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Research Articles

2024

J Nasser, K-M Nam, J Gunawardena,
"A mathematical model clarifies the ABC Score formula used in enhancer-gene prediction"
bioRxiv doi:10.1101/2024.11.29.626072 2024.

L Eckert, M S Vidal-Saez, Z Zhao, J Garcia-Ojalvo, R Martinez-Corral, J Gunawardena
"Biochemically-plausible models of habituation for single-cell learning"
Curr Biol 34:1-13 2024.   Full text   PDF + SI   earlier version on bioRxiv.
press attention — HMS news

R Martinez-Corral, D Friedrich, R Frömmel, L Velten, J Gunawardena, A H DePace
"Emergence of activation or repression in transcriptional control under a fixed molecular context"
bioRxiv doi:10.1101/2024.05.29.596388v1 2024.

D Lu, M Faizi, B Drown, A Simerzin, G Bradshaw, N Kelleher, A Jambhekar, J Gunawardena, G Lahav
"Temporal regulation of the DNA damage response through integration of p53 dynamics and modifications"
Sci Adv 10:eadp2229 2024.   Full text   PDF.

M Faizi, R T Fellers, D Lu, B S Drown, A Jambhekar, G Lahav, N L Kelleher, J Gunawardena
"MSModDetector: a tool for detecting mass shifts and post-translational modifications in individual ion mass spectrometry data"
Bioinformatics 40:btae335 2024.   Full text   PDF   earlier version on bioRxiv.

R Martinez-Corral, K-M Nam, A H DePace, J Gunawardena
"The Hill function is the universal Hopfield barrier for sharpness of input-output responses"
PNAS 121:e2318329121 2024.   Full text   PDF   SI   earlier version on bioRxiv   Kudos.

2023

U Çetiner, J Gunawardena
"Universal bounds on information-processing capabilities of Markov processes"
arXiv doi:2310.10584 2023

K-M Nam, J Gunawardena
"The linear framework II: using graph theory to analyse the transient regime of Markov processes"
Front Cell Dev Biol 11:1233808 2023. Full text   PDF.
Invited contribution to the Research Topic on Network-based Mathematical Modeling in Cell and Developmental Biology.

J A Owen*, P Talla*, J Biddle, J Gunawardena
"Thermodynamic bounds on ultrasensitivity in covalent switching"
Biophys J 122:1-13 2023.   Full text   PDF.

R Martinez-Corral, M Park, K Biette, D Friedrich, C Scholes, A S Khalil, J Gunawardena, A H DePace
"Transcriptional kinetic synergy: a complex landscape revealed by integrating modelling and synthetic biology"
Cell Syst 14:324-39 2023.   Full text   PDF.

2022

U Çetiner, J Gunawardena
"Reformulating non-equilibrium steady states and generalized Hopfield discrimination"
Phys Rev E 106:064128 2022.   PDF.

K-M Nam*, R Martinez-Corral*, J Gunawardena
"The linear framework: using graph theory to reveal the algebra and thermodynamics of biomolecular systems"
Interface Focus 12:20220013 2022. Full text   PDF.   Invited contribution to the Theme Issue on Time Keeping and Decision Making in Living Cells.

J Gunawardena
"Learning outside the brain: integrating cognitive science and systems biology"
Proc IEEE 110:590-612 2022. Full text   PDF.   Invited contribution to the Special Issue on Systems and Synthetic Biology.
press attention — Phys.Org (Ingrid Fadelli).

2021

J W Biddle, R Martinez-Corral, F Wong, J Gunawardena
"Allosteric conformational ensembles have unlimited capacity for integrating information"
eLife 10:e65498 2021. Full text   PDF   earlier version on bioRxiv

S J Gershman, P E M Balbi, C R Gallistel, J Gunawardena
"Reconsidering the evidence for learning in single cells"
eLife 10:e61907 2021. Full text   PDF.
press attention — The Scientist (Catherine Offord)    Unexplainable podcast.

