The Role of Dietary Sugars and De novo Lipogenesis in Non-Alcoholic Fatty Liver Disease

Dietary sugar consumption, in particular sugar-sweetened beverages and the monosaccharide fructose, has been linked to the incidence and severity of non-alcoholic fatty liver disease (NAFLD). Intervention studies in both animals and humans have shown large doses of fructose to be particularly lipogenic. While fructose does stimulate de novo lipogenesis (DNL), stable isotope tracer studies in humans demonstrate quantitatively that the lipogenic effect of fructose is not mediated exclusively by its provision of excess substrates for DNL. The deleterious metabolic effects of high fructose loads appear to be a consequence of altered transcriptional regulatory networks impacting intracellular macronutrient metabolism and altering signaling and inflammatory processes. Uric acid generated by fructose metabolism may also contribute to or exacerbate these effects. Here we review data from human and animal intervention and stable isotope tracer studies relevant to the role of dietary sugars on NAFLD development and progression, in the context of typical sugar consumption patterns and dietary recommendations worldwide. We conclude that the use of hypercaloric, supraphysiological doses in intervention trials has been a major confounding factor and whether or not dietary sugars, including fructose, at typically consumed population levels, effect hepatic lipogenesis and NAFLD pathogenesis in humans independently of excess energy remains unresolved

Non-linear Response of the trap model in the aging regime : Exact results in the strong disorder limit

We study the dynamics of the one dimensional disordered trap model presenting a broad distribution of trapping times $p(\tau) \sim 1/\tau^{1+\mu}$, when an external force is applied from the very beginning at $t=0$, or only after a waiting time $t_w$, in the linear as well as in the non-linear response regime. Using a real-space renormalization procedure that becomes exact in the limit of strong disorder $\mu \to 0$, we obtain explicit results for many observables, such as the diffusion front, the mean position, the thermal width, the localization parameters and the two-particle correlation function. In particular, the scaling functions for these observables give access to the complete interpolation between the unbiased case and the directed case. Finally, we discuss in details the various regimes that exist for the averaged position in terms of the two times and the external field.Comment: 27 pages, 1 eps figur

Role of the enterocyte in fructose-induced hypertriglyceridaemia

Dietary fructose has been linked to an increased post-prandial triglyceride (TG) level; which is an established independent risk factor for cardiovascular disease. Although much research has focused on the effects of fructose consumption on liver-derived very-low density lipoprotein (VLDL); emerging evidence also suggests that fructose may raise post-prandial TG levels by affecting the metabolism of enterocytes of the small intestine. Enterocytes have become well recognised for their ability to transiently store lipids following a meal and to thus control post-prandial TG levels according to the rate of chylomicron (CM) lipoprotein synthesis and secretion. The influence of fructose consumption on several aspects of enterocyte lipid metabolism are discussed; including de novo lipogenesis; apolipoprotein B48 and CM-TG production; based on the findings of animal and human isotopic tracer studies. Methodological issues affecting the interpretation of fructose studies conducted to date are highlighted; including the accurate separation of CM and VLDL. Although the available evidence to date is limited; disruption of enterocyte lipid metabolism may make a meaningful contribution to the hypertriglyceridaemia often associated with fructose consumption

Mesoscale subduction at the Almeria-Oran front. Part 2: biophysical interactions.

This paper presents a detailed diagnostic analysis of hydrographic and current meter data from three, rapidly repeated, fine-scale surveys of the Almeria–Oran front. Instability of the frontal boundary, between surface waters of Atlantic and Mediterranean origin, is shown to provide a mechanism for significant heat transfer from the surface layers to the deep ocean in winter. The data were collected during the second observational phase of the EU funded OMEGA project on RRS Discovery cruise 224 during December 1996. High resolution hydrographic measurements using the towed undulating CTD vehicle, SeaSoar, traced the subduction of Mediterranean Surface Water across the Almeria–Oran front. This subduction is shown to result from a significant baroclinic component to the instability of the frontal jet. The Q-vector formulation of the omega equation is combined with a scale analysis to quantitatively diagnose vertical transport resulting from mesoscale ageostrophic circulation. The analyses are presented and discussed in the presence of satellite and airborne remotely sensed data; which provide the basis for a thorough and novel approach to the determination of observational error

Extensive dissolution of live pteropods in the Southern Ocean

The carbonate chemistry of the surface ocean is rapidly changing with ocean acidification, a result of human activities. In the upper layers of the Southern Ocean, aragonite—a metastable form of calcium carbonate with rapid dissolution kinetics—may become undersaturated by 2050 (ref. 2). Aragonite undersaturation is likely to affect aragonite-shelled organisms, which can dominate surface water communities in polar regions. Here we present analyses of specimens of the pteropod Limacina helicina antarctica that were extracted live from the Southern Ocean early in 2008. We sampled from the top 200m of the water column, where aragonite saturation levels were around 1, as upwelled deep water is mixed with surface water containing anthropogenic CO2. Comparing the shell structure with samples from aragonite-supersaturated regions elsewhere under a scanning electron microscope, we found severe levels of shell dissolution in the undersaturated region alone. According to laboratory incubations of intact samples with a range of aragonite saturation levels, eight days of incubation in aragonite saturation levels of 0.94– 1.12 produces equivalent levels of dissolution. As deep-water upwelling and CO2 absorption by surface waters is likely to increase as a result of human activities2,4, we conclude that upper ocean regions where aragonite-shelled organisms are affected by dissolution are likely to expand

Anomalous diffusion, Localization, Aging and Sub-aging effects in trap models at very low temperature

