BEGIN:VCALENDAR VERSION:2.0 PRODID:researchseminars.org CALSCALE:GREGORIAN X-WR-CALNAME:researchseminars.org BEGIN:VEVENT SUMMARY:Philip Benfey (Duke University & HHMI) DTSTART:20210927T151000Z DTEND:20210927T155000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/1 DESCRIPTION:Title: Modeling for a multicellular organism\nby Philip Benfey (D uke University & HHMI) as part of BIRS workshop: Connecting Network Struct ure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nTo understand the progression from stem cells to differentiated tissues we are exploiting th e simplifying aspects of root development. We have developed new experimen tal\, analytical and imaging methods to identify networks functioning with in different cell types and developmental stages of the root. We are parti cularly interested in a subnetwork that regulates a key asymmetric cell di vision of a stem cell. To quantify dynamic aspects of these networks\, we are employing light-sheet and confocal microscopy to image accumulation of their different components. Analysis of the resulting time series indicat ed that our previous model was not predictive of actual behavior and a new model was needed. How roots explore their soil environment determines the ir ability to acquire nutrients and water. We have identified the molecula r mechanism underlying the circular movement of the root tip known as circ umnutation. In collaboration with Dan Goldman (Physics\, Georgia Tech) and Elliot Hawkes (Engineering\, UC Santa Barbara) we have shown that circumn utation facilitates the root’s ability to avoid obstacles. We are now us ing discrete element modeling to develop simulations of circumnutation tha t predict actual root behavior.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/1/ END:VEVENT BEGIN:VEVENT SUMMARY:Denis Thieffry (Ecole Normale Supérieure) DTSTART:20210927T161000Z DTEND:20210927T165000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/2 DESCRIPTION:Title: Computational methods for the verification of large Boolean mo dels\nby Denis Thieffry (Ecole Normale Supérieure) as part of BIRS wo rkshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\ n\n\nAbstract\nAt the crossroad between biology and computational modellin g\, systems biology has proved to be an important ally to gain a mechanist ic understanding of biological systems. But as our knowledge accumulates\, the size and complexity of mathematical models increase\, calling for the development of efficient dynamical analysis methods. In this respect\, we use generic computational techniques to assess the behaviour of complex c ellular network models. A first approach\, called "model verification"\, e nables the formalisation and the automated verification of validation crit eria for whole models or selected subparts\, thereby greatly facilitating model development. A second approach\, called "value propagation"\, enable s the computation of the impact of specific environmental or genetic condi tions on model dynamics. Both methods were applied to the analysis of a co mphrehensive Boolean model for T cell activation to compare the impacts of two different checkpoint inhibitors currently used in immunotherapies. Th ese methods and models are available in the CoLoMoTo Docker image\, which provides a reproducible modelling environment\, and in an interactive comp anion notebook.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/2/ END:VEVENT BEGIN:VEVENT SUMMARY:Jianhua Xing (University of Pittsburg) DTSTART:20210927T171000Z DTEND:20210927T175000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/3 DESCRIPTION:Title: How does a cell change its phenotype?\nby Jianhua Xing (Un iversity of Pittsburg) as part of BIRS workshop: Connecting Network Struct ure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nMammalian cells as sume different phenotypes that can have drastically different morphology a nd gene expression patterns\, and can change between distinct phenotypes w hen subject to specific stimulation and microenvironment. Recent advances in snapshot single cell techniques further catalyze an emerging field of s tudying cell phenotypic transition (CPT) regulation and dynamics as one of the most exciting frontiers of cell and developmental biology. \n\nMathem atically a stable cell phenotype corresponds to a stable attractor in a mu lti-dimensional state space. How does a cell destabilize its original phen otype and relax to a new attractor? Is it a critical state transition such as pitchfork bifurcation or saddle-node bifurcation? Can we actually foll ow the transition dynamics experimentally? Here I will share our recent ef forts on addressing this fundamental question through live cell imaging/si ngle cell genomics studies and analyzing the data in the context of dynami cal systems theory\, esp. the transition path theory.