Relevant Perturbations Research Articles

Minimal intervention strategies in logical signaling networks with ASP

AbstractProposing relevant perturbations to biological signaling networks is central to many problems in biology and medicine because it allows for enabling or disabling certain biological outcomes. In contrast to quantitative methods that permit fine-grained (kinetic) analysis, qualitative approaches allow for addressing large-scale networks. This is accomplished by more abstract representations such as logical networks. We elaborate upon such a qualitative approach aiming at the computation of minimal interventions in logical signaling networks relying on Kleene's three-valued logic and fixpoint semantics. We address this problem within answer set programming and show that it greatly outperforms previous work using dedicated algorithms.

On the number of relevant operators in asymptotically safe gravity

The asymptotic safety scenario of gravity conjectures that i) the quantum field theory of gravity exists thanks to the presence of a non-trivial ultraviolet fixed point of the renormalization group, and that ii) the fixed point has only a finite number of relevant perturbations, i.e., a finite number of UV-stable directions (or, in other words, a finite number of free parameters to be fixed experimentally). Within the f(R) approximation of the functional renormalization group equation of gravity, we show that assuming the first half of the conjecture to be true, the remaining half follows from general arguments, that is, we show that assuming the existence of a non-trivial fixed point, the fact that the number of relevant directions is finite is a general consequence of the structure of the equations.

Integrative physiology and systems biology: reductionism, emergence and causality

Integrative physiology and systems biology: reductionism, emergence and causality

Applying systems biology methods to the study of human physiology in extreme environments

Systems biology is defined in this review as ‘an iterative process of computational model building and experimental model revision with the aim of understanding or simulating complex biological systems’. We propose that, in practice, systems biology rests on three pillars: computation, the omics disciplines and repeated experimental perturbation of the system of interest. The number of ethical and physiologically relevant perturbations that can be used in experiments on healthy humans is extremely limited and principally comprises exercise, nutrition, infusions (e.g. Intralipid), some drugs and altered environment. Thus, we argue that systems biology and environmental physiology are natural symbionts for those interested in a system-level understanding of human biology. However, despite excellent progress in high-altitude genetics and several proteomics studies, systems biology research into human adaptation to extreme environments is in its infancy. A brief description and overview of systems biology in its current guise is given, followed by a mini review of computational methods used for modelling biological systems. Special attention is given to high-altitude research, metabolic network reconstruction and constraint-based modelling.

Dynamical evolution of high area-to-mass ratio objects in Molniya orbits

For special demands, some notable orbit types have been developed by human, including the Molniya orbits, which have a relatively high eccentricity up to about 0.7, and a period of 12h. Considering that space debris with high area-to-mass ratio (A/M) has been discovered, such objects may also exist in Molniya orbits due to spacecraft and upper stages fragmentation events. However, there are not sufficient studies of the complex dynamical phenomena of such orbits. These studies can enrich the knowledge about the long-term evolution of these orbits, be helpful to propose uncatalogued objects observation and identification, and also set the protected region as well as active debris removal. In this paper, the characteristics of 2:1 resonance of Molniya satellite orbits are studied. A large set of numerical simulations, including all the relevant perturbations, is carried out to further investigate the main characteristics, and special attention is payed to the dynamical evolution of objects with high A/M, particularly affected by the direct solar radiation pressure. The long-term dynamical evolution of orbital elements, as well as the dependency of lifetime on the A/M value, is discussed.

