Identification of potential edible spices as EGFR and EGFR mutant T790M/L858R inhibitors by structure-based virtual screening and molecular dynamics.

Epidermal growth factor receptor (EGFR) tyrosine kinases are overexpressed in several human cancers and could serve as a promising anti-cancer drug target. With this in view, the main aim of the present study was to identify spices having the potential to inhibit EGFR tyrosine kinase. The structure-based virtual screening of spice database consisting of 1439 compounds with EGFR tyrosine kinase (PDB ID: 3W32) was carried out using Glide. Top scored 18 hits (XP Glide Score ≥ -10.0 kcal/mol) was further docked with three EGFR tyrosine kinases and three EGFR T790M/L858R mutants using AutodockVina, followed by ADME filtration. The best three hits were further refined by Molecular Dynamics (MD) simulation and MM-GBSA-based binding energy calculation. The overall docking results of the selected hits with both EGFR and EGFR T790M/L858R were quite satisfactory and showed strong binding compared to the three coligands. Detailed MD analysis of CL_07, AC_11 and AS_49 also showed the stability of the protein-ligand complexes. Moreover, the hits were drug-like, and MM-GBSA binding free energy of CL_07 and AS_49 was established to be far better. AC_11 was found to be similar to the known inhibitor Gefitinib. Most of the potential hits are available in Allium cepa, CL_07 and AS_49 available in Curcuma longa and Allium sativum, respectively. Therefore, these three spices could be used as a potential therapeutic candidate against cancer caused by overexpression of EGFR after validation of the observations of this study in in-vitro experiments. Further extensive work is needed to improve the scaffolds CL_07, AC_11, AC_17, and AS_49 as potential anti-cancer drugs.Communicated by Ramaswamy H. Sarma.

Impact of phase lag on synchronization in frustrated Kuramoto model with higher-order interactions.

The study of first order transition (explosive synchronization) in an ensemble (network) of coupled oscillators has been the topic of paramount interest among the researchers for more than one decade. Several frameworks have been proposed to induce explosive synchronization in a network and it has been reported that phase frustration in a network usually suppresses first order transition in the presence of pairwise interactions among the oscillators. However, on the contrary, by considering networks of phase frustrated coupled oscillators in the presence of higher-order interactions (up to 2-simplexes) we show here, under certain conditions, phase frustration can promote explosive synchronization in a network. A low-dimensional model of the network in the thermodynamic limit is derived using the Ott-Antonsen ansatz to explain this surprising result. Analytical treatment of the low-dimensional model, including bifurcation analysis, explains the apparent counter intuitive result quite clearly.

Perfect synchronization in complex networks with higher-order interactions.

Achieving perfect synchronization in a complex network, specially in the presence of higher-order interactions (HOIs) at a targeted point in the parameter space, is an interesting, yet challenging task. Here we present a theoretical framework to achieve the same under the paradigm of the Sakaguchi-Kuramoto (SK) model. We analytically derive a frequency set to achieve perfect synchrony at some desired point in a complex network of SK oscillators with higher-order interactions. Considering the SK model with HOIs on top of the scale-free, random, and small world networks, we perform extensive numerical simulations to verify the proposed theory. Numerical simulations show that the analytically derived frequency set not only provides stable perfect synchronization in the network at a desired point but also proves to be very effective in achieving a high level of synchronization around it compared to the other choices of frequency sets. The stability and the robustness of the perfect synchronization state of the system are determined using the low-dimensional reduction of the network and by introducing a Gaussian noise around the derived frequency set, respectively.

Crisis-induced flow reversals in magnetoconvection.

We report the occurrence of flow reversals induced by the attractor-merging crisis in Rayleigh-Bénard convection of electrically conducting low-Prandtl-number fluids in the presence of a uniform external horizontal magnetic field. The simultaneous collision of two coexisting chaotic attractors with an unstable fixed point and its associated stable manifold takes place in the higher-dimensional phase space of the system, leading to a single merged chaotic attractor. The effect of strength of the magnetic field on the flow reversal phenomena is also explored in detail.

Transitions in overstable rotating magnetoconvection.