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/3/ END:VEVENT BEGIN:VEVENT SUMMARY:Jay Dunlap (Dartmouth) DTSTART:20210928T151000Z DTEND:20210928T155000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/4 DESCRIPTION:Title: Context for Modeling Circadian Output in Neurospora\nby Ja y Dunlap (Dartmouth) as part of BIRS workshop: Connecting Network Structur e to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nWe seek to model lif e in the 4th dimension\, through time\, and most specifically through the course of a circadian day. All circadian clocks are based on negative fee dback loops that close within the confines of single cells. Evolution has delivered three distinct regulatory architectures for such clocks\, from cyanobacteria\, from plants\, and from fungi and animals. In the latter o f these\, heterodimeric transcription factors (WC-1/WC-2 in Neurospora\, B MAL1/CLOCK in mammals) drive expression of genes encoding “Negative Arm ” proteins which\, in complex with other proteins\, bring kinases to the heterodimer leading to its inactivation. Gradual phosphorylation of the Negative Arm protein(s) leads to their inactivation\; the heterodimer rest arts the cycle. Models differ in the role(s) of phosphorylation and prote in turnover\, and many details are lacking.\n\nCore circadian oscillators with nearly identical regulatory architecture operate in most cells of mam mals and in Neurospora\, but the cell-type-specific biology for which thes e clocks are used is dictated by the spectrum of outputs. In fungi and an imals\, the principal initial means of output is through clock control of transcription. In Neurospora the oscillator results in rhythmic WC-1/WC-2 activity that in turn drives rhythms in expression of about 40% of the ge nome\; in broad terms\, daytime metabolic potential favors catabolism\, en ergy production\, and precursor assembly whereas night activities favor bi osynthesis of cellular components and growth. Over 50 transcription facto rs have been epitope tagged and used for ChIP (chromatin immunoprecipitati on) at multiple times after exposure to light or across the circadian day. These data are being used to assemble the hierarchical transcriptional network governing light and clock regulation. WC-1/WC-2 sits on top of th e networks governing both light and clock regulation\, controlling light- and clock-regulated transcription factors (TFs) that act as second order r egulators\, transducing regulation from light-responses\, or from the core circadian oscillator\, to banks of output clock-controlled genes (ccgs) i ncluding other TFs. \n\nUnderstanding the basic cell and molecular biology of Neurospora provides the foundational context in which productive model ing of circadian output can take place.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/4/ END:VEVENT BEGIN:VEVENT SUMMARY:Jennifer Hurley (Rensselaer Polytechnic Institute) DTSTART:20210928T161000Z DTEND:20210928T165000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/5 DESCRIPTION:Title: Tracking Circadian Post-Transcriptional Regulation to Demonstr ate Clock Control of Metabolism and the Immune Response\nby Jennifer H urley (Rensselaer Polytechnic Institute) as part of BIRS workshop: Connect ing Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\n Circadian rhythms are highly conserved\, roughly 24-hour\, physiological c ycles that\, through the ideal programming of behavior\, are believed to e nhance fitness by ensuring organismal functions are optimally synchronized with the appropriate phase of the circadian day. Disruption of proper cir cadian timing negatively impacts the human long-term medical outlook and o rganismal fitness. Circadian rhythms are controlled via a highly regulated transcription-translation based negative feedback loop\, or clock. The cu rrent paradigm for clock regulation over cellular physiology is that trans criptional activity from the positive arm of the transcription– translat ion negative feedback loop drives the expression of a host of gene promote rs that modulate organismal behavior. However\, mounting evidence suggests that circadian regulation is imparted on cellular physiology beyond the l evel of transcription. We have analyzed the clock output on many levels in Neurospora crassa and murine macrophages over circadian time\, demonstrat ing evidence for extensive post-transcriptional regulation of metabolism a nd the immune response\, both in vitro and in vivo. The next goal of this work is to model the measured output to predict functional results in a mo re directed manner.