Strange metals in one spatial dimension

We consider $1+1$ dimensional $SU(N)$ gauge theory coupled to a multiplet of massive Dirac fermions transforming in the adjoint representation of the gauge group. The only global symmetry of this theory is a $U(1)$ associated with the conserved Dirac fermion number, and we study the theory at variable, nonzero densities. The high density limit is characterized by a deconfined Fermi surface state with Fermi wave vector equal to that of free gauge-charged fermions. Its low energy fluctuations are described by a coset conformal field theory with central charge $c=({N}^{2}\ensuremath{-}1)/3$ and an emergent $\mathcal{N}=(2,2)$ supersymmetry: the $U(1)$ fermion number symmetry becomes an $R$-symmetry. We determine the exact scaling dimensions of the operators associated with Friedel oscillations and pairing correlations. For $N>2$, we find that the symmetries allow relevant perturbations to this state. We discuss aspects of the $N\ensuremath{\rightarrow}\ensuremath{\infty}$ limit, and its possible dual description in ${\mathrm{AdS}}_{3}$ involving string theory or higher-spin gauge theory. We also discuss the low density limit of the theory by computing the low lying bound state spectrum of the large $N$ gauge theory numerically at zero density, using discretized light cone quantization.

Transient growth associated with continuous spectra of the Batchelor vortex

AbstractThe spectrum of the Batchelor vortex can be broadly split into a discrete spectrum, a potential spectrum and a free-stream spectrum where, since the last two spectra are both continuous, they can also be considered as one continuous spectrum. The discrete spectrum has been extensively studied but the continuous spectrum has received limited attention in the context of vortex flow. A local transient growth study is conducted and the contribution of the discrete spectrum and the continuous spectrum to the transient growth is separated by constructing optimal perturbations on the discrete or continuous sub-eigenspaces separately. It is found that the significant transient growth is mainly due to the non-normality of the continuous eigenmodes/spectrum whilst the discrete eigenmodes/spectrum have little contribution to the transient energy growth. A matrix-free method, which reduces to the local analysis when appropriate periodic boundary conditions are imposed, is also applied to investigate the transient growth in both a plane of constant azimuthal angle and a plane constant axial location. Previously studies by other authors have demonstrated that at zero azimuthal wavenumber the transient growth reaches infinitely large values over infinite time intervals while the optimal perturbations are located far from the vortex core. Therefore we limited our scope to small values of the time horizon so as to obtain reasonably strong transient effects stemming from physically relevant optimal perturbations. Two mechanisms of transient growth are observed: namely a redistribution of the azimuthal velocity to the azimuthal vorticity and interaction between out-of-vortex-core structures with those within the vortex core. A direct numerical simulation (DNS) of the vortex perturbed by optimal perturbations is conducted to investigate the nonlinear development of the optimal perturbations. In the azimuthally constant decomposed case, it is found that the optimal perturbation induces a string of bubble structures to be generated as a consequence of the non-orthogonality of continuous eigenmodes and the breakdown bubble is induced by viscous diffusion, while in the axially constant decomposition transient growth analysis, it is observed that the optimal perturbations associated with the continuous eigenmodes drive the vortex to vibrate around the initial vortex centre before eventually returning to its original position at larger times. This transient effect provides a mechanism for the ‘vortex meandering’ observed in previous experimental and numerical studies. These optimal perturbations associated with the continuous spectrum with out-of-vortex-core structures are observed to be activated by anisotropic inflow perturbations in the potential region.

Genome-level transcription data of Yersinia pestis analyzed with a New metabolic constraint-based approach

BackgroundConstraint-based computational approaches, such as flux balance analysis (FBA), have proven successful in modeling genome-level metabolic behavior for conditions where a set of simple cellular objectives can be clearly articulated. Recently, the necessity to expand the current range of constraint-based methods to incorporate high-throughput experimental data has been acknowledged by the proposal of several methods. However, these methods have rarely been used to address cellular metabolic responses to some relevant perturbations such as antimicrobial or temperature-induced stress. Here, we present a new method for combining gene-expression data with FBA (GX-FBA) that allows modeling of genome-level metabolic response to a broad range of environmental perturbations within a constraint-based framework. The method uses mRNA expression data to guide hierarchical regulation of cellular metabolism subject to the interconnectivity of the metabolic network.ResultsWe applied GX-FBA to a genome-scale model of metabolism in the gram negative bacterium Yersinia pestis and analyzed its metabolic response to (i) variations in temperature known to induce virulence, and (ii) antibiotic stress. Without imposition of any a priori behavioral constraints, our results show strong agreement with reported phenotypes. Our analyses also lead to novel insights into how Y. pestis uses metabolic adjustments to counter different forms of stress.ConclusionsComparisons of GX-FBA predicted metabolic states with fluxomic measurements and different reported post-stress phenotypes suggest that mass conservation constraints and network connectivity can be an effective representative of metabolic flux regulation in constraint-based models. We believe that our approach will be of aid in the in silico evaluation of cellular goals under different conditions and can be used for a variety of analyses such as identification of potential drug targets and their action.

