The role of circadian timing system on drug metabolism and detoxification.

INTRODUCTION: It has been known for a long time that the efficiency and toxicity of drugs change during a 24-h period. However, the molecular mechanisms involved in these processes have started to emerge only recently. AREAS COVERED: This review aims to highlight recent discoveries showing the direct role of the molecular circadian clock in xenobiotic metabolism at the transcriptional and post-transcriptional levels in the liver and intestine, and the different ways of elimination of these metabolized drugs via biliary and urine excretions. Most of the related literature focuses on transcriptional regulation by the circadian clock of xenobiotic metabolism in the liver; however, the role of this timing system in the excretion of metabolized drugs and the importance of the kidney in this phenomenon are generally neglected. The goal of this review is to describe the molecular mechanisms involved in rhythmic drug metabolism and excretion. EXPERT OPINION: Chronopharmacology is used to analyze the metabolism of drugs in mammals according to the time of day. The circadian timing system plays a key role in the changes of toxicity of drugs by influencing their metabolisms in the liver and intestine in addition to their excretion via bile flow and urine.

Bioconjugated lanthanide luminescent helicates as multilabels for lab-on-a-chip detection of cancer biomarkers.

The lanthanide binuclear helicate [Eu(2)(L(C2(CO(2)H)))(3)] is coupled to avidin to yield a luminescent bioconjugate EuB1 (Q = 9.3%, tau((5)D(0)) = 2.17 ms). MALDI/TOF mass spectrometry confirms the covalent binding of the Eu chelate and UV-visible spectroscopy allows one to determine a luminophore/protein ratio equal to 3.2. Bio-affinity assays involving the recognition of a mucin-like protein expressed on human breast cancer MCF-7 cells by a biotinylated monoclonal antibody 5D10 to which EuB1 is attached via avidin-biotin coupling demonstrate that (i) avidin activity is little affected by the coupling reaction and (ii) detection limits obtained by time-resolved (TR) luminescence with EuB1 and a commercial Eu-avidin conjugate are one order of magnitude lower than those of an organic conjugate (FITC-streptavidin). In the second part of the paper, conditions for growing MCF-7 cells in 100-200 microm wide microchannels engraved in PDMS are established; we demonstrate that EuB1 can be applied as effectively on this lab-on-a-chip device for the detection of tumour-associated antigens as on MCF-7 cells grown in normal culture vials. In order to exploit the versatility of the ligand used for self-assembling [Ln(2)(L(C2(CO(2)H)))(3)] helicates, which sensitizes the luminescence of both Eu(III) and Tb(III) ions, a dual on-chip assay is proposed in which estrogen receptors (ERs) and human epidermal growth factor receptors (Her2/neu) can be simultaneously detected on human breast cancer tissue sections. The Ln helicates are coupled to two secondary antibodies: ERs are visualized by red-emitting EuB4 using goat anti-mouse IgG and Her2/neu receptors by green-emitting TbB5 using goat anti-rabbit IgG. The fact that the assay is more than 6 times faster and requires 5 times less reactants than conventional immunohistochemical assays provides essential advantages over conventional immunohistochemistry for future clinical biomarker detection.

The Impact of the Electoral System on Political Campaigning : Are Candidates for the Council of States More Moderate than their Fellow Candidates for the National Council ?

It is commonly believed that majority voting enhances parties to cluster around the centre of the political space, whereas proportional systems (PR) foster great ideological divergence. The theoretical arguments for these expectations go back to the work of Downs (1957) and Duverger (1954). More recent studies, however, produced quite contradictory empirical findings. In this paper I will test whether similar arguments hold true for the positioning of candidates campaigning in different electoral systems. The elections for the two chambers of the Swiss Parliament and the data from the Swiss Electoral Studies (SELECTS) and the Swiss Voting Advice Application (VAA) smartvote offer an excellent - almost laboratory like - opportunity to do so empirically. The analyses show clearly, the theoretical claims that majority voting necessarily fosters more moderate positions find no support. The candidates for the Council of States, elected in a majority system, are not more moderate than their fellow party candidates for the National Council which are elected in a PR system.

