatocytes. Using the HepatoNet1 model, we investigated, as another example of a complex metabolic objective dependent on systemic physiological parameters, how the consumption of oxygen, glucose and palmitate is affected when an external nitrogen load is converted in varying proportions to the non-toxic nitrogen compounds: urea, glutamine and alanine. The results reveal strong dependencies between the available level of oxygen and the substrate demand of hepatocytes required for effective ammonia detoxification by the liver.
Oxygen demand is highest if nitrogen is exclusively transformed into urea. At lower fluxes into urea, an intriguing pattern for oxygen demand is predicted: oxygen demand attains a minimum if the nitrogen load is directed to urea, glutamine and alanine with relative fluxes of 0.17, 0.43 and 0.40, respectively (Figure 2A). Oxygen demand in this flux distribution is four times lower than for the maximum (100% urea) and still 77 and 33% lower than using alanine and glutamine as exclusive nitrogen compounds, respectively. This computationally predicted tendency is consistent with the notion that the zonation of ammonia detoxification, that is the preferential conversion of ammonia to urea in periportal hepatocytes and to glutamine in perivenous hepatocytes, is dictated by the availability of oxygen (Gebhardt, 1992; Jungermann and Kietzmann, 2000). The decreased oxygen demand in flux distributions using higher proportions of glutamine or alanine is accompanied by increased uptake of the substrates glucose and palmitate (Figure 2B). This is due to an increased demand of energy and carbon for the amidation and transamination of glutamate and pyruvate to discharge nitrogen in the form of glutamine and alanine, respectively. In terms of both scope and specificity, our model bridges the scale between models constructed specifically to examine distinct metabolic processes of the liver and modeling based on a global representation of human metabolism. The former include models for the interdependence of gluconeogenesis and fatty-acid catabolism (Chalhoub et al, 2007), impairment of glucose production in von Gierke's and Hers' diseases (Beard and Qian, 2005) and other processes (Calik and Akbay, 2000; Stucki and Urbanczik, 2005; Ohno et al, 2008). The hallmark of these models is that each of them focuses on a small number of reactions pertinent to the metabolic function of interest embedded in a customized representation of the principal pathways of central metabolism. HepatoNet1, currently, outperforms liver-specific models computationally predicted (Shlomi et al, 2008) on the basis of global reconstructions of human metabolism (Duarte et al, 2007; Ma and Goryanin, 2008). In contrast to either of the aforementioned modeling scales, HepatoNet1 provides the combination of a system-scale representation of metabolic activities and representation of the cell type-specific physical boundaries and their specific transport capacities. This allows for a highly versatile use of the model for the analysis of various liver-specific physiological functions. Conceptually, from a biological system perspective, this type of model offers a large degree of comprehensiveness, whereas retaining tissue specificity, a fundamental design principle of mammalian metabolism. HepatoNet1 is expected to provide a structural platform for computational studies on liver function. The results presented herein highlight how internal fluxes of hepatocyte metabolism and the interplay with systemic physiological parameters can be analyzed with constraint-based modeling techniques. At the same time, the framework may serve as a scaffold for complementation of kinetic and regulatory properties of enzymes and transporters for analysis of sub-networks with topological or kinetic modeling methods.
We present HepatoNet1, the first reconstruction of a comprehensive metabolic network of the human hepatocyte that is shown to accomplish a large canon of known metabolic liver functions. The network comprises 777 metabolites in six intracellular and two extracellular compartments and 2539 reactions, including 1466 transport reactions. It is based on the manual evaluation of >1500 original scientific research publications to warrant a high-quality evidence-based model. The final network is the result of an iterative process of data compilation and rigorous computational testing of network functionality by means of constraint-based modeling techniques. Taking the hepatic detoxification of ammonia as an example, we show how the availability of nutrients and oxygen may modulate the interplay of various metabolic pathways to allow an efficient response of the liver to perturbations of the homeostasis of blood compounds.
doi:10.1038/msb.2010.62
PMCID: PMC2964118  PMID: 20823849
computational biology; flux balance; liver; minimal flux
7.  Detecting Network Communities: An Application to Phylogenetic Analysis 
PLoS Computational Biology  2011;7(5):e1001131.
This paper proposes a new method to identify communities in generally weighted complex networks and apply it to phylogenetic analysis. In this case, weights correspond to the similarity indexes among protein sequences, which can be used for network construction so that the network structure can be analyzed to recover phylogenetically useful information from its properties. The analyses discussed here are mainly based on the modular character of protein similarity networks, explored through the Newman-Girvan algorithm, with the help of the neighborhood matrix . The most relevant networks are found when the network topology changes abruptly revealing distinct modules related to the sets of organisms to which the proteins belong. Sound biological information can be retrieved by the computational routines used in the network approach, without using biological assumptions other than those incorporated by BLAST. Usually, all the main bacterial phyla and, in some cases, also some bacterial classes corresponded totally (100%) or to a great extent (>70%) to the modules. We checked for internal consistency in the obtained results, and we scored close to 84% of matches for community pertinence when comparisons between the results were performed. To illustrate how to use the network-based method, we employed data for enzymes involved in the chitin metabolic pathway that are present in more than 100 organisms from an original data set containing 1,695 organisms, downloaded from GenBank on May 19, 2007. A preliminary comparison between the outcomes of the network-based method and the results of methods based on Bayesian, distance, likelihood, and parsimony criteria suggests that the former is as reliable as these commonly used methods. We conclude that the network-based method can be used as a powerful tool for retrieving modularity information from weighted networks, which is useful for phylogenetic analysis.
Author Summary
Complex weighted networks have been applied to uncover organizing principles of complex biological, technological, and social systems. We propose herein a new method to identify communities in such structures and apply it to phylogenetic analysis. Recent studies using this theory in genomics and proteomics contributed to the understanding of the structure and dynamics of cellular complex interaction webs. Three main distinct molecular networks have been investigated based on transcriptional and metabolic activity, and on protein interaction. Here we consider the evolutionary relationship between proteins throughout phylogeny, employing the complex network approach to perform a comparative study of the enzymes related to the chitin metabolic pathway. We show how the similarity index of protein sequences can be used for network construction, and how the underlying structure is analyzed by the computational routines of our method to recover useful and sound information for phylogenetic studies. By focusing on the modular character of protein similarity networks, we were successful in matching the identified networks modules to main bacterial phyla, and even some bacterial classes. The network-based method reported here can be used as a new powerful tool for identifying communities in complex networks, retrieving useful information for phylogenetic studies.
doi:10.1371/journal.pcbi.1001131
PMCID: PMC3088654  PMID: 21573202
8.  Information Processing in Bacteria: Memory, Computation, and Statistical Physics: a Key Issues Review 
Outline
Living systems have to constantly sense their external environment and adjust their internal state in order to survive and reproduce. Biological systems, from as complex as the brain to a single E. coli cell, have to process these information in order to make appropriate decisions. How do biological systems sense the external signals? How do they process the information? How do they respond to the signals? Through years of intense study by biologists, many key molecular players and their interactions have been identified in different biological machineries that carry out these signaling functions. However, an integrated, quantitative understanding of the whole system is still lacking for most cellular signaling pathways, not to say the more complicated neural circuits.