Linearization of homogeneous, nearly-isotropic cosmological models

Homogeneous, nearly-isotropic Bianchi cosmological models are considered. Their time evolution is expressed as a complete set of non-interacting linear modes on top of a Friedmann–Robertson–Walker background model. This connects the extensive literature on Bianchi models with the more commonly-adopted perturbation approach to general relativistic cosmological evolution. Expressions for the relevant metric perturbations in familiar coordinate systems can be extracted straightforwardly. Amongst other possibilities, this allows for future analysis of anisotropic matter sources in a more general geometry than usually attempted. We discuss the geometric mechanisms by which maximal symmetry is broken in the context of these models, shedding light on the origin of different Bianchi types. When all relevant length scales are super-horizon, the simplest Bianchi I models emerge (in which anisotropic quantities appear parallel transported). Finally we highlight the existence of arbitrarily long near-isotropic epochs in models of general Bianchi type (including those without an exact isotropic limit).

Improving mesocosm data analysis through individual-based modelling of control population dynamics: a case study with mosquitofish (Gambusia holbrooki)

Experimental ecosystems such as mesocosms have been developed to improve the ecological relevance of ecotoxicity test. However, in mesocosm studies, the number of replicates is limited by practical and financial constraints. In addition, high levels of biological organization are characterized by a high variability of descriptive variables. This variability and the poor number of replicates have been recognized as a major drawback for detecting significant effects of chemicals in mesocosm studies. In this context, a tool able to predict precisely control mesocosms outputs, to which endpoints in mesocosms exposed to chemicals could be compared should constitute a substantial improvement. We evaluated here a solution which consists in stochastic modelling of the control fish populations to assess the probabilistic distributions of population endpoints. An individual-based approach was selected, because it generates realistic fish length distributions and accounts for both individual and environmental sources of variability. This strategy was applied to mosquitofish (Gambusia holbrooki) populations monitored in lentic mesocosms. We chose the number of founders as a so-called "stressor" because subsequent consequences at the population level could be expected. Using this strategy, we were able to detect more significant and biologically relevant perturbations than using classical methods. We conclude that designing an individual-based model is very promising for improving mesocosm data analysis. This methodology is currently being applied to ecotoxicological issues.

Unitary equilibration after a quantum quench of a thermal state

In this work we investigate the equilibration dynamics after a sudden Hamiltonian quench of a quantum spin system initially prepared in a thermal state. To characterize the equilibration we evaluate the Loschmidt echo, a global measure for the degree of distinguishability between the initial and time-evolved quenched states. We present general results valid for small quenches and detailed analysis of the quantum $XY$ chain. The result is that quantum criticality manifests, even at small but finite temperatures, in a universal double-peaked form of the echo statistics and poor equilibration for sufficiently relevant perturbations. In addition, for this model we find a tight lower bound on the Loschmidt echo in terms of the purity of the initial state and the more easily evaluated Hilbert-Schmidt inner product between initial and time-evolved quenched states. This bound allows us to relate the time-averaged Loschmidt echo with the purity of the time-averaged state, a quantity that has been shown to provide an upper bound on the variance of observables.

Xenobiotic metabolomics: major impact on the metabolome.

