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:20260422T185720Z UID:BIRS-21w5005/1 DESCRIPTION:Title: Modeling for a multicellular organism\nby Philip Benfey (Duke Uni versity & HHMI) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nTo understand the progres sion from stem cells to differentiated tissues we are exploiting the simpl ifying aspects of root development. We have developed new experimental\, a nalytical and imaging methods to identify networks functioning within diff erent cell types and developmental stages of the root. We are particularly interested in a subnetwork that regulates a key asymmetric cell division of a stem cell. To quantify dynamic aspects of these networks\, we are emp loying light-sheet and confocal microscopy to image accumulation of their different components. Analysis of the resulting time series indicated that our previous model was not predictive of actual behavior and a new model was needed. How roots explore their soil environment determines their abil ity to acquire nutrients and water. We have identified the molecular mecha nism underlying the circular movement of the root tip known as circumnutat ion. In collaboration with Dan Goldman (Physics\, Georgia Tech) and Elliot Hawkes (Engineering\, UC Santa Barbara) we have shown that circumnutation facilitates the root’s ability to avoid obstacles. We are now using dis crete element modeling to develop simulations of circumnutation that predi ct actual root behavior.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/1/ END:VEVENT BEGIN:VEVENT SUMMARY:Denis Thieffry (Ecole Normale Supérieure) DTSTART:20210927T161000Z DTEND:20210927T165000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/2 DESCRIPTION:Title: Computational methods for the verification of large Boolean models\nby Denis Thieffry (Ecole Normale Supérieure) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAb stract\nAt the crossroad between biology and computational modelling\, sys tems biology has proved to be an important ally to gain a mechanistic unde rstanding of biological systems. But as our knowledge accumulates\, the si ze and complexity of mathematical models increase\, calling for the develo pment of efficient dynamical analysis methods. In this respect\, we use ge neric computational techniques to assess the behaviour of complex cellular network models. A first approach\, called "model verification"\, enables the formalisation and the automated verification of validation criteria fo r whole models or selected subparts\, thereby greatly facilitating model d evelopment. A second approach\, called "value propagation"\, enables the c omputation of the impact of specific environmental or genetic conditions o n model dynamics. Both methods were applied to the analysis of a comphrehe nsive Boolean model for T cell activation to compare the impacts of two di fferent checkpoint inhibitors currently used in immunotherapies. These met hods and models are available in the CoLoMoTo Docker image\, which provide s a reproducible modelling environment\, and in an interactive companion n otebook.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/2/ END:VEVENT BEGIN:VEVENT SUMMARY:Jianhua Xing (University of Pittsburg) DTSTART:20210927T171000Z DTEND:20210927T175000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/3 DESCRIPTION:Title: How does a cell change its phenotype?\nby Jianhua Xing (Universit y of Pittsburg) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nMammalian cells assume di fferent phenotypes that can have drastically different morphology and gene expression patterns\, and can change between distinct phenotypes when sub ject to specific stimulation and microenvironment. Recent advances in snap shot single cell techniques further catalyze an emerging field of studying cell phenotypic transition (CPT) regulation and dynamics as one of the mo st exciting frontiers of cell and developmental biology. \n\nMathematicall y a stable cell phenotype corresponds to a stable attractor in a multi-dim ensional state space. How does a cell destabilize its original phenotype a nd relax to a new attractor? Is it a critical state transition such as pit chfork bifurcation or saddle-node bifurcation? Can we actually follow the transition dynamics experimentally? Here I will share our recent efforts o n addressing this fundamental question through live cell imaging/single ce ll genomics studies and analyzing the data in the context of dynamical sys tems theory\, esp. the transition path theory.