Nuclear magnetic resonance chemical shifts with the statistical average of orbital-dependent model potentials in Kohn-Sham density functional theory

The performance of the SAOP potential for the calculation of NMR chemical shifts was evaluated. SAOP results show considerable improvement with respect to previous potentials, like VWN or BP86, at least for the carbon, nitrogen, oxygen, and fluorine chemical shifts. Furthermore, a few NMR calculations carried out on third period atoms (S, P, and Cl) improved when using the SAOP potential

The dependent variable problem in quantitative studies of Active Labour Market Programmes: uncovering hidden dynamics?

The question of what explains variation in expenditures on Active Labour Market Programs (ALMPs) has attracted significant scholarship in recent years. Significant insights have been gained with respect to the role of employers, unions and dual labour markets, openness, and partisanship. However, there remain significant disagreements with respects to key explanatory variables such the role of unions or the impact of partisanship. Qualitative studies have shown that there are both good conceptual reasons as well as historical evidence that different ALMPs are driven by different dynamics. There is little reason to believe that vastly different programs such as training and employment subsidies are driven by similar structural, interest group or indeed partisan dynamics. The question is therefore whether different ALMPs have the same correlation with different key explanatory variables identified in the literature? Using regression analysis, this paper shows that the explanatory variables identified by the literature have different relation to distinct ALMPs. This refinement adds significant analytical value and shows that disagreements are at least partly due to a dependent variable problem of ‘over-aggregation’.

Frazil dynamics and precipitation in a water column with depth-dependent supercooling

A morphological instability of a mushy layer due to a forced flow in the melt is analysed. The instability is caused by flow induced in the mushy layer by Bernoulli suction at the crests of a sinusoidally perturbed mush–melt interface. The flow in the mushy layer advects heat away from crests which promotes solidification. Two linear stability analyses are presented: the fundamental mechanism for instability is elucidated by considering the case of uniform flow of an inviscid melt; a more complete analysis is then presented for the case of a parallel shear flow of a viscous melt. The novel instability mechanism we analyse here is contrasted with that investigated by Gilpin et al. (1980) and is found to be more potent for the case of newly forming sea ice.

Unrestricted Skyrme-tensor time-dependent Hartree-Fock model and its application to the nuclear response from spherical to triaxial nuclei

The nuclear time-dependent Hartree-Fock model formulated in three-dimensional space, based on the full standard Skyrme energy density functional complemented with the tensor force, is presented. Full self-consistency is achieved by the model. The application to the isovector giant dipole resonance is discussed in the linear limit, ranging from spherical nuclei (16O and 120Sn) to systems displaying axial or triaxial deformation (24Mg, 28Si, 178Os, 190W and 238U). Particular attention is paid to the spin-dependent terms from the central sector of the functional, recently included together with the tensor. They turn out to be capable of producing a qualitative change on the strength distribution in this channel. The effect on the deformation properties is also discussed. The quantitative effects on the linear response are small and, overall, the giant dipole energy remains unaffected. Calculations are compared to predictions from the (quasi)-particle random-phase approximation and experimental data where available, finding good agreement

1,8-Cineol inhibits nuclear translocation of NF-κB p65 and NF-κB-dependent transcriptional activity

Natural plant-derived products are commonly applied to treat a broad range of human diseases, including cancer as well as chronic and acute airway inflammation. In this regard, the monoterpene oxide 1,8-cineol, the active ingredient of the clinically approved drug Soledum®, is well-established for the therapy of airway diseases, such as chronic sinusitis and bronchitis, chronic obstructive pulmonary disease and bronchial asthma. Although clinical trials underline the beneficial effects of 1,8-cineol in treating inflammatory diseases, the molecular mode of action still remains unclear. Here, we demonstrate for the first time a 1,8-cineol-depending reduction of NF-κB-activity in human cell lines U373 and HeLa upon stimulation using lipopolysaccharides (LPS). Immunocytochemistry further revealed a reduced nuclear translocation of NF-κB p65, while qPCR and western blot analyses showed strongly attenuated expression of NF-κB target genes. Treatment with 1,8-cineol further led to increased protein levels of IκBα in an IKK-independent matter, while FRET-analyses showed restoring of LPS-associated loss of interaction between NF-κB p65 and IκBα. We likewise observed reduced amounts of phosphorylated c-Jun N-terminal kinase 1/2 protein in U373 cells after exposure to 1,8-cineol. In addition, 1,8-cineol led to decreased amount of nuclear NF-κB p65 and reduction of its target gene IκBα at protein level in human peripheral blood mononuclear cells. Our findings suggest a novel mode of action of 1,8-cineol through inhibition of nuclear NF-κB p65 translocation via IκBα resulting in decreased levels of proinflammatory NF-κB target genes and may therefore broaden the field of clinical application of this natural drug for treating inflammatory diseases.