To study signaling processes in biology, the key thing to measure is the input-output relationship. The input is the signal itself, such as chemical concentration, external temperature, light (intensity and frequency), and more complex signal such as the face of a cat. The output can be protein conformational changes and covalent modifications (phosphorylation, methylation, etc.), gene expression, cell growth and motility, as well as more complex output such as neuron firing patterns and behaviors of higher animals. Due to the inherent noise in biological systems, the measured input-output dependence is often noisy. These noisy data can be analysed by using powerful tools and concepts from information theory such as mutual information, channel capacity, and maximum entropy hypothesis. This information theory approach has been successfully used to reveal the underlying correlations between key components of the biological networks, to set bounds for the network performance, and to understand possible network architecture in generating the observed correlations. Many such examples appear in recent literature [1, 2, 3, 4, 5, 6]. See [7] for a recent review and references therein.
Although information theory approach provides a general tool in analysing noisy biological data and may be used to suggest possible network architectures in preserving information, it does not reveal the underlying mechanism that leads to the observed input-output relationship, nor does it tell us much about which information is important for the organism and how biological systems use these information to carry out specific functions. To do that, we need to develop models of the biological machineries, e.g., biochemical networks and neural networks, to understand the dynamics of biological information processes. This is a much more difficult task. It requires deep knowledge of the underlying biological network – the main players (nodes) and their interactions (links) – in sufficient details to build a model with predictive power, as well as quantitative input-output measurements of the system under different perturbations (both genetic variations and different external conditions) to test the model predictions to guide further development of the model. Due to the recent insurgency of biological knowledge thanks in part to high throughput methods (sequencing, gene expression microarray, etc.) and development of quantitative in vivo techniques such as various florescence technology, these requirements are starting to be realized in different biological systems. The possible close interaction between quantitative experimentation and theoretical modeling has made systems biology an attractive field for physicists interested in quantitative biology.
In this review, we describe some of the recent work in developing a quantitative predictive model of bacterial chemotaxis, which can be considered as the Hydrogen atom of systems biology. Using statistical physics approaches, such as Ising model and Langevin equation, we study how bacteria, such as E. coli, sense and amplify external signals, how they keep a working memory of the stimuli, and how they use these information to compute the chemical gradient. In particular, we will describe how E. coli cells avoid cross-talk in a heterogeneous receptor cluster to keep a ligand-specific memory. We will also study the thermodynamic costs of adaptation for cells to maintain an accurate memory. The statistical physics based approach described here should be useful in understanding design principles for cellular biochemical circuits in general.
doi:10.1088/0034-4885/79/5/052601
PMCID: PMC4955840  PMID: 27058315
9.  Detecting and Removing Inconsistencies between Experimental Data and Signaling Network Topologies Using Integer Linear Programming on Interaction Graphs 
PLoS Computational Biology  2013;9(9):e1003204.
Cross-referencing experimental data with our current knowledge of signaling network topologies is one central goal of mathematical modeling of cellular signal transduction networks. We present a new methodology for data-driven interrogation and training of signaling networks. While most published methods for signaling network inference operate on Bayesian, Boolean, or ODE models, our approach uses integer linear programming (ILP) on interaction graphs to encode constraints on the qualitative behavior of the nodes. These constraints are posed by the network topology and their formulation as ILP allows us to predict the possible qualitative changes (up, down, no effect) of the activation levels of the nodes for a given stimulus. We provide four basic operations to detect and remove inconsistencies between measurements and predicted behavior: (i) find a topology-consistent explanation for responses of signaling nodes measured in a stimulus-response experiment (if none exists, find the closest explanation); (ii) determine a minimal set of nodes that need to be corrected to make an inconsistent scenario consistent; (iii) determine the optimal subgraph of the given network topology which can best reflect measurements from a set of experimental scenarios; (iv) find possibly missing edges that would improve the consistency of the graph with respect to a set of experimental scenarios the most. We demonstrate the applicability of the proposed approach by interrogating a manually curated interaction graph model of EGFR/ErbB signaling against a library of high-throughput phosphoproteomic data measured in primary hepatocytes. Our methods detect interactions that are likely to be inactive in hepatocytes and provide suggestions for new interactions that, if included, would significantly improve the goodness of fit. Our framework is highly flexible and the underlying model requires only easily accessible biological knowledge. All related algorithms were implemented in a freely available toolbox SigNetTrainer making it an appealing approach for various applications.
Author Summary
Cellular signal transduction is orchestrated by communication networks of signaling proteins commonly depicted on signaling pathway maps. However, each cell type may have distinct variants of signaling pathways, and wiring diagrams are often altered in disease states. The identification of truly active signaling topologies based on experimental data is therefore one key challenge in systems biology of cellular signaling. We present a new framework for training signaling networks based on interaction graphs (IG). In contrast to complex modeling formalisms, IG capture merely the known positive and negative edges between the components. This basic information, however, already sets hard constraints on the possible qualitative behaviors of the nodes when perturbing the network. Our approach uses Integer Linear Programming to encode these constraints and to predict the possible changes (down, neutral, up) of the activation levels of the involved players for a given experiment. Based on this formulation we developed several algorithms for detecting and removing inconsistencies between measurements and network topology. Demonstrated by EGFR/ErbB signaling in hepatocytes, our approach delivers direct conclusions on edges that are likely inactive or missing relative to canonical pathway maps. Such information drives the further elucidation of signaling network topologies under normal and pathological phenotypes.
doi:10.1371/journal.pcbi.1003204
PMCID: PMC3764019  PMID: 24039561
10.  Simultaneous Genome-Wide Inference of Physical, Genetic, Regulatory, and Functional Pathway Components 
PLoS Computational Biology  2010;6(11):e1001009.
Biomolecular pathways are built from diverse types of pairwise interactions, ranging from physical protein-protein interactions and modifications to indirect regulatory relationships. One goal of systems biology is to bridge three aspects of this complexity: the growing body of high-throughput data assaying these interactions; the specific interactions in which individual genes participate; and the genome-wide patterns of interactions in a system of interest. Here, we describe methodology for simultaneously predicting specific types of biomolecular interactions using high-throughput genomic data. This results in a comprehensive compendium of whole-genome networks for yeast, derived from ∼3,500 experimental conditions and describing 30 interaction types, which range from general (e.g. physical or regulatory) to specific (e.g. phosphorylation or transcriptional regulation). We used these networks to investigate molecular pathways in carbon metabolism and cellular transport, proposing a novel connection between glycogen breakdown and glucose utilization supported by recent publications. Additionally, 14 specific predicted interactions in DNA topological change and protein biosynthesis were experimentally validated. We analyzed the systems-level network features within all interactomes, verifying the presence of small-world properties and enrichment for recurring network motifs. This compendium of physical, synthetic, regulatory, and functional interaction networks has been made publicly available through an interactive web interface for investigators to utilize in future research at http://function.princeton.edu/bioweaver/.