2020

F Wong, J Gunawardena
"Gene regulation in and out of equilibrium"
Annu Rev Biophys 49:199-226 2020. e-print

K-M Nam, B M Gyori, S V Amethyst, D J Bates, J Gunawardena
"Robustness and parameter geography in post-translational modification systems"
PLoS Comput Biol 16:e1007573 2020.    doi:10.1371/journal.pcbi.1007573    PDF

J W Biddle, J Gunawardena
"Reversal symmetries for cyclic paths away from thermodynamic equilibrium"
Phys Rev E 101:062125 2020. PDF+SI

2019

J P Dexter*, S Prabakaran*, J Gunawardena "A complex hierarchy of avoidance behaviours in a single-cell eukaryote"
Curr Biol 29:4323-9 2019.   full text   PDF+SI   minor correction   Wallace Marshall's commentary     H1Connect
press attention —
HMS news   The Scientist (Ruth Williams)   ScienceNews   ScienceAlert    SciTechDaily   ZME Science  Live Science  National Geographic (Russian)  Batrachospermum Magazine (Russian)   Numerama (French)   Technologie Média (French)   WDR5 Quarks (German radio broadcast 10 Dec 2019, segment 6-12mins)   Swarajya (Indian, in English)   Parsing Science   Scientific American

A Barabanschikov, J Gunawardena,
"Monostationarity and multistationarity in tree networks of Goldbeter-Koshland loops"
Bull Math Biol 81:2463-509 2019. PDF

J Park, J Estrada, G Johnson, C Ricci-Tam, M Bragdon, Y Shulgina, A Cha, J Gunawardena, A H DePace
"Dissecting the sharp response of a canonical developmental enhancer reveals multiple sources of cooperativity"
eLife 8:e41266 2019. Full text   PDF

J W Biddle, M Nguyen, J Gunawardena
"Negative reciprocity, not ordered assembly, underlies the interaction of Sox2 and Oct4 on DNA"
eLife 8:e41017 2019. Full text   PDF.

2018

D Agarwal, R T Fellers, B P Early, D Lu, C J DeHart, P D Compton, P M Thomas, G Lahav, N L Kelleher, J Gunawardena
"Analysing protein post-translational modform regions by linear programming",
bioRxiv doi:10.1101/456640, 2018.

C J DeHart, L Fornelli, L C Anderson, R T Fellers, D Lu, C L Hendrickson, G Lahav, J Gunawardena, N L Kelleher
"A multi-modal proteomics strategy for characterizing posttranslational modifications of tumor suppressor p53 reveals many sites but few modified forms",
bioRxiv doi:10.1101/455527, 2018.

J P Dexter, P S Ward, T Dasgupta, A M Hosios, J Gunawardena, M G Vander Heiden
"Lack of evidence for substrate channeling or flux between wild-type and mutant isocitrate dehydrogenase to produce 2-hydroxyglutarate"
J Biol Chem 293:20051-61 2018. PDF    Supplementary Figure
this paper was selected for a special virtual issue on cancer biology

F Wong, A Dutta, D Chowdhury, J Gunawardena
"Structural conditions on complex networks for the Michaelis-Menten input-output response"
PNAS 115:9738-43 2018.   doi:10.1073/pnas.1808053115   PDF   SI

J P Dexter, J W Biddle, J Gunawardena
"Model discrimination for Ca2+-dependent regulation of myosin light chain kinase in smooth muscle contraction"
FEBS Letters 592:2811-21 2018.   doi:10.1002/1873-3468.13207   PDF

F Wong, A Amir, J Gunawardena
"Energy-speed-accuracy relation in complex networks for biological discrimination"
Phys Rev E 98:012420 2018. PDF   Supplementary Information   arXiv:1710.06038[q-bio.MN]