The classical Rayleigh-Bénard convection (RBC) system is known to exhibit either subcritical or supercritical transition to convection in the presence or absence of rotation and/or magnetic field. However, the simultaneous exhibition of subcritical and supercritical branches of convection in plane layer RBC depending on the initial conditions, to the best of our knowledge, has not been reported so far. Here, we report the phenomenon of simultaneous occurrence of subcritical and supercritical branches of convection in overstable RBC of electrically conducting low Prandtl number fluids (liquid metals) in the presence of an external uniform horizontal magnetic field and rotation about the vertical axis. Extensive three-dimensional (3D) direct numerical simulations (DNS) and low-dimensional modeling of the system, performed in the ranges 750≤Ta≤3000 and 0

Amplification of explosive width in complex networks.

We present an adaptive coupling strategy to induce hysteresis/explosive synchronization in complex networks of phase oscillators (Sakaguchi-Kuramoto model). The coupling strategy ensures explosive synchronization with significant explosive width enhancement. Results show the robustness of the strategy, and the strategy can diminish (by inducing enhanced hysteresis loop) the contrarian impact of phase frustration in the network, irrespective of the network structure or frequency distributions. Additionally, we design a set of frequency for the oscillators, which eventually ensure complete in-phase synchronization behavior among these oscillators (with enhanced explosive width) in the case of adaptive-coupling scheme. Based on a mean-field analysis, we develop a semi-analytical formalism, which can accurately predict the backward transition of the synchronization order parameter.

Synchronization transition in Sakaguchi-Kuramoto model on complex networks with partial degree-frequency correlation.

We investigate transition to synchronization in the Sakaguchi-Kuramoto (SK) model on complex networks analytically as well as numerically. Natural frequencies of a percentage (f) of higher degree nodes of the network are assumed to be correlated with their degrees and that of the remaining nodes are drawn from some standard distribution, namely, Lorentz distribution. The effects of variation of f and phase frustration parameter α on transition to synchronization are investigated in detail. Self-consistent equations involving critical coupling strength (λc) and group angular velocity (Ωc) at the onset of synchronization have been derived analytically in the thermodynamic limit. For the detailed investigation, we considered the SK model on scale-free (SF) as well as Erdos-Rényi (ER) networks. Interestingly, explosive synchronization (ES) has been observed in both networks for different ranges of values of α and f. For SF networks, as the value of f is set within 10%≤f≤70%, the range of the values of α for existence of the ES is greatly enhanced compared to the fully degree-frequency correlated case when scaling exponent γ<3. ES is also observed in SF networks with γ>3, which is never observed in fully degree-frequency correlated environment. On the other hand, for random networks, ES observed is in a narrow window of α when the value of f is taken within 30%≤f≤50%. In all the cases, critical coupling strengths for transition to synchronization computed from the analytically derived self-consistent equations show a very good agreement with the numerical results. Finally, we observe ES in the metabolic network of the roundworm Caenorhabditis elegans in partially degree-frequency correlated environment.

Emergent dynamics in delayed attractive-repulsively coupled networks.

We investigate different emergent dynamics, namely, oscillation quenching and revival of oscillation, in a global network of identical oscillators coupled with diffusive (positive) delay coupling as it is perturbed by symmetry breaking localized repulsive delayed interaction. Starting from the oscillatory state (OS), we systematically identify three types of transition phenomena in the parameter space: (1) The system may reach inhomogeneous steady states from the homogeneous steady state sometimes called as the transition from amplitude death (AD) to oscillation death (OD) state, i.e., OS-AD-OD scenario, (2) Revival of oscillation (OS) from the AD state (OS-AD-OS), and (3) Emergence of the OD state from the oscillatory state (OS) without passing through AD, i.e., OS-OD. The dynamics of each node in the network is assumed to be governed either by the identical limit cycle Stuart-Landau system or by the chaotic Rössler system. Based on clustering behavior observed in the oscillatory network, we derive a reduced low-dimensional model of the large network. Using the reduced model, we investigate the effect of time delay on these transitions and demarcate OS, AD, and OD regimes in the parameter space. We also explore and characterize the bifurcation transitions present in both systems. The generic behavior of the low dimensional model and full network is found to match satisfactorily.

