Pseudogenes in the ENCODE regions: consensus annotation, analysis of transcription, and evolution

Arising from either retrotransposition or genomic duplication of functional genes, pseudogenes are “genomic fossils” valuable for exploring the dynamics and evolution of genes and genomes. Pseudogene identification is an important problem in computational genomics, and is also critical for obtaining an accurate picture of a genome’s structure and function. However, no consensus computational scheme for defining and detecting pseudogenes has been developed thus far. As part of the ENCyclopedia Of DNA Elements (ENCODE) project, we have compared several distinct pseudogene annotation strategies and found that different approaches and parameters often resulted in rather distinct sets of pseudogenes. We subsequently developed a consensus approach for annotating pseudogenes (derived from protein coding genes) in the ENCODE regions, resulting in 201 pseudogenes, two-thirds of which originated from retrotransposition. A survey of orthologs for these pseudogenes in 28 vertebrate genomes showed that a significant fraction (∼80%) of the processed pseudogenes are primate-specific sequences, highlighting the increasing retrotransposition activity in primates. Analysis of sequence conservation and variation also demonstrated that most pseudogenes evolve neutrally, and processed pseudogenes appear to have lost their coding potential immediately or soon after their emergence. In order to explore the functional implication of pseudogene prevalence, we have extensively examined the transcriptional activity of the ENCODE pseudogenes. We performed systematic series of pseudogene-specific RACE analyses. These, together with complementary evidence derived from tiling microarrays and high throughput sequencing, demonstrated that at least a fifth of the 201 pseudogenes are transcribed in one or more cell lines or tissues.

Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Event-related potential analyses via single-subject topographic classification.

Introduction: Responses to external stimuli are typically investigated by averaging peri-stimulus electroencephalography (EEG) epochs in order to derive event-related potentials (ERPs) across the electrode montage, under the assumption that signals that are related to the external stimulus are fixed in time across trials. We demonstrate the applicability of a single-trial model based on patterns of scalp topographies (De Lucia et al, 2007) that can be used for ERP analysis at the single-subject level. The model is able to classify new trials (or groups of trials) with minimal a priori hypotheses, using information derived from a training dataset. The features used for the classification (the topography of responses and their latency) can be neurophysiologically interpreted, because a difference in scalp topography indicates a different configuration of brain generators. An above chance classification accuracy on test datasets implicitly demonstrates the suitability of this model for EEG data. Methods: The data analyzed in this study were acquired from two separate visual evoked potential (VEP) experiments. The first entailed passive presentation of checkerboard stimuli to each of the four visual quadrants (hereafter, "Checkerboard Experiment") (Plomp et al, submitted). The second entailed active discrimination of novel versus repeated line drawings of common objects (hereafter, "Priming Experiment") (Murray et al, 2004). Four subjects per experiment were analyzed, using approx. 200 trials per experimental condition. These trials were randomly separated in training (90%) and testing (10%) datasets in 10 independent shuffles. In order to perform the ERP analysis we estimated the statistical distribution of voltage topographies by a Mixture of Gaussians (MofGs), which reduces our original dataset to a small number of representative voltage topographies. We then evaluated statistically the degree of presence of these template maps across trials and whether and when this was different across experimental conditions. Based on these differences, single-trials or sets of a few single-trials were classified as belonging to one or the other experimental condition. Classification performance was assessed using the Receiver Operating Characteristic (ROC) curve. Results: For the Checkerboard Experiment contrasts entailed left vs. right visual field presentations for upper and lower quadrants, separately. The average posterior probabilities, indicating the presence of the computed template maps in time and across trials revealed significant differences starting at ~60-70 ms post-stimulus. The average ROC curve area across all four subjects was 0.80 and 0.85 for upper and lower quadrants, respectively and was in all cases significantly higher than chance (unpaired t-test, p<0.0001). In the Priming Experiment, we contrasted initial versus repeated presentations of visual object stimuli. Their posterior probabilities revealed significant differences, which started at 250ms post-stimulus onset. The classification accuracy rates with single-trial test data were at chance level. We therefore considered sub-averages based on five single trials. We found that for three out of four subjects' classification rates were significantly above chance level (unpaired t-test, p<0.0001). Conclusions: The main advantage of the present approach is that it is based on topographic features that are readily interpretable along neurophysiologic lines. As these maps were previously normalized by the overall strength of the field potential on the scalp, a change in their presence across trials and between conditions forcibly reflects a change in the underlying generator configurations. The temporal periods of statistical difference between conditions were estimated for each training dataset for ten shuffles of the data. Across the ten shuffles and in both experiments, we observed a high level of consistency in the temporal periods over which the two conditions differed. With this method we are able to analyze ERPs at the single-subject level providing a novel tool to compare normal electrophysiological responses versus single cases that cannot be considered part of any cohort of subjects. This aspect promises to have a strong impact on both basic and clinical research.