P D Compton, N L Kelleher, J Gunawardena
"Estimating the distribution of protein post-translational modification states by mass-spectrometry"
J Prot Res 17:2727-34 2018.   doi:10.1021/acs.jproteome.8b00150   PDF   Supplementary Information

R Aebersold, J N Agar, I J Amster, M S Baker, C R Bertozzi, E S Boja, C E Costello, B F Cravatt, C Fenselau, B A Garcia, Y Ge, J Gunawardena, R C Hendrickson, P J Hergenrother, C G Huber, A R Ivanov, O N Jensen, M C Jewett, N L Kelleher, L L Kiessling, N J Krogan, M R Larsen, J A Loo, R R Ogorzalek Loo, E Lundberg, M J MacCoss, P Mallick, V K Mootha, M Mrksich, T W Muir, S M Patrie, J J Pesavento, S J Pitteri, H Rodriguez, A Saghatelian, W Sandoval, H Schlüter, S Sechi, S A Slavoff, L M Smith, M P Snyder, P M Thomas, M Uhlén, J E Van Eyk, M Vidal, D R Walt, F M White, E R Williams, T Wohlschlager, V H Wysocki, N A Yates, N L Young, B Zhang
"How many human proteoforms are there?"
Nat Chem Biol 14:206-214 2018. PDF

2017

T Ahsendorf, F-J Müller, V Topkar, J Gunawardena, R Eils
"Transcription factors, coregulators, and epigenetic marks are linearly correlated and highly redundant"
PLoS ONE 12:e0186324 2017. Full text   PDF.

M M Slabodnick, J G Ruby, S B Reiff, E C Swart, S Gosai, S Prabakaran, E Witkowska, G E Larue, S Fisher, R M Freeman Jr, J Gunawardena, W Chu, N A Stover, B D Gregory, M Nowacki, J Derisi, S W Roy, W F Marshall, P Sood
"The macronuclear genome of Stentor coeruleus reveals tiny introns in a giant cell"
Curr Biol 27:569-75 2017.
PDF.

H Qi, C Despres, S Prabakaran, F X Cantrelle, B Chambraud, J Gunawardena, G Lippens, C Smet-Nocca, I Landrieu
"The study of posttranslational modifications of Tau protein by nuclear magnetic resonance spectroscopy: phosphorylation of Tau protein by ERK2 recombinant kinase and rat brain extract, and acetylation by recombinant CREB-binding protein"
Methods Mol Biol 1253:179-213 2017.
PDF.

2016

J Estrada, F Wong, A DePace, J Gunawardena
"Information integration and energy expenditure in gene regulation"
Cell 166:234-44 2016.
Full text   PDF   Supplemental Information.
For his contribution to this paper, Javier Estrada was awarded the Young Investigator Award at the 2016 International Conference on Systems Biology in Barcelona.

J Estrada*, N Andrew*, D Gibson, F Chang, F Gnad, J Gunawardena
"Cellular interrogation: exploiting cell-to-cell variability to discriminate regulatory mechanisms in oscillatory signalling"
PLoS Comput Biol 12:e1004995 2016. Full text   PDF.

H Qi, S Prabakaran, F-C Cantrelle, B Chambraud, J Gunawardena, G Lippens, I Landrieu
"Characterization of neuronal tau protein as a target of extracellular-signal-regulated kinase"
J Biol Chem 291:7742-53 2016.
PDF.

M Malleshaiah, M Padi, P Rué, J Quackenbush, A Martinez-Arias, J Gunawardena
"Nac1 coordinates a sub-network of pluripotency factors to regulate embryonic stem cell differentiation"
Cell Reports 14:1181-94 2016. Full text   PDF.

2015

S L Field*, T Dasgupta*, H Bulsara, R S Savage, J Adebayo, M Cummings, J Gunawardena, N M Orsi
"Bayesian modelling suggests that IL-12 (p40), IL-13 and MCP-1 drive murine inflammatory networks in vivo"
BMC Syst Biol 9:76 2015. Full text   PDF   Amalgamated Additional Files.

