Stochastic paleoclimatology: Modeling the EPICA ice core climate records.

We analyze and model the stochastic behavior of paleoclimate time series and assess the implications for the coupling of climate variables during the Pleistocene glacial cycles. We examine 800 kiloyears of carbon dioxide, methane, nitrous oxide, and temperature proxy data from the European Project for Ice Coring in Antarctica (EPICA) Dome-C ice core, which are characterized by 100 ky glacial cycles overlain by fluctuations across a wide range of timescales. We quantify this behavior through multifractal time-weighted detrended fluctuation analysis, which distinguishes near-red-noise and white-noise behavior below and above the 100 ky glacial cycle, respectively, in all records. This allows us to model each time series as a one-dimensional periodic nonautonomous stochastic dynamical system, and assess the stability of physical processes and the fidelity of model-simulated time series. We extend this approach to a four-variable model with intervariable coupling terms, which we interpret in terms of possible interrelationships among the four time series. Within the framework of our coupling coefficients, we find that carbon dioxide and temperature act to stabilize each other and methane and nitrous oxide, whereas the latter two destabilize each other and carbon dioxide and temperature. We also compute the response function for each pair of variables to assess the model performance by comparison to the data and confirm the model predictions regarding stability amongst variables. Taken together, our results are consistent with glacial pacing dominated by carbon dioxide and temperature that is modulated by terrestrial biosphere feedbacks associated with methane and nitrous oxide emissions.

Structural analysis of HyFlex EDM instruments.

AIM: To compare the phase transformation behaviour, the microstructure, the nano-hardness and the surface chemistry of electro-discharge machined HyFlex EDM instruments with conventionally manufactured HyFlex CM. METHODOLOGY: New and laboratory used HyFlex EDM were examined by X-ray diffraction (XRD) and differential scanning calorimetry (DSC). Nano-hardness and modulus of elasticity were also investigated using a maximum load of 20 mN with a minimum of 40 significant indentations for each sample. Raman spectroscopy and field emission-scanning electron microscope (FE-SEM) were used to assess the surface chemistry of HyFlex EDM. HyFlex CM were subjected to the same investigations and used as a comparison. Nano-indentation data were statistically analysed using the Student's t-test. RESULTS: XRD analysis on HyFlex EDM revealed the presence of martensite and rhombohedral R-phase, while a mixture of martensite and austenite structure was identified in HyFlex CM. DSC analysis also disclosed higher austenite finish (Af) temperatures for electro-discharge machining (EDM) instruments. Significant differences in nano-hardness and modulus of elasticity were found between EDM and CM files (P < 0.05). FE-SEM and EDS analyses confirmed that both new EDM and CM files were covered by an oxide layer. Micro-Raman spectroscopy assessed the presence of rutile-TiO2 . CONCLUSIONS: HyFlex EDM revealed peculiar structural properties, such as increased phase transformation temperatures and hardness. Present results corroborated previous findings and shed light on the enhanced mechanical behaviour of these instruments.

Correlation between in vivo stresses and oxidation of UHMWPE in total hip arthroplasty.

The possibility of in vivo, stress-induced oxidation in orthopaedic UHMWPE has been investigated. EtO sterilised, uncrosslinked UHMWPE liners, explanted or shelf-aged, have been collected. Linear wear and wear rate were assessed and FTIR spectroscopy was employed to detect oxidation and to build up oxidation products spatial maps across the liners section. Oxidation profiles have been compared to stress distribution profiles, resulting from a FE analysis conducted on the same liners geometries and couplings. It was found that oxidised and stressed areas followed the same asymmetrical, localized distribution profile. It was therefore possible to establish a correlation between stressed areas and observed oxidation.

Analytical solution of stochastic resonance in the nonadiabatic regime.

We generalize stochastic resonance to the nonadiabatic limit by treating the double-well potential using two quadratic potentials. We use a singular perturbation method to determine an approximate analytical solution for the probability density function that asymptotically connects local solutions in boundary layers near the two minima with those in the region of the maximum that separates them. The validity of the analytical solution is confirmed numerically. Free from the constraints of the adiabatic limit, the approach allows us to predict the escape rate from one stable basin to another for systems experiencing a more complex periodic forcing.

Oxidatively modified HDLs are potent inhibitors of cholesterol biosynthesis in human skin fibroblasts.

