Diverse mechanisms underlying the regulation of ion channels by carbon monoxide

Carbon monoxide (CO) is firmly established as an important, physiological signalling molecule as well as a potent toxin. Through its ability to bind metal-containing proteins, it is known to interfere with a number of intracellular signalling pathways, and such actions can account for its physiological and pathological effects. In particular, CO can modulate the intracellular production of reactive oxygen species, NO and cGMP levels, as well as regulate MAPK signalling. In this review, we consider ion channels as more recently discovered effectors of CO signalling. CO is now known to regulate a growing number of different ion channel types, and detailed studies of the underlying mechanisms of action are revealing unexpected findings. For example, there are clear areas of contention surrounding its ability to increase the activity of high conductance, Ca2+ -sensitive K+ channels. More recent studies have revealed the ability of CO to inhibit T-type Ca2+ channels and have unveiled a novel signalling pathway underlying tonic regulation of this channel. It is clear that the investigation of ion channels as effectors of CO signalling is in its infancy, and much more work is required to fully understand both the physiological and the toxic actions of this gas. Only then can its emerging use as a therapeutic tool be fully and safely exploited.

TNF-alpha mediated transport of NF-kappaB to the nucleus is independent of the cytoskeleton-based transport system in non-neuronal cells

In unstimulated cells, proteins of the nuclear factor kappaB (NF-kappaB) transcription factor family are sequestered in the cytoplasm through interactions with IkappaB inhibitor proteins. Tumor necrosis factor alpha (TNF-alpha) activates the degradation of IkappaB-alpha and the nuclear import of cytoplasmic NF-kappaB. Nuclear localization of numerous cellular proteins is mediated by the ability of the cytoskeleton, usually microtubules, to direct their perinuclear accumulation. In a former study we have shown that activated NF-kappaB rapidly moves from distal processes in neurons towards the nucleus. The fast transport rate suggests the involvement of motor proteins in the transport of NF-kappaB. Here we address the question how NF-kappaB arrives at the nuclear membrane before import in non-neuronal cells, i.e., by diffusion alone or with the help of active transport mechanisms. Using confocal microscopy imaging and analysis of nuclear protein extracts, we show that NF-kappaB movement through the cytoplasm to the nucleus is independent of the cytoskeleton, in the three cell lines investigated here. Additionally we demonstrate that NF-kappaB p65 is not associated with the dynein/dynactin molecular motor complex. We propose that cells utilize two distinct mechanisms of NF-kappaB transport: (1) signaling via diffusion over short distances in non-neuronal cells and (2) transport via motor proteins that move along the cytoskeleton in neuronal processes where the distances between sites of NF-kappaB activation and nucleus can be vast.

Growth and Melting of Metallic Nanoclusters in Glass: A Review of Recent Investigations

The mechanisms of nucleation and growth and the solid-to-liquid transition of metallic nanoclusters embedded in sodium borate glass were recently studied in situ via small-angle X-ray scattering (SAXS) and wide-an-le X-ray scattering (WAXS). SAXS results indicate that, under isothermal annealing conditions, the formation and growth of Bi or Ag nanoclusters embedded in sodium borate glass occurs through two successive stages after a short incubation period. The first stage is characterized by the nucleation and growth of spherical metal clusters promoted by the diffusion of Bi or Ag atoms through the initially supersaturated glass phase. The second stage is named the coarsening stage and occurs when the (Bi- or Ag-) doping level of the vitreous matrix is close to the equilibrium value. The experimental results demonstrated that, at advanced stages of the growth process, the time dependence of the average radius and density number of the clusters is in agreement with the classical Lifshitz-Slyozov-Waoner (LSW) theory. However, the radius distribution function is better described by a lognormal function than by the function derived from the theoretical LSW model. From the results of SAXS measurements at different temperatures, the activation energies for the diffusion of Ag and Bi through sodium borate glass were determined. In addition, via combination of the results of simultaneous WAXS and SAXS measurements at different temperatures, the crystallographic structure and the dependence of melting temperature T(m) on crystal radius R of Bi nanocrystals were established. The experimental results indicate that T(m) is a linear and decreasing function of nanocrystal reciprocal radius 1/R, in agreement with the Couchman and Jesser theoretical model. Finally, a weak contraction in the lattice parameters of Bi nanocrystals with respect to bulk crystals was established.

