Fsp27/CIDEC is a CREB target gene induced during early fasting in liver and regulated by FA oxidation rate

FSP27 (CIDEC in humans) is a protein associated with lipid droplets that downregulates the fatty acid oxidation (FAO) rate when it is overexpressed. However, little is known about its physiological role in liver. Here, we show that fasting regulates liver expression of Fsp27 in a time-dependent manner. Thus, during the initial stages of fasting a maximal induction of 800-fold was achieved, while during the later phase of fasting, Fsp27 expression decreased. The early response to fasting can be explained by a canonical PKA-CREB-CRTC2 signaling pathway since: i) CIDEC expression was induced by forskolin, ii) Fsp27 promoter activity was increased by CREB, and iii) Fsp27 expression was upregulated in the liver of Sirt1 knockout animals. Interestingly, pharmacological (etomoxir) or genetic (Hmgcs2 interference) inhibition of the FAO rate increases the in vivo expression of Fsp27 during fasting. Similarly, CIDEC expression was upregulated in HepG2 cells by either etomoxir or HMGCS2 interference. Our data indicate that there is a kinetic mechanism of auto-regulation between short- and long-term fasting, by which free fatty acids delivered to the liver during early fasting are accumulated/exported by FSP27/CIDEC, while over longer periods of fasting they are degraded in the mitochondria through the carnitine palmitoyl transferase (CPT) system.

Issue of time in generally covariant theories and the Komar-Bergmann approach to observables in general relativity

Diffeomorphism-induced symmetry transformations and time evolution are distinct operations in generally covariant theories formulated in phase space. Time is not frozen. Diffeomorphism invariants are consequently not necessarily constants of the motion. Time-dependent invariants arise through the choice of an intrinsic time, or equivalently through the imposition of time-dependent gauge fixation conditions. One example of such a time-dependent gauge fixing is the Komar-Bergmann use of Weyl curvature scalars in general relativity. An analogous gauge fixing is also imposed for the relativistic free particle and the resulting complete set time-dependent invariants for this exactly solvable model are displayed. In contrast with the free particle case, we show that gauge invariants that are simultaneously constants of motion cannot exist in general relativity. They vary with intrinsic time.

Scaling calculation of isoscalar giant resonances in relativistic Thomas-Fermi theory

We derive analytical expressions for the excitation energy of the isoscalar giant monopole and quadrupole resonances in finite nuclei, by using the scaling method and the extended ThomasFermi approach to relativistic mean-field theory. We study the ability of several nonlinear σω parameter sets of common use in reproducing the experimental data. For monopole oscillations the calculations agree better with experiment when the nuclear matter incompressibility of the relativistic interaction lies in the range 220260 MeV. The breathing-mode energies of the scaling method compare satisfactorily with those obtained in relativistic RPA and time-dependent mean-field calculations. For quadrupole oscillations, all the analyzed nonlinear parameter sets reproduce the empirical trends reasonably well.

Dissociation from BiP and Retrotranslocation of Unassembled Immunoglobulin Light Chains Are Tightly Coupled to Proteasome Activity

Unassembled immunoglobulin light chains expressed by the mouse plasmacytoma cell line NS1 (KNS1) are degraded in vivo with a half-life of 50-60 min in a way that closely resembles endoplasmic reticulum (ER)-associated degradation (Knittler et al., 1995). Here we show that the peptide aldehydes MG132 and PS1 and the specific proteasome inhibitor lactacystin effectively increased the half-life of KNS1, arguing for a proteasome-mediated degradation pathway. Subcellular fractionation and protease protection assays have indicated an ER localization of KNS1 upon proteasome inhibition. This was independently confirmed by the analysis of the folding state of KNS1and size fractionation experiments showing that the immunoglobulin light chain remained bound to the ER chaperone BiP when the activity of the proteasome was blocked. Moreover, kinetic studies performed in lactacystin-treated cells revealed a time-dependent increase in the physical stability of the BiP-KNS1complex, suggesting that additional proteins are present in the older complex. Together, our data support a model for ER-associated degradation in which both the release of a soluble nonglycosylated protein from BiP and its retrotranslocation out of the ER are tightly coupled with proteasome activity.

