Endocannabinoids, FOXO and the metabolic syndrome: redox, function and tipping point--the view from two systems

The endocannabinoid system (ECS) was only 'discovered' in the 1990s. Since then, many new ligands have been identified, as well as many new intracellular targets--ranging from the PPARs, to mitochondria, to lipid rafts. It was thought that blocking the CB-1 receptor might reverse obesity and the metabolic syndrome. This was based on the idea that the ECS was dysfunctional in these conditions. This has met with limited success. The reason may be that the ECS is a homeostatic system, which integrates energy seeking and storage behaviour with resistance to oxidative stress. It could be viewed as having thrifty actions. Thriftiness is an innate property of life, which is programmed to a set point by both environment and genetics, resulting in an epigenotype perfectly adapted to its environment. This thrifty set point can be modulated by hormetic stimuli, such as exercise, cold and plant micronutrients. We have proposed that the physiological and protective insulin resistance that underlies thriftiness encapsulates something called 'redox thriftiness', whereby insulin resistance is determined by the ability to resist oxidative stress. Modern man has removed most hormetic stimuli and replaced them with a calorific sedentary lifestyle, leading to increased risk of metabolic inflexibility. We suggest that there is a tipping point where lipotoxicity in adipose and hepatic cells induces mild inflammation, which switches thrifty insulin resistance to inflammation-driven insulin resistance. To understand this, we propose that the metabolic syndrome could be seen from the viewpoint of the ECS, the mitochondrion and the FOXO group of transcription factors. FOXO has many thrifty actions, including increasing insulin resistance and appetite, suppressing oxidative stress and shifting the organism towards using fatty acids. In concert with factors such as PGC-1, they also modify mitochondrial function and biogenesis. Hence, the ECS and FOXO may interact at many points; one of which may be via intracellular redox signalling. As cannabinoids have been shown to modulate reactive oxygen species production, it is possible that they can upregulate anti-oxidant defences. This suggests they may have an 'endohormetic' signalling function. The tipping point into the metabolic syndrome may be the result of a chronic lack of hormetic stimuli (in particular, physical activity), and thus, stimulus for PGC-1, with a resultant reduction in mitochondrial function and a reduced lipid capacitance. This, in the context of a positive calorie environment, will result in increased visceral adipose tissue volume, abnormal ectopic fat content and systemic inflammation. This would worsen the inflammatory-driven pathological insulin resistance and inability to deal with lipids. The resultant oxidative stress may therefore drive a compensatory anti-oxidative response epitomised by the ECS and FOXO. Thus, although blocking the ECS (e.g. via rimonabant) may induce temporary weight loss, it may compromise long-term stress resistance. Clues about how to modulate the system more safely are emerging from observations that some polyphenols, such as resveratrol and possibly, some phytocannabinoids, can modulate mitochondrial function and might improve resistance to a modern lifestyle.

Lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe?

The metabolic syndrome may have its origins in thriftiness, insulin resistance and one of the most ancient of all signalling systems, redox. Thriftiness results from an evolutionarily-driven propensity to minimise energy expenditure. This has to be balanced with the need to resist the oxidative stress from cellular signalling and pathogen resistance, giving rise to something we call 'redox-thriftiness'. This is based on the notion that mitochondria may be able to both amplify membrane-derived redox growth signals as well as negatively regulate them, resulting in an increased ATP/ROS ratio. We suggest that 'redox-thriftiness' leads to insulin resistance, which has the effect of both protecting the individual cell from excessive growth/inflammatory stress, while ensuring energy is channelled to the brain, the immune system, and for storage. We also suggest that fine tuning of redox-thriftiness is achieved by hormetic (mild stress) signals that stimulate mitochondrial biogenesis and resistance to oxidative stress, which improves metabolic flexibility. However, in a non-hormetic environment with excessive calories, the protective nature of this system may lead to escalating insulin resistance and rising oxidative stress due to metabolic inflexibility and mitochondrial overload. Thus, the mitochondrially-associated resistance to oxidative stress (and metabolic flexibility) may determine insulin resistance. Genetically and environmentally determined mitochondrial function may define a 'tipping point' where protective insulin resistance tips over to inflammatory insulin resistance. Many hormetic factors may induce mild mitochondrial stress and biogenesis, including exercise, fasting, temperature extremes, unsaturated fats, polyphenols, alcohol, and even metformin and statins. Without hormesis, a proposed redox-thriftiness tipping point might lead to a feed forward insulin resistance cycle in the presence of excess calories. We therefore suggest that as oxidative stress determines functional longevity, a rather more descriptive term for the metabolic syndrome is the 'lifestyle-induced metabolic inflexibility and accelerated ageing syndrome'. Ultimately, thriftiness is good for us as long as we have hormetic stimuli; unfortunately, mankind is attempting to remove all hormetic (stressful) stimuli from his environment.