Excuse me, but your accent is very unusual. The complexity of establishing third languages in Inglourious Basterds. Applying a model of translation analysis to dubbing

The growing multilingual trend in movie production comes with a challenge for dubbing translators since they are increasingly confronted with more than one source language. The main purpose of this master’s thesis is to provide a case study on how these third languages (see CORRIUS and ZABALBEASCOA 2011) are rendered. Another aim is to put a particular focus on their textual and narrative functions and detect possible shifts that might occur in translations. By applying a theoretical model for translation analysis (CORRIUS and ZABALBEASCOA 2011), this study describes how third languages are rendered in the German, Spanish, and Italian dubbed versions of the 2009 Tarantino movie Inglourious Basterds. A broad range of solution-types are thereby revealed and prevalent restrictions of the translation process identified. The target texts are brought in context with some sociohistorical aspects of dubbing in order to detect prevalent norms of the respective cultures andto discuss the acceptability of translations (TOURY 1995). The translatability potential of even highly complex multilingual audiovisual texts is demonstrated in this study. Moreover, proposals for further studies in multilingual audiovisual translation are outlined and the potential for future investigations in this field thereby emphasised.

Adaptive strategy for the statistical analysis of connectomes.

We study an adaptive statistical approach to analyze brain networks represented by brain connection matrices of interregional connectivity (connectomes). Our approach is at a middle level between a global analysis and single connections analysis by considering subnetworks of the global brain network. These subnetworks represent either the inter-connectivity between two brain anatomical regions or by the intra-connectivity within the same brain anatomical region. An appropriate summary statistic, that characterizes a meaningful feature of the subnetwork, is evaluated. Based on this summary statistic, a statistical test is performed to derive the corresponding p-value. The reformulation of the problem in this way reduces the number of statistical tests in an orderly fashion based on our understanding of the problem. Considering the global testing problem, the p-values are corrected to control the rate of false discoveries. Finally, the procedure is followed by a local investigation within the significant subnetworks. We contrast this strategy with the one based on the individual measures in terms of power. We show that this strategy has a great potential, in particular in cases where the subnetworks are well defined and the summary statistics are properly chosen. As an application example, we compare structural brain connection matrices of two groups of subjects with a 22q11.2 deletion syndrome, distinguished by their IQ scores.

Characterization of olive oil by carbon isotope analysis of individual fatty acids: Implications for authentication

The fatty acids of olive oils of distinct quality grade from the most important European Union (EU) producer countries were chemically and isotopically characterized. The analytical approach utilized combined capillary column gas chromatography-mass spectrometry (GC/MS) and the novel technique of compound-specific isotope analysis (CSIA) through gas chromatography coupled to a stable isotope ratio mass spectrometer (IRMS) via a combustion (C) interface (GC/C/IRMS). This approach provides further insights into the control of the purity and geographical origin of oils sold as cold-pressed extra virgin olive oil with certified origin appellation. The results indicate that substantial enrichment in heavy carbon isotope (C-13) of the bulk oil and of individual fatty acids are related to (1) a thermally induced degradation due to deodorization or steam washing of the olive oils and (2) the potential blend with refined olive oil or other vegetable oils. The interpretation of the data is based on principal component analysis of the fatty acids concentrations and isotopic data (delta(13)C(oil), delta(13)C(16:0), delta(13)C(18:1)) and on the delta(13)C(16:0) vs delta(13)C(18:1) covariations. The differences in the delta(13)C values of palmitic and oleic acids are discussed in terms of biosynthesis of these acids in the plant tissue and admixture of distinct oils.

Blood pressure and cognitive function: a prospective analysis among adolescents in Seychelles

Objective: An inverse relationship between blood pressure and cognitive function has been found in adults, but limited data are available in adolescents and young adults. We prospectively examined the relation between blood pressure and cognitive function in adolescence. Methods: We examined the association between BP measured at the ages of 12-15 years in school surveys and cognitive endpoints measured in the Seychelles Child Development Study at ages 17 (n=407) and 19 (n=429) years respectively. We evaluated multiple domains of cognition based on subtests of the Cambridge Neurological Test Automated Battery (CANTAB), the Woodcock Johnson Test of Scholastic Achievement (WJTA), the Finger Tapping test (FT) and the Kaufman Brief Intelligence Test (K-BIT). We used age-, sex- and height-specific z-scores of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP). Results: Six out of the 21 cognitive endpoints tested were associated with BP. However, none of these associations were found to hold for both males and females or for different subtests within the same neurodevelopmental domain or for both SBP and DBP. Most of these associations disappeared when analyses were adjusted for selected potential confounding factors such as socio-economic status, birth weight, gestational age, body mass index, alcohol consumption, blood glucose, and total n-3 and n-6 polyunsaturated fats. Conclusions: Our findings do not support a consistent association between BP and subsequent performance on tests assessing various cognitive domains in adolescents.