Polyphenol intake and mortality risk: a re-analysis of the PREDIMED trial

Background: Polyphenols may lower the risk of cardiovascular disease (CVD) and other chronic diseases due to their antioxidant and anti-inflammatory properties, as well as their beneficial effects on blood pressure, lipids and insulin resistance. However, no previous epidemiological studies have evaluated the relationship between the intake of total polyphenols intake and polyphenol subclasses with overall mortality. Our aim was to evaluate whether polyphenol intake is associated with all-cause mortality in subjects at high cardiovascular risk. Methods: We used data from the PREDIMED study, a 7,447-participant, parallel-group, randomized, multicenter, controlled five-year feeding trial aimed at assessing the effects of the Mediterranean Diet in primary prevention of cardiovascular disease. Polyphenol intake was calculated by matching food consumption data from repeated food frequency questionnaires (FFQ) with the Phenol-Explorer database on the polyphenol content of each reported food. Hazard ratios (HR) and 95% confidence intervals (CI) between polyphenol intake and mortality were estimated using time-dependent Cox proportional hazard models. Results: Over an average of 4.8 years of follow-up, we observed 327 deaths. After multivariate adjustment, we found a 37% relative reduction in all-cause mortality comparing the highest versus the lowest quintiles of total polyphenol intake (hazard ratio (HR) = 0.63; 95% CI 0.41 to 0.97; P for trend = 0.12). Among the polyphenol subclasses, stilbenes and lignans were significantly associated with reduced all-cause mortality (HR =0.48; 95% CI 0.25 to 0.91; P for trend = 0.04 and HR = 0.60; 95% CI 0.37 to 0.97; P for trend = 0.03, respectively), with no significant associations apparent in the rest (flavonoids or phenolic acids). Conclusions: Among high-risk subjects, those who reported a high polyphenol intake, especially of stilbenes and lignans, showed a reduced risk of overall mortality compared to those with lower intakes. These results may be useful to determine optimal polyphenol intake or specific food sources of polyphenols that may reduce the risk of all-cause mortality.

Diseño e implementación de un sistema PDM

En aquest projecte s'ha realitzat el disseny i la implementació d'un sistema PDM genèric mitjançant el qual sigui posible crear i gestionar la informació relacionada amb un producte. Amb aquesta eina web realitzada fent ús del patró d'arquitectura MVC, es pretèn disminuir la pèrdua de temps i de dades a la organització de dades de disseny, millorar la productivitat i augmentar la col·laboració.

Análisis y sintonización de aplicaciones paralelas/distribuidas de bioinformática: caso de estudio mpiBLAST