Determination of Very Slow Diffusion of Paramagnetic Ions by NMR Spectroscopy

In this paper, we propose a new method of measuring the very slow paramagnetic ion diffusion coefficient using a commercial high-resolution spectrometer. If there are distinct paramagnetic ions influencing the hydrogen nuclear magnetic relaxation time differently, their diffusion coefficients can be measured separately. A cylindrical phantom filled with Fricke xylenol gel solution and irradiated with gamma rays was used to validate the method. The Fricke xylenol gel solution was prepared with 270 Bloom porcine gelatin, the phantom was irradiated with gamma rays originated from a (60)Co source and a high-resolution 200 MHz nuclear magnetic resonance (NMR) spectrometer was used to obtain the phantom (1)H profile in the presence of a linear magnetic field gradient. By observing the temporal evolution of the phantom NMR profile, an apparent ferric ion diffusion coefficient of 0.50 mu m(2)/ms due to ferric ions diffusion was obtained. In any medical process where the ionizing radiation is used, the dose planning and the dose delivery are the key elements for the patient safety and success of treatment. These points become even more important in modern conformal radio therapy techniques, such as stereotactic radiosurgery, where the delivered dose in a single session of treatment can be an order of magnitude higher than the regular doses of radiotherapy. Several methods have been proposed to obtain the three-dimensional (3-D) dose distribution. Recently, we proposed an alternative method for the 3-D radiation dose mapping, where the ionizing radiation modifies the local relative concentration of Fe(2+)/Fe(3+) in a phantom containing Fricke gel and this variation is associated to the MR image intensity. The smearing of the intensity gradient is proportional to the diffusion coefficient of the Fe(3+) and Fe(2+) in the phantom. There are several methods for measurement of the ionic diffusion using NMR, however, they are applicable when the diffusion is not very slow.

The best are never normal : exploring the distribution of firm performance

Competitive Strategy literature predicts three different mechanisms of performance generation, thus distinguishing between firms that have competitive advantage, firms that have competitive disadvantage or firms that have neither. Nonetheless, previous works in the field have fitted a single normal distribution to model firm performance. Here, we develop a new approach that distinguishes among performance generating mechanisms and allows the identification of firms with competitive advantage or disadvantage. Theorizing on the positive feedback loops by which firms with competitive advantage have facilitated access to acquire new resources, we proposed a distribution we believe data on firm performance should follow. We illustrate our model by assessing its fit to data on firm performance, addressing its theoretical implications and comparing it to previous works.

Pool of Resistance Mechanisms to Glyphosate in Digitaria insularis

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Effect of density on population development in the Amazon River prawn Macrobrachium amazonicum

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

Influence of Heat Treatment on the Anelastic Properties of MgB(2)

The discovery of the superconductivity of MgB(2) was of great importance, because this material is one of the few known binary compounds and has one of the highest critical temperatures (39 degrees K). As MgB(2) is a granular compound, it is fundamentally important to understand the mechanisms of the interaction of the defects and the crystalline lattice, in addition to the eventual processes involving the grain boundaries that compose the material. In this sense, the mechanical spectroscopy measurements constitute a powerful tool for this study, because through them we can obtain important information about phase transitions, the behavior of interstitial or substitutional elements, dislocations, grain boundaries, diffusion, instabilities, and other imperfections of the lattice. For this paper, the samples were prepared using the PIT method and were characterized by density, X-ray diffraction, scanning electron microscopy, electric resistivity, magnetization, and mechanical spectroscopy. The samples were measured in their as-cast condition and after an ultra-high-vacuum heat treatment. The results showed complex spectra, in which were identified relaxation processes due to dislocation movement, interaction among interstitial elements and dislocations, auto-diffusion, and movement of grain boundaries. Some of these processes disappeared with the heat treatment.

Role of pressor mechanisms from the NTS and CVLM in control of arterial pressure

In the present study, we investigated the effects of inhibition of the caudal ventrolateral medulla (CVLM) with the GABA(A) agonist muscimol combined with the blockade of glutamatergic mechanism in the nucleus of the solitary tract (NTS) with kynurenic acid (kyn) on mean arterial pressure (MAP), heart rate (HR), and regional vascular resistances. In male Holtzman rats anesthetized intravenously with urethane/chloralose, bilateral injections of muscimol (120 pmol) into the CVLM or bilateral injections of kyn (2.7 nmol) into the NTS alone increased MAP to 186 +/- 11 and to 142 +/- 6 mmHg, respectively, vs. control: 105 +/- 4 mmHg; HR to 407 +/- 15 and to 412 +/- 18 beats per minute (bpm), respectively, vs. control: 352 +/- 12 bpm; and renal, mesenteric and hindquarter vascular resistances. However, in rats with the CVLM bilaterally blocked by muscimol, additional injections of kyn into the NTS reduced MAP to 88 +/- 5 mmHg and mesenteric and hindquarter vascular resistances below control baseline levels. Moreover, in rats with the glutamatergic mechanisms of the NTS blocked by bilateral injections of kyn, additional injections of muscimol into the CVLM also reduced MAP to 92 +/- 2 mmHg and mesenteric and hindquarter vascular resistances below control baseline levels. Simultaneous blockade of NTS and CVLM did not modify the increase in HR but also abolished the increase in renal vascular resistance produced by each treatment alone. The results suggest that important pressor mechanisms arise from the NTS and CVLM to control vascular resistance and arterial pressure under the conditions of the present study.