Only subtle protein conformational adaptations are required for ligand binding to thyroid hormone receptors: Simulations using a novel multipoint steered molecular dynamics approach

Thyroid hormone receptors (TR) are hormone-dependent transcription regulators that play a major role in human health, development, and metabolic functions. The thyroid hormone resistance syndrome, diabetes, obesity, and some types of cancer are just a few examples of important diseases that are related to TR malfunctioning, particularly impaired hormone binding. Ligand binding to and dissociation from the receptor ultimately control gene transcription and, thus, detailed knowledge of binding and release mechanisms are fundamental for the comprehension of the receptor`s biological function and development of pharmaceuticals. In this work, we present the first computational study of ligand entry into the ligand binding domain (LBD) of a nuclear receptor. We report molecular dynamics simulations of ligand binding to TRs using a generalization of the steered molecular dynamics technique designed to perform single-molecule pulling simulations along arbitrarily nonlinear driving pathways. We show that only gentle protein movements and conformational adaptations are required for ligand entry into the LBDs and that the magnitude of the forces applied to assist ligand binding are of the order of the forces involved in ligand dissociation. Our simulations suggest an alternative view for the mechanisms ligand binding and dissociation of ligands from nuclear receptors in which ligands can simply diffuse through the protein surface to reach proper positioning within the binding pocket. The proposed picture indicates that the large-amplitude protein motions suggested by the apo- and holo-RXR alpha crystallographic structures are not required, reconciling conformational changes of LBDs required for ligand entry with other nuclear receptors apo-structures that resemble the ligand-bound LBDs.

Ligand dissociation from estrogen receptor is mediated by receptor dimerization: Evidence from molecular dynamics simulations

Estrogen Receptor (ER) is an important target for pharmaceutical design. Like other ligand-dependent transcription factors, hormone binding regulates ER transcriptional activity. Nevertheless, the mechanisms by which ligands enter and leave ERs and other nuclear receptors remain poorly understood. Here, we report results of locally enhanced sampling molecular dynamics simulations to identify dissociation pathways of two ER ligands [the natural hormone 17 beta-estradiol (E-2) and the selective ER modulator raloxifene (RAL)] from the human ER alpha ligand-binding domain in monomeric and dimeric forms. E-2 dissociation occurs via three different pathways in ER monomers. One resembles the mousetrap mechanism (Path I), involving repositioning of helix 12 (H12), others involve the separation of H8 and H11 (Path II), and a variant of this pathway at the bottom of the ligand-binding domain (Path II`). RAL leaves the receptor through Path I and a Path I variant in which the ligand leaves the receptor through the loop region between H11 and H12 (Path I`). Remarkably, ER dimerization strongly suppresses Paths II and II` for E-2 dissociation and modifies RAL escape routes. We propose that differences in ligand release pathways detected in the simulations for ER monomers and dimers provide an explanation for previously observed effects of ER quaternary state on ligand dissociation rates and suggest that dimerization may play an important, and hitherto unexpected, role in regulation of ligand dissociation rates throughout the nuclear receptor family.