En termes de temps d'execució i ús de dades, les aplicacions paral·leles/distribuïdes poden tenir execucions variables, fins i tot quan s'empra el mateix conjunt de dades d'entrada. Existeixen certs aspectes de rendiment relacionats amb l'entorn que poden afectar dinàmicament el comportament de l'aplicació, tals com: la capacitat de la memòria, latència de la xarxa, el nombre de nodes, l'heterogeneïtat dels nodes, entre d'altres. És important considerar que l'aplicació pot executar-se en diferents configuracions de maquinari i el desenvolupador d'aplicacions no port garantir que els ajustaments de rendiment per a un sistema en particular continuïn essent vàlids per a d'altres configuracions. L'anàlisi dinàmica de les aplicacions ha demostrat ser el millor enfocament per a l'anàlisi del rendiment per dues raons principals. En primer lloc, ofereix una solució molt còmoda des del punt de vista dels desenvolupadors mentre que aquests dissenyen i evaluen les seves aplicacions paral·leles. En segon lloc, perquè s'adapta millor a l'aplicació durant l'execució. Aquest enfocament no requereix la intervenció de desenvolupadors o fins i tot l'accés al codi font de l'aplicació. S'analitza l'aplicació en temps real d'execució i es considra i analitza la recerca dels possibles colls d'ampolla i optimitzacions. Per a optimitzar l'execució de l'aplicació bioinformàtica mpiBLAST, vam analitzar el seu comportament per a identificar els paràmetres que intervenen en el rendiment d'ella, com ara: l'ús de la memòria, l'ús de la xarxa, patrons d'E/S, el sistema de fitxers emprat, l'arquitectura del processador, la grandària de la base de dades biològica, la grandària de la seqüència de consulta, la distribució de les seqüències dintre d'elles, el nombre de fragments de la base de dades i/o la granularitat dels treballs assignats a cada procés. El nostre objectiu és determinar quins d'aquests paràmetres tenen major impacte en el rendiment de les aplicacions i com ajustar-los dinàmicament per a millorar el rendiment de l'aplicació. Analitzant el rendiment de l'aplicació mpiBLAST hem trobat un conjunt de dades que identifiquen cert nivell de serial·lització dintre l'execució. Reconeixent l'impacte de la caracterització de les seqüències dintre de les diferents bases de dades i una relació entre la capacitat dels workers i la granularitat de la càrrega de treball actual, aquestes podrien ser sintonitzades dinàmicament. Altres millores també inclouen optimitzacions relacionades amb el sistema de fitxers paral·lel i la possibilitat d'execució en múltiples multinucli. La grandària de gra de treball està influenciat per factors com el tipus de base de dades, la grandària de la base de dades, i la relació entre grandària de la càrrega de treball i la capacitat dels treballadors.

Optimal exponent heat balance and refined integral methods applied to Stefan problems

When using a polynomial approximating function the most contentious aspect of the Heat Balance Integral Method is the choice of power of the highest order term. In this paper we employ a method recently developed for thermal problems, where the exponent is determined during the solution process, to analyse Stefan problems. This is achieved by minimising an error function. The solution requires no knowledge of an exact solution and generally produces significantly better results than all previous HBI models. The method is illustrated by first applying it to standard thermal problems. A Stefan problem with an analytical solution is then discussed and results compared to the approximate solution. An ablation problem is also analysed and results compared against a numerical solution. In both examples the agreement is excellent. A Stefan problem where the boundary temperature increases exponentially is analysed. This highlights the difficulties that can be encountered with a time dependent boundary condition. Finally, melting with a time-dependent flux is briefly analysed without applying analytical or numerical results to assess the accuracy.

Exploring the conditions for a mortality crisis: bringing context back into the debate

This study engages with the debate over the mortality crises in the former Soviet Union and Central and Eastern Europe by 1) considering at length and as complementary to each other the two most prominent explanations for the post-communist mortality crisis, stress and alcohol consumption; 2) emphasizing the importance of context by exploiting systematic similarities and differences across the region. Differential mortality trajectories reveal three country groups that cluster both spatially and in terms of economic transition experiences. The first group are the countries furthest west in which mortality rates increased minimally after the transition began. The second group experienced a severe increase in mortality rates in the early 1990s, but recovered previous levels within a few years. These countries are located peripherally to Russia and its nearest neighbours. The final group consists of countries that experienced two mortality increases or in which mortality levels had not recovered to pre-transition levels well into the 21st century. Cross-sectional time-series data analyses of men’s and women’s age and cause-specific death rates reveal that the clustering of these countries and their mortality trajectories can be partially explained by the economic context, which is argued to be linked to stress and alcohol consumption. Above and beyond many basic differences in the country groups that are held constant—including geographically and historically shared cultural, lifestyle and social characteristics—poor economic conditions account for a remarkably consistent share of excess age-specific and cause-specific deaths.

A subsampling approach to estimating the distribution of diversing statistics with application to assessing financial market risks

In this paper we propose a subsampling estimator for the distribution ofstatistics diverging at either known rates when the underlying timeseries in strictly stationary abd strong mixing. Based on our results weprovide a detailed discussion how to estimate extreme order statisticswith dependent data and present two applications to assessing financialmarket risk. Our method performs well in estimating Value at Risk andprovides a superior alternative to Hill's estimator in operationalizingSafety First portofolio selection.