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/3/ END:VEVENT BEGIN:VEVENT SUMMARY:Jay Dunlap (Dartmouth) DTSTART:20210928T151000Z DTEND:20210928T155000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/4 DESCRIPTION:Title: Context for Modeling Circadian Output in Neurospora\nby Jay Dunla p (Dartmouth) as part of BIRS workshop: Connecting Network Structure to it s Dynamics: Fantasy or Reality?\n\n\nAbstract\nWe seek to model life in th e 4th dimension\, through time\, and most specifically through the course of a circadian day. All circadian clocks are based on negative feedback l oops that close within the confines of single cells. Evolution has delive red three distinct regulatory architectures for such clocks\, from cyanoba cteria\, from plants\, and from fungi and animals. In the latter of these \, heterodimeric transcription factors (WC-1/WC-2 in Neurospora\, BMAL1/CL OCK in mammals) drive expression of genes encoding “Negative Arm” prot eins which\, in complex with other proteins\, bring kinases to the heterod imer leading to its inactivation. Gradual phosphorylation of the Negative Arm protein(s) leads to their inactivation\; the heterodimer restarts the cycle. Models differ in the role(s) of phosphorylation and protein turno ver\, and many details are lacking.\n\nCore circadian oscillators with nea rly identical regulatory architecture operate in most cells of mammals and in Neurospora\, but the cell-type-specific biology for which these clocks are used is dictated by the spectrum of outputs. In fungi and animals\, the principal initial means of output is through clock control of transcri ption. In Neurospora the oscillator results in rhythmic WC-1/WC-2 activit y that in turn drives rhythms in expression of about 40% of the genome\; i n broad terms\, daytime metabolic potential favors catabolism\, energy pro duction\, and precursor assembly whereas night activities favor biosynthes is of cellular components and growth. Over 50 transcription factors have been epitope tagged and used for ChIP (chromatin immunoprecipitation) at m ultiple 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 the networ ks governing both light and clock regulation\, controlling light- and cloc k-regulated transcription factors (TFs) that act as second order regulator s\, transducing regulation from light-responses\, or from the core circadi an oscillator\, to banks of output clock-controlled genes (ccgs) including other TFs. \n\nUnderstanding the basic cell and molecular biology of Neur ospora provides the foundational context in which productive modeling of c ircadian output can take place.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/4/ END:VEVENT BEGIN:VEVENT SUMMARY:Jennifer Hurley (Rensselaer Polytechnic Institute) DTSTART:20210928T161000Z DTEND:20210928T165000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/5 DESCRIPTION:Title: Tracking Circadian Post-Transcriptional Regulation to Demonstrate Clo ck Control of Metabolism and the Immune Response\nby Jennifer Hurley ( Rensselaer Polytechnic Institute) as part of BIRS workshop: Connecting Net work Structure to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nCircadi an rhythms are highly conserved\, roughly 24-hour\, physiological cycles t hat\, through the ideal programming of behavior\, are believed to enhance fitness by ensuring organismal functions are optimally synchronized with t he appropriate phase of the circadian day. Disruption of proper circadian timing negatively impacts the human long-term medical outlook and organism al fitness. Circadian rhythms are controlled via a highly regulated transc ription-translation based negative feedback loop\, or clock. The current p aradigm for clock regulation over cellular physiology is that transcriptio nal activity from the positive arm of the transcription– translation neg ative feedback loop drives the expression of a host of gene promoters that modulate organismal behavior. However\, mounting evidence suggests that c ircadian regulation is imparted on cellular physiology beyond the level of transcription. We have analyzed the clock output on many levels in Neuros pora crassa and murine macrophages over circadian time\, demonstrating evi dence for extensive post-transcriptional regulation of metabolism and 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 more dire cted manner.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/5/ END:VEVENT BEGIN:VEVENT SUMMARY:Jan Skotheim (Stanford University) DTSTART:20210929T151000Z DTEND:20210929T155000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/7 DESCRIPTION:Title: Towards a reduced view of biosynthesis and its geometric limits: A ca se study of budding yeast transcription\nby Jan Skotheim (Stanford Uni versity) as part of BIRS workshop: Connecting Network Structure to its Dyn amics: Fantasy or Reality?