Author Summary
To maintain the complexity of living biological systems, many proteins must interact in a coordinated manner to integrate their unique functions into a cooperative system. Pathways are typically constructed to capture modular subsets of this dynamic network, each made up of a collection of biomolecular interactions of diverse types that together carry out a specific cellular function. Deciphering these pathways at a global level is a crucial step for unraveling systems biology, aiding at every level from basic biological understanding to translational biomarker and drug target discovery. The combination of high-throughput genomic data with advanced computational methods has enabled us to infer the first genome-wide compendium of bimolecular pathway networks, comprising 30 distinct bimolecular interaction types. We demonstrate that this interaction network compendium, derived from ∼3,500 experimental conditions, can be used to direct a range of biomedical hypothesis generation and testing. We show that our results can be used to predict novel protein interactions and new pathway components, and also that they enable system-level analysis to investigate the network characteristics of cell-wide regulatory circuits. The resulting compendium of biological networks is made publicly available through an interactive web interface to enable future research in other biological systems of interest.
doi:10.1371/journal.pcbi.1001009
PMCID: PMC2991250  PMID: 21124865
11.  Perturbation Biology: Inferring Signaling Networks in Cellular Systems 
PLoS Computational Biology  2013;9(12):e1003290.
We present a powerful experimental-computational technology for inferring network models that predict the response of cells to perturbations, and that may be useful in the design of combinatorial therapy against cancer. The experiments are systematic series of perturbations of cancer cell lines by targeted drugs, singly or in combination. The response to perturbation is quantified in terms of relative changes in the measured levels of proteins, phospho-proteins and cellular phenotypes such as viability. Computational network models are derived de novo, i.e., without prior knowledge of signaling pathways, and are based on simple non-linear differential equations. The prohibitively large solution space of all possible network models is explored efficiently using a probabilistic algorithm, Belief Propagation (BP), which is three orders of magnitude faster than standard Monte Carlo methods. Explicit executable models are derived for a set of perturbation experiments in SKMEL-133 melanoma cell lines, which are resistant to the therapeutically important inhibitor of RAF kinase. The resulting network models reproduce and extend known pathway biology. They empower potential discoveries of new molecular interactions and predict efficacious novel drug perturbations, such as the inhibition of PLK1, which is verified experimentally. This technology is suitable for application to larger systems in diverse areas of molecular biology.
Author Summary
Drugs that target specific effects of signaling proteins are promising agents for treating cancer. One of the many obstacles facing optimal drug design is inadequate quantitative understanding of the coordinated interactions between signaling proteins. De novo model inference of network or pathway models refers to the algorithmic construction of mathematical predictive models from experimental data without dependence on prior knowledge. De novo inference is difficult because of the prohibitively large number of possible sets of interactions that may or may not be consistent with observations. Our new method overcomes this difficulty by adapting a method from statistical physics, called Belief Propagation, which first calculates probabilistically the most likely interactions in the vast space of all possible solutions, then derives a set of individual, highly probable solutions in the form of executable models. In this paper, we test this method on artificial data and then apply it to model signaling pathways in a BRAF-mutant melanoma cancer cell line based on a large set of rich output measurements from a systematic set of perturbation experiments using drug combinations. Our results are in agreement with established biological knowledge, predict novel interactions, and predict efficacious drug targets that are specific to the experimental cell line and potentially to related tumors. The method has the potential, with sufficient systematic perturbation data, to model, de novo and quantitatively, the effects of hundreds of proteins on cellular responses, on a scale that is currently unreachable in diverse areas of cell biology. In a disease context, the method is applicable to the computational design of novel combination drug treatments.
doi:10.1371/journal.pcbi.1003290
PMCID: PMC3868523  PMID: 24367245
12.  Heterogeneous Network Edge Prediction: A Data Integration Approach to Prioritize Disease-Associated Genes 
PLoS Computational Biology  2015;11(7):e1004259.
The first decade of Genome Wide Association Studies (GWAS) has uncovered a wealth of disease-associated variants. Two important derivations will be the translation of this information into a multiscale understanding of pathogenic variants and leveraging existing data to increase the power of existing and future studies through prioritization. We explore edge prediction on heterogeneous networks—graphs with multiple node and edge types—for accomplishing both tasks. First we constructed a network with 18 node types—genes, diseases, tissues, pathophysiologies, and 14 MSigDB (molecular signatures database) collections—and 19 edge types from high-throughput publicly-available resources. From this network composed of 40,343 nodes and 1,608,168 edges, we extracted features that describe the topology between specific genes and diseases. Next, we trained a model from GWAS associations and predicted the probability of association between each protein-coding gene and each of 29 well-studied complex diseases. The model, which achieved 132-fold enrichment in precision at 10% recall, outperformed any individual domain, highlighting the benefit of integrative approaches. We identified pleiotropy, transcriptional signatures of perturbations, pathways, and protein interactions as influential mechanisms explaining pathogenesis. Our method successfully predicted the results (with AUROC = 0.79) from a withheld multiple sclerosis (MS) GWAS despite starting with only 13 previously associated genes. Finally, we combined our network predictions with statistical evidence of association to propose four novel MS genes, three of which (JAK2, REL, RUNX3) validated on the masked GWAS. Furthermore, our predictions provide biological support highlighting REL as the causal gene within its gene-rich locus. Users can browse all predictions online (http://het.io). Heterogeneous network edge prediction effectively prioritized genetic associations and provides a powerful new approach for data integration across multiple domains.
Author Summary
For complex human diseases, identifying the genes harboring susceptibility variants has taken on medical importance. Disease-associated genes provide clues for elucidating disease etiology, predicting disease risk, and highlighting therapeutic targets. Here, we develop a method to predict whether a given gene and disease are associated. To capture the multitude of biological entities underlying pathogenesis, we constructed a heterogeneous network, containing multiple node and edge types. We built on a technique developed for social network analysis, which embraces disparate sources of data to make predictions from heterogeneous networks. Using the compendium of associations from genome-wide studies, we learned the influential mechanisms underlying pathogenesis. Our findings provide a novel perspective about the existence of pervasive pleiotropy across complex diseases. Furthermore, we suggest transcriptional signatures of perturbations are an underutilized resource amongst prioritization approaches. For multiple sclerosis, we demonstrated our ability to prioritize future studies and discover novel susceptibility genes. Researchers can use these predictions to increase the statistical power of their studies, to suggest the causal genes from a set of candidates, or to generate evidence-based experimental hypothesis.
doi:10.1371/journal.pcbi.1004259
PMCID: PMC4497619  PMID: 26158728
13.  Organization of Physical Interactomes as Uncovered by Network Schemas 
PLoS Computational Biology  2008;4(10):e1000203.
Large-scale protein-protein interaction networks provide new opportunities for understanding cellular organization and functioning. We introduce network schemas to elucidate shared mechanisms within interactomes. Network schemas specify descriptions of proteins and the topology of interactions among them. We develop algorithms for systematically uncovering recurring, over-represented schemas in physical interaction networks. We apply our methods to the S. cerevisiae interactome, focusing on schemas consisting of proteins described via sequence motifs and molecular function annotations and interacting with one another in one of four basic network topologies. We identify hundreds of recurring and over-represented network schemas of various complexity, and demonstrate via graph-theoretic representations how more complex schemas are organized in terms of their lower-order constituents. The uncovered schemas span a wide range of cellular activities, with many signaling and transport related higher-order schemas. We establish the functional importance of the schemas by showing that they correspond to functionally cohesive sets of proteins, are enriched in the frequency with which they have instances in the H. sapiens interactome, and are useful for predicting protein function. Our findings suggest that network schemas are a powerful paradigm for organizing, interrogating, and annotating cellular networks.
