Genomic determinants of the efficiency of internal ribosomal entry sites of viral and cellular origin

Summary : Internal ribosome entry sites (IRES) are used by viruses as a strategy to bypass inhibition of cap-dependent translation that commonly results from viral infection. IRES are also used in eukaryotic cells to control mRNA translation under conditions of cellular stress (apoptosis, heat shock) or during the G2 phase of the cell cycle when general protein synthesis is inhibited. Variation in cellular expression levels has been shown to be inherited. Expression is controlled, among others, by transcriptional factors and by the efficiency of cap-mediated translation and ribosome activity. We aimed at identifying genomic determinants of variability in IRES-mediated translation of two representative IRES [Encephalomyocarditis virus (EMCV) and X-linked Inhibitor-of-Apoptosis (XIAP) IRES]. We used bicistronic lentiviral constructions expressing two fluorescent reporter transgenes. Lentiviruses were used to transduce seven different laboratory cell lines and B lymphoblastoid cell lines from the Centre d'Etude du Polymorphisme Humain (CEPH; 15 pedigrees; n=209); representing an in vitro approach to family structure allowing genome scan analyses. The relative expression of the two markers was assessed by FACS. IRES efficiency varies according to cellular background, but also varies, for a same cell type, among individuals. The control of IRES activity presents an inherited component (h2) of 0.47 and 0.36 for EMCV and XIAP IRES, respectively. A genome scan identified a suggestive Quantitative Trait Loci (LOD 2.35) involved in the control of XIAP IRES activity. Résumé : Les sites internes d'entrée des ribosomes (IRES = internal ribosome entry sites) sont utilisés par les virus comme une stratégie afin d'outrepasser l'inhibition de traduction qui résulte communément d'une infection virale. Les IRES sont également utilisés par les cellules eucaryotes pour contrôler la traduction de l'ARN messager dans des conditions de stress cellulaire (apoptose, choc thermique) ou durant la phase G2 du cycle cellulaire, situations durant lesquelles la synthèse générale des protéines est inhibée. La variation des niveaux d'expression cellulaire de transcription est un caractère héréditaire. L'expression des gènes est contrôlée entre autre par les facteurs de transcription et par l'efficacité de la traduction initiée par la coiffe ainsi que par l'activité des ribosomes. Durant cette étude nous avons eu pour but d'identifier les déterminants génomiques responsables de la variabilité de la traduction contrôlée par l'IRES. Ceci a été effectué en étudiant deux IRES représentatifs : l'IRES du virus de l'encéphalomyocardite (EMCV) et l'IRES de l'inhibiteur de l'apoptose XIAP (X-linked Inhibitor-of-Apoptosis). Nous avons utilisés des lentivirus délivrant un transgène bicistronique codant pour deux gènes rapporteurs fluorescents. Ces lentivirus ont été utilisés pour transduire sept différentes lignées cellulaires de laboratoire et des lignées cellulaires lymphoblastoïdes B du Centre d'Etude du Polymorphisme Humain (CEPH; 15 pedigrees; n=209) qui représentent une approche in vitro de la structure familiale et qui permettent des analyses par balayage du génome. L'expression relative des deux marqueurs fluorescents a été analysée par FACS. Nos résultats montrent que l'efficacité des IRES varie en fonction du type de cellules. Il varie aussi, pour le même type de cellules, selon les individus. Le contrôle de l'activité de l'IRES est un caractère héritable (héritabilité h2) de 0.47 et 0.36 pour les IRES de EMCV et XIAP respectivement. Le balayage du génome a permis l'identification d'un locus à effets quantitatifs [QTL Quantitative Trait Loci (LOD 2.35)] impliqué dans le contôle de l'activité de l'IRES de XIAP.

