On a series of Goldbach and Euler

Theorem 1 of Euler s paper of 1737 'Variae Observationes Circa Series Infinitas', states the astonishing result that the series of all unit fractions whose denominators are perfect powers of integers minus unity has sum one. Euler attributes the Theorem to Goldbach. The proof is one of those examples of misuse of divergent series to obtain correct results so frequent during the seventeenth and eighteenth centuries. We examine this proof closelyand, with the help of some insight provided by a modern (and completely dierent) proof of the Goldbach-Euler Theorem, we present a rational reconstruction in terms which could be considered rigorous by modern Weierstrassian standards. At the same time, with a few ideas borrowed from nonstandard analysis we see how the same reconstruction can be also be considered rigorous by modern Robinsonian standards. This last approach, though, is completely in tune with Goldbach and Euler s proof. We hope to convince the reader then how, a few simple ideas from nonstandard analysis, vindicate Euler's work.

Death and resurrection of the human IRGM gene

Immunity-related GTPases (IRG) play an important role in defense against intracellular pathogens. One member of this gene family in humans, IRGM, has been recently implicated as a risk factor for Crohn's disease. We analyzed the detailed structure of this gene family among primates and showed that most of the IRG gene cluster was deleted early in primate evolution, after the divergence of the anthropoids from prosimians ( about 50 million years ago). Comparative sequence analysis of New World and Old World monkey species shows that the single-copy IRGM gene became pseudogenized as a result of an Alu retrotransposition event in the anthropoid common ancestor that disrupted the open reading frame (ORF). We find that the ORF was reestablished as a part of a polymorphic stop codon in the common ancestor of humans and great apes. Expression analysis suggests that this change occurred in conjunction with the insertion of an endogenous retrovirus, which altered the transcription initiation, splicing, and expression profile of IRGM. These data argue that the gene became pseudogenized and was then resurrected through a series of complex structural events and suggest remarkable functional plasticity where alleles experience diverse evolutionary pressures over time. Such dynamism in structure and evolution may be critical for a gene family locked in an arms race with an ever-changing repertoire of intracellular parasites.

GSVA: gene set variation analysis for microarray and RNA-seq data

Gene set enrichment (GSE) analysis is a popular framework for condensing information from gene expression profiles into a pathway or signature summary. The strengths of this approach over single gene analysis include noise and dimension reduction, as well as greater biological interpretability. As molecular profiling experiments move beyond simple case-control studies, robust and flexible GSE methodologies are needed that can model pathway activity within highly heterogeneous data sets. To address this challenge, we introduce Gene Set Variation Analysis (GSVA), a GSE method that estimates variation of pathway activity over a sample population in an unsupervised manner. We demonstrate the robustness of GSVA in a comparison with current state of the art sample-wise enrichment methods. Further, we provide examples of its utility in differential pathway activity and survival analysis. Lastly, we show how GSVA works analogously with data from both microarray and RNA-seq experiments. GSVA provides increased power to detect subtle pathway activity changes over a sample population in comparison to corresponding methods. While GSE methods are generally regarded as end points of a bioinformatic analysis, GSVA constitutes a starting point to build pathway-centric models of biology. Moreover, GSVA contributes to the current need of GSE methods for RNA-seq data. GSVA is an open source software package for R which forms part of the Bioconductor project and can be downloaded at http://www.bioconductor.org.

Genome sequence of Plesiomonas shigelloides strain 302-73 (serotype O1)

Plesiomonas shigelloides, the only species of the genus, is an emergent pathogenic bacterium associated with human diarrheal and extraintestinal disease. We present the whole-genome sequence analysis of the representative strain for the O1 serotype (strain 302-73), providing a tool for studying bacterial outbreaks, virulence factors, and accurate diagnostic methods.