Author Summary
Large-scale networks of protein-protein interactions provide a view into the workings of the cell. However, these interaction maps do not come with a key for interpreting them, so it is necessary to develop methods that shed light on their functioning and organization. We propose the language of network schemas for describing recurring patterns of specific types of proteins and their interactions. That is, network schemas describe proteins and specify the topology of interactions among them. A single network schema can describe, for example, a common template that underlies several distinct cellular pathways, such as signaling pathways. We develop a computational methodology for identifying network schemas that are recurrent and over-represented in the network, even given the distributions of their constituent components. We apply this methodology to the physical interaction network in S. cerevisiae and begin to build a hierarchy of schemas starting with the four simplest topologies. We validate the biological relevance of the schemas that we find, discuss the insights our findings lend into the organization of interactomes, touch upon cross-genomic aspects of schema analysis, and show how to use schemas to annotate uncharacterized protein families.
doi:10.1371/journal.pcbi.1000203
PMCID: PMC2561054  PMID: 18949022
14.  The topology of the bacterial co-conserved protein network and its implications for predicting protein function 
BMC Genomics  2008;9:313.
Background
Protein-protein interactions networks are most often generated from physical protein-protein interaction data. Co-conservation, also known as phylogenetic profiles, is an alternative source of information for generating protein interaction networks. Co-conservation methods generate interaction networks among proteins that are gained or lost together through evolution. Co-conservation is a particularly useful technique in the compact bacteria genomes. Prior studies in yeast suggest that the topology of protein-protein interaction networks generated from physical interaction assays can offer important insight into protein function. Here, we hypothesize that in bacteria, the topology of protein interaction networks derived via co-conservation information could similarly improve methods for predicting protein function. Since the topology of bacteria co-conservation protein-protein interaction networks has not previously been studied in depth, we first perform such an analysis for co-conservation networks in E. coli K12. Next, we demonstrate one way in which network connectivity measures and global and local function distribution can be exploited to predict protein function for previously uncharacterized proteins.
Results
Our results showed, like most biological networks, our bacteria co-conserved protein-protein interaction networks had scale-free topologies. Our results indicated that some properties of the physical yeast interaction network hold in our bacteria co-conservation networks, such as high connectivity for essential proteins. However, the high connectivity among protein complexes in the yeast physical network was not seen in the co-conservation network which uses all bacteria as the reference set. We found that the distribution of node connectivity varied by functional category and could be informative for function prediction. By integrating of functional information from different annotation sources and using the network topology, we were able to infer function for uncharacterized proteins.
Conclusion
Interactions networks based on co-conservation can contain information distinct from networks based on physical or other interaction types. Our study has shown co-conservation based networks to exhibit a scale free topology, as expected for biological networks. We also revealed ways that connectivity in our networks can be informative for the functional characterization of proteins.
doi:10.1186/1471-2164-9-313
PMCID: PMC2488357  PMID: 18590549
15.  A New Method for the Discovery of Essential Proteins 
PLoS ONE  2013;8(3):e58763.
Background
Experimental methods for the identification of essential proteins are always costly, time-consuming, and laborious. It is a challenging task to find protein essentiality only through experiments. With the development of high throughput technologies, a vast amount of protein-protein interactions are available, which enable the identification of essential proteins from the network level. Many computational methods for such task have been proposed based on the topological properties of protein-protein interaction (PPI) networks. However, the currently available PPI networks for each species are not complete, i.e. false negatives, and very noisy, i.e. high false positives, network topology-based centrality measures are often very sensitive to such noise. Therefore, exploring robust methods for identifying essential proteins would be of great value.
Method
In this paper, a new essential protein discovery method, named CoEWC (Co-Expression Weighted by Clustering coefficient), has been proposed. CoEWC is based on the integration of the topological properties of PPI network and the co-expression of interacting proteins. The aim of CoEWC is to capture the common features of essential proteins in both date hubs and party hubs. The performance of CoEWC is validated based on the PPI network of Saccharomyces cerevisiae. Experimental results show that CoEWC significantly outperforms the classical centrality measures, and that it also outperforms PeC, a newly proposed essential protein discovery method which outperforms 15 other centrality measures on the PPI network of Saccharomyces cerevisiae. Especially, when predicting no more than 500 proteins, even more than 50% improvements are obtained by CoEWC over degree centrality (DC), a better centrality measure for identifying protein essentiality.
Conclusions
We demonstrate that more robust essential protein discovery method can be developed by integrating the topological properties of PPI network and the co-expression of interacting proteins. The proposed centrality measure, CoEWC, is effective for the discovery of essential proteins.
doi:10.1371/journal.pone.0058763
PMCID: PMC3605424  PMID: 23555595
16.  Linkers of Cell Polarity and Cell Cycle Regulation in the Fission Yeast Protein Interaction Network 
PLoS Computational Biology  2012;8(10):e1002732.
The study of gene and protein interaction networks has improved our understanding of the multiple, systemic levels of regulation found in eukaryotic and prokaryotic organisms. Here we carry out a large-scale analysis of the protein-protein interaction (PPI) network of fission yeast (Schizosaccharomyces pombe) and establish a method to identify ‘linker’ proteins that bridge diverse cellular processes - integrating Gene Ontology and PPI data with network theory measures. We test the method on a highly characterized subset of the genome consisting of proteins controlling the cell cycle, cell polarity and cytokinesis and identify proteins likely to play a key role in controlling the temporal changes in the localization of the polarity machinery. Experimental inspection of one such factor, the polarity-regulating RNB protein Sts5, confirms the prediction that it has a cell cycle dependent regulation. Detailed bibliographic inspection of other predicted ‘linkers’ also confirms the predictive power of the method. As the method is robust to network perturbations and can successfully predict linker proteins, it provides a powerful tool to study the interplay between different cellular processes.
Author Summary
Analysis of protein interaction networks has been of use as a means to grapple with the complexity of the interactome of biological organisms. So far, network based approaches have only been used in a limited number of organisms due to the lack of high-throughput experiments. In this study, we investigate by graph theoretical network analysis approaches the protein-protein interaction network of fission yeast, and present a new network measure, linkerity, that predicts the ability of certain proteins to function as bridges between diverse cellular processes. We apply this linkerity measure to a highly conserved and coupled subset of the fission yeast network, consisting of the proteins that regulate cell cycle, polarized cell growth, and cell division. In depth literature analysis confirms that several proteins identified as linkers of cell polarity regulation are indeed also associated with cell cycle and/or cell division control. Similarly, experimental testing confirms that a mostly uncharacterized polarity regulator identified by the method as an important linker is regulated by the cell cycle, as predicted.
doi:10.1371/journal.pcbi.1002732
PMCID: PMC3475659  PMID: 23093924
17.  Dominating Biological Networks 
PLoS ONE  2011;6(8):e23016.
Proteins are essential macromolecules of life that carry out most cellular processes. Since proteins aggregate to perform function, and since protein-protein interaction (PPI) networks model these aggregations, one would expect to uncover new biology from PPI network topology. Hence, using PPI networks to predict protein function and role of protein pathways in disease has received attention. A debate remains open about whether network properties of “biologically central (BC)” genes (i.e., their protein products), such as those involved in aging, cancer, infectious diseases, or signaling and drug-targeted pathways, exhibit some topological centrality compared to the rest of the proteins in the human PPI network.