J P Dexter*, T Dasgupta*, J Gunawardena
"Invariants reveal multiple forms of robustness in bifunctional enzyme systems"
Integr Biol 7:883-94 2015.   PDF   Cover  Supplementary Mathematica notebook.

J P Dexter, P Xu, J Gunawardena, M N McClean
"Robust network structure of the Sln1-Ypd1-Ssk1 three-component phospho-relay prevents unintended activation of the HOG MAPK pathway in Saccharomyces cerevisiae"
BMC Syst Biol 9:17 2015. Full text   PDF   Supplementary Information.

2014

T Ahsendorf*, F Wong*, R Eils, J Gunawardena
"A framework for modelling gene regulation which accommodates non-equilibrium mechanisms"
BMC Biol 12:102 2014. Full text   PDF   Additional File
BMC Biology commentary.

S Prabakaran*, M Hemberg*, R Chauhan*, D Winter, R Tweedie-Cullen, C Dittrich, E Hong, J Gunawardena, H Steen, G Kreiman, J A Steen
"Quantitative profiling of peptides from RNAs classified as non-coding"
Nat Commun doi:10.1038/ncomms6429 2014. Preview   PDF  Supplementary Information.

S Prabakaran, J Gunawardena, E Sontag
"Paradoxical results in perturbation-based biological network reconstruction"
Biophys J 106:2720-8 2014. PDF   Supplementary Information.

J Gunawardena
"Models in biology: 'accurate descriptions of our pathetic thinking'".  Invited review.
BMC Biol 12:29 2014. Full text   PDF
Blog       H1Connect   Nature comment.

T Dasgupta*, D H Croll*, J A Owen*, M G Vander Heiden, J W Locasale, U Alon, L C Cantley, J Gunawardena
"A fundamental trade-off in covalent switching and its circumvention by enzyme bifunctionality in glucose homeostasis"
J Biol Chem 289:13010-25 2014. PDF.

J Gunawardena
"Time-scale separation: Michaelis and Menten's old idea, still bearing fruit".   Invited review.
FEBS J 281:473-88 2014. PDF.

2013

I Mirzaev, J Gunawardena
"Laplacian dynamics on general graphs"
Bull Math Biol 75:2118-49 2013. PDF.

N Hao, B A Budnik, J Gunawardena, E K O'Shea
"Tunable signal processing through modular control of transcription factor translocation"
Science 339:460-4 2013.   PDF
Editor's choice in Sci Signal and research highlight in Nat Rev Genet.

J P Dexter, J Gunawardena
"Dimerization and bifunctionality confer robustness to the isocitrate dehydrogenase regulatory system in Escherichia coli"
J Biol Chem 288:5770-8 2013. PDF. Supplementary Mathematica notebook and accompanying Mathematica package.

2012

Y Xu, J Gunawardena
"Realistic enzymology for post-translational modification: zero-order ultrasensitivity revisited"
J Theor Biol 311:139-52 2012. PDF.

R L Karp*, M Peréz Millán*, T Dasgupta*, A Dickenstein, J Gunawardena
"Complex-linear invariants of biochemical reaction networks"
J Theor Biol 311:130-8 2012. PDF   Supplementary information.

S Prabakaran, G Lippens, H Steen, J Gunawardena
"Post-translational modification: nature's escape from genetic imprisonment and the basis for dynamic information encoding"
WIREs Systems Biology and Medicine 4:565-83 2012. PDF.

J Gunawardena
"A linear framework for time-scale separation in nonlinear biochemical systems"
PLoS ONE 7:e36321 2012
The published version of this paper on the PLoS ONE site had typesetting and figure reference errors that were introduced by PLoS ONE during publication. These errors have finally been corrected in the online version and in the PDF.   Supplementary information.
Earlier version on arXiv.