Determinants of school efficiency : The case of primary schools in the State of Geneva, Switzerland

The public primary school system in the State of Geneva, Switzerland, is characterized by centrally evaluated pupil performance measured with the use of standardized tests. As a result, consistent data are collected among the system. The 2010-2011 dataset is used to develop a two-stage data envelopment analysis (DEA) of school efficiency. In the first stage, DEA is employed to calculate an individual efficiency score for each school. It shows that, on average, each school could reduce its inputs by 7% whilst maintaining the same quality of pupil performance. The cause of inefficiency lies in perfectible management. In the second stage, efficiency is regressed on school characteristics and environmental variables;external factors outside of the control of headteachers. The model is tested for multicollinearity, heteroskedasticity and endogeneity. Four variables are identified as statistically significant. School efficiency is negatively influenced by (1) the provision of special education, (2) the proportion of disadvantaged pupils enrolled at the school and (3) operations being held on multiple sites, but positively influenced by school size (captured by the number of pupils). The proportion of allophone pupils; schools located in urban areas and the provision of reception classes for immigrant pupils are not significant. Although the significant variables influencing school efficiency are outside of the control of headteachers, it is still possible to either boost the positive impact or curb the negative impact. Dans le canton de Genève (Suisse), les écoles publiques primaires sont caractérisées par un financement assuré par les collectivités publiques (canton et communes) et par une évaluation des élèves à l'aide d'épreuves standardisées à trois moments distincts de leur scolarité. Cela permet de réunir des informations statistiques consistantes. La base de données de l'année 2010-2011 est utilisée dans une analyse en deux étapes de l'efficience des écoles. Dans une première étape, la méthode d'analyse des données par enveloppement (DEA) est utilisée pour calculer un score d'efficience pour chaque école. Cette analyse démontre que l'efficience moyenne des écoles s'élève à 93%. Chaque école pourrait, en moyenne, réduire ses ressources de 7% tout en conservant constants les résultats des élèves aux épreuves standardisées. La source de l'inefficience réside dans un management des écoles perfectible. Dans une seconde étape, les scores d'efficience sont régressés sur les caractéristiques des écoles et sur des variables environnementales. Ces variables ne sont pas sous le contrôle (ou l'influence) des directeurs d'école. Le modèle est testé pour la multicolinéartié, l'hétéroscédasticité et l'endogénéité. Quatre variables sont statistiquement significatives. L'efficience des écoles est influencée négativement par (1) le fait d'offrir un enseignement spécialisé en classe séparée, (2) la proporition d'élèves défavorisés et (3) le fait d'opérer sur plusieurs sites différents. L'efficience des écoles est influencée positivement par la taille de l'école, mesurée par le nombre d'élèves. La proporition d'élèves allophones, le fait d'être situé dans une zone urbaine et d'offrir des classes d'accueil pour les élèves immigrants constituent autant de variables non significatives. Le fait que les variables qui influencent l'efficience des écoles ne soient pas sous le contrôle des directeurs ne signifie pas qu'il faille céder au fatalisme. Différentes pistes sont proposées pour permettre soit de réduire l'impact négatif soit de tirer parti de l'impact positif des variables significatives.

Genomic determinants of the efficiency of internal ribosomal entry sites of viral and cellular origin

Variation in cellular gene expression levels has been shown to be inherited. Expression is controlled at transcriptional and post-transcriptional levels. Internal ribosome entry sites (IRES) are used by viruses to bypass inhibition of cap-dependent translation, and by eukaryotic cells to control translation under conditions when protein synthesis is inhibited. We aimed at identifying genomic determinants of variability in IRES-mediated translation of viral [Encephalomyocarditis virus (EMCV)] and cellular IRES [X-linked inhibitor-of-apoptosis (XIAP) and c-myc]. Bicistronic lentiviral constructs expressing two fluorescent reporters were used to transduce laboratory and B lymphoblastoid cell lines [15 CEPH pedigrees (n = 205) and 50 unrelated individuals]. IRES efficiency varied according to cell type and among individuals. Control of IRES activity has a significant genetic component (h(2) of 0.47 and 0.36 for EMCV and XIAP, respectively). Quantitative linkage analysis identified a suggestive locus (LOD 2.35) on chromosome 18q21.2, and genome-wide association analysis revealed of a cluster of SNPs on chromosome 3, intronic to the FHIT gene, marginally associated (P = 5.9E-7) with XIAP IRES function. This study illustrates the in vitro generation of intermediate phenotypes by using cell lines for the evaluation of genetic determinants of control of elements such as IRES.