To help resolve this debate, we design new network-based approaches and apply them to get new insight into biological function and disease. We hypothesize that BC genes have a topologically central (TC) role in the human PPI network. We propose two different concepts of topological centrality. We design a new centrality measure to capture complex wirings of proteins in the network that identifies as TC those proteins that reside in dense extended network neighborhoods. Also, we use the notion of domination and find dominating sets (DSs) in the PPI network, i.e., sets of proteins such that every protein is either in the DS or is a neighbor of the DS. Clearly, a DS has a TC role, as it enables efficient communication between different network parts.
We find statistically significant enrichment in BC genes of TC nodes and outperform the existing methods indicating that genes involved in key biological processes occupy topologically complex and dense regions of the network and correspond to its “spine” that connects all other network parts and can thus pass cellular signals efficiently throughout the network. To our knowledge, this is the first study that explores domination in the context of PPI networks.
doi:10.1371/journal.pone.0023016
PMCID: PMC3162560  PMID: 21887225
18.  Multi-tissue Analysis of Co-expression Networks by Higher-Order Generalized Singular Value Decomposition Identifies Functionally Coherent Transcriptional Modules 
PLoS Genetics  2014;10(1):e1004006.
Recent high-throughput efforts such as ENCODE have generated a large body of genome-scale transcriptional data in multiple conditions (e.g., cell-types and disease states). Leveraging these data is especially important for network-based approaches to human disease, for instance to identify coherent transcriptional modules (subnetworks) that can inform functional disease mechanisms and pathological pathways. Yet, genome-scale network analysis across conditions is significantly hampered by the paucity of robust and computationally-efficient methods. Building on the Higher-Order Generalized Singular Value Decomposition, we introduce a new algorithmic approach for efficient, parameter-free and reproducible identification of network-modules simultaneously across multiple conditions. Our method can accommodate weighted (and unweighted) networks of any size and can similarly use co-expression or raw gene expression input data, without hinging upon the definition and stability of the correlation used to assess gene co-expression. In simulation studies, we demonstrated distinctive advantages of our method over existing methods, which was able to recover accurately both common and condition-specific network-modules without entailing ad-hoc input parameters as required by other approaches. We applied our method to genome-scale and multi-tissue transcriptomic datasets from rats (microarray-based) and humans (mRNA-sequencing-based) and identified several common and tissue-specific subnetworks with functional significance, which were not detected by other methods. In humans we recapitulated the crosstalk between cell-cycle progression and cell-extracellular matrix interactions processes in ventricular zones during neocortex expansion and further, we uncovered pathways related to development of later cognitive functions in the cortical plate of the developing brain which were previously unappreciated. Analyses of seven rat tissues identified a multi-tissue subnetwork of co-expressed heat shock protein (Hsp) and cardiomyopathy genes (Bag3, Cryab, Kras, Emd, Plec), which was significantly replicated using separate failing heart and liver gene expression datasets in humans, thus revealing a conserved functional role for Hsp genes in cardiovascular disease.
Author Summary
Complex biological interactions and processes can be modelled as networks, for instance metabolic pathways or protein-protein interactions. The growing availability of large high-throughput data in several experimental conditions now permits the full-scale analysis of biological interactions and processes. However, no reliable and computationally efficient methods for simultaneous analysis of multiple large-scale interaction datasets (networks) have been developed to date. To overcome this shortcoming, we have developed a new computational framework that is parameter-free, computationally efficient and highly reliable. We showed how these distinctive properties make it a useful tool for real genomic data exploration and analyses. Indeed, in extensive simulation studies and real-data analyses we have demonstrated that our method outperformed existing approaches in terms of efficiency and, most importantly, reproducibility of the results. Beyond the computational advantages, we illustrated how our method can be effectively applied to leverage the vast stream of genome-scale transcriptional data that has risen exponentially over the last years. In contrast with existing approaches, using our method we were able to identify and replicate multi-tissue gene co-expression networks that were associated with specific functional processes relevant to phenotypic variation and disease in rats and humans.
doi:10.1371/journal.pgen.1004006
PMCID: PMC3879165  PMID: 24391511
19.  Plato's Cave Algorithm: Inferring Functional Signaling Networks from Early Gene Expression Shadows 
PLoS Computational Biology  2010;6(6):e1000828.
Improving the ability to reverse engineer biochemical networks is a major goal of systems biology. Lesions in signaling networks lead to alterations in gene expression, which in principle should allow network reconstruction. However, the information about the activity levels of signaling proteins conveyed in overall gene expression is limited by the complexity of gene expression dynamics and of regulatory network topology. Two observations provide the basis for overcoming this limitation: a. genes induced without de-novo protein synthesis (early genes) show a linear accumulation of product in the first hour after the change in the cell's state; b. The signaling components in the network largely function in the linear range of their stimulus-response curves. Therefore, unlike most genes or most time points, expression profiles of early genes at an early time point provide direct biochemical assays that represent the activity levels of upstream signaling components. Such expression data provide the basis for an efficient algorithm (Plato's Cave algorithm; PLACA) to reverse engineer functional signaling networks. Unlike conventional reverse engineering algorithms that use steady state values, PLACA uses stimulated early gene expression measurements associated with systematic perturbations of signaling components, without measuring the signaling components themselves. Besides the reverse engineered network, PLACA also identifies the genes detecting the functional interaction, thereby facilitating validation of the predicted functional network. Using simulated datasets, the algorithm is shown to be robust to experimental noise. Using experimental data obtained from gonadotropes, PLACA reverse engineered the interaction network of six perturbed signaling components. The network recapitulated many known interactions and identified novel functional interactions that were validated by further experiment. PLACA uses the results of experiments that are feasible for any signaling network to predict the functional topology of the network and to identify novel relationships.
Author Summary
Elucidating the biochemical interactions in living cells is essential to understanding their behavior under various external conditions. Some of these interactions occur between signaling components with many active states, and their activity levels may be difficult to measure directly. However, most methods to reverse engineer interaction networks rely on measuring gene activity at steady state under various cellular stimuli. Such gene measurements therefore ignore the intermediate effects of signaling components, and cannot reliably convey the interactions between the signaling components themselves. We propose using the changes in activity of early genes shortly after the stimulus to infer the functional interactions between the unmeasured signaling components. The change in expression in such genes at these times is directly and linearly affected by the signaling components, since there is insufficient time for other genes to be transcribed and interfere with the early genes' expression. We present an algorithm that uses such measurements to reverse engineer the functional interaction network between signaling components, and also provides a means for testing these predictions. The algorithm therefore uses feasible experiments to reconstruct functional networks. We applied the algorithm to experimental measurements and uncovered known interactions, as well as novel interactions that were then confirmed experimentally.
doi:10.1371/journal.pcbi.1000828
PMCID: PMC2891706  PMID: 20585619
20.  Automated identification of pathways from quantitative genetic interaction data 
We present a novel Bayesian learning method that reconstructs large detailed gene networks from quantitative genetic interaction (GI) data.The method uses global reasoning to handle missing and ambiguous measurements, and provide confidence estimates for each prediction.Applied to a recent data set over genes relevant to protein folding, the learned networks reflect known biological pathways, including details such as pathway ordering and directionality of relationships.The reconstructed networks also suggest novel relationships, including the placement of SGT2 in the tail-anchored biogenesis pathway, a finding that we experimentally validated.
