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.

Structured RNAs in the ENCODE selected regions of the human genome

Functional RNA structures play an important role both in the context of noncoding RNA transcripts as well as regulatory elements in mRNAs. Here we present a computational study to detect functional RNA structures within the ENCODE regions of the human genome. Since structural RNAs in general lack characteristic signals in primary sequence, comparative approaches evaluating evolutionary conservation of structures are most promising. We have used three recently introduced programs based on either phylogenetic–stochastic context-free grammar (EvoFold) or energy directed folding (RNAz and AlifoldZ), yielding several thousand candidate structures (corresponding to ∼2.7% of the ENCODE regions). EvoFold has its highest sensitivity in highly conserved and relatively AU-rich regions, while RNAz favors slightly GC-rich regions, resulting in a relatively small overlap between methods. Comparison with the GENCODE annotation points to functional RNAs in all genomic contexts, with a slightly increased density in 3′-UTRs. While we estimate a significant false discovery rate of ∼50%–70% many of the predictions can be further substantiated by additional criteria: 248 loci are predicted by both RNAz and EvoFold, and an additional 239 RNAz or EvoFold predictions are supported by the (more stringent) AlifoldZ algorithm. Five hundred seventy RNAz structure predictions fall into regions that show signs of selection pressure also on the sequence level (i.e., conserved elements). More than 700 predictions overlap with noncoding transcripts detected by oligonucleotide tiling arrays. One hundred seventy-five selected candidates were tested by RT-PCR in six tissues, and expression could be verified in 43 cases (24.6%).

The DART classification of unannotated transcription within the ENCODE regions: associating transcription with known and novel loci

For the ∼1% of the human genome in the ENCODE regions, only about half of the transcriptionally active regions (TARs) identified with tiling microarrays correspond to annotated exons. Here we categorize this large amount of “unannotated transcription.” We use a number of disparate features to classify the 6988 novel TARs—array expression profiles across cell lines and conditions, sequence composition, phylogenetic profiles (presence/absence of syntenic conservation across 17 species), and locations relative to genes. In the classification, we first filter out TARs with unusual sequence composition and those likely resulting from cross-hybridization. We then associate some of those remaining with proximal exons having correlated expression profiles. Finally, we cluster unclassified TARs into putative novel loci, based on similar expression and phylogenetic profiles. To encapsulate our classification, we construct a Database of Active Regions and Tools (DART.gersteinlab.org). DART has special facilities for rapidly handling and comparing many sets of TARs and their heterogeneous features, synchronizing across builds, and interfacing with other resources. Overall, we find that ∼14% of the novel TARs can be associated with known genes, while ∼21% can be clustered into ∼200 novel loci. We observe that TARs associated with genes are enriched in the potential to form structural RNAs and many novel TAR clusters are associated with nearby promoters. To benchmark our classification, we design a set of experiments for testing the connectivity of novel TARs. Overall, we find that 18 of the 46 connections tested validate by RT-PCR and four of five sequenced PCR products confirm connectivity unambiguously.

Prominent use of distal 5’ transcription start sites and discovery of a large number of additional exons in ENCODE regions

This report presents systematic empirical annotation of transcript products from 399 annotated protein-coding loci across the 1% of the human genome targeted by the Encyclopedia of DNA elements (ENCODE) pilot project using a combination of 5' rapid amplification of cDNA ends (RACE) and high-density resolution tiling arrays. We identified previously unannotated and often tissue- or cell-line-specific transcribed fragments (RACEfrags), both 5' distal to the annotated 5' terminus and internal to the annotated gene bounds for the vast majority (81.5%) of the tested genes. Half of the distal RACEfrags span large segments of genomic sequences away from the main portion of the coding transcript and often overlap with the upstream-annotated gene(s). Notably, at least 20% of the resultant novel transcripts have changes in their open reading frames (ORFs), most of them fusing ORFs of adjacent transcripts. A significant fraction of distal RACEfrags show expression levels comparable to those of known exons of the same locus, suggesting that they are not part of very minority splice forms. These results have significant implications concerning (1) our current understanding of the architecture of protein-coding genes; (2) our views on locations of regulatory regions in the genome; and (3) the interpretation of sequence polymorphisms mapping to regions hitherto considered to be "noncoding," ultimately relating to the identification of disease-related sequence alterations.

