Elucidating the genotype-phenotype map by automatic enumeration and analysis of the phenotypic repertoire.

BackgroundThe gap between genotype and phenotype is filled by complex biochemical systems most of which are poorly understood. Because these systems are complex, it is widely appreciated that quantitative understanding can only be achieved with the aid of mathematical models. However, formulating models and measuring or estimating their numerous rate constants and binding constants is daunting. Here we present a strategy for automating difficult aspects of the process.MethodsThe strategy, based on a system design space methodology, is applied to a class of 16 designs for a synthetic gene oscillator that includes seven designs previously formulated on the basis of experimentally measured and estimated parameters.ResultsOur strategy provides four important innovations by automating: (1) enumeration of the repertoire of qualitatively distinct phenotypes for a system; (2) generation of parameter values for any particular phenotype; (3) simultaneous realization of parameter values for several phenotypes to aid visualization of transitions from one phenotype to another, in critical cases from functional to dysfunctional; and (4) identification of ensembles of phenotypes whose expression can be phased to achieve a specific sequence of functions for rationally engineering synthetic constructs. Our strategy, applied to the 16 designs, reproduced previous results and identified two additional designs capable of sustained oscillations that were previously missed.ConclusionsStarting with a system's relatively fixed aspects, its architectural features, our method enables automated analysis of nonlinear biochemical systems from a global perspective, without first specifying parameter values. The examples presented demonstrate the efficiency and power of this automated strategy

Regulatory Design Governing Progression of Population Growth Phases in Bacteria

It has long been noted that batch cultures inoculated with resting bacteria exhibit a progression of growth phases traditionally labeled lag, exponential, pre-stationary and stationary. However, a detailed molecular description of the mechanisms controlling the transitions between these phases is lacking. A core circuit, formed by a subset of regulatory interactions involving five global transcription factors (FIS, HNS, IHF, RpoS and GadX), has been identified by correlating information from the well- established transcriptional regulatory network of Escherichia coli and genome-wide expression data from cultures in these different growth phases. We propose a functional role for this circuit in controlling progression through these phases. Two alternative hypotheses for controlling the transition between the growth phases are first, a continuous graded adjustment to changing environmental conditions, and second, a discontinuous hysteretic switch at critical thresholds between growth phases. We formulate a simple mathematical model of the core circuit, consisting of differential equations based on the power-law formalism, and show by mathematical and computer-assisted analysis that there are critical conditions among the parameters of the model that can lead to hysteretic switch behavior, which – if validated experimentally – would suggest that the transitions between different growth phases might be analogous to cellular differentiation. Based on these provocative results, we propose experiments to test the alternative hypotheses

Phenomenological Lambda-Nuclear Interactions

Variational Monte Carlo calculations for ${_{\Lambda}^4}H$ (ground and excited states) and ${_{\Lambda}^5}He$ are performed to decipher information on ${\Lambda}$-nuclear interactions. Appropriate operatorial nuclear and ${\Lambda}$-nuclear correlations have been incorporated to minimize the expectation values of the energies. We use the Argonne $\upsilon_{18}$ two-body NN along with the Urbana IX three-body NNN interactions. The study demonstrates that a large part of the splitting energy in ${_{\Lambda}^4}H$ ($0^+-1^+$) is due to the three-body ${\Lambda}$ NN forces. $_{\Lambda}^{17}O$ hypernucleus is analyzed using the {\it s}-shell results. $\Lambda$ binding to nuclear matter is calculated within the variational framework using the Fermi-Hypernetted-Chain technique. There is a need to correctly incorporate the three-body ${\Lambda}$ NN correlations for $\Lambda$ binding to nuclear matter.Comment: 18 pages (TeX), 2 figure

Acoustic radiation controls friction: Evidence from a spring-block experiment

Brittle failures of materials and earthquakes generate acoustic/seismic waves which lead to radiation damping feedbacks that should be introduced in the dynamical equations of crack motion. We present direct experimental evidence of the importance of this feedback on the acoustic noise spectrum of well-controlled spring-block sliding experiments performed on a variety of smooth surfaces. The full noise spectrum is quantitatively explained by a simple noisy harmonic oscillator equation with a radiation damping force proportional to the derivative of the acceleration, added to a standard viscous term.Comment: 4 pages including 3 figures. Replaced with version accepted in PR

Neutron matter at zero temperature with auxiliary field diffusion Monte Carlo

The recently developed auxiliary field diffusion Monte Carlo method is applied to compute the equation of state and the compressibility of neutron matter. By combining diffusion Monte Carlo for the spatial degrees of freedom and auxiliary field Monte Carlo to separate the spin-isospin operators, quantum Monte Carlo can be used to simulate the ground state of many nucleon systems (A\alt 100). We use a path constraint to control the fermion sign problem. We have made simulations for realistic interactions, which include tensor and spin--orbit two--body potentials as well as three-nucleon forces. The Argonne $v_8'$ and $v_6'$ two nucleon potentials plus the Urbana or Illinois three-nucleon potentials have been used in our calculations. We compare with fermion hypernetted chain results. We report results of a Periodic Box--FHNC calculation, which is also used to estimate the finite size corrections to our quantum Monte Carlo simulations. Our AFDMC results for $v_6$ models of pure neutron matter are in reasonably good agreement with equivalent Correlated Basis Function (CBF) calculations, providing energies per particle which are slightly lower than the CBF ones. However, the inclusion of the spin--orbit force leads to quite different results particularly at relatively high densities. The resulting equation of state from AFDMC calculations is harder than the one from previous Fermi hypernetted chain studies commonly used to determine the neutron star structure.Comment: 15 pages, 15 tables and 5 figure

Four-Body Bound State Calculations in Three-Dimensional Approach

The four-body bound state with two-body interactions is formulated in Three-Dimensional approach, a recently developed momentum space representation which greatly simplifies the numerical calculations of few-body systems without performing the partial wave decomposition. The obtained three-dimensional Faddeev-Yakubovsky integral equations are solved with two-body potentials. Results for four-body binding energies are in good agreement with achievements of the other methods.Comment: 29 pages, 2 eps figures, 8 tables, REVTeX

Spin-Isospin Structure and Pion Condensation in Nucleon Matter

We report variational calculations of symmetric nuclear matter and pure neutron matter, using the new Argonne v18 two-nucleon and Urbana IX three-nucleon interactions. At the equilibrium density of 0.16 fm^-3 the two-nucleon densities in symmetric nuclear matter are found to exhibit a short-range spin-isospin structure similar to that found in light nuclei. We also find that both symmetric nuclear matter and pure neutron matter undergo transitions to phases with pion condensation at densities of 0.32 fm^-3 and 0.2 fm^-3, respectively. Neither transtion occurs with the Urbana v14 two-nucleon interaction, while only the transition in neutron matter occurs with the Argonne v14 two-nucleon interaction. The three-nucleon interaction is required for the transition to occur in symmetric nuclear matter, whereas the the transition in pure neutron matter occurs even in its absence. The behavior of the isovector spin-longitudinal response and the pion excess in the vicinity of the transition, and the model dependence of the transition are discussed.Comment: 44 pages RevTeX, 15 postscript figures. Minor modifications to original postin