Porting and performance analysis of EC-Earth System on the BSC-MareNostrum Supercomputer

Earth System Models (ESM) have been successfuly developed over past few years, and are currently beeing used for simulating present day-climate, seasonal to interanual predictions of climate change. The supercomputer performance plays an important role in climate modeling since one of the challenging issues for climate modellers is to efficiently and accurately couple earth System components on present day computers architectures. At the Barcelona Supercomputing Center (BSC), we work with the EC- Earth System Model. The EC- Earth is an ESM, which currently consists of an atmosphere (IFS) and an ocean (NEMO) model that communicate with each other through the OASIS coupler. Additional modules (e.g. for chemistry and vegetation ) are under development. The EC-Earth ESM has been ported successfully over diferent high performance computin platforms (e.g, IBM P6 AIX, CRAY XT-5, Intelbased Linux Clusters, SGI Altix) at diferent sites in Europ (e.g., KNMI, ICHEC, ECMWF). The objective of the first phase of the project was to identify and document the issues related with the portability and performance of EC-Earth on the MareNostrum supercomputer, a System based on IBM PowerPC 970MP processors and run under a Linux Suse Distribution. EC-Earth was successfully ported to MareNostrum, and a compilation incompatibilty was solved by a two step compilation approach using XLF version 10.1 and 12.1 compilers. In addition, the EC-Earth performance was analyzed with respect to escalability and trace analysis with the Paravear software. This analysis showed that EC-Earth with a larger number of IFS CPUs (<128) is not feasible at the moment since some issues exists with the IFS-NEMO balance and MPI Communications.

Time-resolved lanthanide luminescence for lab-on-a-chip detection of biomarkers on cancerous tissues.

PDMS-based microfluidic devices combined with lanthanide-based immunocomplexes have been successfully tested for the multiplex detection of biomarkers on cancerous tissues, revealing an enhanced sensitivity compared to classical organic dyes.

The impact of the reference price system on the pharmaceutical market: A theoretical approach

This article analyses the impact of the reference pricesystem on the price-setting strategies of thepharmaceutical firms and on the level of generic usage.This model is the first to take explicitly into accountthe impact of the reference price mechanism on the levelof competition between brand-name and generic drugs andnational pharmaceutical spending. We consider aduopolistic model with one firm producing the brand-namedrug, whose patent has already expired, and the otherproducing the corresponding generic version. We work ina partial equilibrium framework where firms set pricessequentially and consumers face heterogeneous switchingcosts.We show that brand producers compensate thedecline of profits by selling greater quantities insteadof charging higher prices, thus fostering pricecompetition in the pharmaceutical market. This result isa consequence of both the assumption of a verticallydifferentiated model and the introduction of thereference price system.

Pilot Project for a Hybrid Road-Flooding Forecasting System on Squaw Creek, TR-642

A network of 25 sonic stage sensors were deployed in the Squaw Creek basin upstream from Ames Iowa to determine if the state-of-the-art distributed hydrological model CUENCAS can produce reliable information for all road crossings including those that cross small creeks draining basins as small as 1 sq. mile. A hydraulic model was implemented for the major tributaries of the Squaw Creek where IFC sonic instruments were deployed and it was coupled to CUENCAS to validate the predictions made at small tributaries in the basin. This study demonstrates that the predictions made by the hydrological model at internal locations in the basins are as accurate as the predictions made at the outlet of the basin. Final rating curves based on surveyed cross sections were developed for the 22 IFC-bridge sites that are currently operating, and routine forecast is provided at those locations (see IFIS). Rating curves were developed for 60 additional bridge locations in the basin, however, we do not use those rating curves for routine forecast because the lack of accuracy of LiDAR derived cross sections is not optimal. The results of our work form the basis for two papers that have been submitted for publication to the Journal of Hydrological Engineering. Peer review of our work will gives a strong footing to our ability to expand our results from the pilot Squaw Creek basin to all basins in Iowa.

Impact of the Advisa MRI pacing system on the diagnostic quality of cardiac MR images and contraction patterns of cardiac muscle during scans: Advisa MRI randomized clinical multicenter study results.

BACKGROUND: The Advisa MRI system is designed to safely undergo magnetic resonance imaging (MRI). Its influence on image quality is not well known. OBJECTIVE: To evaluate cardiac magnetic resonance (CMR) image quality and to characterize myocardial contraction patterns by using the Advisa MRI system. METHODS: In this international trial with 35 participating centers, an Advisa MRI system was implanted in 263 patients. Of those, 177 were randomized to the MRI group and 150 underwent MRI scans at the 9-12-week visit. Left ventricular (LV) and right ventricular (RV) cine long-axis steady-state free precession MR images were graded for quality. Signal loss along the implantable pulse generator and leads was measured. The tagging CMR data quality was assessed as the percentage of trackable tagging points on complementary spatial modulation of magnetization acquisitions (n=16) and segmental circumferential fiber shortening was quantified. RESULTS: Of all cine long-axis steady-state free precession acquisitions, 95% of LV and 98% of RV acquisitions were of diagnostic quality, with 84% and 93%, respectively, being of good or excellent quality. Tagging points were trackable from systole into early diastole (360-648 ms after the R-wave) in all segments. During RV pacing, tagging demonstrated a dyssynchronous contraction pattern, which was not observed in nonpaced (n = 4) and right atrial-paced (n = 8) patients. CONCLUSIONS: In the Advisa MRI study, high-quality CMR images for the assessment of cardiac anatomy and function were obtained in most patients with an implantable pacing system. In addition, this study demonstrated the feasibility of acquiring tagging data to study the LV function during pacing.