We study in details the dynamics of the one dimensional symmetric trap model, via a real-space renormalization procedure which becomes exact in the limit of zero temperature. In this limit, the diffusion front in each sample consists in two delta peaks, which are completely out of equilibrium with each other. The statistics of the positions and weights of these delta peaks over the samples allows to obtain explicit results for all observables in the limit $T \to 0$. We first compute disorder averages of one-time observables, such as the diffusion front, the thermal width, the localization parameters, the two-particle correlation function, and the generating function of thermal cumulants of the position. We then study aging and sub-aging effects : our approach reproduces very simply the two different aging exponents and yields explicit forms for scaling functions of the various two-time correlations. We also extend the RSRG method to include systematic corrections to the previous zero temperature procedure via a series expansion in $T$. We then consider the generalized trap model with parameter $\alpha \in [0,1]$ and obtain that the large scale effective model at low temperature does not depend on $\alpha$ in any dimension, so that the only observables sensitive to $\alpha$ are those that measure the `local persistence', such as the probability to remain exactly in the same trap during a time interval. Finally, we extend our approach at a scaling level for the trap model in $d=2$ and obtain the two relevant time scales for aging properties.Comment: 33 pages, 3 eps figure

Dissolution dominating calcification process in polar pteropods close to the point of aragonite undersaturation

Thecosome pteropods are abundant upper-ocean zooplankton that build aragonite shells. Ocean acidification results in the lowering of aragonite saturation levels in the surface layers, and several incubation studies have shown that rates of calcification in these organisms decrease as a result. This study provides a weight-specific net calcification rate function for thecosome pteropods that includes both rates of dissolution and calcification over a range of plausible future aragonite saturation states (Omega_Ar). We measured gross dissolution in the pteropod Limacina helicina antarctica in the Scotia Sea (Southern Ocean) by incubating living specimens across a range of aragonite saturation states for a maximum of 14 days. Specimens started dissolving almost immediately upon exposure to undersaturated conditions (Omega_Ar,0.8), losing 1.4% of shell mass per day. The observed rate of gross dissolution was different from that predicted by rate law kinetics of aragonite dissolution, in being higher at Var levels slightly above 1 and lower at Omega_Ar levels of between 1 and 0.8. This indicates that shell mass is affected by even transitional levels of saturation, but there is, nevertheless, some partial means of protection for shells when in undersaturated conditions. A function for gross dissolution against Var derived from the present observations was compared to a function for gross calcification derived by a different study, and showed that dissolution became the dominating process even at Omega_Ar levels close to 1, with net shell growth ceasing at an Omega_Ar of 1.03. Gross dissolution increasingly dominated net change in shell mass as saturation levels decreased below 1. As well as influencing their viability, such dissolution of pteropod shells in the surface layers will result in slower sinking velocities and decreased carbon and carbonate fluxes to the deep ocean

Slow relaxation due to optimization and restructuring: Solution on a hierarchical lattice

Motivated by the large strain shear of loose granular materials we introduced a model which consists of consecutive optimization and restructuring steps leading to a self organization of a density field. The extensive connections to other models of statistical phyics are discussed. We investigate our model on a hierarchical lattice which allows an exact asymptotic renormalization treatment. A surprisingly close analogy is observed between the simulation results on the regular and the hierarchical lattices. The dynamics is characterized by the breakdown of ergodicity, by unusual system size effects in the development of the average density as well as by the age distribution, the latter showing multifractal properties.Comment: 11 pages, 7 figures revtex, submitted to PRE see also: cond-mat/020920

Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor in vivo Using Fluorinated Bisquinolines

Antimalarials can interact with heme covalently, by - interactions or hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen due to electronic rather than steric factors. In gas phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF3 group occupied the 7-position. Hence, trifluromethyl groups buttressing quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/6- 31+G*) and crystal structure of (±)-trans-N1,N2-bis-(2,8-ditrifluoromethylquinolin-4- yl)cyclohexane-1,2-diamine were used to reveal preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III)state which has important implications for the future rational design of 4- aminoquinoline antimalarials

Southern San Andreas-San Jacinto fault system slip rates estimated from earthquake cycle models constrained by GPS and interferometric synthetic aperture radar observations

We use ground geodetic and interferometric synthetic aperture radar satellite observations across the southern San Andreas (SAF)-San Jacinto (SJF) fault systems to constrain their slip rates and the viscosity structure of the lower crust and upper mantle on the basis of periodic earthquake cycle, Maxwell viscoelastic, finite element models. Key questions for this system are the SAF and SJF slip rates, the slip partitioning between the two main branches of the SJF, and the dip of the SAF. The best-fitting models generally have a high-viscosity lower crust (η = 10^(21) Pa s) overlying a lower-viscosity upper mantle (η = 10^(19) Pa s). We find considerable trade-offs between the relative time into the current earthquake cycle of the San Jacinto fault and the upper mantle viscosity. With reasonable assumptions for the relative time in the earthquake cycle, the partition of slip is fairly robust at around 24–26 mm/a for the San Jacinto fault system and 16–18 mm/a for the San Andreas fault. Models for two subprofiles across the SAF-SJF systems suggest that slip may transfer from the western (Coyote Creek) branch to the eastern (Clark-Superstition hills) branch of the SJF from NW to SE. Across the entire system our best-fitting model gives slip rates of 2 ± 3, 12 ± 9, 12 ± 9, and 17 ± 3 mm/a for the Elsinore, Coyote Creek, Clark, and San Andreas faults, respectively, where the large uncertainties in the slip rates for the SJF branches reflect the large uncertainty in the slip rate partitioning within the SJF system