Xenobiotics are encountered by humans on a daily basis and include drugs, environmental pollutants, cosmetics, and even components of the diet. These chemicals undergo metabolism and detoxication to produce numerous metabolites, some of which have the potential to cause unintended effects such as toxicity. They can also block the action of enzymes or receptors used for endogenous metabolism or affect the efficacy and/or bioavailability of a coadministered drug. Therefore, it is essential to determine the full metabolic effects that these chemicals have on the body. Metabolomics, the comprehensive analysis of small molecules in a biofluid, can reveal biologically relevant perturbations that result from xenobiotic exposure. This review discusses the impact that genetic, environmental, and gut microflora variation has on the metabolome, and how these variables may interact, positively and negatively, with xenobiotic metabolism.

Electron scattering from domain walls in ferromagnetic Luttinger liquids

We study the properties of interacting electrons in a one-dimensional conduction band coupled to bulk noncollinear ferromagnetic order. The specific form of noncollinearity we consider is that of an extended domain wall. The presence of ferromagnetic order breaks spin-charge separation and the domain wall introduces a spin-dependent scatterer active over the length of the wall $\ensuremath{\lambda}$. Both forward and backward scattering off the domain wall can be relevant perturbations of the Luttinger liquid and we discuss the possible low-temperature phases. Our main finding is that backward scattering, while determining the ultimate low-temperature physics, only becomes important at temperatures $T/J<\mathrm{exp}(\ensuremath{-}\ensuremath{\lambda}/{\ensuremath{\lambda}}_{+})$, with $J$ being the magnetic exchange and ${\ensuremath{\lambda}}_{+}$ the backward scattering length scale. In physical realizations, $\ensuremath{\lambda}\ensuremath{\gg}{\ensuremath{\lambda}}_{+}$ and the physics will be dominated by forward scattering, which can lead to a charge-conducting but spin-insulating phase. In a perturbative regime at higher temperatures we furthermore calculate the spin and charge densities around the domain wall and quantitatively discuss the interaction-induced changes.

Renormalization group for non-relativistic fermions

A brief introduction is given to the renormalization group for non-relativistic fermions at finite density. It is shown that Landau's theory of the Fermi liquid arises as a fixed point (with the Landau parameters as marginal couplings) and its instabilities as relevant perturbations. Applications to related areas, nuclear matter, quark matter and quantum dots, are briefly discussed. The focus will be on explaining the main ideas to people in related fields, rather than addressing the experts.

Finding the trigger to Iapetus’ odd global albedo pattern: Dynamics of dust from Saturn’s irregular satellites

The leading face of Saturn’s moon Iapetus, Cassini Regio, has an albedo only one tenth that on its trailing side. The origin of this enigmatic dichotomy has been debated for over 40 years, but with new data, a clearer picture is emerging. Motivated by Cassini radar and imaging observations, we investigate Soter’s model of dark exogenous dust striking an originally brighter Iapetus by modeling the dynamics of the dark dust from the ring of the exterior retrograde satellite Phoebe under the relevant perturbations. In particular, we study the particles’ probabilities of striking Iapetus, as well as their expected spatial distribution on the Iapetian surface. We find that, of the long-lived particles (≳5 μm), most particle sizes (≳10 μm) are virtually certain to strike Iapetus, and their calculated distribution on the surface matches up well with Cassini Regio’s extent in its longitudinal span. The satellite’s polar regions are observed to be bright, presumably because ice is deposited there. Thus, in the latitudinal direction we estimate polar dust deposition rates to help constrain models of thermal migration invoked to explain the bright poles (Spencer, J.R., Denk, T. [2010]. Science 327, 432–435). We also analyze dust originating from other irregular outer moons, determining that a significant fraction of that material will eventually coat Iapetus—perhaps explaining why the spectrum of Iapetus’ dark material differs somewhat from that of Phoebe. Finally we track the dust particles that do not strike Iapetus, and find that most land on Titan, with a smaller fraction hitting Hyperion. As has been previously conjectured, such exogenous dust, coupled with Hyperion’s chaotic rotation, could produce Hyperion’s roughly isotropic, moderate-albedo surface.

