Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism

Inbred strains of mice differ in susceptibility to atherogenesis when challenged with a high fat, high cholesterol diet containing 0.5% cholic acid. Studies of recombinant inbred (RI) strains derived from the susceptible strain C57BL/6J (B6) and the resistant strains C3H/HeJ (C3H) and BALB/cJ have revealed an association between fatty streak lesion size and a decrease in high density lipoprotein (HDL) levels on the diet. To better understand the genetic factors contributing to HDL metabolism and atherogenesis in response to the diet, we studied mice derived from an intercross between B6 and C3H using a complete linkage map approach. A total of 185 female progeny were typed for 134 genetic markers spanning the mouse genome, resulting in an average interval of about 10 cM between markers. A locus on distal chromosome 1 containing the apolipoprotein AII gene was linked to HDL-cholesterol levels on both the chow and the atherogenic diets, but this locus did not contribute to the decrease in HDL-cholesterol in response to the diet. At least three distinct genetic loci, on chromosomes 3, 5, and 11, exhibited evidence of linkage to a decrease in HDL-cholesterol after a dietary challenge. Since a bile acid (cholic acid) is required for the diet induced changes in HDL levels and for atherogenesis in these strains, we examined cholesterol-7-alpha hydroxylase (C7AH) expression. Whereas B6 mice exhibited a large decrease in C7AH mRNA levels in response to the diet, C3H showed an increase. Among the intercross mice, multiple loci contributed to the regulation of C7AH mRNA levels in response to the diet, the most notable of which coincided with the loci on chromosomes 3, 5, and 11 controlling HDL levels in response to the diet. None of these loci were linked to the C7AH structural gene which we mapped to proximal chromosome 4. These studies reveal coordinate regulation of C7AH expression and HDL levels, and they indicate that the genetic factors controlling HDL levels are more complex than previously suggested by studies of RI strains. Furthermore, we observed that two of the loci for C7AH expression contributed to differences in gallstone formation between these strains.     

Solutions of the BCM learning rule in a network of lateral interacting nonlinear neurons.

We introduce a new method for obtaining the fixed points for neurons that follow the BCM learning rule. The new formalism, which is based on the objective function formulation, permits analysis of a laterally connected network of nonlinear neurons and allows explicit calculation of the fixed points under various network conditions. We show that the stable fixed points, in terms of the postsynaptic activity, are not altered by the lateral connectivity or nonlinearity. We show that the lateral connectivity alters the probability of attaining different states in a network of interacting neurons. We further show the exact alteration in presynaptic weights as a result of the neuronal nonlinearity.     

Effect of notch severity on fatigue fracture in a rubber-modified glassy polymer

The research concerned the effect of notch severity on the fatigue behaviour of series of rubber-modified glassy polymers, consisting of a styrene-acrylonitrile copolymer with different amounts of an olefin rubber. Tests were conducted under displacement control and two different loading conditions. Both stages of fatigue lifetimes, that is, fracture initiation and crack propagation, were examined. It was observed that the initial notch severity determines the duration of the crack-initiation stage, while crack propagation does not depend on it. The crack velocity appears to be controlled by the maximum applied stress intensity factor, and the correlation does not depend on the rubber content. The results obtained have been interpreted by considering three different zones in the specimen during the fracture process: a far-field viscoelastic continuum, a process zone and a failure zone.     

Exertional fatigue, sleep loss, and negative energy balance increase susceptibility to hypothermia

The purpose of this study was to determine how chronic exertional fatigue and sleep deprivation coupled with negative energy balance affect thermoregulation during cold exposure. Eight men wearing only shorts and socks sat quietly during 4-h cold air exposure (10 degreesC) immediately after (<2 h, A) they completed 61 days of strenuous military training (energy expenditure approximately 4,150 kcal/day, energy intake approximately 3,300 kcal/day, sleep approximately 4 h/day) and again after short (48 h, SR) and long (109 days, LR) recovery. Body weight decreased 7.4 kg from before training to A, then increased 6.4 kg by SR, with an additional 6.4 kg increase by LR. Body fat averaged 12% during A and SR and increased to 21% during LR. Rectal temperature (Tre) was lower before and during cold air exposure for A than for SR and LR. Tre declined during cold exposure in A and SR but not LR. Mean weighted skin temperature (Tsk) during cold exposure was higher in A and SR than in LR. Metabolic rate increased during all cold exposures, but it was lower during A and LR than SR. The mean body temperature (0.67 Tre + 0.33 Tsk) threshold for increasing metabolism was lower during A than SR and LR. Thus chronic exertional fatigue and sleep loss, combined with underfeeding, reduced tissue insulation and blunted metabolic heat production, which compromised maintenance of body temperature. A short period of rest, sleep, and refeeding restored the thermogenic response to cold, but thermal balance in the cold remained compromised until after several weeks of recovery when tissue insulation had been restored.     