Recent developments have enabled large-scale quantitative measurement of genetic interactions (GIs) that report on the extent to which the activity of one gene is dependent on a second. It has long been recognized (Avery and Wasserman, 1992; Hartman et al, 2001; Segre et al, 2004; Tong et al, 2004; Drees et al, 2005; Schuldiner et al, 2005; St Onge et al, 2007; Costanzo et al, 2010) that functional dependencies revealed by GI data can provide rich information regarding underlying biological pathways. Further, the precise phenotypic measurements provided by quantitative GI data can provide evidence for even more detailed aspects of pathway structure, such as differentiating between full and partial dependence between two genes (Drees et al, 2005; Schuldiner et al, 2005; St Onge et al, 2007; Jonikas et al, 2009) (Figure 1A). As GI data sets become available for a range of quantitative phenotypes and organisms, such patterns will allow researchers to elucidate pathways important to a diverse set of biological processes.
We present a new method that exploits the high-quality, quantitative nature of recent GI assays to automatically reconstruct detailed multi-gene pathway structures, including the organization of a large set of genes into coherent pathways, the connectivity and ordering within each pathway, and the directionality of each relationship. We introduce activity pathway networks (APNs), which represent functional dependencies among a set of genes in the form of a network. We present an automatic method to efficiently reconstruct APNs over large sets of genes based on quantitative GI measurements. This method handles uncertainty in the data arising from noise, missing measurements, and data points with ambiguous interpretations, by performing global reasoning that combines evidence from multiple data points. In addition, because some structure choices remain uncertain even when jointly considering all measurements, our method maintains multiple likely networks, and allows computation of confidence estimates over each structure choice.
We applied our APN reconstruction method to the recent high-quality GI data set of Jonikas et al (2009), which examined the functional interaction between genes that contribute to protein folding in the ER. Specifically, Jonikas et al used the cell's endogenous sensor (the unfolded protein response), to first identify several hundred yeast genes with functions in endoplasmic reticulum folding and then systematically characterized their functional interdependencies by measuring unfolded protein response levels in double mutants. Our analysis produced an ensemble of 500 likelihood-weighted APNs over 178 genes (Figure 2).
We performed an aggregate evaluation of our results by comparing to known biological relationships between gene pairs, including participation in pathways according to the Kyoto Encyclopedia of Genes and Genomes (KEGG), correlation of chemical genomic profiles in a recent high-throughput assay (Hillenmeyer et al, 2008) and similarity of Gene Ontology (GO) annotations. In each evaluation performed, our reconstructed APNs were significantly more consistent with the known relationships than either the raw GI values or the Pearson correlation between profiles of GI values.
Importantly, our approach provides not only an improved means for defining pairs or groups of related genes, but also enables the identification of detailed multi-gene network structures. In many cases, our method successfully reconstructed known cellular pathways, including the ER-associated degradation (ERAD) pathway, and the biosynthesis of N-linked glycans, ranking them among the highest confidence structures. In-depth examination of the learned network structures indicates agreement with many known details of these pathways. In addition, quantitative analysis indicates that our learned APNs are indicative of ordering within KEGG-annotated biological pathways.
Our results also suggest several novel relationships, including placement of uncharacterized genes into pathways, and novel relationships between characterized genes. These include the dependence of the J domain chaperone JEM1 on the PDI homolog MPD1, dependence of the Ubiquitin-recycling enzyme DOA4 on N-linked glycosylation, and the dependence of the E3 Ubiquitin ligase DOA10 on the signal peptidase complex subunit SPC2. Our APNs also place the poorly characterized TPR-containing protein SGT2 upstream of the tail-anchored protein biogenesis machinery components GET3, GET4, and MDY2 (also known as GET5), suggesting that SGT2 has a function in the insertion of tail-anchored proteins into membranes. Consistent with this prediction, our experimental analysis shows that sgt2Δ cells show a defect in localization of the tail-anchored protein GFP-Sed5 from punctuate Golgi structures to a more diffuse pattern, as seen in other genes involved in this pathway.
Our results show that multi-gene, detailed pathway networks can be reconstructed from quantitative GI data, providing a concrete computational manifestation to intuitions that have traditionally accompanied the manual interpretation of such data. Ongoing technological developments in both genetics and imaging are enabling the measurement of GI data at a genome-wide scale, using high-accuracy quantitative phenotypes that relate to a range of particular biological functions. Methods based on RNAi will soon allow collection of similar data for human cell lines and other mammalian systems (Moffat et al, 2006). Thus, computational methods for analyzing GI data could have an important function in mapping pathways involved in complex biological systems including human cells.
High-throughput quantitative genetic interaction (GI) measurements provide detailed information regarding the structure of the underlying biological pathways by reporting on functional dependencies between genes. However, the analytical tools for fully exploiting such information lag behind the ability to collect these data. We present a novel Bayesian learning method that uses quantitative phenotypes of double knockout organisms to automatically reconstruct detailed pathway structures. We applied our method to a recent data set that measures GIs for endoplasmic reticulum (ER) genes, using the unfolded protein response as a quantitative phenotype. The results provided reconstructions of known functional pathways including N-linked glycosylation and ER-associated protein degradation. It also contained novel relationships, such as the placement of SGT2 in the tail-anchored biogenesis pathway, a finding that we experimentally validated. Our approach should be readily applicable to the next generation of quantitative GI data sets, as assays become available for additional phenotypes and eventually higher-level organisms.
doi:10.1038/msb.2010.27
PMCID: PMC2913392  PMID: 20531408
computational biology; genetic interaction; pathway reconstruction; probabilistic methods
21.  Emergence of Switch-Like Behavior in a Large Family of Simple Biochemical Networks 
PLoS Computational Biology  2011;7(5):e1002039.
Bistability plays a central role in the gene regulatory networks (GRNs) controlling many essential biological functions, including cellular differentiation and cell cycle control. However, establishing the network topologies that can exhibit bistability remains a challenge, in part due to the exceedingly large variety of GRNs that exist for even a small number of components. We begin to address this problem by employing chemical reaction network theory in a comprehensive in silico survey to determine the capacity for bistability of more than 40,000 simple networks that can be formed by two transcription factor-coding genes and their associated proteins (assuming only the most elementary biochemical processes). We find that there exist reaction rate constants leading to bistability in ∼90% of these GRN models, including several circuits that do not contain any of the TF cooperativity commonly associated with bistable systems, and the majority of which could only be identified as bistable through an original subnetwork-based analysis. A topological sorting of the two-gene family of networks based on the presence or absence of biochemical reactions reveals eleven minimal bistable networks (i.e., bistable networks that do not contain within them a smaller bistable subnetwork). The large number of previously unknown bistable network topologies suggests that the capacity for switch-like behavior in GRNs arises with relative ease and is not easily lost through network evolution. To highlight the relevance of the systematic application of CRNT to bistable network identification in real biological systems, we integrated publicly available protein-protein interaction, protein-DNA interaction, and gene expression data from Saccharomyces cerevisiae, and identified several GRNs predicted to behave in a bistable fashion.
