Oncogene-mediated nuclear accumulation of lactate promotes epigenetic alterations to induce cancer cell proliferation.

Homeobox gene families are associated with embryonic development and organogenesis. Pieces of evidence suggest that these Homeobox genes are also crucial in facilitating oncogenesis when mutated or overexpressed. Paired homeodomain transcription factor-2 (PITX2), one of the members of this family, is involved in oncogenic regulation apart from its different development regulatory functions. PITX2 has been earlier shown to induce ovarian cancer cell proliferation through the activation of different signaling cascades. Increased cancer cell proliferation requires a constant supply of nutrients for both adenosine triphosphate and biomass synthesis, which is facilitated by altered cancer cell metabolism that includes enhanced glucose uptake and increased glycolytic rate. This present study highlights the involvement of PITX2 in enhancing the cellular glycolysis pathway in ovarian cancer cells through protein kinase B-phosphorylation (phospho-AKT). PITX2 expression correlates positively with that of the glycolytic rate-determining enzyme, lactate dehydrogenase-A (LDHA), in both high-grade serous ovarian cancer tissues and common ovarian cancer cell lines. Interestingly, transient localization of enzymatically active LDHA in the nucleus was observed in PITX2-overexpressed ovarian cancer cells. This nuclear LDHA produces higher concentrations of the glycolytic end product, lactate, which accumulates in the nuclear compartment resulting in decreased histone deacetylase (HDAC1/2) expression and increased histone acetylation at H3/H4. However, the mechanistic details of lactate-HDAC interaction are still elusive in the earlier reports. Our in silico studies elaborated on the interaction dynamics of lactate in the HDAC catalytic core through ligand-binding studies and molecular dynamics simulation approaches. Blocking lactate production by silencing LDHA reduced cancer cell proliferation. Thus, PITX2-induced epigenetic changes can lead to high cellular proliferation and increase the size of tumors in syngeneic mice as well. Taken together, this is the first report of its kind to show that the developmental regulatory homeobox gene PITX2 could enhance oncogenesis through enhanced glycolysis of tumor cells followed by epigenetic modifications.

Coupling conditions for globally stable and robust synchrony of chaotic systems.

We propose a set of general coupling conditions to select a coupling profile (a set of coupling matrices) from the linear flow matrix of dynamical systems for realizing global stability of complete synchronization (CS) in identical systems and robustness to parameter perturbation. The coupling matrices define the coupling links between any two oscillators in a network that consists of a conventional diffusive coupling link (self-coupling link) as well as a cross-coupling link. The addition of a selective cross-coupling link in particular plays constructive roles that ensure the global stability of synchrony and furthermore enables robustness of synchrony against small to nonsmall parameter perturbation. We elaborate the general conditions for the selection of coupling profiles for two coupled systems, three- and four-node network motifs analytically as well as numerically using benchmark models, the Lorenz system, the Hindmarsh-Rose neuron model, the Shimizu-Morioka laser model, the Rössler system, and a Sprott system. The role of the cross-coupling link is, particularly, exemplified with an example of a larger network, where it saves the network from a breakdown of synchrony against large parameter perturbation in any node. The perturbed node in the network transits from CS to generalized synchronization (GS) when all the other nodes remain in CS. The GS is manifested by an amplified response of the perturbed node in a coherent state.

Emergent hybrid synchronization in coupled chaotic systems.

We evidence an interesting kind of hybrid synchronization in coupled chaotic systems where complete synchronization is restricted to only a subset of variables of two systems while other subset of variables may be in a phase synchronized state or desynchronized. Such hybrid synchronization is a generic emergent feature of coupled systems when a controller based coupling, designed by the Lyapunov function stability, is first engineered to induce complete synchronization in the identical case, and then a large parameter mismatch is introduced. We distinguish between two different hybrid synchronization regimes that emerge with parameter perturbation. The first, called hard hybrid synchronization, occurs when the coupled systems display global phase synchronization, while the second, called soft hybrid synchronization, corresponds to a situation where, instead, the global synchronization feature no longer exists. We verify the existence of both classes of hybrid synchronization in numerical examples of the Rössler system, a Lorenz-like system, and also in electronic experiment.