Determinants of school efficiency : The case of primary schools in the State of Geneva, Switzerland

Purpose The purpose of this paper is (1) to measure school technical efficiency and (2) to identify the determinants of primary school performance. Design/methodology/approach A two-stage Data Envelopment Analysis (DEA) of school efficiency is conducted. At the first stage, DEA is employed to calculate an individual efficiency score for each school. At the second stage, efficiency is regressed on school characteristics and environmental variables. Findings The mean technical efficiency of schools in the State of Geneva is equal to 93%. By improving the operation of schools, 7% (100 - 93) of inputs could be saved, representing 17'744'656.2 Swiss francs in 2010. School efficiency is negatively influenced by (1) operations being held on multiple sites, (2) the proportion of disadvantaged pupils enrolled at the school and (3) the provision of special education, but positively influenced by school size (captured by the number of pupils). Practical implications Technically, the determinants of school efficiency are outside of the control of the headteachers. However, it is still possible to either boost the positive impact or curb the negative impact. Potential actions are discussed. Originality/value Unlike most similar studies, the model in this study is tested for multicollinearity, heteroskedasticity and endogeneity. It is therefore robust. Moreover, one explanatory variable of school efficiency (operations being held on multiple sites) is a truly original variable as it has never been tested so far.

Determinants of technical efficiency of freshwater prawn farming in southwestern Bangladesh

This paper estimates a translog stochastic production function to examine the determinants of technical efficiency of freshwater prawn farming in Bangladesh. Primary data has been collected using random sampling from 90 farmers of three villages in southwestern Bangladesh. Prawn farming displayed much variability in technical efficiency ranging from 9.50 to 99.94% with mean technical efficiency of 65%, which suggested a substantial 35% of potential output can be recovered by removing inefficiency. For a land scarce country like Bangladesh this gain could help increase income and ensure better livelihood for the farmers. Based on the translog production function specification, farmers could be made scale efficient by providing more input to produce more output. The results suggest that farmers’ education and non-farm income significantly improve efficiency whilst farmers’ training, farm distance from the water canal and involvement in fish farm associations reduces efficiency. Hence, the study proposes strategies such as less involvement in farming-related associations and raising the effective training facilities of the farmers as beneficial adjustments for reducing inefficiency. Moreover, the key policy implication of the analysis is that investment in primary education would greatly improve technical efficiency.

Application of a double bootstrap to investigation of determinants of technical efficiency of farms in Central Europe

The paper provides one of the first applications of the double bootstrap procedure (Simar and Wilson 2007) in a two-stage estimation of the effect of environmental variables on non-parametric estimates of technical efficiency. This procedure enables consistent inference within models explaining efficiency scores, while simultaneously producing standard errors and confidence intervals for these efficiency scores. The application is to 88 livestock and 256 crop farms in the Czech Republic, split into individual and corporate.

Application of a double bootstrap to investigation of determinants of technical efficiency of farms in Central Europe

The paper provides one of the first applications of the double bootstrap procedure (Simar and Wilson 2007) in a two-stage estimation of the effect of environmental variables on non-parametric estimates of technical efficiency. This procedure enables consistent inference within models explaining efficiency scores, while simultaneously producing standard errors and confidence intervals for these efficiency scores. The application is to 88 livestock and 256 crop farms in the Czech Republic, split into individual and corporate.

Major determinants of photoinduced cell death: Subcellular localization versus photosensitization efficiency

We present a study on whether and to what extent subcellular localization may compete favorably with photosensitization efficiency with respect to the overall efficiency of photoinduced cell death. We have compared the efficiency with which two cationic photosensitizers, namely methylene blue (MB) and crystal violet (CV), induce the photoinduced death of human cervical adenocarcinoma (HeLa) cells. Whereas MB is well known to generate singlet oxygen and related triplet excited species with high quantum yields in a variety of biological and chemical environments (i.e., acting as a typical type II photosensitizer), the highly mitochondria-specific CV produces triplet species and singlet oxygen with low yields, acting mostly via the classical type I mechanism (e.g., via free radicals). The findings described here indicate that the presumably more phototoxic type II photosensitizer (MB) does not lead to higher degrees of cell death compared to the type I (CV) photosensitizer. In fact, CV kills cells with the same efficiency as MB, generating at least 10 times fewer photoinduced reactive species. Therefore, subcellular localization is indeed more important than photochemical reactivity in terms of overall cell killing, with mitochondrial localization representing a highly desirable property for the development of more specific/efficient photosensitizers for photodynamic therapy applications. (C) 2011 Elsevier Inc. All rights reserved.