New Directions in Toxicity Testing

In 2007, the U.S. National Research Council (NRC) published a groundbreaking report entitled Toxicity Testing in the 21st Century: A Vision and a Strategy. The purpose of this report was to develop a long-range strategic plan to update and advance the way environmental agents are tested for toxicity. The vision focused on the identification of critical perturbations of toxicity pathways that lead to adverse human health outcomes using modern scientific tools and technologies. This review describes how emerging scientific methods will move the NRC vision forward and improve the manner in which the potential health risks associated with exposure to environmental agents are assessed. The new paradigm for toxicity testing is compatible with the widely used four-stage risk assessment framework originally proposed by the NRC in 1983 in the so-called Red Book. The Nrf2 antioxidant pathway provides a detailed example of how relevant pathway perturbations will be identified within the context of the new NRC vision for the future of toxicity testing. The implications of the NRC vision for toxicity testing for regulatory risk assessment are also discussed.

Exact Crossover Green Function in the Two-Channel and Two-Impurity Kondo Models

Symmetry-breaking perturbations destabilize the critical points of the two-channel and two-impurity Kondo models, thereby leading to a crossover from non-Fermi liquid behavior to standard Fermi liquid physics. Here we use an analogy between this crossover and one occurring in the boundary Ising model to calculate the full crossover Green function analytically. In remarkable agreement with our numerical renormalization group calculations, the single exact function applies for an arbitrary mixture of the relevant perturbations in each model. This rich behavior resulting from finite channel asymmetry, interlead charge transfer, and/or magnetic field should be observable in quantum dot or tunneling experiments.

Analysis of Insect-Inspired Wingstroke KinematicPerturbations for Longitudinal Control

I NSECTS display remarkable agility and flight-path control in the execution of their everyday tasks, all in the face of significant environmental uncertainties. Maneuvering forces are typically generated by small kinematic perturbations to high-frequency wing motions, such as changes in stroke amplitude, timing of wing rotation, or stroke plane tilting [1]. This clever approach of coupling high-frequency actuation with low-frequency rigid-body motion eliminates the need in most species for active sensing on and active deformation of the wing surface, otherwise evident in their avian [2] and mammalian [3] aerobatic counterparts. Previous analysis of insect-inspired flapping-wing locomotion has examined wing kinematic trajectories from the perspective of maximizing lift [4,5] or minimizing required power [6]. With the introduction of new tools to extract the finewingstroke towingstroke kinematics of insects from high-speed videography [7,8], a number of species-specific control strategies for maneuvering have been identified. In addition, with the development of microscale vehicles that can potentially generate lift forces greater than their weight [9], stability and control aspects of the problem are now a focal point of research. Despite the critical need, the inherent complexity of small-scale flapping flight aerodynamics has obscured a control-theoretic analysis of both biologically relevant and engineered wing kinematic perturbation strategies.While the detailed aerodynamic mechanisms involved in small-scale flight are still an area of active research [10], recent efforts have in fact yielded several approaches for extraction of reduced-order linear time-invariant (LTI) flight dynamics, either for single-degree-of-freedom experimental cases [11,12], direct analytic methods [13], or more general computationally [14] and spectrally derived models [15]. Such formulations are amenable to application of linear control analysis tools, and they should provide the next level of insight. Reachability (or more traditionally, controllability) characterizes the amount of control one has over the state of a system through the choice of the input. This is an important topic for small-scale flapping-wingmicro air vehicle (MAV)designers for several reasons. Size, weight, and power (SWAP) constraints are very stringent at this scale, and reductions in complexity that promote robustness and weight reduction are encouraged. In addition, these vehicles are intended to operate in gusty and possibly cluttered environments, and a high level of platformmaneuverability and actuation authority will be crucial to achieving robust flight-path control in the face of these uncertainties. This Note explores the reachable state space associated with biologically inspired kinematic control strategies seen in longitudinal motion about hover. In Sec. II, a frequency-based system identificationmethodology for identifying the stability derivatives of a small-scale flapping microsystem about hover is outlined, along with the control derivatives for biologically relevant wing kinematic perturbations for maneuvering. Section III applies controllability analysis tools to interpret these biologically relevant control strategies for MAV design, using the example of an MAV with Drosophila-like parameters.