F Gnad, J. Estrada, J Gunawardena
"Proteus: a web-based, context-specific modelling tool"
Bioinformatics 28:1284-6 2012. Full text   PDF.

2011

S L Harvey, G Enciso, N E Dephoure, S P Gygi, J Gunawardena, D R Kellogg
"A phosphatase threshold sets the level of Cdk1 activity in early mitosis in budding yeast"
Mol Biol Cell 22:3595-608 2011. Full text   PDF.

S Prabakaran, R A Everley, I Landrieu, J-M Wieruszeski, G Lippens, H Steen, J Gunawardena
"Comparative analysis of Erk phosphorylation suggests a mixed strategy for measuring phospho-form distributions"
Mol Sys Biol 7:482 2011. Full text   PDF   Supplementary Information
This was a featured paper in Molecular Systems Biology.

F Gnad, J Gunawardena, M Mann
"PHOSIDA 2011: the posttranslational modification database"
Nucleic Acids Res 39:253-60 2011. PDF
This was a featured article in Nucleic Acids Research.

2010

F Gnad, F Forner, D F Zielinska, E Birney, J Gunawardena, M Mann
"Evolutionary constraints of phosphorylation in eukaryotes, prokaryotes and mitochondria"
Mol Cell Proteomics, 9:2642-53 2010. PDF.

2009

M. Thomson, J Gunawardena
"The rational parameterisation theorem for multisite post-translational modification systems"
J Theor Biol 261:626-36 2009. PDF.

M Thomson, J Gunawardena
"Unlimited multistability in multisite phosphorylation systems"
Nature 460:274-7 2009. doi:10.1038/nature08102. PDF   SI   earlier version on arXiv.

A Mallavarapu, M Thomson, B Ullian, J Gunawardena
"Programming with models: modularity and abstraction provide powerful capabilities for systems biology"
J Roy Soc Interface 6:257-70 2009. full text   PDF   earlier version on arXiv.

2008 and earlier

A K Manrai, J Gunawardena
"The geometry of multisite phosphorylation"
Biophys J 95:5533-43 2008. PDF Supplementary Mathematica notebook.

N Andrew, D Craig, J P Urbanski, J Gunawardena, T Thorsen
"Microfluidic temporal cell stimulation"
Proceedings of the 12th International Conference on Miniaturized Systems for the Life Sciences, μTAS 2008. PDF.

J Gunawardena
"Signals and systems: towards a systems biology of signal transduction"
Invited paper for the Special Issue on Computational Systems Biology
Proc IEEE 96:1386-97 2008. PDF.

J Gunawardena
"Distributivity and processivity in multisite phosphorylation can be distinguished through steady-state invariants"
Biophys J 93:3828-34 2007. PDF.

J Gunawardena
"Multisite protein phosphorylation makes a good threshold but can be a poor switch"
PNAS 102:14617-22 2005. PDF.

Essays

M. Malleshaiah J Gunawardena
"Cybernetics redux: an outside-in strategy for unraveling cellular function"
Dev Cell 36:2-4 2016. PDF   H1Connect
Preview of Mitchell, Wei & Lim, "Oscillatory stress stimulation uncovers Achilles' heel of the yeast MAPK signaling network", Science350:1379-83 2015

J Gunawardena
"Beware the tail that wags the dog: informal and formal models in biology".   Invited perspective.
Mol Biol Cell 25:3441-4 2014. PDF.

J Gunawardena
"Biology is more theoretical than physics".   Invited perspective.
Mol Biol Cell 24:1827-9 2013. PDF.

J Gunawardena
"Silicon dreams of cells into symbols"
Nat Biotech 30:838-40 2012. PDF
News & Views on Karr et al, "A whole-cell computational model predicts phenotype from genotype", Cell 150:389-401 2012.

J Gunawardena
"Some lessons about models from Michaelis and Menten".   Invited perspective.
Mol Biol Cell 23:517-9 2012. PDF.