Recovery mechanisms of Arctic summer sea ice

We examine the recovery of Arctic sea ice from prescribed ice-free summer conditions in simulations of 21st century climate in an atmosphere–ocean general circulation model. We find that ice extent recovers typically within two years. The excess oceanic heat that had built up during the ice-free summer is rapidly returned to the atmosphere during the following autumn and winter, and then leaves the Arctic partly through increased longwave emission at the top of the atmosphere and partly through reduced atmospheric heat advection from lower latitudes. Oceanic heat transport does not contribute significantly to the loss of the excess heat. Our results suggest that anomalous loss of Arctic sea ice during a single summer is reversible, as the ice–albedo feedback is alleviated by large-scale recovery mechanisms. Hence, hysteretic threshold behavior (or a “tipping point”) is unlikely to occur during the decline of Arctic summer sea-ice cover in the 21st century.

Feature-point detection using distance transforms: Application to tracking tropical convective complexes

The identification, tracking, and statistical analysis of tropical convective complexes using satellite imagery is explored in the context of identifying feature points suitable for tracking. The feature points are determined based on the shape of complexes using the distance transform technique. This approach has been applied to the determination feature points for tropical convective complexes identified in a time series of global cloud imagery. The feature points are used to track the complexes, and from the tracks statistical diagnostic fields are computed. This approach allows the nature and distribution of organized deep convection in the Tropics to be explored.

Realizability of Point Processes

There are various situations in which it is natural to ask whether a given collection of k functions, ρ j (r 1,…,r j ), j=1,…,k, defined on a set X, are the first k correlation functions of a point process on X. Here we describe some necessary and sufficient conditions on the ρ j ’s for this to be true. Our primary examples are X=ℝ d , X=ℤ d , and X an arbitrary finite set. In particular, we extend a result by Ambartzumian and Sukiasian showing realizability at sufficiently small densities ρ 1(r). Typically if any realizing process exists there will be many (even an uncountable number); in this case we prove, when X is a finite set, the existence of a realizing Gibbs measure with k body potentials which maximizes the entropy among all realizing measures. We also investigate in detail a simple example in which a uniform density ρ and translation invariant ρ 2 are specified on ℤ; there is a gap between our best upper bound on possible values of ρ and the largest ρ for which realizability can be established.

Electronic structure of point defects in controlled self-doping of the TiO2 (110) surface: Combined photoemission spectroscopy and density functional theory study

Point defects in metal oxides such as TiO2 are key to their applications in numerous technologies. The investigation of thermally induced nonstoichiometry in TiO2 is complicated by the difficulties in preparing and determining a desired degree of nonstoichiometry. We study controlled self-doping of TiO2 by adsorption of 1/8 and 1/16 monolayer Ti at the (110) surface using a combination of experimental and computational approaches to unravel the details of the adsorption process and the oxidation state of Ti. Upon adsorption of Ti, x-ray and ultraviolet photoemission spectroscopy (XPS and UPS) show formation of reduced Ti. Comparison of pure density functional theory (DFT) with experiment shows that pure DFT provides an inconsistent description of the electronic structure. To surmount this difficulty, we apply DFT corrected for on-site Coulomb interaction (DFT+U) to describe reduced Ti ions. The optimal value of U is 3 eV, determined from comparison of the computed Ti 3d electronic density of states with the UPS data. DFT+U and UPS show the appearance of a Ti 3d adsorbate-induced state at 1.3 eV above the valence band and 1.0 eV below the conduction band. The computations show that the adsorbed Ti atom is oxidized to Ti2+ and a fivefold coordinated surface Ti atom is reduced to Ti3+, while the remaining electron is distributed among other surface Ti atoms. The UPS data are best fitted with reduced Ti2+ and Ti3+ ions. These results demonstrate that the complexity of doped metal oxides is best understood with a combination of experiment and appropriate computations.

Strategic management of non-point source pollution from sewage sludge

In the UK, the recycling of sewage sludge to land is expected to double by 2006 but the security of this route is threatened by environmental concerns and health scares. Strategic investment is needed to ensure sustainable and secure sludge recycling outlets. At present, the security of this landbank for sludge recycling is determined by legislation relating to nutrient rather than potentially toxic elements (PTEs) applications to land - especially the environmental risk linked to soil phosphorus (P) saturation. We believe that not all land has an equal risk of contributing nutrients derived from applications to land to receiving waters. We are currently investigating whether it is possible to minimise nutrient loss by applying sludge to land outside Critical Source Areas (CSAs) regardless of soil P Index status. Research is underway to develop a predictive and spatially-sensitive, semi-distributed model of critical thresholds for sludge application that goes beyond traditional 'end-of-pipe" or "edge-of-field" modelling, to include hydrological flow paths and delivery mechanisms to receiving waters from non-point sources at the catchment scale.

