Multiple functionalities of biochemical reaction networks

We consider a biological cell as a highly nterconnected network of chemical reactions, which is constituted of a large number of semi-autonomous functional modules. Depending on the global state of the network, the separate functional modules may display qualitatively different behavior. As an example, we study a conceptual network of phosphorylation cycles, for which the steady-state concentration of an output compound depends on the concentrations of two input enzymes. We show that the input-output relation depends on the expression of the proteins in the network. Hence changes in protein expression, due to changes in the global regulatory network of the cell, can change the functionality of the module. In this specific example, changed expression of two proteins is sufficient to switch between the functionalities of various logical gates

Simulated evolution of mass conserving reaction networks

With the rise of systems biology, the systematic analysis and construction of behavioral mechanisms in both natural and artificial biochemical networks has become a vital part of understanding and predicting the inner workings of intracellular signaling networks. As a modeling platform, artificial chemistries are commonly adopted to study and construct artificial reaction network motifs that exhibit complex computational behaviors. Here, we present a genetic algorithm to evolve networks that can compute elementary mathematical functions by transforming initial input molecules into the steady state concentrations of output molecules. Morespecifically, the proposed algorithm implicitly guarantees mass conservation through an atom based description of the molecules and reaction networks. We discuss the adopted approach for the artificial evolution of these chemical networks, evolve networks to compute the square root function. Finally,we provide an extensive deterministic and stochastic analysis of a core square root network motif present in these resulting networks, confirming that the motif is indeed capable of computing the square root function

Observation of novel edge excitations of a two-dimensional electron liquid on helium in a magnetic field

Low-frequency edge excitations in a magnetic field of the two-dimensional electron system on liquid helium are studied. It is found that, in addition to the conventional edge magnetoplasma resonances, novel resonances of smaller amplitude appear at lower frequencies at

Hemichannel-Mediated and pH-Based Feedback from Horizontal Cells to Cones in the Vertebrate Retina

Background: Recent studies designed to identify the mechanism by which retinal horizontal cells communicate with cones have implicated two processes. According to one account, horizontal cell hyperpolarization induces an increase in pH withinthe synaptic cleft that activates the calcium current (Ca2+-current) in cones, enhancing transmitter release. An alternative account suggests that horizontal cell hyperpolarization increases the Ca2+-current to promote transmitter release through ahemichannel-mediated ephaptic mechanism.Methodology/Principal Findings: To distinguish between these mechanisms, we interfered with the pH regulating systems in the retina and studied the effects on the feedback responses of cones and horizontal cells. We found that the pH buffers HEPES and Tris partially inhibit feedback responses in cones and horizontal cells and lead to intracellular acidification ofneurons. Application of 25 mM acetate, which does not change the extracellular pH buffer capacity, does lead to both intracellular acidification and inhibition of feedback. Because intracellular acidification is known to inhibit hemichannels, the key experiment used to test the pH hypothesis, i.e. increasing the extracellular pH buffer capacity, does not discriminatebetween a pH-based feedback system and a hemichannel-mediated feedback system. To test the pH hypothesis in a manner independent of artificial pH-buffer systems, we studied the effect of interfering with the endogenous pH buffer, the bicarbonate/carbonic anhydrase system. Inhibition of carbonic anhydrase allowed for large changes in pH in the synapticcleft of bipolar cell terminals and cone terminals, but the predicted enhancement of the cone feedback responses, according to the pH-hypothesis, was not observed. These experiments thus failed to support a proton mediated feedback mechanism. The alternative hypothesis, the hemichannel-mediated ephaptic feedback mechanism, was therefore studied experimentally, and its feasibility was buttressed by means of a quantitative computer model of the cone/horizontal cellsynapse.Conclusion: We conclude that the data presented in this paper offers further support for physiologically relevant ephaptic interactions in the retina

One-Dimensional Birth-Death Process and Delbr\"{u}ck-Gillespie Theory of Mesoscopic Nonlinear Chemical Reactions

