Basophil models of homeopathy: a sceptical view

This paper examines the activation and inhibition of activation of human basophils. After a brief description of human basophils, different methods to determine basophil activation are discussed with a special emphasis on the use of flow cytometric methods, as these circumvent the potential problems of assays based on the loss of colour by activated basophils. The activation of human basophils by ultra-high dilutions of anti-IgE is discussed. The majority of the paper describes the inhibition of basophil activation by ultra-high dilutions of histamine. The results from published papers are described and discussed.

Abeta oligomer toxicity inhibitor protects memory in models of synaptic toxicity

BACKGROUND AND PURPOSE:

Amyloid-ß (Aß) aggregation into synaptotoxic, prefibrillar oligomers is a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The pharmacological and neuroprotective properties of a novel Aß aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic Aß(1-42) and cell-derived Aß oligomers.
EXPERIMENTAL APPROACH:

Surface plasmon resonance studies measured binding of SEN1269 to Aß(1-42) . Thioflavin-T fluorescence and MTT assays were used to measure its ability to block Aß(1-42) -induced aggregation and reduction in cell viability. In vitro and in vivo long-term potentiation (LTP) experiments measured the effect of SEN1269 on deficits induced by synthetic Aß(1-42) and cell-derived Aß oligomers. Following i.c.v. administration of the latter, a complex (alternating-lever cyclic ratio) schedule of operant responding measured effects on memory in freely moving rats.
KEY RESULTS:

SEN1269 demonstrated direct binding to monomeric Aß(1-42) , produced a concentration-related blockade of Aß(1-42) aggregation and protected neuronal cell lines exposed to Aß(1-42) . In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by Aß(1-42) and cell-derived Aß oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived Aß oligomers.
CONCLUSIONS AND IMPLICATIONS:

SEN1269 protected cells exposed to Aß(1-42) , displayed central activity with respect to reducing Aß-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to Aß-induced neurodegeneration. It represents a promising lead for designing inhibitors of Aß-mediated synaptic toxicity as potential neuroprotective agents for treating AD.

CoMFA and homology-based models of the glycine binding site of N-methyl-D-aspartate receptor

Homology modeling was used to build 3D models of the N-methyl-D-aspartate (NMDA) receptor glycine binding site on the basis of an X-ray structure of the water-soluble AMPA-sensitive receptor. The docking of agonists and antagonists to these models was used to reveal binding modes of ligands and to explain known structure-activity relationships. Two types of quantitative models, 3D-QSAR/CoMFA and a regression model based on docking energies, were built for antagonists (derivatives of 4-hydroxy-2-quinolone, quinoxaline-2,3-dione, and related compounds). The CoMFA steric and electrostatic maps were superimposed on the homology-based model, and a close correspondence was marked. The derived computational models have permitted the evaluation of the structural features crucial for high glycine binding site affinity and are important for the design of new ligands.

Beyond the ideal free distribution: More general models of predator distribution

The ideal free distribution model which relates the spatial distribution of mobile consumers to that of their resource is shown to be a limiting case of a more general model which we develop using simple concepts of diffusion. We show how the ideal free distribution model can be derived from a more general model and extended by incorporating simple models of social influences on predator spacing. First, a free distribution model based on patch switching rules, with a power-law interference term, which represents instantaneous biased diffusion is derived. A social bias term is then introduced to represent the effect of predator aggregation on predator fitness, separate from any effects which act through intake rate. The social bias term is expanded to express an optimum spacing for predators and example solutions of the resulting biased diffusion models are shown. The model demonstrates how an empirical interference coefficient, derived from measurements of predator and prey densities, may include factors expressing the impact of social spacing behaviour on fitness. We conclude that empirical values of log predator/log prey ratio may contain information about more than the relationship between consumer and resource densities. Unlike many previous models, the model shown here applies to conditions without continual input. (C) 1997 Academic Press Limited.</p>

Modelling road traffic accidents using macroscopic second-order models of traffic flow

In this paper, we introduce a macroscopic model for road traffic accidents along highway sections. We discuss the motivation and the derivation of such a model, and we present its mathematical properties. The results are presented by means of examples where a section of a crowded one-way highway contains in the middle a cluster of drivers whose dynamics are prone to road traffic accidents. We discuss the coupling conditions and present some existence results of weak solutions to the associated Riemann Problems. Furthermore, we illustrate some features of the proposed model through some numerical simulations. © The authors 2012.

Physical Models of Wind Instruments : A Generalized Excitation Coupled with a Modular Tube Simulation Platform

To develop real-time simulations of wind instruments, digital waveguides filters can be used as an efficient representation of the air column. Many aerophones are shaped as horns which can be approximated using conical sections. Therefore the derivation of conical waveguide filters is of special interest. When these filters are used in combination with a generalized reed excitation, several classes of wind instruments can be simulated. In this paper we present the methods for transforming a continuous description of conical tube segments to a discrete filter representation. The coupling of the reed model with the conical waveguide and a simplified model of the termination at the open end are described in the same way. It turns out that the complete lossless conical waveguide requires only one type of filter.Furthermore, we developed a digital reed excitation model, which is purely based on numerical integration methods, i.e., without the use of a look-up table.

The alterations of Ca2+/Calmodulin/CaMKII/CaV1.2 signaling in experimental models of Alzheimer's disease and vascular dementia

The two critical forms of dementia are Alzheimer's disease (AD) and vascular dementia (VD).The alterations of Ca2+/calmodulin/CaMKII/CaV1.2 signaling in AD and VD have not been well elucidated. Here we have demonstrated changes in the levels of CaV1.2, calmodulin, p-CaMKII, p-CREB and BDNF proteins by Western blot analysis and the co-localization of p-CaMKII/CaV1.2 by double-labeling immunofluorescence in the hippocampus of APP/PS1 mice and VD gerbils. Additionally, expression of these proteins and intracellular calcium levels were examined in cultured neurons treated with Aß1–42. The expression of CaV1.2 protein was increased in VD gerbils and in cultured neurons but decreased in APP/PS1 mice; the expression of calmodulin protein was increased in APP/PS1 mice and VD gerbils; levels of p-CaMKII, p-CREB and BDNF proteins were decreased in AD and VD models. The number of neurons in which p-CaMKII and CaV1.2 were co-localized, was decreased in the CA1 and CA3 regions in two models. Intracellular calcium was increased in the cultured neurons treated with Aß1–42. Collectively, our results suggest that the alterations in CaV1.2, calmodulin, p-CaMKII, p-CREB and BDNF can be reflective of an involvement in the impairment in memory and cognition in AD and VD models.

Light curves for off-centre ignition models of Type Ia supernovae

Motivated by recent models involving off-centre ignition of Type Ia supernova explosions, we undertake three-dimensional time-dependent radiation transport simulations to investigate the range of bolometric light-curve properties that could be observed from supernovae in which there is a lop-sided distribution of the products from nuclear burning. We consider both a grid of artificial toy models which illustrate the conceivable range of effects and a recent three-dimensional hydrodynamical explosion model. We find that observationally significant viewing angle effects are likely to arise in such supernovae and that these may have important ramifications for the interpretation of the observed diversity of Type Ia supernova and the systematic uncertainties which relate to their use as standard candles in contemporary cosmology. © 2007 RAS.