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Synthetic biology aims to design de novo biological systems and reengineer existing ones. These efforts have mostly focused on transcriptional circuits, with reengineering of signaling circuits hampered by limited understanding of their systems dynamics and experimental challenges. Bacterial two-component signaling systems offer a rich diversity of sensory systems that are built around a core phosphotransfer reaction between histidine kinases and their output response regulator proteins, and thus are a good target for reengineering through synthetic biology. Here, we explore the signal-response relationship arising from a specific motif found in two-component signaling. In this motif, a single histidine kinase (HK) phosphotransfers reversibly to two separate output response regulator (RR) proteins. We show that, under the experimentally observed parameters from bacteria and yeast, this motif not only allows rapid signal termination, whereby one of the RRs acts as a phosphate sink towards the other RR (i.e. the output RR), but also implements a sigmoidal signal-response relationship. We identify two mathematical conditions on system parameters that are necessary for sigmoidal signal-response relationships and define key parameters that control threshold levels and sensitivity of the signal-response curve. We confirm these findings experimentally, by in vitro reconstitution of the one HK-two RR motif found in the Sinorhizobium meliloti chemotaxis pathway and measuring the resulting signal-response curve. We find that the level of sigmoidality in this system can be experimentally controlled by the presence of the sink RR, and also through an auxiliary protein that is shown to bind to the HK (yielding Hill coefficients of above 7). These findings show that the one HK-two RR motif allows bacteria and yeast to implement tunable switch-like signal processing and provides an ideal basis for developing threshold devices for synthetic biology applications.
Pubmed ID: 25357192 RIS Download
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XPPAUT is a tool for solving differential equations, difference equations, delay equations, functional equations, boundary value problems, and stochastic equations. It evolved from a chapter written by John Rinzel and me on the qualitative theory of nerve membranes and eventually became a commercial product for MSDOS computers called PHASEPLANE. It is now available as a program running under X11 and Windows. The code brings together a number of useful algorithms and is extremely portable. All the graphics and interface are written completely in Xlib which explains the somewhat idiosyncratic and primitive widgets interface. XPP contains the code for the popular bifurcation program, AUTO . Thus, you can switch back and forth between XPP and AUTO, using the values of one program in the other and vice-versa. I have put a ``friendly'' face on AUTO as well. You do not need to know much about it to play around with it. XPP has the capabilities for handling up to 590 differential equations. There are over a dozen solvers including several for stiff systems, a solver for integral equations and a symplectic solver. Up to 10 graphics windows can be visible at once and a variety of color combinations is supported. PostScript output is supported as well as GIF and animator GIF movies Post processing is easy and includes the ability to make histograms, FFTs and applying functions to columns of your data. Equilibria and linear stability as well as one-dimensional invariant sets can be computed. Nullclines and flow fields aid in the qualitative understanding of two-dimensional models. Poincare maps and equations on cylinders and tori are also supported. Some useful averaging theory tricks and various methods for dealing with coupled oscillators are included primarily because that is what I do for a living. Equations with Dirac delta functions are allowable. I have added an animation package that allows you to create animated versions of your simulations, such as a little pendulum moving back and forth or lamprey swimming. See toys! for examples. There is a curve-fitter based on the Marquardt-Levenberg algorithm which lets you fit data points to the solutions to dynamical systems. It is possible to automatically generate "movies'' of three-dimensional views of attractors or parametric changes in the attractor as some parameters vary. Dynamically link to external subroutines XPP has been successfully compiled on a SPARC II under OpenLook, a SPARC 1.5 running generic X, a NeXT running X11R4, a DEC 5000, a PC using Linux or Windows, and SGI and an HP 730. It also runs under Win95/NT/98 if you have an X-Server. I cannot vouch for other platforms but it has been compiled on the IBM RS6000. Building XPP requires only the standard C compiler, and Xlib. Look at the any README files that come with the distribution for solutions to common compilation problems.
View all literature mentionsNon profit, private research and education institution that performs molecular and genetic research used to generate methods for better diagnostics and treatments for cancer and neurological diseases. Research of cancer causing genes and their respective signaling pathways, mutations and structural variations of the human genome that could cause neurodevelopmental and neurodegenerative illnesses such as autism, schizophrenia, and Alzheimer's and Parkinson's diseases and also research in plant genetics and quantitative biology.
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