A Unified Genomic Mechanism of Cell-Fate Change

The purpose of our studies is to elucidate the nature of massive control of whole genome expression with a particular emphasis on cell-fate change. Whole genome expression is coordinated by the emergence of a critical point (CP: a peculiar set of bi-phasic genes) through the genome-engine. In response to stimuli, the genome expression self-organizes three critical states, each exhibiting distinct collective behaviors with its center of mass acting as a local attractor, coexisting with whole genome attractor (GA). Genome-engine mechanism accounts for local attractors interaction in phase space. The CP acts as the organizing center of cell-fate change, and its activation makes local perturbation spread over the genome affecting GA. The activation of CP is in turn elicited by hot-spots genes with elevated temporal variance, normally in charge to keep genome expression at pace with microenvironment fluctuations. When hot-spots oscillation exceeds a given threshold, the CP synchronizes with the GA driving genome expression state transition. The expression synchronization wave invading the entire genome depends on the power law fusion-bursting dynamics of silencing pericentromere-associated heterochromatin domains and the consequent folding-unfolding status of transcribing euchromatin domains. The proposed mechanism is a unified step toward a time-evolutional transition theory of biological regulation.

Long Time Behaviour of a Local Perturbation in the Isotropic XY Chain Under Periodic Forcing

We study the isotropic XY quantum spin chain with a time-periodic transverse magnetic field acting on a single site. The asymptotic dynamics is described by a highly resonant Floquet–Schrödinger equation, for which we show the existence of a periodic solution if the forcing frequency is away from a discrete set of resonances. This in turn implies the state of the quantum spin chain to be asymptotically a periodic function synchronised with the forcing, also at arbitrarily low non-resonant frequencies. The behaviour at the resonances remains a challenging open problem.

Galactic bar resonances inferred from kinematically hot stars in Gaia EDR3

ABSTRACT Using a numerical simulation of an isolated barred disc galaxy, we first demonstrate that the resonances of the inner bar structure induce more prominent features in the action space distribution for the kinematically hotter stars, which are less sensitive to the local perturbation, such as the transient spiral arms. Then, we analyse the action distribution for the kinematically hotter stars selected from the Gaia EDR3 data as the stars with higher values of radial and vertical actions. We find several resonance features, including two new features, in the angular momentum distribution similar to what are seen in our numerical simulations. We show that the bar pattern speeds of about Ωbar ∼ 34 and 42 km s−1 kpc−1 explain all these features equally well. The resonance features we find correspond to the inner 4:1, co-rotation (CR), outer 4:1, outer Lindblad, and outer 4:3 (CR, outer 4:1, outer Lindblad, outer 4:3, and outer 1:1) resonances, when Ωbar ∼ 34 (42) km s−1 kpc−1 is assumed.

The Optimal Lipid Chain Length of a Membrane-Permeabilizing Lipopeptide Results From the Balance of Membrane Partitioning and Local Damage

Pseudodesmin A (PSD) is a cyclic lipodepsipeptide produced by Pseudomonas that kills certain bacteria at MIC1/2 in the single micromolar range, probably by permeabilizing their cellular membranes. Synthetic PSD variants, where the native decanoic (C10) acyl chain is varied in length from C4 to C8 and C12 to C14 carbons, were described to be not or less active against a panel of gram-positive strains, as compared to native PSD-C10. Here, we test the membrane-permeabilizing activity of PSD-C4 through PSD-C14 in terms of calcein release from liposomes, which is characterized in detail by the fluorescence-lifetime based leakage assay. Antagonistic concentrations and their chain length dependence agree well for liposome leakage and antimicrobial activity. The optimal chain length is governed by a balance between membrane partitioning (favoring longer chains) and the local perturbation or “damage” inflicted by a membrane-bound molecule (weakening for longer chains). Local perturbation, in turn, may involve at least two modes of action. Asymmetry stress between outer and inner leaflet builds up as the lipopeptides enter the outer leaflet and when it reaches a system-specific stability threshold, it causes a transient membrane failure that allows for the flip of some molecules from the outer to the inner leaflet. This cracking-in may be accompanied by transient, incomplete leakage from the aqueous cores of the liposomes observed, typically, for some seconds or less. The mismatch of the lipopeptide with the lipid leaflet geometry, expressed for example in terms of a spontaneous curvature, has two effects. First, it affects the threshold for transient leakage as described. Second, it controls the rate of equilibrium leakage proceeding as the lipopeptide has reached sufficient local concentrations in both leaflets to form quasi-toroidal defects or pores. Both modes of action, transient and equilibrium leakage, synergize for intermediate chain lengths such as the native, i.e., for PSD-C10. These mechanisms may also account for the reported chain-length dependent specificities of antibiotic action against the target bacteria.