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/5/ END:VEVENT BEGIN:VEVENT SUMMARY:Jan Skotheim (Stanford University) DTSTART:20210929T151000Z DTEND:20210929T155000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/7 DESCRIPTION:Title: Towards a reduced view of biosynthesis and its geometric limit s: A case study of budding yeast transcription\nby Jan Skotheim (Stanf ord University) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nA defining feature of cel l growth is that protein and mRNA amounts scale with cell size so that con centrations remain approximately constant\, thereby ensuring similar react ion rates and efficient biosynthesis. A key component of this biosynthetic scaling is the scaling of mRNA amounts with cell size\, which occurs even among cells with the same DNA template copy number. Here\, we identify RN A polymerase II as a major limiting factor increasing transcription with c ell size. Other components of the transcriptional machinery are only minim ally limiting and the chromatin environment is largely invariant with size . However\, RNA polymerase II activity does not increase in direct proport ion to cell size\, inconsistent with previously proposed DNA-titration mod els. Instead\, our data support a dynamic equilibrium model where the rate of polymerase loading is proportional to the unengaged nuclear polymerase concentration. This sublinear transcriptional increase is then balanced b y a compensatory increase in mRNA stability as cells get larger. Taken tog ether\, our results show how limiting RNA polymerase II and feedback on mR NA stability work in concert to ensure the precise scaling of mRNA amounts across the physiological cell size range.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/7/ END:VEVENT BEGIN:VEVENT SUMMARY:John Tyson (Virginia Polytechnic Institute & State University) DTSTART:20210929T161000Z DTEND:20210929T165000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/8 DESCRIPTION:Title: Information Processing in Living Organisms: Network Dynamics t o Cell Physiology\nby John Tyson (Virginia Polytechnic Institute & Sta te University) as part of BIRS workshop: Connecting Network Structure to i ts Dynamics: Fantasy or Reality?\n\n\nAbstract\nIn his new book 'What Is L ife\,' Paul Nurse describes five 'great ideas' in biology\; the fifth is ' Life is Information'. In this lecture I will discuss some of the molecular mechanisms that process information in living cells\, with focus on regul ation of the cell division cycle. I will show how dynamical systems theory \, especially bifurcation diagrams\, can be used to understand the biochem ical networks that control cell growth and division. I will present a 'dyn amical paradigm for molecular systems biology' and what it implies for fut ure research and education in the field.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/8/ END:VEVENT BEGIN:VEVENT SUMMARY:Bree Cummins (Montana State University) DTSTART:20210929T171000Z DTEND:20210929T175000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/9 DESCRIPTION:Title: Discovering Genetic Network Interactions Through Iterative Hyp othesis Reduction\nby Bree Cummins (Montana State University) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nTime series transcriptomics and proteomics data t ypically record expression levels of thousands of gene products. Discoveri ng the important elements of these data for a specific experimental questi on is daunting given the combinatorial nature of the problem. Myself and m y collaborators take the approach that a sequential set of software tools can reduce hypothesis space tremendously. I will discuss the performance o f a set of tools that aims to discover “core oscillators” or clock-lik e genetic networks that control highly stereotyped cellular phenomena such as the cell cycle and the circadian rhythm. We first reduce the space of potential gene products from thousands to tens\, then the space of possibl e interactions from hundreds to tens\, and then we refine this collection of interactions by considering global network dynamics and reducing networ k space from a factorial down to tens or hundreds again. The first two ste ps are exhaustive but the last depends on local sampling around an initial guess. We show that this set of software tools is in principle capable of finding core oscillator interactions from high-dimensional data\, althoug h sometimes the results are surprising and hard to quantify.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/9/ END:VEVENT BEGIN:VEVENT SUMMARY:Enoch Yeung (Santa Barbara) DTSTART:20210930T151000Z DTEND:20210930T155000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/10 DESCRIPTION:Title: Data-Driven Mathematical Approaches to Biological Network Sen sor Placement & Design\nby Enoch Yeung (Santa Barbara) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Realit y?