J Gunawardena
"Biological systems theory"
Science 328:581-2 2010. PDF
News & Views on G Shinar, M Feinberg, "Structural sources of robustness in biochemical reaction networks", Science 327:1389-91 2010.

Book chapters

G Lippens, J Gunawardena, I Landrieu, C Smet-Nocca, S Prabakaran, B Parent, A Leroy, I Huvent
"Post-translational modifications of the proteome: the example of tau in the neuron and the brain"
In J Loscalzo, A-L Barabási, E K Silverman (editors), Network Medicine. Complex Systems in Human Disease and Therapeutics, Harvard University Press, Cambridge MA USA, 2017. HUP.

J Gunawardena
"Models in systems biology: minimalist versus exhaustive strategies"
In B Engquist (editor), Encyclopedia of Applied and Computational Methods, Springer-Verlag, Berlin, Germany, 2015. Springer.

J Gunawardena
"Modeling of interaction networks in the cell: theory and mathematical methods"
In H Weinstein (editor), Simulation and Modeling, pages 243-67. Volume 9 of E Egelman (editor), Comprehensive Biophysics, Academic Press, Oxford. 2012. Elsevier.

J Gunawardena "Models in systems biology: the parameter problem and the meanings of robustness"
In H. Lodhi, S. Muggleton (editors), Elements of Computational Systems Biology, John Wiley and Sons, New York, 2010. PDF.

Theses

S Haque
"Graph-theoretic approaches to biochemical reaction networks"
Harvard University PhD Thesis 2024.

K-M Nam
"Algebraic approaches to molecular information processing"
Harvard University PhD Thesis 2021.

J Dexter
"Quantitative approaches to cellular information processing and metabolic regulation"
Harvard University PhD Thesis 2018.

M Lipson
"Differential and graphical approaches to multistability for chemical reaction networks"
Harvard University Senior Honours Thesis, Hoopes Prize, 2007. q-bio.MN:0709.0125.

Unpublished notes

Yen-Der Li
"Cell density affects Erk signaling heterogeneity"
Summer research presentation, 2013. PDF.

J Gunawardena
"Chemical Reaction Network Theory for in-silico biologists"
Preprint, 2003. PDF.

J Gunawardena
"Notes on Metabolic Control Analysis"
Preprint, 2002. PDF.

Posters

C J DeHart, L Fornelli, L C Anderson, J W Sikora, D Agarwal, D Lu, P D Compton, C L Hendrickson, P M Thomas, G Lahav, J Gunawardena, N L Kelleher
"A multi-modal proteomics strategy for characterizing in vitro p53 modforms"
American Society for Mass Spectrometry (ASMS) Annual Conference, Indianopolis, Indiana, June 2017. Poster.

C J DeHart, L Fornelli, O S Skinner, L C Anderson, P D Compton, C L Hendrickson, P M Thomas, G Lahav, J Gunawardena, N L Kelleher
"Mapping p53 proteoforms by native and denaturing top-down mass spectrometry"
American Society for Mass Spectrometry (ASMS) Annual Conference, San Antonio, Texas, June 2016. Poster.

M Malleshaiah, M Padi, P Rue, J Quackenbush, A Martinez-Arias, J Gunawardena
"Nac1 coordinates a sub-network of pluripotency factors to regulate embryonic stem cell differentiation"
International Society for Stem Cell Research Conference, San Francisco, June 2016. Poster.

Gunawardena Lab
"Cellular information processing", Harvard Undergraduate Life Sciences Research Fair, 2016. Poster.

M Cummings, T Dasgupta, J Adebayo, G Mappa, R Hutson, N Wilkinson, J Gunawardena, N M Orsi
"Cytokine networks in endometrial carcinogenesis"
UK Pathological Society, Dublin, Ireland, June 2015. Poster
Awarded 2nd prize by the UK Pathological Society.

 

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