Plus and minus ends of microtubule respond asymmetrically to kinesin binding by a long range directionally driven allosteric mechanism

Many members in the kinesin superfamily walk predominantly towards the plus end of the microtubule (MT) in a hand-over-hand manner. Despite great progress in elucidating the mechanism of stepping kinetics, the origin of stepping directionality is not fully understood. To provide quantitative insights into this important issue, we represent the structures of conventional kinesin (Kin1), MT, and the Kin1-MT complex using the elastic network model, and calculate the residue-dependent responses to a local perturbation in these constructs. Fluctuations in the residues in the β domain of the α/β-tubulin are distinct from the α domain. Surprisingly, the Kin1-induced asymmetry, which is more pronounced in α/β-tubulin in the plus end of MT than in the minus end, propagates spatially across multiple α/β-tubulin dimers. Kin1 binding expands the MT lattice by mechanical stresses, resulting in a transition in the cleft of α/β tubulin dimer between a closed (CC for closed cleft) state (not poised for Kin1 to bind) to an open (OC for open cleft) binding competent state. The long-range asymmetric responses in the MT, leading to the creation of OC states with high probability in several α/β dimers on the plus end of the bound Kin1, is needed for the motor to take multiple steps towards the plus end of the MT. Reciprocally, kinesin binding to the MT stiffens the residues in the MT binding region, induces correlations between switches I and II in the motor, and enhances fluctuations in ADP and the residues in the binding pocket. Our findings explain both the directionality of stepping and MT effects on a key step in the catalytic cycle of Kin1.

A Scattering Problem for a Local Perturbation of an Open Periodic Waveguide

In this paper we consider the propagation of waves in an open waveguide in R^2 where the index of refraction is a local perturbation of a function which is periodic along the axis of the waveguide and equal to one outside a strip of finite width. Motivated by the limiting absorption principle (proven in an ealier paper by the author for the case of an open waveguide in the half space) we formulate a radiation condition which allows the existence of propagating modes and prove uniqueness, existence, and stability of a solution. In the last part we investigate the decay properties of the radiating part in the direction of periodicity and orthogonal to it.

Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition

Poxviruses are dangerous pathogens, which can cause fatal infection in unvaccinated individuals. The causative agent of smallpox in humans, variola virus, is closely related to the bovine vaccinia virus, yet the molecular basis of their selectivity is currently incompletely understood. Here, we examine the role of the electrostatics in the selectivity of the smallpox protein SPICE and vaccinia protein VCP toward the human and bovine complement protein C3b, a key component of the complement immune response. Electrostatic calculations, in-silico alanine-scan and electrostatic hotspot analysis, as introduced by Kieslich and Morikis (PLoS Comput. Biol. 2012), are used to assess the electrostatic complementarity and to identify sites resistant to local perturbation where the electrostatic potential is likely to be evolutionary conserved. The calculations suggest that the bovine C3b is electrostatically prone to selectively bind its VCP ligand. On the other hand, the human isoform of C3b exhibits a lower electrostatic complementarity toward its SPICE ligand. Yet, the human C3b displays a highly preserved electrostatic core, which suggests that this isoform could be less selective in binding different ligands like SPICE and the human Factor H. This is supported by experimental cofactor activity assays revealing that the human C3b is prone to bind both SPICE and Factor H, which exhibit diverse electrostatic properties. Additional investigations considering mutants of SPICE and VCP that revert their selectivity reveal an “electrostatic switch” into the central modules of the ligands, supporting the critical role of the electrostatics in the selectivity. Taken together, these evidences provide insights into the selectivity mechanism of the complement regulator proteins encoded by the variola and vaccinia viruses to circumvent the complement immunity and exert their pathogenic action. These fundamental aspects are valuable for the development of novel vaccines and therapeutic strategies.

Small defects reconstruction in waveguides from multifrequency one-side scattering data

<p style='text-indent:20px;'>Localization and reconstruction of small defects in acoustic or electromagnetic waveguides is of crucial interest in nondestructive evaluation of structures. The aim of this work is to present a new multi-frequency inversion method to reconstruct small defects in a 2D waveguide. Given one-side multi-frequency wave field measurements of propagating modes, we use a Born approximation to provide a <inline-formula><tex-math id="M1">\begin{document}$ \text{L}^2 $\end{document}</tex-math></inline-formula>-stable reconstruction of three types of defects: a local perturbation inside the waveguide, a bending of the waveguide, and a localized defect in the geometry of the waveguide. This method is based on a mode-by-mode spacial Fourier inversion from the available partial data in the Fourier domain. Indeed, in the available data, some high and low spatial frequency information on the defect are missing. We overcome this issue using both a compact support hypothesis and a minimal smoothness hypothesis on the defects. We also provide a suitable numerical method for efficient reconstruction of such defects and we discuss its applications and limits.</p>