\n\n\nAbstract\nNatural biological networks remain a vastly untapped res ervoir of biological control mechanisms and biochemical sensors. Rather than relying on literature surveys to mine new biological function\, I int roduce a data-driven approach to discovering biological sensors from kinet ic transcriptomics data. The approach couples operator-theoretic methods and spectral analysis with classical measures of observability\, but requ ires adaptation when treating experimental biological data. I then show h ow a broader class of these data-driven mathematical methods can be used t o inform design of novel biological networks\, to approximate arbitrary us er-defined specifications on desired network behavior. I will present bo th theoretical motivation and experimental validation of most of these ide as.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/10/ END:VEVENT BEGIN:VEVENT SUMMARY:Reka Albert (Pennsylvania State University) DTSTART:20210930T161000Z DTEND:20210930T165000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/11 DESCRIPTION:Title: Connecting network structure and dynamics through stable moti fs\nby Reka Albert (Pennsylvania State University) as part of BIRS wor kshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n \n\nAbstract\nMy group is using network science and discrete dynamic model ing to understand the emergent properties of biological systems at multipl e levels of organization. As an example\, we think of cell types as attrac tors of a dynamic system of interacting (macro)molecules\, and we aim to f ind the network patterns that determine these attractors. We use the accu mulated knowledge gained from specific models to draw general conclusions that connect a network's structure and dynamics. An example of such a gene ral connection is our identification of stable motifs\, which are self-sus taining cyclic structures that determine trap subspaces of the system’s state space. If the system's trajectory enters such a subspace\, it cannot exit unless specific control is exerted on the nodes of the respective st able motif. We have shown that control of stable motifs can guide the sys tem into a desired attractor. We implemented the methodologies of stable m otif based attractor identification and control in Boolean systems in a ne w software library called pystablemotifs. We have translated the concept o f stable motif to a broad class of continuous (ODE-based) models. I propos e that the concept of stable motifs could be used to guide the mapping be tween network structure and dynamics.\n\nRepresentative references:\n1. JC Rozum\, R Albert\, Identifying (un)controllable dynamical behavior in com plex networks\, PLOS Computational Biology 14\, e1006630 (2018).\n2. JC Ro zum\, JGT Zanudo\, X Gan\, D Deritei\, R Albert\, Parity and time reversal elucidate both decision-making in empirical models and attractor scaling in critical Boolean networks\, Science Advances 7 (29)\, eabf8124 (2021).\ n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/11/ END:VEVENT BEGIN:VEVENT SUMMARY:Alan Veliz-Cuba (University of Dayton) DTSTART:20210930T171000Z DTEND:20210930T175000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/12 DESCRIPTION:Title: Discrete and algebraic approaches to study the relationship b etween structure and dynamics\nby Alan Veliz-Cuba (University of Dayto n) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nIn this talk\, we will see frameworks to study the problem of predicting dynamics from network structure and the problem of inferring network structure from dynamics. To infer dynamical properties of a system from its structure\, we use the topological feature s of the network such as the way subnetworks are connected\, and then use a version of the inclusion-exclusion principle on dynamics. To infer the s tructure of a network from its dynamics\, we encode all possible networks that fit the given dynamics as an ideal of polynomials and then use tools from algebraic geometry to find the most likely networks.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/12/ END:VEVENT BEGIN:VEVENT SUMMARY:Michael Savageau (University of California\, Davis) DTSTART:20211001T151000Z DTEND:20211001T155000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/13 DESCRIPTION:Title: Circumventing the Parameter Values Bottleneck: Addressing the Challenge by Development of Phenotype-Centric Modeling Strategies\nby Michael Savageau (University of California\, Davis) as part of BIRS works hop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n \nAbstract\nMy research in Biochemical Systems Theory in collaboration wit h colleagues has shown that the architecture of mechanistic models can pre dict numerous properties within and among biochemical phenotypes without k nowledge of the underlying biochemical kinetic parameters. In the past de cade\, this research led to the development of a novel phenotype-centric m odeling strategy with several advantages beyond those of the conventional simulation-centric approach. Here I report on work done in collaboration with Miguel Valderrama-Gómez aimed at extending the phenotype-centric app roach to address one of the most fundamental problems in population geneti cs and evolution: predicting the distribution of phenotype diversity gene rated by mutation and made available for innovation by selection. I show that minimal knowledge of the molecular system allows prediction of phenot ype-specific mutation rate constants and equilibrium distributions of phen otype diversity in populations undergoing steady-state exponential growth. As a proof-of-principle\, I provide a case study involving a small molec ular system\, a primordial circadian clock\, and suggest experimental appr oaches for testing the theory.