Measuring Pavement Profile at the Slip-Form Paver, May 2005

Pavement profile or smoothness has been identified nationally as a good measure of highway user satisfaction. This has led highway engineers to measure profiles of both operating and new highways. Operational highway profiles are often measured with high-speed inertial profilers. New highway profiles are usually measured with profilographs in order to establish incentives or disincentives for pavement construction. In most cases, these two processes do not measure the same value from the “cradle to grave” life of pavements. In an attempt to correct the inconsistency between measuring techniques, lightweight profilers intended to produce values to be used for construction acceptance are being made that measure the same profile as high-speed inertial profilers. Currently, two profiler systems have been identified that can measure pavement profile during construction. This research has produced a field evaluation of the two systems. The profilers evaluated in this study are able to detect roughness in the final profile, including localized roughness and roughness at joints. Dowel basket ripple is a significant source of pavement surface roughness. The profilers evaluated in this study are able to detect dowel basket ripple with enough clarity to warn the paving crew. String-line disturbances degrade smoothness. The profilers evaluated in this study are able to detect some string-line disturbances during paving operations. The profilers evaluated in this study are not currently able to produce the same absolute International Roughness Index (IRI) values on the plastic concrete that can be measured by inertial profilers on the hardened concrete. Construction application guidelines are provided.

Stringless Portland Cement Concrete Paving, February 2004

This report describes results from a study evaluating the use of stringless paving using a combination of global positioning and laser technologies. CMI and Geologic Computer Systems developed this technology and successfully implemented it on construction earthmoving and grading projects. Concrete paving is a new area for considering this technology. Fred Carlson Co. agreed to test the stringless paving technology on two challenging concrete paving projects located in Washington County, Iowa. The evaluation was conducted on two paving projects in Washington County, Iowa, during the summer of 2003. The research team from Iowa State University monitored the guidance and elevation conformance to the original design. They employed a combination of physical depth checks, surface location and elevation surveys, concrete yield checks, and physical survey of the control stakes and string line elevations. A final check on profile of the pavement surface was accomplished by the use of the Iowa Department of Transportation Light Weight Surface Analyzer (LISA). Due to the speed of paving and the rapid changes in terrain, the laser technology was abandoned for this project. Total control of the guidance and elevation controls on the slip-form paver were moved from string line to global positioning systems (GPS). The evaluation was a success, and the results indicate that GPS control is feasible and approaching the desired goals of guidance and profile control with the use of three dimensional design models. Further enhancements are needed in the physical features of the slipform paver oil system controls and in the computer program for controlling elevation.

The Drosophila cdc25 homolog twine is required for meiosis.

We have identified a second cdc25 homolog in Drosophila. In contrast to string (the first homolog identified in Drosophila) this second homolog, twine, does not function in the mitotic cell cycle, but is specialized for meiosis. Expression of twine was observed exclusively in male and female gonads. twine transcripts are present in germ cells during meiosis, and appear only late during gametogenesis, well after the end of the mitotic germ cell divisions. The sterile Drosophila mutant, mat(2)synHB5, which had previously been isolated and mapped to the same genomic region as twine (35F), was found to carry a missense mutation in the twine gene. This missense mutation in twine abolished its ability to complement a mutation in Schizosaccharomyces pombe cdc25. Phenotypic analysis of mat(2)synHB5 mutant flies revealed a complete block of meiosis in males and severe meiotic defects in females.

Role of the superior parietal lobules in letter-identity processing within strings: FMRI evidence from skilled and dyslexic readers.

Traditionally, the ventral occipito-temporal (vOT) area, but not the superior parietal lobules (SPLs), is thought as belonging to the neural system of visual word recognition. However, some dyslexic children who exhibit a visual attention span disorder - i.e. poor multi-element parallel processing - further show reduced SPLs activation when engaged in visual multi-element categorization tasks. We investigated whether these parietal regions further contribute to letter-identity processing within strings. Adult skilled readers and dyslexic participants with a visual attention span disorder were administered a letter-string comparison task under fMRI. Dyslexic adults were less accurate than skilled readers to detect letter identity substitutions within strings. In skilled readers, letter identity differs related to enhanced activation of the left vOT. However, specific neural responses were further found in the superior and inferior parietal regions, including the SPLs bilaterally. Two brain regions that are specifically related to substituted letter detection, the left SPL and the left vOT, were less activated in dyslexic participants. These findings suggest that the left SPL, like the left vOT, may contribute to letter string processing.