Dragon-king-like extreme events in coupled bursting neurons.

We present evidence of extreme events in two Hindmarsh-Rose (HR) bursting neurons mutually interacting via two different coupling configurations: chemical synaptic- and gap junctional-type diffusive coupling. A dragon-king-like probability distribution of the extreme events is seen for combinations of synaptic coupling where small- to medium-size events obey a power law and the larger events that cross an extreme limit are outliers. The extreme events originate due to instability in antiphase synchronization of the coupled systems via two different routes, intermittency and quasiperiodicity routes to complex dynamics for purely excitatory and inhibitory chemical synaptic coupling, respectively. For a mixed type of inhibitory and excitatory chemical synaptic interactions, the intermittency route to extreme events is only seen. Extreme events with our suggested distribution is also seen for gap junctional-type diffusive, but repulsive, coupling where the intermittency route to complexity is found. A simple electronic experiment using two diffusively coupled analog circuits of the HR neuron model, but interacting in a repulsive way, confirms occurrence of the dragon-king-like extreme events.

Extreme events in the forced Liénard system.

We observe extremely large amplitude intermittent spikings in a dynamical variable of a periodically forced Liénard-type oscillator and characterize them as extreme events, which are rare, but recurrent and larger in amplitude than a threshold. The extreme events occur via two processes, an interior crisis and intermittency. The probability of occurrence of the events shows a long-tail distribution in both the cases. We provide evidence of the extreme events in an experiment using an electronic analog circuit of the Liénard oscillator that shows good agreement with our numerical results.

Transition to synchrony in degree-frequency correlated Sakaguchi-Kuramoto model.

We investigate transition to synchrony in degree-frequency correlated Sakaguchi-Kuramoto (SK) model on complex networks both analytically and numerically. We analytically derive self-consistent equations for group angular velocity and order parameter for the model in the thermodynamic limit. Using the self-consistent equations we investigate transition to synchronization in SK model on uncorrelated scale-free (SF) and Erdos-Rényi (ER) networks in detail. Depending on the degree distribution exponent (γ) of SF networks and phase-frustration parameter, the population undergoes from first-order transition [explosive synchronization (ES)] to second-order transition and vice versa. In ER networks transition is always second order irrespective of the values of the phase-lag parameter. We observe that the critical coupling strength for the onset of synchronization is decreased by phase-frustration parameter in case of SF network where as in ER network, the phase-frustration delays the onset of synchronization. Extensive numerical simulations using SF and ER networks are performed to validate the analytical results. An analytical expression of critical coupling strength for the onset of synchronization is also derived from the self-consistent equations considering the vanishing order parameter limit.

Bursting dynamics in a population of oscillatory and excitable Josephson junctions.

We report an emergent bursting dynamics in a globally coupled network of mixed population of oscillatory and excitable Josephson junctions. The resistive-capacitive shunted junction (RCSJ) model of the superconducting device is considered for this study. We focus on the parameter regime of the junction where its dynamics is governed by the saddle-node on invariant circle (SNIC) bifurcation. For a coupling value above a threshold, the network splits into two clusters when a reductionism approach is applied to reproduce the bursting behavior of the large network. The excitable junctions effectively induce a slow dynamics on the oscillatory units to generate parabolic bursting in a broad parameter space. We reproduce the bursting dynamics in a mixed population of dynamical nodes of the Morris-Lecar model.

Diverse routes of transition from amplitude to oscillation death in coupled oscillators under additional repulsive links.

We report the existence of diverse routes of transition from amplitude death to oscillation death in three different diffusively coupled systems, which are perturbed by a symmetry breaking repulsive coupling link. For limit-cycle systems the transition is through a pitchfork bifurcation, as has been noted before, but in chaotic systems it can be through a saddle-node or a transcritical bifurcation depending on the nature of the underlying dynamics of the individual systems. The diversity of the routes and their dependence on the complex dynamics of the coupled systems not only broadens our understanding of this important phenomenon but can lead to potentially new practical applications.

Transition from amplitude to oscillation death in a network of oscillators.