Author Summary
Switch-like behavior is found across a wide range of biological systems, and as a result there is significant interest in identifying the various ways in which biochemical reactions can be combined to yield a switch-like response. In this work we use a set of mathematical tools from chemical reaction network theory that provide information about the steady-states of a reaction network irrespective of the values of network rate constants, to conduct a large computational study of a family of model networks consisting of only two protein-coding genes. We find that a large majority of these networks (∼90%) have (for some set of parameters) the mathematical property known as bistability and can behave in a switch-like manner. Interestingly, the capacity for switch-like behavior is often maintained as networks increase in size through the introduction of new reactions. We then demonstrate using published yeast data how theoretical parameter-free surveys such as this one can be used to discover possible switch-like circuits in real biological systems. Our results highlight the potential usefulness of parameter-free modeling for the characterization of complex networks and to the study of network evolution, and are suggestive of a role for it in the development of novel synthetic biological switches.
doi:10.1371/journal.pcbi.1002039
PMCID: PMC3093349  PMID: 21589886
22.  Queueing up for enzymatic processing: correlated signaling through coupled degradation 
Overloaded enzymatic processes are shown to create indirect coupling between upstream components in cellular networks. This has important implications for the design of synthetic biology devices and for our understanding of currently inexplicable links within endogenous biological systems.
Queueing theory is used to investigate how ‘waiting lines' can lead to correlations between proteins that are coupled solely through a downstream set of common enzymes.The Escherichia coli ClpXP degradation machinery serves as a model processing system, and significant cross-talk arises between two independent networks that involve proteins tagged for removal by this shared enzymatic process.Computational modeling demonstrates how a native stress response network implements coupling due to queueing, helping to confer the rapid build-up of the master stress regulator when needed and its rapid removal from the system when stress-free conditions are restored.Implications of queueing-based coupling are significant for synthetic biology approaches, as degradation tagging, which is often used to ensure the critical rapid decay of network components, can lead to synchronized behavior between otherwise independent networks.
High-throughput technologies have led to the generation of complex wiring diagrams as a post-sequencing paradigm for depicting the interactions between vast and diverse cellular species. While these diagrams are useful for analyzing biological systems on a large scale, a detailed understanding of the molecular mechanisms that underlie the observed network connections is critical for the further development of systems and synthetic biology. Here, we use queueing theory to investigate how ‘waiting lines' can lead to correlations between protein ‘customers' that are coupled solely through a downstream set of enzymatic ‘servers'. Using the E. coli ClpXP degradation machine as a model processing system, we observe significant cross-talk between two networks that are indirectly coupled through a common set of processors. We further illustrate the implications of enzymatic queueing using a synthetic biology application, in which two independent synthetic networks demonstrate synchronized behavior when common ClpXP machinery is overburdened. Our results demonstrate that such post-translational processes can lead to dynamic connections in cellular networks and may provide a mechanistic understanding of existing but currently inexplicable links.
doi:10.1038/msb.2011.94
PMCID: PMC3737734  PMID: 22186735
ClpXP; protein degradation; queueing; synthetic biology
23.  A Multi-Method Approach for Proteomic Network Inference in 11 Human Cancers 
PLoS Computational Biology  2016;12(2):e1004765.
Protein expression and post-translational modification levels are tightly regulated in neoplastic cells to maintain cellular processes known as ‘cancer hallmarks’. The first Pan-Cancer initiative of The Cancer Genome Atlas (TCGA) Research Network has aggregated protein expression profiles for 3,467 patient samples from 11 tumor types using the antibody based reverse phase protein array (RPPA) technology. The resultant proteomic data can be utilized to computationally infer protein-protein interaction (PPI) networks and to study the commonalities and differences across tumor types. In this study, we compare the performance of 13 established network inference methods in their capacity to retrieve the curated Pathway Commons interactions from RPPA data. We observe that no single method has the best performance in all tumor types, but a group of six methods, including diverse techniques such as correlation, mutual information, and regression, consistently rank highly among the tested methods. We utilize the high performing methods to obtain a consensus network; and identify four robust and densely connected modules that reveal biological processes as well as suggest antibody–related technical biases. Mapping the consensus network interactions to Reactome gene lists confirms the pan-cancer importance of signal transduction pathways, innate and adaptive immune signaling, cell cycle, metabolism, and DNA repair; and also suggests several biological processes that may be specific to a subset of tumor types. Our results illustrate the utility of the RPPA platform as a tool to study proteomic networks in cancer.
Author Summary
Pan-cancer proteomic datasets from The Cancer Genome Atlas provide a unique opportunity to study the functions of proteins in human cancers. Such datasets, where proteins are measured in different conditions and where correlations are informative, can enable the discovery of potentially causal protein-protein interactions, which may in turn shed light on the function of proteins. However, it has been shown that the dominant correlations in a system can be the result of parallel transitive (i.e. indirect) interactions. A wide suite of computational methods has been proposed in the literature for the discrimination between direct and transitive interactions. These methods have been extensively tested for their performance in gene regulatory network inference due to the prevalence of mRNA data. However, the understanding of the performance and limitations of these methods in retrieving curated pathway interactions is lacking. Here, we utilize a high-throughput proteomic dataset from The Cancer Genome Atlas to systematically test different families of network inference methods. We observe that most methods are able to achieve a similar level of performance provided their parameter space is sufficiently explored; but a group of six methods consistently rank highly among the tested methods. The protein-protein interactions inferred by the high-performing methods reveal the pathways that are shared by or specific to different cancer types.
doi:10.1371/journal.pcbi.1004765
PMCID: PMC4771175  PMID: 26928298
24.  Novel Insights through the Integration of Structural and Functional Genomics Data with Protein Networks 
Journal of structural biology  2012;179(3):320-326.
In recent years, major advances in genomics, proteomics, macromolecular structure determination, and the computational resources capable of processing and disseminating the large volumes of data generated by each have played major roles in advancing a more systems-oriented appreciation of biological organization. One product of systems biology has been the delineation of graph models for describing genome-wide protein-protein interaction networks. The network organization and topology which emerges in such models may be used to address fundamental questions in an array of cellular processes, as well as biological features intrinsic to the constituent proteins (or “nodes”) themselves. However, graph models alone constitute an abstraction which neglects the underlying biological and physical reality that the network’s nodes and edges are highly heterogeneous entities. Here, we explore some of the advantages of introducing a protein structural dimension to such models, as the marriage of conventional network representations with macromolecular structural data helps to place static node-and-edge constructs in a biologically more meaningful context. We emphasize that 3D protein structures constitute a valuable conceptual and predictive framework by discussing examples of the insights provided, such as enabling in silico predictions of protein-protein interactions, providing rational and compelling classification schemes for network elements, as well as revealing interesting intrinsic differences between distinct node types, such as disorder and evolutionary features, which may then be rationalized in light of their respective functions within networks.
doi:10.1016/j.jsb.2012.02.001
PMCID: PMC4830681  PMID: 22343087
25.  Proteomic snapshot of the EGF-induced ubiquitin network 
In this work, the authors report the first proteome-wide analysis of EGF-regulated ubiquitination, revealing surprisingly pervasive growth factor-induced ubiquitination across a broad range of cellular systems and signaling pathways.