On Certain Greedoid Polyhedra, Partially Indexable Scheduling Problems, and Extended Restless Bandit Allocation Indices

We present a polyhedral framework for establishing general structural properties on optimal solutions of stochastic scheduling problems, where multiple job classes vie for service resources: the existence of an optimal priority policy in a given family, characterized by a greedoid (whose feasible class subsets may receive higher priority), where optimal priorities are determined by class-ranking indices, under restricted linear performance objectives (partial indexability). This framework extends that of Bertsimas and Niño-Mora (1996), which explained the optimality of priority-index policies under all linear objectives (general indexability). We show that, if performance measures satisfy partial conservation laws (with respect to the greedoid), which extend previous generalized conservation laws, then the problem admits a strong LP relaxation over a so-called extended greedoid polytope, which has strong structural and algorithmic properties. We present an adaptive-greedy algorithm (which extends Klimov's) taking as input the linear objective coefficients, which (1) determines whether the optimal LP solution is achievable by a policy in the given family; and (2) if so, computes a set of class-ranking indices that characterize optimal priority policies in the family. In the special case of project scheduling, we show that, under additional conditions, the optimal indices can be computed separately for each project (index decomposition). We further apply the framework to the important restless bandit model (two-action Markov decision chains), obtaining new index policies, that extend Whittle's (1988), and simple sufficient conditions for their validity. These results highlight the power of polyhedral methods (the so-called achievable region approach) in dynamic and stochastic optimization.

As práticas de responsabilidade social organizacional: uma análise nas empresas cabo-verdianas

A responsabilidade social organizacional (RSO) constitui um assunto cada vez mais discutido no seio dos diversos sectores e é considerado importante na gestão das organizações. As acções de responsabilidade social, gradualmente, têm vindo a tornar-se um diferencial em termos de estratégia e competitividade, contribuindo, no seu todo, para a sustentabilidade da sociedade e das pessoas que nela vivem. Assim, torna-se importante compreender a forma como as organizações e seus gestores entendem e assumem o seu compromisso para com todos os stakeholders, bem como despertar-lhes o interesse para os benefícios e vantagens que poderão obter com a prática e implementação de uma gestão da responsabilidade social nas organizações. Apesar de as práticas de RSO constituírem ainda um assunto muito recente em Cabo Verde, já é notável o crescimento das acções desencadeadas pelas organizações em prol de uma sociedade mais justa, responsável e transparente. Com o objectivo de identificar as práticas de responsabilidade social das organizações cabo-verdianas na sua vertente económica, social e ambiental, o presente trabalho inclui uma análise quantitativa e qualitativa, feita a partir da aplicação de um inquérito por questionário, com questões fechadas, complementado por questões abertas. Assim foi realizada uma pesquisa exploratória-descritiva nas organizações, escolhidas em função da sua notoriedade e da sua posição estratégica para o desenvolvimento do país. Entre os principais resultados obtidos pode-se destacar a preocupação com questões ambientais, o respeito pela Lei laboral e apoio regular às comunidades. Dos resultados obtidos e da análise efectuada, pode-se concluir que a cultura da RSO nas organizações cabo-verdianas, ainda se apresenta de forma incipiente. Espera-se, com este trabalho, explicitar o carácter estratégico da responsabilidade social organizacional, bem como fomentar reflexões posteriores de forma a efectivar uma mudança de cultura, levando gestores, colaboradores, e demais stakeholders a desenvolverem o interesse sobre esta matéria, uma vez que a RSO não é apenas um assunto das grandes empresas, mas sim, de todos nós. Social organizational responsibility (SOR) is an increasingly discussed subject amongst several sectors and it’s considered as extremely important on organization management. The social responsibility actions have gradually becoming a disparity regarding strategy and competitivety, contribution in its whole for the society’s and its inhabitant’s sustainability. Thus, it’s important to identify the way the organizations and its managers understand and assume their commitment with the stakeholders, as well as to bring up their interest for the benefits and advantages that they may obtain with the social responsibility management practice on the organizations. Although the SOR practices are still considered as a recent subject in Cape Verde, it’s already noticeable the organizations actions growth towards a fairer, responsible and transparent society. Aiming to identify the capeverdian social organizational responsibility practices on its economical, social and environmental string, this written presentation includes a quantitative and qualitative analysis, with closed questions, completed by open ones. It was therefore performed an explanatory-descriptive research for the organizations, each chosen regarding their notoriety and strategic position for the country’s development. Amongst the main results we may enhance the concern on environmental issues, the respect for the Labour law and the regular support for the communities. From the obtained results and the analysis done, we may conclude that the SOR culture on the Capeverdian organizations is still considered as quite insipient. With this written presentation, it’s expected to explain the social organizational responsibility strategic character, as well as to enhance the posterior reflections in order to implement a cultural change, influencing the managers, co-workers and remaining stakeholders to develop their interest on the subject, once the SOR should not only be some big companies issue, but instead, one regarding all of us.