Orbital evolution of the first upper stages used for the new European and Chinese navigation satellite systems

The solutions adopted for the disposal of the upper stages used to put in orbit the first satellites of the new European (Galileo) and Chinese (Beidou) navigation constellations were analyzed. The orbit evolution of the rocket bodies was modeled for 200 years, taking into account all relevant perturbations, and the chosen disposal options were evaluated in terms of their long-term consequences for the debris environment. The results obtained, when applicable, were also discussed in the context of the eccentricity instability problem, pointed out in previous studies. In addition, the long-term evolution of the fragments resulting from a Beidou rocket body breakup, and of simulated high area-to-mass ratio objects released in the disposal orbits of the first two Galileo upper stages, was investigated. Eight out of ten Beidou upper stages were found to have an orbital lifetime <25 years and the other two resulted in a dwell time of approximately 6 years below 2000 km. It was also found that the perigee heights of the two upper stages used to deploy the first Galileo test spacecraft will remain more than 169 km above the constellation nominal altitude, never crossing the existing or planned navigation systems. In spite of an inclination resonance possibly leading to the exponential growth of the eccentricity over several decades, the optimal choice of the disposal orbital elements was able to prevent such an outcome, by maintaining the orbit nearly circular. Therefore, the upper stage disposal strategies used so far for Beidou and Galileo have generally been quite successful in averting the long-term interference of such rocket bodies with the navigation constellations, provided that accidental breakups are prevented.

Robustness analysis of culturing perturbations on Escherichia coli colony biofilm beta-lactam and aminoglycoside antibiotic tolerance

BackgroundBiofilms are ubiquitous. For instance, the majority of medical infections are thought to involve biofilms. However even after decades of investigation, the in vivo efficacy of many antimicrobial strategies is still debated suggesting there is a need for better understanding of biofilm antimicrobial tolerances. The current study's goal is to characterize the robustness of biofilm antibiotic tolerance to medically and industrially relevant culturing perturbations. By definition, robust systems will return similar, predictable responses when perturbed while non-robust systems will return very different and potentially unpredictable responses. The predictability of an antibiotic tolerance response is essential to developing, testing, and employing antimicrobial strategies.ResultsThe antibiotic tolerance of Escherichia coli colony biofilms was tested against beta-lactam and aminoglycoside class antibiotics. Control scenario tolerances were compared to tolerances under culturing perturbations including 1) different nutritional environments 2) different temperatures 3) interruption of cellular quorum sensing and 4) different biofilm culture ages. Here, antibiotic tolerance was defined in terms of culturable biofilm cells recovered after a twenty four hour antibiotic treatment.Colony biofilm antibiotic tolerances were not robust to perturbations. Altering basic culturing parameters like nutritional environment or temperature resulted in very different, non-intuitive antibiotic tolerance responses. Some minor perturbations like increasing the glucose concentration from 0.1 to 1 g/L caused a ten million fold difference in culturable cells over a twenty four hour antibiotic treatment.ConclusionsThe current study presents a basis for robustness analysis of biofilm antibiotic tolerance. Biofilm antibiotic tolerance can vary in unpredictable manners based on modest changes in culturing conditions. Common antimicrobial testing methods, which only consider a single culturing condition, are not desirable since slight culturing variations can lead to very different outcomes. The presented data suggest it is essential to test antimicrobial strategies over a range of culturing perturbations relevant to the targeted application. In addition, the highly dynamic antibiotic tolerance responses observed here may explain why some current antimicrobial strategies occasionally fail.