\n\n\nAbstract\nA defining feature of cell growt h is that protein and mRNA amounts scale with cell size so that concentrat ions remain approximately constant\, thereby ensuring similar reaction rat es and efficient biosynthesis. A key component of this biosynthetic scalin g is the scaling of mRNA amounts with cell size\, which occurs even among cells with the same DNA template copy number. Here\, we identify RNA polym erase II as a major limiting factor increasing transcription with cell siz e. Other components of the transcriptional machinery are only minimally li miting and the chromatin environment is largely invariant with size. Howev er\, RNA polymerase II activity does not increase in direct proportion to cell size\, inconsistent with previously proposed DNA-titration models. In stead\, our data support a dynamic equilibrium model where the rate of pol ymerase loading is proportional to the unengaged nuclear polymerase concen tration. This sublinear transcriptional increase is then balanced by a com pensatory increase in mRNA stability as cells get larger. Taken together\, our results show how limiting RNA polymerase II and feedback on mRNA stab ility work in concert to ensure the precise scaling of mRNA amounts across the physiological cell size range.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/7/ END:VEVENT BEGIN:VEVENT SUMMARY:John Tyson (Virginia Polytechnic Institute & State University) DTSTART:20210929T161000Z DTEND:20210929T165000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/8 DESCRIPTION:Title: Information Processing in Living Organisms: Network Dynamics to Cell Physiology\nby John Tyson (Virginia Polytechnic Institute & State Univ ersity) as part of BIRS workshop: Connecting Network Structure to its Dyna mics: Fantasy or Reality?\n\n\nAbstract\nIn his new book 'What Is Life\,' Paul Nurse describes five 'great ideas' in biology\; the fifth is 'Life is Information'. In this lecture I will discuss some of the molecular mechan isms that process information in living cells\, with focus on regulation o f the cell division cycle. I will show how dynamical systems theory\, espe cially bifurcation diagrams\, can be used to understand the biochemical ne tworks that control cell growth and division. I will present a 'dynamical paradigm for molecular systems biology' and what it implies for future res earch and education in the field.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/8/ END:VEVENT BEGIN:VEVENT SUMMARY:Bree Cummins (Montana State University) DTSTART:20210929T171000Z DTEND:20210929T175000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/9 DESCRIPTION:Title: Discovering Genetic Network Interactions Through Iterative Hypothesis Reduction\nby Bree Cummins (Montana State University) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Realit y?\n\n\nAbstract\nTime series transcriptomics and proteomics data typicall y record expression levels of thousands of gene products. Discovering the important elements of these data for a specific experimental question is d aunting given the combinatorial nature of the problem. Myself and my colla borators take the approach that a sequential set of software tools can red uce hypothesis space tremendously. I will discuss the performance of a set of tools that aims to discover “core oscillators” or clock-like genet ic networks that control highly stereotyped cellular phenomena such as the cell cycle and the circadian rhythm. We first reduce the space of potenti al gene products from thousands to tens\, then the space of possible inter actions from hundreds to tens\, and then we refine this collection of inte ractions by considering global network dynamics and reducing network space from a factorial down to tens or hundreds again. The first two steps 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 findin g core oscillator interactions from high-dimensional data\, although somet imes the results are surprising and hard to quantify.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/9/ END:VEVENT BEGIN:VEVENT SUMMARY:Enoch Yeung (Santa Barbara) DTSTART:20210930T151000Z DTEND:20210930T155000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/10 DESCRIPTION:Title: Data-Driven Mathematical Approaches to Biological Network Sensor Pla cement & Design\nby Enoch Yeung (Santa Barbara) as part of BIRS worksh op: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\ nAbstract\nNatural biological networks remain a vastly untapped reservoir of biological control mechanisms and biochemical sensors. Rather than re lying on literature surveys to mine new biological function\, I introduce a data-driven approach to discovering biological sensors from kinetic tran scriptomics data. The approach couples operator-theoretic methods and sp ectral analysis with classical measures of observability\, but requires ad aptation when treating experimental biological data. I then show how a br oader class of these data-driven mathematical methods can be used to infor m design of novel biological networks\, to approximate arbitrary user-defi ned specifications on desired network behavior. I will present both theo retical motivation and experimental validation of most of these ideas.