Pliensbachian magnetostratigraphy: new data from Paris Basin (France)

Sampling of an industrial drill string from the northeastern Paris Basin (Montcornet, France) provides early Jurassic magnetostratigraphic data coupled with biochronological control. About 375 paleomagnetic samples were obtained from a 145 m thick series of Pliensbachian rocks. A composite demagnetization thermal up to 300 C and an alternating field up to 80 mT were used to separate the magnetic components. A low unblocking temperature component (<250degreesC) with an inclination of about 64 is interpreted as a present-day field overprint. The characteristic remanent component with both normal and reversed antipodal directions was isolated between 5 and 50 mT. Twenty-nine polarity intervals were recognized. Correlation of these new results from the Paris Basin with data from the Breggia Gorge section (Ticino, southern Alps, Switzerland), which is generally considered as the reference section for Pliensbachian magnetostratigraphy, reveals almost identical patterns of magnetic polarity reversals. However, the correlation implies significant paleontological age discrepancies. Revised age assignments of biostratigraphic data of Breggia as well as an objective evaluation of the uncertainties on zonal boundaries in both Breggia and Moncornet resolve the initial discrepancies between magnetostratigraphic correlations and biostratigraphic ages. Hence, the sequence of magnetic reversals is significantly strengthened and the age calibration is notably improved for the Pliensbachian, a stage for which sections combining adequate magnetic signal and biostratigraphic constraints are still very few. (C) 2002 Elsevier Science B.V. All rights reserved.

Locating emergency services with priority rules: The priority queuing covering location problem

One of the assumptions of the Capacitated Facility Location Problem (CFLP) is thatdemand is known and fixed. Most often, this is not the case when managers take somestrategic decisions such as locating facilities and assigning demand points to thosefacilities. In this paper we consider demand as stochastic and we model each of thefacilities as an independent queue. Stochastic models of manufacturing systems anddeterministic location models are put together in order to obtain a formula for thebacklogging probability at a potential facility location.Several solution techniques have been proposed to solve the CFLP. One of the mostrecently proposed heuristics, a Reactive Greedy Adaptive Search Procedure, isimplemented in order to solve the model formulated. We present some computationalexperiments in order to evaluate the heuristics performance and to illustrate the use ofthis new formulation for the CFLP. The paper finishes with a simple simulationexercise.

Optimised search heuristic combining valid inequalities and tabu search

This paper presents an Optimised Search Heuristic that combines a tabu search method with the verification of violated valid inequalities. The solution delivered by the tabu search is partially destroyed by a randomised greedy procedure, and then the valid inequalities are used to guide the reconstruction of a complete solution. An application of the new method to the Job-Shop Scheduling problem is presented.

Convertibility, currency controls and the cost of capital in Western Europe, 1950-1999

For most of the post-war period, Europe s capital markets remained largely closed to international capital flows. Thispaper explores the costs of this policy. Using an event-study methodology, I examine the extent to which restrictions ofcurrent and capital account convertibility affected stock returns. The delayed introduction of full currency convertibilityincreased the cost of capital. Also, a string of measures designed to reduce capital mobility before the ultimate collapseof the Bretton Woods System had considerable negative effects. These findings offer an explanation for the mountingevidence suggesting that capital account liberalization facilitates growth.

On certain greedoid polyhedra, partially indexable scheduling problems and extended restless bandit allocation indices

We present a polyhedral framework for establishing general structural properties on optimal solutions of stochastic scheduling problems, where multiple job classes vie for service resources: the existence of an optimal priority policy in a given family, characterized by a greedoid(whose feasible class subsets may receive higher priority), where optimal priorities are determined by class-ranking indices, under restricted linear performance objectives (partial indexability). This framework extends that of Bertsimas and Niño-Mora (1996), which explained the optimality of priority-index policies under all linear objectives (general indexability). We show that, if performance measures satisfy partial conservation laws (with respect to the greedoid), which extend previous generalized conservation laws, then theproblem admits a strong LP relaxation over a so-called extended greedoid polytope, which has strong structural and algorithmic properties. We present an adaptive-greedy algorithm (which extends Klimov's) taking as input the linear objective coefficients, which (1) determines whether the optimal LP solution is achievable by a policy in the given family; and (2) if so, computes a set of class-ranking indices that characterize optimal priority policies in the family. In the special case of project scheduling, we show that, under additional conditions, the optimal indices can be computed separately for each project (index decomposition). We further apply the framework to the important restless bandit model (two-action Markov decision chains), obtaining new index policies, that extend Whittle's (1988), and simple sufficient conditions for their validity. These results highlight the power of polyhedral methods (the so-called achievable region approach) in dynamic and stochastic optimization.