U.S. Universities’ Net Returns from Patenting and Licensing: A Quantile Regression Analysis, September 2006

In line with the rights and incentives provided by the Bayh-Dole Act of 1980, U.S. universities have increased their involvement in patenting and licensing activities through their own technology transfer offices. Only a few U.S. universities are obtaining large returns, however, whereas others are continuing with these activities despite negligible or negative returns. We assess the U.S. universities’ potential to generate returns from licensing activities by modeling and estimating quantiles of the distribution of net licensing returns conditional on some of their structural characteristics. We find limited prospects for public universities without a medical school everywhere in their distribution. Other groups of universities (private, and public with a medical school) can expect significant but still fairly modest returns only beyond the 0.9th quantile. These findings call into question the appropriateness of the revenue-generating motive for the aggressive rate of patenting and licensing by U.S. universities.

Identification of novel elements of the Drosophila blisterome sheds light on potential pathological mechanisms of several human diseases.

Main developmental programs are highly conserved among species of the animal kingdom. Improper execution of these programs often leads to progression of various diseases and disorders. Here we focused on Drosophila wing tissue morphogenesis, a fairly complex developmental program, one of the steps of which - apposition of the dorsal and ventral wing sheets during metamorphosis - is mediated by integrins. Disruption of this apposition leads to wing blistering which serves as an easily screenable phenotype for components regulating this process. By means of RNAi-silencing technique and the blister phenotype as readout, we identify numerous novel proteins potentially involved in wing sheet adhesion. Remarkably, our results reveal not only participants of the integrin-mediated machinery, but also components of other cellular processes, e.g. cell cycle, RNA splicing, and vesicular trafficking. With the use of bioinformatics tools, these data are assembled into a large blisterome network. Analysis of human orthologues of the Drosophila blisterome components shows that many disease-related genes may contribute to cell adhesion implementation, providing hints on possible mechanisms of these human pathologies.

An investigation of the potential of DIP-STR markers for DNA mixture analyses

The genetic characterization of unbalanced mixed stains remains an important area where improvement is imperative. In fact, using the standard tools of forensic DNA profiling (i.e., STR markers), the profile of the minor contributor in mixed DNA stains cannot be successfully detected if its quantitative share of DNA is less than 10% of the mixed trace. This is due to the fact that the major contributor's profile "masks" that of the minor contributor. Besides known remedies to this problem, such as Y-STR analysis, a new compound genetic marker that consists of a Deletion/Insertion Polymorphism (DIP) linked to a Short Tandem Repeat (STR) polymorphism, has recently been developed and proposed [1]. These novel markers are called DIP-STR markers. This paper compares, from a statistical and forensic perspective, the potential usefulness of these novel DIP-STR markers (i) with traditional STR markers in cases of moderately unbalanced mixtures, and (ii) with Y-STR markers in cases of female-male mixtures. This is done through a comparison of the distribution of 100,000 likelihood ratio values obtained using each method on simulated mixtures. This procedure is performed assuming, in turn, the prosecution's and the defence's point of view.

Prevalence of comedications and effect of potential drug-drug interactions in the Swiss HIV Cohort Study.

BACKGROUND: Potential drug-drug interactions (PDDIs) might expand with new combination antiretroviral therapies (ART) and polypharmacy related to increasing age and comorbidities. We investigated the prevalence of comedications and PDDIs within a large HIV cohort, and their effect on ART efficacy and tolerability. METHODS: All medications were prospectively recorded in 1,497 ART-treated patients and screened for PDDIs using a customized version of the Liverpool drug interactions database. RESULTS: Overall, 68% (1,013/1,497) of patients had a comedication and 40% (599/1,497) had > or = 1 PDDI. Among patients with comedication, 2% (21/1,013) had red-flag interactions (contraindicated) and 59% (597/1,013) had orange-flag interactions (potential dose adjustment and/or close monitoring required). The latter involved mainly central nervous system drugs (49%), cardiovascular drugs (34%) and methadone (19%). In the multivariate analysis, factors associated with having a comedication were advanced age, female gender, obesity and HCV infection. Independent risk factors for PDDIs were regimens combining protease inhibitors and non-nucleoside reverse transcriptase inhibitors (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.44-6.48), > or = 2 comedications (OR 1.89, 95% CI 1.32-2.70), current illicit drug use (OR 2.00, 95% CI 1.29-3.10) and patients with HCV infection (OR 1.74, 95% CI 1.19-2.56). Viral response was similar in patients with and without PDDIs (84.5% versus 86.4%; P=0.386). During follow-up, ART was modified in 134 patients with comedication regardless of the presence of PDDIs (P=0.524). CONCLUSIONS: PDDIs increase with complex ART and comorbidities. No adverse effect was noted on ART efficacy or tolerability; however, most PDDIs affected comedication but were manageable through dose adjustment or monitoring.