We report a transition from a homogeneous steady state (HSS) to inhomogeneous steady states (IHSSs) in a network of globally coupled identical oscillators. We perturb a synchronized population of oscillators in the network with a few local negative or repulsive mean field links. The whole population splits into two clusters for a certain number of repulsive mean field links and a range of coupling strength. For further increase of the strength of interaction, these clusters collapse into a HSS followed by a transition to IHSSs where all the oscillators populate either of the two stable steady states. We analytically determine the origin of HSS and its transition to IHSS in relation to the number of repulsive mean-field links and the strength of interaction using a reductionism approach to the model network. We verify the results with numerical examples of the paradigmatic Landau-Stuart limit cycle system and the chaotic Rössler oscillator as dynamical nodes. During the transition from HSS to IHSSs, the network follows the Turing type symmetry breaking pitchfork or transcritical bifurcation depending upon the system dynamics.

Oscillation death in diffusively coupled oscillators by local repulsive link.

A death of oscillation is reported in a network of coupled synchronized oscillators in the presence of additional repulsive coupling. The repulsive link evolves as an averaging effect of mutual interaction between two neighboring oscillators due to a local fault and the number of repulsive links grows in time when the death scenario emerges. Analytical condition for oscillation death is derived for two coupled Landau-Stuart systems. Numerical results also confirm oscillation death in chaotic systems such as a Sprott system and the Rössler oscillator. We explore the effect in large networks of globally coupled oscillators and find that the number of repulsive links is always fewer than the size of the network.

Pattern dynamics near inverse homoclinic bifurcation in fluids.

We report the pattern dynamics in the vicinity of an inverse homoclinic bifurcation in an extended dissipative system. We observe, in direct numerical simulations of three dimensional Rayleigh-Bénard convection with stress-free top and bottom plates, a spontaneous breaking of a competition of two mutually perpendicular sets of oscillating cross rolls to one of two possible sets of oscillating cross rolls as the Rayleigh number is raised above a critical value. The time period of the oscillating cross-roll patterns diverges and shows scaling behavior near the bifurcation point. This is an example of a transition from nonlocal to local pattern dynamics near an inverse homoclinic bifurcation. We also present a simple four-mode model that captures the pattern dynamics quite well.

Lag synchronization and scaling of chaotic attractor in coupled system.

We report a design of delay coupling for lag synchronization in two unidirectionally coupled chaotic oscillators. A delay term is introduced in the definition of the coupling to target any desired lag between the driver and the response. The stability of the lag synchronization is ensured by using the Hurwitz matrix stability. We are able to scale up or down the size of a driver attractor at a response system in presence of a lag. This allows compensating the attenuation of the amplitude of a signal during transmission through a delay line. The delay coupling is illustrated with numerical examples of 3D systems, the Hindmarsh-Rose neuron model, the Rössler system, a Sprott system, and a 4D system. We implemented the coupling in electronic circuit to realize any desired lag synchronization in chaotic oscillators and scaling of attractors.

Dynamics of zero-Prandtl number convection near onset.

We present a detailed bifurcation scenario of zero-Prandtl number Rayleigh-Bénard convection using direct numerical simulations (DNS) and a 27-mode low-dimensional model containing the most energetic modes of DNS. The bifurcation analysis reveals a rich variety of convective flow patterns and chaotic solutions, some of which are common to that of the 13-mode model of Pal et al. [EPL 87, 54003 (2009)]. We also observed a set of periodic and chaotic wavy rolls in DNS and in the model similar to those observed in experiments and numerical simulations. The time period of the wavy rolls is closely related to the eigenvalues of the stability matrix of the Hopf bifurcation points at the onset of convection. This time period is in good agreement with the experimental results for low-Prandtl number fluids. The chaotic attractor of the wavy roll solutions is born through a quasiperiodic and phase-locking route to chaos.

Wavy stripes and squares in zero-Prandtl-number convection.

A simple model to explain the numerically observed behavior of chaotically varying stripes and square patterns in zero-Prandtl-number convection in Boussinesq fluid is presented. The nonlinear interaction of mutually perpendicular sets of wavy rolls, via higher-order modes, may lead to a competition between the two sets of rolls. The appearance of square patterns is due to a secondary forward bifurcation from a set of wavy rolls. The statistics of the spatially averaged energy signal shows a power-law behavior.