Benchmarking and comparison of nature-inspired population-based continuous optimisation algorithms

This paper describes an experimental investigation into four nature-inspired population-based continuous optimisation methods: the Bees Algorithm, Evolutionary Algorithms, Particle Swarm Optimisation, and the Artificial Bee Colony algorithm. The aim of the proposed study is to understand and compare the specific capabilities of each optimisation algorithm. For each algorithm, thirty-two configurations covering different combinations of operators and learning parameters were examined. In order to evaluate the optimisation procedures, twenty-five function minimisation benchmarks were designed by the authors. The proposed set of benchmarks includes many diverse fitness landscapes, and constitutes a contribution to the systematic study of optimisation techniques and operators. The experimental results highlight the strengths and weaknesses of the algorithms and configurations tested. The existence and extent of origin and alignment search biases related to the use of different recombination operators are highlighted. The analysis of the results reveals interesting regularities that help to identify some of the crucial issues in the choice and configuration of the search algorithms.     

Solid-state magic-angle spinning NMR of outer-membrane protein G from Escherichia coli

Uniformly 13C-,15N-labelled outer-membrane protein G (OmpG) from Escherichia coli was expressed for structural studies by solid-state magic-angle spinning (MAS) NMR. Inclusion bodies of the recombinant, labelled protein were purified under denaturing conditions and refolded in detergent. OmpG was reconstituted into lipid bilayers and several milligrams of two-dimensional crystals were obtained. Solid-state MAS NMR spectra showed signals with an apparent line width of 80-120 Hz (including homonuclear scalar couplings). Signal patterns for several amino acids, including threonines, prolines and serines were resolved and identified in 2D proton-driven spin-diffusion (PDSD) spectra.     

Sensitivity analysis techniques applied to a revised model of molybdenum biokinetics

A revised model of molybdenum biokinetics in humans was recently developed on the basis of experimental data gathered in specific investigations conducted with stable tracers. The model can be used for radiation protection purposes, and it is also a suitable working tool for designing new investigations aimed at further improvements to the model. For the latter goal, a sensitivity analysis was performed in order to determine the most significant model parameters in relation to output measurements performed in studies of molybdenum metabolism. A typical sensitivity analysis approach was adopted, considering the effects in variation of model parameters on the time courses of model outputs such as urinary excretion and blood clearance. A recent new sensitivity technique was considered too, based on the calculation of the so-called generalised sensitivity functions. This combines the sensitivities of the model output with respect to model parameters (as in the typical sensitivity analysis method), with the sensitivities of parameter estimates with respect to changes in model outputs. The results obtained in this analysis suggests that data collected in the first 7 h are critical for the definition of the process of blood clearance and related parameters, whereas reliable information at later times is required for a proper characterisation of urinary excretion.     

Guidance on internal dose assessments from monitoring data (project IDEAS)

Several international inter-comparison exercises on intake and internal dose assessments from monitoring data led to the conclusion that the results calculated by different participants varied significantly, mainly due to the broad variety of methods and assumptions applied in the assessment procedure. Based on these experiences, the need of harmonisation of the procedures has been formulated as an EU research project under the 5th Framework Programme, with the aim of developing general guidelines for standardising assessments of intakes and internal doses. In the IDEAS project, eight institutions from seven European countries are participating, also using inputs from internal dosimetry professionals from across Europe to ensure broad consensus in the outcome of the project. To ensure that the guidelines are applicable to a wide range of practical situations, the first step will be to compile a database on well documented cases of internal contamination. In parallel, an improved version of existing software will be developed and distributed to the partners for further use. Many cases from the database will be evaluated independently by more partners using the same software and the results will be discussed and the draft guidelines prepared. The guidelines will then be revised and refined on the basis of the experiences and discussions of two workshops, and an intercomparison exercise organised in the frame of the project which will be open to all internal dosimetry professionals.