Amplified response in coupled chaotic oscillators by induced heterogeneity.

The phenomenon of emergent amplified response is reported in two unidirectionally coupled identical chaotic systems when heterogeneity as a parameter mismatch is introduced in a state of complete synchrony. The amplified response emerges from the interplay of heterogeneity and a type of cross-feedback coupling. It is reflected as an expansion of the response attractor in some directions in the state space of the coupled system. The synchronization manifold is simply rotated by the parameter detuning while its stability in the transverse direction is still maintained. The amplification factor is linearly related to the amount of parameter detuning. The phenomenon is elaborated with examples of the paradigmatic Lorenz system, the Shimizu-Morioka single-mode laser model, the Rössler system, and a Sprott system. Experimental evidence of the phenomenon is obtained in an electronic circuit. The method may provide an engineering tool for distortion-free amplification of chaotic signals.

Design and synthesis of regioisomeric triazole based peptidomimetic macrocycles and their dipole moment controlled self-assembly.

Two peptidomimetic macrocycles, regioisomeric in terms of the position of triazole/amide, have been synthesized. Both undergo self-assembly in a parallel manner but in solvents of opposite polarity, ascribed to (ß, ß) and (ß-D, ß-L) hydrogen bonding leading to formation of two different unique classes of organic nanostructures.

Enhancing synchrony in chaotic oscillators by dynamic relaying.

In a chain of mutually coupled oscillators, the coupling threshold for synchronization between the outermost identical oscillators decreases when a type of impurity (in terms of parameter mismatch) is introduced in the inner oscillator(s). The outer oscillators interact indirectly via dynamic relaying, mediated by the inner oscillator(s). We confirm this enhancing of critical coupling in the chaotic regimes of the Lorenz system, in the Rössler system in the absence of coupling delay, and in the Mackey-Glass system with delay coupling. The enhancing effect is experimentally verified in the electronic circuit of Rössler oscillators.

Simultaneous parallel and antiparallel self-assembly in a triazole/amide macrocycle conformationally homologous to D-,L-α-amino acid based cyclic peptides: NMR and molecular modeling study.

A 1,4-linked triazole/amide based peptidomimetic macrocycle, synthesized from a triazole amide oligomer of cis-furanoid sugar triazole amino acids, possesses a conformation resembling the D-,L-α-amino acid based cyclic peptides despite having uniform backbone chirality. It undergoes a unique mode of self-assembly through an antiparallel backbone to backbone intermolecular H-bonding involving amide NH and triazole N2/N3 as well as parallel stacking via amide NH and carbonyl oxygen H-bonding, leading to the formation of a tubular nanostructure.

Engineering synchronization of chaotic oscillators using controller based coupling design.

We propose a general formulation of coupling for engineering synchronization in chaotic oscillators for unidirectional as well as bidirectional mode. In the synchronization regimes, it is possible to amplify or to attenuate a chaotic attractor with respect to other chaotic attractors. Numerical examples are presented for a Lorenz system, Rössler oscillator, and a Sprott system. We physically realized the controller based coupling design in electronic circuits to verify the theory. We extended the theory to a network of coupled oscillators and provided a numerical example with four Sprott oscillators.

Designing coupling for synchronization and amplification of chaos.

We propose a design of coupling for stable synchronization and antisynchronization in chaotic systems under parameter mismatch. The antisynchronization is independent of the specific symmetry (reflection symmetry, axial symmetry, or other) of a dynamical system. In the synchronization regimes, we achieve amplification (attenuation) of a chaotic driver in a response oscillator. Numerical examples of a Lorenz system, Rössler oscillator, and Sprott system are presented. Experimental evidence is shown using an electronic version of the Sprott system.