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/13/ END:VEVENT BEGIN:VEVENT SUMMARY:William Cannon (Pacific Northwest National Lab and UC Riverside) DTSTART:20211001T161000Z DTEND:20211001T165000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/14 DESCRIPTION:Title: Learning Regulation from the Ground Up: Combining Natural Sel ection\, Thermodynamics and Data\nby William Cannon (Pacific Northwest National Lab and UC Riverside) as part of BIRS workshop: Connecting Netwo rk Structure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nModeling cells has many challenges: data is sparse\, noisy\, and measured over a po pulation instead of over individuals or cell compartments. Moreover\, para meters needed to build kinetic and thermodynamic models are extremely labo r intensive to obtain. This makes building a physics-based model a very ha rd problem. We address this challenge by taking advantage of the fact that natural selection selects for the most optimal individuals out of all sol utions. We formulate fitness from a thermodynamic perspective to obtain th e most likely model parameters\, and then use data to constrain the soluti on space. Rate parameters that are reasonable and statistically the most l ikely can be inferred in this way. Then we predict regulation of the cellu lar system using one of two approaches: Assuming that we have an optimal c ontrol problem and using control theory to infer regulation\, or widely sa mple the solution space for regulation using reinforcement learning. The r esult is a model with reasonable parameters and predicts regulation for ce ntral metabolism that agrees with the literature.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/14/ END:VEVENT BEGIN:VEVENT SUMMARY:Theodore Perkins (Ottawa Hospital Research Institute / University of Ottawa) DTSTART:20211001T171000Z DTEND:20211001T175000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/15 DESCRIPTION:Title: Absolute Quantification of Transcription Factors Reveals Prin ciples of Gene Regulation in Erythropoiesis\nby Theodore Perkins (Otta wa Hospital Research Institute / University of Ottawa) as part of BIRS wor kshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n \n\nAbstract\nDynamic cellular processes such as differentiation are drive n by changes in the abundances of transcription factors (TFs). However\, d espite years of studies\, our knowledge about the protein copy number of T Fs in the nucleus is limited. We developed a quantitative targeted mass sp ectrometry approach that allowed us to determine the absolute abundances o f 103 TFs and co-factors during the course of human erythropoiesis\, provi ding a dynamic and quantitative scale for TFs in the nucleus. Furthermore\ , we established the first gene regulatory network of erythropoietic cell fate commitment that integrates temporal protein stoichiometry data with m RNA measurements. The model revealed quantitative imbalances in TFs' cross -antagonistic relationships underlying lineage determination. We also made the surprising discovery that\, in the nucleus\, co-repressors are dramat ically more abundant than co-activators at the protein level\, but not at the RNA level\, with profound implications for understanding transcription al regulation.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/15/ END:VEVENT BEGIN:VEVENT SUMMARY:Marcio Gameiro (Rutgers University) DTSTART:20210928T171000Z DTEND:20210928T175000Z DTSTAMP:20260404T042105Z UID:BIRS-21w5005/16 DESCRIPTION:Title: Characterizing robust dynamics in regulatory networksCircadia n Post-Transcriptional Regulation to Demonstrate Clock Control of Metaboli sm and the Immune Response\nby Marcio Gameiro (Rutgers University) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fanta sy or Reality?\n\n\nAbstract\nWe present DSGRN (Dynamics Signatures Genera ted by Regulatory Networks) which is a mathematically rigorous and computa tionally efficient method to describe the global dynamics of a regulatory network over all parameter values. In this talk we will describe the detai ls of DSGRN and discuss how it can be used to rank all 3-node networks acc ording to how well they can act as a robust bi-stable switch.\n LOCATION:https://stable.researchseminars.org/talk/BIRS-21w5005/16/ END:VEVENT END:VCALENDAR