The determinants of firms' performance:can finance constraints improve technical efficiency?

This paper analyses the mechanisms through which binding finance constraints can induce debt-constrained firms to improve technical efficiency to guarantee positive profits. This hypothesis is tested on a sample of firms belonging to the Italian manufacturing. Technical efficiency scores are computed by estimating parametric production frontiers using the one stage approach as in Battese and Coelli [Battese, G., Coelli, T., 1995. A model for technical efficiency effects in a stochastic frontier production function for panel data. Empirical Economics 20, 325-332]. The results support the hypothesis that a restriction in the availability of financial resources can affect positively efficiency. © 2004 Elsevier B.V. All rights reserved.

Molecular determinants of ligand specificity in carbohydrate-binding modules: an NMR and X-ray crystallography integrated study

Dissertação para obtenção do Grau de Doutor em Bioquímica – Ramo Bioquímica Estrutural

A green future for European electricity? :Energy sources, policies and further determinants of the household price of electricity

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Economics from the NOVA – School of Business and Economics

The determinants of net interest margins & net interest spreads in the Russian & Japanese Commercial Banking sectors

This study presents an empirical investigation of the determinants of net interest margins and spreads in the Russian and Japanese banking sectors with a particular focus on commercial banks. Net interest mar-gins and spreads serve as indicators of financial intermediation efficiency. This paper employed a bank-level unbalanced panel dataset prolonging from 2005 to 2014. My main empirical results show that bank characteristics explain the most of the variation in not only net interest margins but also in spreads. Capi-talization, liquidity risk, inflation, economic growth, private and government debt are important determi-nants of margin in Russia. In Japan to the contrary loan and deposit market concentration along with bank size do predominate. Common significant variables in both countries are the substitution effect, cost effi-ciency and profitability. Turning to net interest spreads, micro- and macro-specific variables are the main significant drivers in Russia. I reach the conclusion that there are no significant determinants of net interest spreads in Japan within the original selection of variables, but operating efficiency and deposits to total funding seem to prevail. In both countries, there are solid differences in the net interest margins as well as spreads once the pre- and the post-crisis periods are considered.

Is it redistribution or centralization? On the determinants of government investment in infrastructure

The dilemma efficiency versus equity, together with political partisan interests, has received increasing attention to explain the territorial allocation of investments. However, centralization intended to introduce or reinforce hierarchization in the political system has not been object as of now of empirical analysis. Our main contribution to the literature is providing evidence that meta-political objectives related to the ordering of political power and administration influence regional investment. In this way, we find evidence that network mode’s (roads and railways) investment programs are influenced by the centralization strategy of investing near to the political capital, while investment effort in no-network modes (airports and ports) appears to be positively related to distance. Since investment in surface transportation infrastructures is much higher than that in airports and ports, and taken into account that regions surrounding the political capital are poorer than the average, we suggest that centralization rather than redistribution has been the driver for the concentration of public investment on these regions.

Entry and transcription as key determinants of differences in CD4 T-cell permissiveness to human immunodeficiency virus type 1 infection.

Isolated primary human cells from different donors vary in their permissiveness-the ability of cells to be infected and sustain the replication of human immunodeficiency virus type 1 (HIV-1). We used replicating HIV-1 and single-cycle lentivirus vectors in a population approach to identify polymorphic steps during viral replication. We found that phytohemagglutinin-stimulated CD4(+) CD45RO(+) CD57(-) T cells from healthy blood donors (n = 128) exhibited a 5.2-log-unit range in virus production. For 20 selected donors representing the spectrum of CD4 T-cell permissiveness, we could attribute up to 42% of the total variance in virus production to entry factors and 48% to postentry steps. Efficacy at key intracellular steps of the replicative cycle (reverse transcription, integration, transcription and splicing, translation, and budding and release) varied from 0.71 to 1.45 log units among donors. However, interindividual differences in transcription efficiency alone accounted for 64 to 83% of the total variance in virus production that was attributable to postentry factors. While vesicular stomatitis virus G protein-mediated fusion was more efficacious than CCR5/CD4 entry, the latter resulted in greater transcriptional activity per proviral copy. The phenotype of provirus transcription was stable over time, indicating that it represents a genetic trait.