Estimating detailed soil water profile records from point measurements

Temporal and spatial patterns of soil water content affect many soil processes including evaporation, infiltration, ground water recharge, erosion and vegetation distribution. This paper describes the analysis of a soil moisture dataset comprising a combination of continuous time series of measurements at a few depths and locations, and occasional roving measurements at a large number of depths and locations. The objectives of the paper are: (i) to develop a technique for combining continuous measurements of soil water contents at a limited number of depths within a soil profile with occasional measurements at a large number of depths, to enable accurate estimation of the soil moisture vertical pattern and the integrated profile water content; and (ii) to estimate time series of soil moisture content at locations where there are just occasional soil water measurements available and some continuous records from nearby locations. The vertical interpolation technique presented here can strongly reduce errors in the estimation of profile soil water and its changes with time. On the other hand, the temporal interpolation technique is tested for different sampling strategies in space and time, and the errors generated in each case are compared.

Evaluating the risk of non-point source pollution from biosolids: integrated modelling of nutrient losses at field and catchment scales

A semi-distributed model, INCA, has been developed to determine the fate and distribution of nutrients in terrestrial and aquatic systems. The model simulates nitrogen and phosphorus processes in soils, groundwaters and river systems and can be applied in a semi-distributed manner at a range of scales. In this study, the model has been applied at field to sub-catchment to whole catchment scale to evaluate the behaviour of biosolid-derived losses of P in agricultural systems. It is shown that process-based models such as INCA, applied at a wide range of scales, reproduce field and catchment behaviour satisfactorily. The INCA model can also be used to generate generic information for risk assessment. By adjusting three key variables: biosolid application rates, the hydrological connectivity of the catchment and the initial P-status of the soils within the model, a matrix of P loss rates can be generated to evaluate the behaviour of the model and, hence, of the catchment system. The results, which indicate the sensitivity of the catchment to flow paths, to application rates and to initial soil conditions, have been incorporated into a Nutrient Export Risk Matrix (NERM).

Approximate factorization constraint preconditioners for saddle-point matrices

We consider the application of the conjugate gradient method to the solution of large, symmetric indefinite linear systems. Special emphasis is put on the use of constraint preconditioners and a new factorization that can reduce the number of flops required by the preconditioning step. Results concerning the eigenvalues of the preconditioned matrix and its minimum polynomial are given. Numerical experiments validate these conclusions.

The point source method for inverse scattering in the time domain

Many recent inverse scattering techniques have been designed for single frequency scattered fields in the frequency domain. In practice, however, the data is collected in the time domain. Frequency domain inverse scattering algorithms obviously apply to time-harmonic scattering, or nearly time-harmonic scattering, through application of the Fourier transform. Fourier transform techniques can also be applied to non-time-harmonic scattering from pulses. Our goal here is twofold: first, to establish conditions on the time-dependent waves that provide a correspondence between time domain and frequency domain inverse scattering via Fourier transforms without recourse to the conventional limiting amplitude principle; secondly, we apply the analysis in the first part of this work toward the extension of a particular scattering technique, namely the point source method, to scattering from the requisite pulses. Numerical examples illustrate the method and suggest that reconstructions from admissible pulses deliver superior reconstructions compared to straight averaging of multi-frequency data. Copyright (C) 2006 John Wiley & Sons, Ltd.

The point-source method for 3D reconstructions for the Helmholtz and Maxwell equations

We use the point-source method (PSM) to reconstruct a scattered field from its associated far field pattern. The reconstruction scheme is described and numerical results are presented for three-dimensional acoustic and electromagnetic scattering problems. We give new proofs of the algorithms, based on the Green and Stratton-Chu formulae, which are more general than with the former use of the reciprocity relation. This allows us to handle the case of limited aperture data and arbitrary incident fields. Both for 3D acoustics and electromagnetics, numerical reconstructions of the field for different settings and with noisy data are shown. For shape reconstruction in acoustics, we develop an appropriate strategy to identify areas with good reconstruction quality and combine different such regions into one joint function. Then, we show how shapes of unknown sound-soft scatterers are found as level curves of the total reconstructed field.