Validation of a computer-assisted system on classifying lower third molars

Objectives: The present study evaluates the reliability of the Radio Memory® software (Radio Memory; Belo Horizonte,Brasil.) on classifying lower third molars, analyzing intra- and interexaminer agreement of the results. Study Design: An observational, descriptive study of 280 lower third molars was made. The corresponding orthopantomographs were analyzed by two examiners using the Radio Memory® software. The exam was repeated 30 days after the first observation by each examiner. Both intra- and interexaminer agreement were determined using the SPSS v 12.0 software package for Windows (SPSS; Chicago, USA). Results: Intra- and interexaminer agreement was shown for both the Pell & Gregory and the Winter classifications, p<0.01, with 99% significant correlation between variables in all the cases. Conclusions: The use of Radio Memory® software for the classification of lower third molars is shown to be a valid alternative to the conventional method (direct evaluation on the orthopantomograph), for both clinical and investigational applications.

The Impact of National Innovation System on Entrepreneurial Venture Creation Process

The important role of entrepreneurship in countries’ economic development and overall society well-being is widely recognized by researchers, experts as well as policy makers. Every phase of the process of starting a new business is related to the interaction with at least one player of country innovation system and therefore the efficiency of this interaction may have an influence on the success of whole entrepreneurial process and consequently on the willingness of potential entrepreneurs to engage into this process. The study proposes a System Dynamics model for studying the impact of National Innovation System (NIS) on the entrepreneurial venture creation process. The developed model also takes country population aspect into account and provides results for estimation the effect various demographic tendencies on the process performance. The special impact is made on possible ways to facilitate the development of entrepreneurial framework conditions. Business incubators are seen as one of the effective tool for accomplishing such task. The study also provides the result for estimation of possible impact arising from properly functioned Business Incubators.

Effect of trellising system on grape and wine composition of Syrah vines grown in the cerrado region of Minas Gerais

Based on the concept that the trellising system affects not only sunlight interception and carbon assimilation, but also the fruitzone microclimate, which has a great impact on fruit composition and consequently on wine quality, the effect of two trellising systems - Vertical Shoot Position (VSP) and modified Geneva Double Curtain (GDC) - on wine and berry composition of Syrah grapes grown in João Pinheiro, Northeast region of Minas Gerais State, Brazil was investigated. The parameters such as pH, berry size and weight, and seeds total phenolic contents were not affected by the training system. The GDC system produced fruits with the highest Brix and lowest titratable acidity. Berries from the VSP system presented lower anthocyanin concentration than those from the GDC system. Similar results were found for the total phenolic content of the skin of grape berries from the VSP system. GDC wines were characterized by high anthocyanin content and red color, resulting in wines with high color intensity. These data suggest that in the tropical region of Minas Gerais state, with high temperature and high sunlight intensity, the trellising system, which protects bunches against excessive radiation, should be chosen.

Effect of rural transportation system on agricultural productivity in Oyo State, Nigeria

Food farming in Oyo North, Nigeria is characterised by an increasing use of Intermediary Mode of Transportation (IMT) to ease inputs and outputs mobility and farm access. To assess the influence on food farmer’s productivity, a random sample of 230 respondents was selected and data collected on their socio-economic and farm specific characteristics. Descriptive statistics, Herfindhal Index and Technical Efficiency Approach were used to analyse the data. The results indicate that majority of food farmers were in their middle age with mean age of 50 years and most of them used one plot at a location between 5 and 10km to their village of residence. They acquired land by inheritance and practiced intensive crop diversification as risk management strategy. The transportation modes used in addition to walking include bicycle, motorcycle, and car with increasing trend in the use of motorcycle. The mean Technical Efficiency (TE) of food farmers was 0.82 with significant inefficiency effects. The inefficiency analysis indicates positive effect of distance, crop diversification and un-tarred type of road on farmer’s productivity, while poor level of education among farmers, use of bicycle; trekking and weekly working time negatively affect farmer’s efficiency. The negative effect of trekking and use of bicycle and the excess working time suggest the adoption of more IMT of motorized type to optimize farming time and increase farmer’s productivity.