Epidermal growth factor (EGF) triggers a novel ubiquitin (Ub)-based signaling cascade that appears to intersect both housekeeping and regulatory circuitries of cellular physiology.The EGF-regulated Ubiproteome includes scores ubiquitinating and deubiquitinating enzymes, suggesting that the Ub signal might be rapidly transmitted and amplified through the Ub machinery.The EGF-Ubiproteome overlaps significantly with the EGF-phosphotyrosine proteome, pointing to a possible crosstalk between these two signaling mechanisms.The significant number of biological insights uncovered in our study (among which EphA2 as a novel, downstream ubiquitinated target of EGF receptor) illustrates the general relevance of such proteomic screens and calls for further analysis of the dynamics of the Ubiproteome.
Ubiquitination is a process by which one or more ubiquitin (Ub) monomers or chains are covalently attached to target proteins by E3 ligases. Deubiquitinating enzymes (DUBs) revert Ub conjugation, thus ensuring a dynamic equilibrium between pools of ubiquitinated and deubiquitinated proteins (Amerik and Hochstrasser, 2004). Traditionally, ubiquitination has been associated with protein degradation; however, it is now becoming apparent that this post-translation modification is an important signaling mechanism that can modulate the function, localization and protein/protein interaction abilities of targets (Mukhopadhyay and Riezman, 2007; Ravid and Hochstrasser, 2008).
One of the best-characterized signaling pathways involving ubiquitination is the epidermal growth factor (EGF)-induced pathway. Upon EGF stimulation, a variety of proteins are subject to Ub modification. These include the EGF receptor (EGFR), which undergoes both multiple monoubiquitination (Haglund et al, 2003) and K63-linked polyubiquitination (Huang et al, 2006), as well as components of the downstream endocytic machinery, which are modified by monoubiquitination (Polo et al, 2002; Mukhopadhyay and Riezman, 2007). Ubiquitination of the EGFR has been shown to have an impact on receptor internalization, intracellular sorting and metabolic fate (Acconcia et al, 2009). However, little is known about the wider impact of EGF-induced ubiquitination on cellular homeostasis and on the pleiotropic biological functions of the EGFR. In this paper, we attempt to address this issue by characterizing the repertoire of proteins that are ubiquitinated upon EGF stimulation, i.e., the EGF-Ubiproteome.
To achieve this, we employed two different purification procedures (endogenous—based on the purification of proteins modified by endogenous Ub from human cells; tandem affinity purification (TAP)—based on the purification of proteins modified by an ectopically expressed tagged-Ub from mouse cells) with stable isotope labeling with amino acids in cell culture-based MS to obtain both steady-state Ubiproteomes and EGF-induced Ubiproteomes. The steady-state Ubiproteomes consist of 1175 and 582 unambiguously identified proteins for the endogenous and TAP approaches, respectively, which we largely validated. Approximately 15% of the steady-state Ubiproteome was EGF-regulated at 10 min after stimulation; 176 of 1175 in the endogenous approach and 105 of 582 in the TAP approach. Both hyper- and hypoubiquitinated proteins were detected, indicating that EGFR-mediated signaling can modulate the ubiquitin network in both directions. Interestingly, many E2, E3 and DUBs were present in the EGF-Ubiproteome, suggesting that the Ub signal might be rapidly transmitted and amplified through the Ub machinery. Moreover, analysis of Ub-chain topology, performed using mass spectrometry and specific abs, suggested that the K63-linkage was the major Ub-based signal in the EGF-induced pathway.
To obtain a higher-resolution molecular picture of the EGF-regulated Ub network, we performed a network analysis on the non-redundant EGF-Ubiproteome (265 proteins). This analysis revealed that in addition to well-established liaisons with endocytosis-related pathways, the EGF-Ubiproteome intersects many circuitries of intracellular signaling involved in, e.g., DNA damage checkpoint regulation, cell-to-cell adhesion mechanisms and actin remodeling (Figure 5A).
Moreover, the EGF-Ubiproteome was enriched in hubs, proteins that can establish multiple protein/protein interaction and thereby regulate the organization of networks. These results are indicative of a crosstalk between EGFR-activated pathways and other signaling pathways through the Ub-network.
As EGF binding to its receptor also triggers a series of phosphorylation events, we examined whether there was any overlap between our EGF-Ubiproteome and published EGF-induced phosphotyrosine (pY) proteomes (Blagoev et al, 2004; Oyama et al, 2009; Hammond et al, 2010). We observed a significant overlap between ubiquitinated and pY proteins: 23% (61 of 265) of the EGF-Ubiproteome proteins were also tyrosine phosphorylated. Pathway analysis of these 61 Ub/pY-containing proteins revealed a significant enrichment in endocytic and signal-transduction pathways, while ‘hub analysis' revealed that Ub/pY-containing proteins are enriched in highly connected proteins to an even greater extent than Ub-containing proteins alone. These data point to a complex interplay between the Ub and pY networks and suggest that the flow of information from the receptor to downstream signaling molecules is driven by two complementary and interlinked enzymatic cascades: kinases/phosphatases and E3 ligases/DUBs.
Finally, we provided a proof of principle of the biological relevance of our EGF-Ubiproteome. We focused on EphA2, a receptor tyrosine kinase, which is involved in development and is often overexpressed in cancer (Pasquale, 2008). We started from the observation that EphA2 is present in the EGF-Ubiproteome and that proteins of the EGF-Ubiproteome are enriched in the Ephrin receptor signaling pathway(s). We confirmed the MS data by demonstrating that the EphA2 is ubiquitinated upon EGF stimulation. Moreover, EphA2 also undergoes tyrosine phosphorylation, indicating crosstalk between the two receptors. The EGFR kinase domain was essential for these modifications of EphA2, and a partial co-internalization with EGFR upon EGF activation was clearly detectable. Finally, we demonstrated by knockdown of EphA2 in MCF10A cells that this receptor is critically involved in EGFR biological outcomes, such as proliferation and migration (Figure 7).
Overall, our results unveil the complex impact of growth factor signaling on Ub-based intracellular networks to levels that extend well beyond what might have been expected and highlight the ‘resource' feature of our EGF-Ubiproteome.
The activity, localization and fate of many cellular proteins are regulated through ubiquitination, a process whereby one or more ubiquitin (Ub) monomers or chains are covalently attached to target proteins. While Ub-conjugated and Ub-associated proteomes have been described, we lack a high-resolution picture of the dynamics of ubiquitination in response to signaling. In this study, we describe the epidermal growth factor (EGF)-regulated Ubiproteome, as obtained by two complementary purification strategies coupled to quantitative proteomics. Our results unveil the complex impact of growth factor signaling on Ub-based intracellular networks to levels that extend well beyond what might have been expected. In addition to endocytic proteins, the EGF-regulated Ubiproteome includes a large number of signaling proteins, ubiquitinating and deubiquitinating enzymes, transporters and proteins involved in translation and transcription. The Ub-based signaling network appears to intersect both housekeeping and regulatory circuitries of cellular physiology. Finally, as proof of principle of the biological relevance of the EGF-Ubiproteome, we demonstrated that EphA2 is a novel, downstream ubiquitinated target of epidermal growth factor receptor (EGFR), critically involved in EGFR biological responses.
doi:10.1038/msb.2010.118
PMCID: PMC3049407  PMID: 21245847
EGF; network; proteomics; signaling; ubiquitin

Results 1-25 (2040340)