The effects of anticalcification treatments and hydration on the molecular dynamics of bovine pericardium collagen as revealed by (13)C solid-state NMR

This article describes a solid-state NMR (SSNMR) investigation of the influence of hydration and chemical cross-linking on the molecular dynamics of the constituents of the bovine pericardium (BP) tissues and its relation to the mechanical properties of the tissue. Samples of natural phenetylamine-diepoxide (DE)- and glutaraldehyde (GL)-fixed BP were investigated by (13)C cross-polarization SSNMR to probe the dynamics of the collagen, and the results were correlated to the mechanical properties of the tissues, probed by dynamical mechanical analysis. For samples of natural BP, the NMR results show that the higher the hydration level the more pronounced the molecular dynamics of the collagen backbone and sidechains, decreasing the tissue`s elastic modulus. In contrast, in DE- and GL-treated samples, the collagen molecules are more rigid, and the hydration seems to be less effective in increasing the collagen molecular dynamics and reducing the mechanical strength of the samples. This is mostly attributed to the presence of cross-links between the collagen plates, which renders the collagen mobility less dependent on the water absorption in chemically treated samples. Copyright (C) 2010 John Wiley & Sons, Ltd.

A nuclear magnetic resonance study of 7Li dynamics in polyether-urethane based solid polymer electrolytes

Nuclear magnetic resonance (NMR) is a technique that allows the probing of the dynamics of specific magnetically active nuclei. In the present study a polyethylene glycol network containing varying concentrations of LiClO₄ have been studied using ⁷Li NMR relaxation techniques. A plasticiser, tetraglyme, has been added to several samples to improve the mobility of the polymer and thus of the ionic species. The effects of tetraglyme and salt concentration on the cationic mobility and environment have been investigated using T₁ and T₂ relaxation experiments, with the presence of two cationic species of differing relaxation times (and possibly mobility) reported. The results are discussed with relevance to conductivity measurements made on similar samples.

Sodium ion dynamics in a sulfonate based ionomer system studied by 23Na solid-state nuclear magnetic resonance and impedance spectroscopy

A poly(2-acrylamido-2-methyl-1-propane-sulphonate) (PAMPS) ionomer containing both sodium and quaternary ammonium cations functionalised with an ether group, has been characterised in terms of its thermal properties, ionic conductivity and sodium ion dynamics. The ether oxygen was incorporated to reduce the Na+ association with the anionic sulfonate groups tethered to the polymer backbone, thereby promoting ion dissociation and ultimately enhancing the ionic conductivity. This functionalised ammonium cation led to a significant reduction in the ionomer Tg compared to an analogue system without an ether group, resulting in an increase in ionic conductivity of approximately four orders of magnitude. The sodium ion dynamics were probed by 23Na solid-state NMR, which allowed the signals from the dissociated (mobile) and bound Na+ cations to be distinguished. This demonstrates the utility of 23Na solid-state NMR as a probe of sodium dynamics in ionomer systems.

Culture-dependent and culture-independent characterization of microorganisms associated with Aedes aegypti (Diptera: Culicidae) (L.) and dynamics of bacterial colonization in the midgut

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

CHARGED PARTICLE DYNAMICS IN TIME DEPENDENT MAGNETIC FIELDS

In this work we study the behavior of charged particles immersed in a peculiar configuration of magnetic fields, which has a main constant field B(0) and a superimposed, transversal perturbation field B(1) sin(omega(p)t), with B(1) << B(0). By taking Cartesian coordinates and placing B(0) along the z axis and B(1) sin (omega(p)t) on the x axis, an analytical solution for y(t) may be obtained by solving an integrodifferential equation. Besides, the solution z(t) also exhibits a very interesting dynamics, and the entire system is conditioned by resonances between the particle orbit frequencies and the frequency of the magnetic transversal perturbation, omega(p). In this work we also discuss numerical simulations for the related particle trajectories, as well as potential applications in the context of separation phenomena.

PRODUCTION of THERMAL PHOTONS IN VISCOUS FLUID DYNAMICS WITH TEMPERATURE-DEPENDENT SHEAR VISCOSITY

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Scaling dynamics for a particle in a time-dependent potential well

Some dynamical properties for a classical particle confined in an infinitely deep box of potential containing a periodically oscillating square well are studied. The dynamics of the system is described by using a two-dimensional non-linear area-preserving map for the variables energy and time. The phase space is mixed and the chaotic sea is described using scaling arguments. Scaling exponents are obtained as a function of all the control parameters, extending the previous results obtained in the literature. (c) 2012 Elsevier B.V. All rights reserved.

CRITICAL EXPONENTS and SCALING PROPERTIES FOR THE CHAOTIC DYNAMICS of A PARTICLE IN A TIME-DEPENDENT POTENTIAL BARRIER

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)