Propolis: Is there a potential for the development of new drugs?

Introduction: Propolis has plenty of biological and pharmacological properties and its mechanisms of action have been widely investigated in the last years, using different experimental models in vitro and in vivo. Researchers have been interested in the investigation of isolated compounds responsible for propolis action; however, there is lack of clinical research on the effects of propolis.Strategy and objectives: Since propolis-containing products have been marketed and humans have used propolis for different purposes, the goal of this review is to discuss the potential of propolis for the development of new drugs, by comparing data from the literature that suggest candidate areas for the establishment of drugs against tumors, infections, allergy, diabetes, ulcers and with immunomodulatory action.Conclusions: The efficacy of propolis in different protocols in vitro and in vivo suggests its therapeutic properties, but before establishing a strategy using this bee product, it is necessary to study: (a) the chemical nature of the propolis sample. (b) Propolis efficacy should be compared to well-established parameters, e.g. positive or negative controls in the experiments. Moreover, possible interactions between propolis and other medicines should be investigated in humans as well. (c) Clinical investigation is needed to evaluate propolis potential in patients or healthy individuals, to understand under which conditions propolis may promote health. Data point out the importance of this research field not only for the readers and researchers in the scientific community waiting for further clarification on the potential of propolis but also for the pharmaceutical industry that looks for new drugs. (C) 2010 Elsevier B.V. All rights reserved.

Transient and d.c. analysis of the operation mechanism of light-emitting electrochemical cells

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

Configuration-dependent diffusion can shift the kinetic transition state and barrier height of protein folding

We show that diffusion can play an important role in protein-folding kinetics. We explicitly calculate the diffusion coefficient of protein folding in a lattice model. We found that diffusion typically is configuration- or reaction coordinate-dependent. The diffusion coefficient is found to be decreasing with respect to the progression of folding toward the native state, which is caused by the collapse to a compact state constraining the configurational space for exploration. The configuration- or position-dependent diffusion coefficient has a significant contribution to the kinetics in addition to the thermodynamic free-energy barrier. It effectively changes (increases in this case) the kinetic barrier height as well as the position of the corresponding transition state and therefore modifies the folding kinetic rates as well as the kinetic routes. The resulting folding time, by considering both kinetic diffusion and the thermodynamic folding free-energy profile, thus is slower than the estimation from the thermodynamic free-energy barrier with constant diffusion but is consistent with the results from kinetic simulations. The configuration- or coordinate-dependent diffusion is especially important with respect to fast folding, when there is a small or no free-energy barrier and kinetics is controlled by diffusion. Including the configurational dependence will challenge the transition state theory of protein folding. The classical transition state theory will have to be modified to be consistent. The more detailed folding mechanistic studies involving phi value analysis based on the classical transition state theory also will have to be modified quantitatively.

Structure and aggregation kinetics of vinyltriethoxysilane-derived organic/silica hybrids

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

Gelation of siloxane-poly(oxypropylene) composites

The viscoelastic properties of siloxane-poly(oxypropylene) (PPO) nanocomposites prepared by the sol-gel process has been analyzed during gelation by dynamic rheological measurements. The changes of storage and loss moduli, complex viscosity and phase angle has been measured as a function of time showing the newtonian viscosity of the sol in the initial step of gelation, and its progressive transformation to a viscoelastic gel. The rheologic properties have been correlated to mass fractal, nearly linear growth models and percolation theory. This study, completed by quasi-elastic light scattering and Si-29 solid state nuclear magnetic resonance measurements, shows that the mechanisms of gelation of siloxane-PPO hybrids depend on the molecular weight of the polymer and on the pH of the hybrid sol. For hybrids prepared in acid medium, a polymerization involving silicon reactive species located at the extremity of the polymer chains and presenting a functionality f = 2 occurs, forming a fractal structure during the first stage of sol-gel transition. For samples prepared under neutral pH, the fractal growth is only observed for hybrids containing short polymer chains (M-w similar to 130 gmol(-1)). The fractal dimensionality determined from the change in the rheological properties, indicates that the fractal growth mechanism changes from reaction-limited to diffusion-limited aggregation when the molecular weight of the PPO increases from 130 to 4000 gmol(-1) and as catalyst conditions change from acidic to neutral. Near the gel point, these hybrid gels have the typical scaling behavior expected from percolation theory. (C) 2002 Elsevier B.V. B.V. All rights reserved.

Effect of lithium doping on the evolution of rheological and structural properties during gelation of siloxane-poly(oxypropylene) nanocomposites

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