Several biological properties of lipoproteins are modified by oxidative reactions. Modified lipoproteins are rapidly degraded by macrophages, and this is likely to be a major pathway for the formation of foam cells in the early phases of atherosclerosis. The effect of modification on other aspects of cholesterol homeostasis has, however, received lesser attention. In this study, the influence of copper ion- as well as rat aortic smooth muscle cell-oxidation-modified high density lipoprotein (HDL) on cholesterol biosynthesis in human skin fibroblasts has been investigated. Modified lipoproteins eluted at higher ionic strength than did control HDL on a Mono-Q 5/5 anion-exchange column. However, only copper ion-modified HDLs displayed greater electrophoretic mobility than did control lipoproteins on agarose gel electrophoresis. Both control and modified HDLs decreased cholesterol esterification in fibroblasts. On the other hand, whereas control HDLs were virtually ineffective in modulating cholesterol biosynthesis, modified HDLs had a significant suppressing effect. This was observed in normal as well as low density lipoprotein (LDL) receptor-defective fibroblasts, which are unresponsive to the LDL-mediated downregulation of cholesterol synthesis. These results are consistent with the concept that oxidative modification of HDLs drastically alters their effect on cholesterol homeostasis in fibroblasts. The data furthermore suggest the existence of a lipoprotein pathway for cholesterol biosynthesis regulation that is independent of the LDL receptor-mediated pathway. Downregulation of cholesterol biosynthesis would be a new function for oxidatively modified lipoproteins.

FCE 27677: a novel inhibitor of acyl-CoA: cholesterol acyltransferase with potent oral hypolipidemic activity.

FCE 27677 ([(-)N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2- (4-dimethylaminophenyl)-4,5 dimethyl-dioxolan-2-yl]methylurea) is a new systemically available ACAT inhibitor belonging to the class of ketalic disubstituted ureas. When tested in microsomes from rabbit intestine, aorta and liver, it inhibited the enzyme with IC50 of 9.31, 6.99 and 92.2 nM, respectively. It had no effect on plasma LCAT and intestinal cytosolic cholesterol esterases and, when tested in a tissue culture system, it did not interfere with the synthesis of cholesterol, triglycerides, and phospholipids. Enzyme inhibition kinetics indicated that FCE 27677 is a non-competitive inhibitor of the enzyme with respect to acylCoA and to cholesterol. When administered mixed to a 1.5% cholesterol and 0.5% sodium cholate-enriched diet to rats, it prevented the development of hypercholesterolemia with ED50 of 0.35 mg kg-1 day-1. Given in a single oral dose to hypercholesterolemic rats it significantly reduced both the plasma lipid levels and the hepatic cholesteryl ester content within 6 h from gavage. VLDL and LDL levels and composition were also significantly affected. Similar effects were observed when the drug was given mixed to a regular chow diet for 4 weeks to hypercholesterolemic rabbits. These results are consistent with the idea that systemically available ACAT inhibitors can affect the composition and the metabolism of the atherogenic cholesteryl ester-rich VLDL and LDL. ACAT inhibitors appear promising for the correction of dyslipoproteinemias secondary to lipoprotein overproduction, and in reducing the atherogenic index of apoB-100 containing lipoproteins.

Inhibition of acyl-CoA: cholesterol acyltransferase decreases apolipoprotein B-100-containing lipoprotein secretion from HepG2 cells.

There is evidence that the overproduction of apoB-100-containing lipoproteins by the liver is the underlying event in some forms of dyslipoproteinemia. This metabolic status is associated to an increased risk of developing premature coronary artery disease CAD. The conclusions from previous studies suggested that the availability to the hepatocytes of cholesterol that is readily esterified is an important determinant for VLDL and LDL secretion. In the present study, we set out to investigate the effect of the specific stimulation and inhibition of the rate-limiting enzyme of the cholesterol esterification, acyl-CoA:cholesterol acyltransferase (ACAT, E.C. 2.3.1.26), on the lipid and on the apoB-100 secretion rate from a human hepatoma cell line (HepG2). When the specific ACAT inhibitor FCE 27677 (10-5 M) was added to the cultures, a decrease of the cellular cholesteryl ester content and at the same time a significant reduction of the neutral lipids and of the apoB-100 secretion rate were noticed. The stimulation of ACAT by 25-hydroxycholesterol (20 microgram/ml) caused a 4-fold increase of the cellular cholesteryl ester content and a 2-fold increase of the lipoprotein secretion rate. FCE 27677 (10-5 M to 10-7 M) prevented the effects elicited by the oxysterol. On the contrary, lovastatin (10-6 M) and gemfibrozil (10-6 M) had no effect. The analysis of the lipid and of the apolipoprotein composition of the lipoproteins secreted in the medium revealed that ACAT inhibition had the dual effect of both decreasing the number of apoB-100-containing lipoproteins secreted as well as their cholesteryl ester load. Altogether, these data support the idea of a close relationship between ACAT activation, leading to increased cholesteryl ester availability, and apoB-100-containing lipoprotein secretion. It is speculated that ACAT inhibitors may prove useful for the treatment of human dyslipoproteinemias caused by the hepatic overproduction of apoB-100-containing lipoproteins.