Wage determination in the Spanish industry

In this paper we estimate wage equations for the Spanish industryusing time series data on 85 industrial sectors, which allows us todistinguish between aggregate and sector specific effects in wagedetermination. Industry wages respond mainly to economy wide labourmarket conditions and to a much lesser extent to sector specificproductivity gains. The size of the insider effect has not remainedstable through the sample period. The estimated equations show a strongtransitory effect of unemployment on wages, which is in accordancewith the non--stationarity of the Spanish unemployment rate. Thishysteresis effect seems well accounted for by the sharp rise in theproportion of long term unemployment.

Single mothers and incentives to work: The French experience

This paper analyzes the effect of the 1998 reform of the French single parents allowanceon the labor supply of single mothers with very young children. The reform aimed atencouraging participation by allowing eligible single parents to accumulate benefits andlabor earnings for a limited period of time. Using data from the French EmploymentSurvey, the analysis shows that single mothers affected by the reform had experienced asignificant increase in their employment rate four years after the reform wasimplemented. During the same period, the employment rate of married mothers withyoung children did not experience a significant change, suggesting that at least part ofthe increase was a consequence of the reform. These results provide some evidence thatbenefit schedules that provide financial incentives to work can have significant effectsin getting single moms back to work, even in the presence of very young children.

Unified formalism for non-autonomous mechanical systems

We present a unified geometric framework for describing both the Lagrangian and Hamiltonian formalisms of regular and non-regular time-dependent mechanical systems, which is based on the approach of Skinner and Rusk (1983). The dynamical equations of motion and their compatibility and consistency are carefully studied, making clear that all the characteristics of the Lagrangian and the Hamiltonian formalisms are recovered in this formulation. As an example, it is studied a semidiscretization of the nonlinear wave equation proving the applicability of the proposed formalism.

Defective TNF-alpha-mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice

This study addressed the contribution of acidic sphingomyelinase (ASMase) in TNF-alpha-mediated hepatocellular apoptosis. Cultured hepatocytes depleted of mitochondrial glutathione (mGSH) became sensitive to TNF-alpha, undergoing a time-dependent apoptotic cell death preceded by mitochondrial membrane depolarization, cytochrome c release, and caspase activation. Cyclosporin A treatment rescued mGSH-depleted hepatocytes from TNF-alpha-induced cell death. In contrast, mGSH-depleted hepatocytes deficient in ASMase were resistant to TNF-alpha-mediated cell death but sensitive to exogenous ASMase. Furthermore, although in vivo administration of TNF-alpha or LPS to galactosamine-pretreated ASMase(+/+) mice caused liver damage, ASMase(-/-) mice exhibited minimal hepatocellular injury. To analyze the requirement of ASMase, we assessed the effect of glucosylceramide synthetase inhibition on TNF-alpha-mediated apoptosis. This approach, which blunted glycosphingolipid generation by TNF-alpha, protected mGSH-depleted ASMase(+/+) hepatocytes from TNF-alpha despite enhancement of TNF-alpha-stimulated ceramide formation. To further test the involvement of glycosphingolipids, we focused on ganglioside GD3 (GD3) because of its emerging role in apoptosis through interaction with mitochondria. Analysis of the cellular redistribution of GD3 by laser scanning confocal microscopy revealed the targeting of GD3 to mitochondria in ASMase(+/+) but not in ASMase(-/-) hepatocytes. However, treatment of ASMase(-/-) hepatocytes with exogenous ASMase induced the colocalization of GD3 and mitochondria. Thus, ASMase contributes to TNF-alpha-induced hepatocellular apoptosis by promoting the mitochondrial targeting of glycosphingolipids.

Differential equations driven by fractional Brownian motion

A global existence and uniqueness result of the solution for multidimensional, time dependent, stochastic differential equations driven by a fractional Brownian motion with Hurst parameter H> is proved. It is shown, also, that the solution has finite moments. The result is based on a deterministic existence and uniqueness theorem whose proof uses a contraction principle and a priori estimates.