Analysis of the process of translation of knowledge regarding early childhood at the undergraduate level

Objective To analyze innovative contents on Early Child Development Promotion. Method This action-research involves nine faculties from four Higher Education Institutions at inner-state of São Paulo, Brazil.Data were collected by syllabi analyses (2009-2011), interviews and focus group. We have adopted an ECDP underpinning from international consensus, thus evaluating KT Results We have found relevant incorporation between teaching and extension in Nursing (87,5%) and Psychology (75%) undergraduate courses, while Pedagogy was restricted to teaching. Conclusion This KT evaluation has evinced innovative potential of extension, regardless teaching and research, for a better Early Childhood.


Violence as a research object and intervention in the health field: an analysis from the production of the Research Group on Gender, Health and Nursingi

The study aimed to describe how violence is revealed in the production of the Research Group on Gender, Health and Nursing. This is a historical research of qualitative approach, which evaluated the production of the Research Group, through content analysis. The results show gender as a central category in determining violence and health practices. This aspect determines limitations on professional practices of coping, such as the invisibility of the problem. The female autonomy, the use of alcohol and drugs and social vulnerability play an important relation with the phenomenon and the bond is revealed as potentiality of health practices to address the problem. Conclusion: The gender perspective in nursing research is an innovative field and counter-hegemonic, a possibility to assume a meaning of praxis by transforming potential of understanding and modes of intervention in the phenomenon of gender violence.

Morphostructural analysis of an alpine debris flows catchment: implication for debris supply

Rock slope instabilities are implicitly linked to the supply of sediment and debris recharging channels prone to debris flow. Hence, the incorporation of bedrock structure and terrain morphology can be relevant in the analysis of sediment budget and debris flow hazard assessment. Here, the mode of debris production of the Manival catchment (northern French Alps) is documented by the study of its morphostructural aspects extracted from high resolution DEM. Terrain implication in the process of debris supply is evaluated by: a) A systematic classification of the major morphological units based on the slope gradient that enables a spatial analysis of zones of debris production and deposition. b) A detailed structural analysis performed on DEM in order to identify potential unstable slopes. c) An analysis of the gullies orientation that informs in term of structural control of the sources zones. d) Localisation of high density joints sets that document about whether sources of continuous debris production are controlled by the structural setting of the catchment. These DEM-based indicators can be used as proxies for assessing the influences of the current topography and enable to quantify a degree of susceptibility to mass wasting and hillslope erosion activity. This present contribution suggests some directions for characterizing sediment flux dynamic in small alpine catchment.

Alu expression in human cell lines and their retrotranspositional potential.

BACKGROUND: The vast majority of the 1.1 million Alu elements are retrotranspositionally inactive, where only a few loci referred to as 'source elements' can generate new Alu insertions. The first step in identifying the active Alu sources is to determine the loci transcribed by RNA polymerase III (pol III). Previous genome-wide analyses from normal and transformed cell lines identified multiple Alu loci occupied by pol III factors, making them candidate source elements. FINDINGS: Analysis of the data from these genome-wide studies determined that the majority of pol III-bound Alus belonged to the older subfamilies Alu S and Alu J, which varied between cell lines from 62.5% to 98.7% of the identified loci. The pol III-bound Alus were further scored for estimated retrotransposition potential (ERP) based on the absence or presence of selected sequence features associated with Alu retrotransposition capability. Our analyses indicate that most of the pol III-bound Alu loci candidates identified lack the sequence characteristics important for retrotransposition. CONCLUSIONS: These data suggest that Alu expression likely varies by cell type, growth conditions and transformation state. This variation could extend to where the same cell lines in different laboratories present different Alu expression patterns. The vast majority of Alu loci potentially transcribed by RNA pol III lack important sequence features for retrotransposition and the majority of potentially active Alu loci in the genome (scored high ERP) belong to young Alu subfamilies. Our observations suggest that in an in vivo scenario, the contribution of Alu activity on somatic genetic damage may significantly vary between individuals and tissues.