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/10/ END:VEVENT BEGIN:VEVENT SUMMARY:Reka Albert (Pennsylvania State University) DTSTART:20210930T161000Z DTEND:20210930T165000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/11 DESCRIPTION:Title: Connecting network structure and dynamics through stable motifs\ nby Reka Albert (Pennsylvania State University) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAbs tract\nMy group is using network science and discrete dynamic modeling to understand the emergent properties of biological systems at multiple level s of organization. As an example\, we think of cell types as attractors of a dynamic system of interacting (macro)molecules\, and we aim to find the network patterns that determine these attractors. We use the accumulated knowledge gained from specific models to draw general conclusions that co nnect a network's structure and dynamics. An example of such a general con nection is our identification of stable motifs\, which are self-sustaining cyclic structures that determine trap subspaces of the system’s state s pace. If the system's trajectory enters such a subspace\, it cannot exit u nless specific control is exerted on the nodes of the respective stable mo tif. We have shown that control of stable motifs can guide the system int o a desired attractor. We implemented the methodologies of stable motif ba sed attractor identification and control in Boolean systems in a new softw are library called pystablemotifs. We have translated the concept of stabl e motif to a broad class of continuous (ODE-based) models. I propose that the concept of stable motifs could be used to guide the mapping between n etwork structure and dynamics.\n\nRepresentative references:\n1. JC Rozum\ , R Albert\, Identifying (un)controllable dynamical behavior in complex ne tworks\, PLOS Computational Biology 14\, e1006630 (2018).\n2. JC Rozum\, J GT Zanudo\, X Gan\, D Deritei\, R Albert\, Parity and time reversal elucid ate both decision-making in empirical models and attractor scaling in crit ical Boolean networks\, Science Advances 7 (29)\, eabf8124 (2021).\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/11/ END:VEVENT BEGIN:VEVENT SUMMARY:Alan Veliz-Cuba (University of Dayton) DTSTART:20210930T171000Z DTEND:20210930T175000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/12 DESCRIPTION:Title: Discrete and algebraic approaches to study the relationship between structure and dynamics\nby Alan Veliz-Cuba (University of Dayton) as p art of BIRS workshop: Connecting Network Structure to its Dynamics: Fantas y or Reality?\n\n\nAbstract\nIn this talk\, we will see frameworks to stud y the problem of predicting dynamics from network structure and the proble m of inferring network structure from dynamics. To infer dynamical propert ies of a system from its structure\, we use the topological features of th e network such as the way subnetworks are connected\, and then use a versi on of the inclusion-exclusion principle on dynamics. To infer the structur e of a network from its dynamics\, we encode all possible networks that fi t the given dynamics as an ideal of polynomials and then use tools from al gebraic geometry to find the most likely networks.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/12/ END:VEVENT BEGIN:VEVENT SUMMARY:Michael Savageau (University of California\, Davis) DTSTART:20211001T151000Z DTEND:20211001T155000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/13 DESCRIPTION:Title: Circumventing the Parameter Values Bottleneck: Addressing the Challe nge by Development of Phenotype-Centric Modeling Strategies\nby Michae l Savageau (University of California\, Davis) as part of BIRS workshop: Co nnecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAbstr act\nMy research in Biochemical Systems Theory in collaboration with colle agues has shown that the architecture of mechanistic models can predict nu merous properties within and among biochemical phenotypes without knowledg e of the underlying biochemical kinetic parameters. In the past decade\, this research led to the development of a novel phenotype-centric modeling strategy with several advantages beyond those of the conventional simulat ion-centric approach. Here I