As a mathematical theory for the stochasstic, nonlinear dynamics of individuals within a population, Delbr\"{u}ck-Gillespie process (DGP) $n(t)\in\mathbb{Z}^N$, is a birth-death system with state-dependent rates which contain the system size $V$ as a natural parameter. For large $V$, it is intimately related to an autonomous, nonlinear ordinary differential equation as well as a diffusion process. For nonlinear dynamical systems with multiple attractors, the quasi-stationary and stationary behavior of such a birth-death process can be underestood in terms of a separation of time scales by a $T^*\sim e^{\alpha V}$ $(\alpha>0)$: a relatively fast, intra-basin diffusion for $t\ll T^*$ and a much slower inter-basin Markov jump process for $t\gg T^*$. In the present paper for one-dimensional systems, we study both stationary behavior ($t=\infty$) in terms of invariant distribution $p_n^{ss}(V)$, and finite time dynamics in terms of the mean first passsage time (MFPT) $T_{n_1\rightarrow n_2}(V)$. We obtain an asymptotic expression of MFPT in terms of the "stochastic potential" $\Phi(x,V)=-(1/V)\ln p^{ss}_{xV}(V)$. We show in general no continuous diffusion process can provide asymptotically accurate representations for both the MFPT and the $p_n^{ss}(V)$ for a DGP. When $n_1$ and $n_2$ belong to two different basins of attraction, the MFPT yields the $T^*(V)$ in terms of $\Phi(x,V)\approx \phi_0(x)+(1/V)\phi_1(x)$. For systems with a saddle-node bifurcation and catastrophe, discontinuous "phase transition" emerges, which can be characterized by $\Phi(x,V)$ in the limit of $V\rightarrow\infty$. In terms of time scale separation, the relation between deterministic, local nonlinear bifurcations and stochastic global phase transition is discussed. The one-dimensional theory is a pedagogic first step toward a general theory of DGP.Comment: 32 pages, 3 figure

DARTpaths, an in silico platform to investigate molecular mechanisms of compounds

SUMMARY: Xpaths is a collection of algorithms that allow for the prediction of compound-induced molecular mechanisms of action by integrating phenotypic endpoints of different species; and proposes follow-up tests for model organisms to validate these pathway predictions. The Xpaths algorithms are applied to predict developmental and reproductive toxicity (DART) and implemented into an in silico platform, called DARTpaths. AVAILABILITY AND IMPLEMENTATION: All code is available on GitHub https://github.com/Xpaths/dartpaths-app under Apache license 2.0, detailed overview with demo is available at https://www.vivaltes.com/dartpaths/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online

Synaptic Transmission from Horizontal Cells to Cones Is Impaired by Loss of Connexin Hemichannels

In the vertebrate retina, horizontal cells generate the inhibitory surround of bipolar cells, an essential step in contrast enhancement. For the last decades, the mechanism involved in this inhibitory synaptic pathway has been a major controversy in retinal research. One hypothesis suggests that connexin hemichannels mediate this negative feedback signal; another suggests that feedback is mediated by protons. Mutant zebrafish were generated that lack connexin 55.5 hemichannels in horizontal cells. Whole cell voltage clamp recordings were made from isolated horizontal cells and cones in flat mount retinas. Light-induced feedback from horizontal cells to cones was reduced in mutants. A reduction of feedback was also found when horizontal cells were pharmacologically hyperpolarized but was absent when they were pharmacologically depolarized. Hemichannel currents in isolated horizontal cells showed a similar behavior. The hyperpolarization-induced hemichannel current was strongly reduced in the mutants while the depolarization-induced hemichannel current was not. Intracellular recordings were made from horizontal cells. Consistent with impaired feedback in the mutant, spectral opponent responses in horizontal cells were diminished in these animals. A behavioral assay revealed a lower contrast-sensitivity, illustrating the role of the horizontal cell to cone feedback pathway in contrast enhancement. Model simulations showed that the observed modifications of feedback can be accounted for by an ephaptic mechanism. A model for feedback, in which the number of connexin hemichannels is reduced to about 40%, fully predicts the specific asymmetric modification of feedback. To our knowledge, this is the first successful genetic interference in the feedback pathway from horizontal cells to cones. It provides direct evidence for an unconventional role of connexin hemichannels in the inhibitory synapse between horizontal cells and cones. This is an important step in resolving a long-standing debate about the unusual form of (ephaptic) synaptic transmission between horizontal cells and cones in the vertebrate retina