report on work done in collaboration with Mi guel Valderrama-Gómez aimed at extending the phenotype-centric approach t o address one of the most fundamental problems in population genetics and evolution: predicting the distribution of phenotype diversity generated b y mutation and made available for innovation by selection. I show that mi nimal knowledge of the molecular system allows prediction of phenotype-spe cific mutation rate constants and equilibrium distributions of phenotype d iversity in populations undergoing steady-state exponential growth. As a proof-of-principle\, I provide a case study involving a small molecular sy stem\, a primordial circadian clock\, and suggest experimental approaches for testing the theory.\n LOCATION:https://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:20260422T185720Z UID:BIRS-21w5005/14 DESCRIPTION:Title: Learning Regulation from the Ground Up: Combining Natural Selection\ , Thermodynamics and Data\nby William Cannon (Pacific Northwest Nation al Lab and UC Riverside) as part of BIRS workshop: Connecting Network Stru cture to its Dynamics: Fantasy or Reality?\n\n\nAbstract\nModeling cells h as many challenges: data is sparse\, noisy\, and measured over a populatio n instead of over individuals or cell compartments. Moreover\, parameters needed to build kinetic and thermodynamic models are extremely labor inten sive to obtain. This makes building a physics-based model a very hard prob lem. We address this challenge by taking advantage of the fact that natura l selection selects for the most optimal individuals out of all solutions. We formulate fitness from a thermodynamic perspective to obtain the most likely model parameters\, and then use data to constrain the solution spac e. Rate parameters that are reasonable and statistically the most likely c an be inferred in this way. Then we predict regulation of the cellular sys tem using one of two approaches: Assuming that we have an optimal control problem and using control theory to infer regulation\, or widely sample th e solution space for regulation using reinforcement learning. The result i s a model with reasonable parameters and predicts regulation for central m etabolism that agrees with the literature.\n LOCATION:https://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:20260422T185720Z UID:BIRS-21w5005/15 DESCRIPTION:Title: Absolute Quantification of Transcription Factors Reveals Principles of Gene Regulation in Erythropoiesis\nby Theodore Perkins (Ottawa Hosp ital Research Institute / University of Ottawa) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or Reality?\n\n\nAbs tract\nDynamic cellular processes such as differentiation are driven by ch anges in the abundances of transcription factors (TFs). However\, despite years of studies\, our knowledge about the protein copy number of TFs in t he nucleus is limited. We developed a quantitative targeted mass spectrome try approach that allowed us to determine the absolute abundances of 103 T Fs and co-factors during the course of human erythropoiesis\, providing a dynamic and quantitative scale for TFs in the nucleus. Furthermore\, we es tablished the first gene regulatory network of erythropoietic cell fate co mmitment that integrates temporal protein stoichiometry data with mRNA mea surements. The model revealed quantitative imbalances in TFs' cross-antago nistic relationships underlying lineage determination. We also made the su rprising discovery that\, in the nucleus\, co-repressors are dramatically more abundant than co-activators at the protein level\, but not at the RNA level\, with profound implications for understanding transcriptional regu lation.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/15/ END:VEVENT BEGIN:VEVENT SUMMARY:Marcio Gameiro (Rutgers University) DTSTART:20210928T171000Z DTEND:20210928T175000Z DTSTAMP:20260422T185720Z UID:BIRS-21w5005/16 DESCRIPTION:Title: Characterizing robust dynamics in regulatory networksCircadian Post- Transcriptional Regulation to Demonstrate Clock Control of Metabolism and the Immune Response\nby Marcio Gameiro (Rutgers University) as part of BIRS workshop: Connecting Network Structure to its Dynamics: Fantasy or R eality?\n\n\nAbstract\nWe present DSGRN (Dynamics Signatures Generated by Regulatory Networks) which is a mathematically rigorous and computationall y efficient method to describe the global dynamics of a regulatory network over all parameter values. In this talk we will describe the details of D SGRN and discuss how it can be used to rank all 3-node networks according to how well they can act as a robust bi-stable switch.\n LOCATION:https://researchseminars.org/talk/BIRS-21w5005/16/ END:VEVENT END:VCALENDAR