O6-Methylguanine-DNA methyltransferase protein expression by immunohistochemistry in brain and non-brain systemic tumours: systematic review and meta-analysis of correlation with methylation-specific polymerase chain reaction

Background: The DNA repair protein O6-Methylguanine-DNA methyltransferase (MGMT) confers resistance to alkylating agents. Several methods have been applied to its analysis, with methylation-specific polymerase chain reaction (MSP) the most commonly used for promoter methylation study, while immunohistochemistry (IHC) has become the most frequently used for the detection of MGMT protein expression. Agreement on the best and most reliable technique for evaluating MGMT status remains unsettled. The aim of this study was to perform a systematic review and meta-analysis of the correlation between IHC and MSP. Methods A computer-aided search of MEDLINE (1950-October 2009), EBSCO (1966-October 2009) and EMBASE (1974-October 2009) was performed for relevant publications. Studies meeting inclusion criteria were those comparing MGMT protein expression by IHC with MGMT promoter methylation by MSP in the same cohort of patients. Methodological quality was assessed by using the QUADAS and STARD instruments. Previously published guidelines were followed for meta-analysis performance. Results Of 254 studies identified as eligible for full-text review, 52 (20.5%) met the inclusion criteria. The review showed that results of MGMT protein expression by IHC are not in close agreement with those obtained with MSP. Moreover, type of tumour (primary brain tumour vs others) was an independent covariate of accuracy estimates in the meta-regression analysis beyond the cut-off value. Conclusions Protein expression assessed by IHC alone fails to reflect the promoter methylation status of MGMT. Thus, in attempts at clinical diagnosis the two methods seem to select different groups of patients and should not be used interchangeably.

Caracterització estructural i funcional del gen de la miogenia en l’orada (Sparus aurata )

Report for the scientific sojourn at the University of Maryland Biotechnology Institute from February to August 2007. Myogenesis of skeletal muscles in vertebrates is controlled by extracellular signalling molecules together with intracellular transcription factors. Among the transcriptional factors, the members of the myogenic regulatory family play important roles regulating skeletal muscle development and growth. To characterize the gene structure and expression of fish myogenin, we have isolated the myogenin genomic gene and cDNA from gilthead seabream (Sparus aurata) and analyzed the genomic structure, pattern of expression and the regulation of musclespecific expression. Sequence analysis revealed that the seabream myogenin shares a similar gene structure with other fish myogenins, with three exons, two introns and the highly conserved bHLH domain. Expression studies demonstrated that myogenin is expressed in both slow and fast muscles as well as in muscle cells in primary culture. In situ hybridization showed that myogenin was specifically expressed in developing somites of seabream embryos. Promoter activity analysis demonstrated that the myogenin promoter could drive green fluorescence protein expression in muscle cells of zebrafish embryos, as well as in myofibers of adult zebrafish and juvenile seabream.

Series enlazadas de algunos agregados económicos nacionales y regionales, 1955-2007 Versión 2.1

I construct "homogeneous" series of GVA at current and constant prices, employment and population for the Spain and its regions covering the period 1955-2007. The series are obtained by linking the Regional Accounts of the National Statistical Institute with the series constructed by Julio Alcaide and his team for the BBVA Foundation. The "switching point" at which this last source stops being used as a reference to construct the linked series is determined using a procedure that allows me to estimate which of the two competing series would produce an estimator with the lowest MSE when it is used as dependent variable in a regression on an arbitrary independent variable. To the extent that it is possible, the difference between the two series found at the point of linkage is distributed between the initial levels of the older series and its subsequent growth using external estimates of the relevant variables at the beginning of the sample period.

Integrated assessment of agricultural sustainability: the pros and cons of reductionism

In this paper I review a series of theoretical concepts that are relevant for the integrated assessment of agricultural sustainability but that are not generally included in the curriculum of the various scientific disciplines dealing with quantitative analysis of agriculture. I first illustrate with plain narratives and concrete examples that sustainability is an extremely complex issue requiring the simultaneous consideration of several aspects, which cannot be reduced into a single indicator of performance. Following, I justify this obvious need for multi-criteria analysis with theoretical concepts dealing with the epistemological predicament of complexity, starting from classic philosophical lessons to arrive to recent developments in complex system theory, in particular Rosen´s theory of modelling relation which is essential to analyze the quality of any quantitative representation. The implications of these theoretical concepts are then illustrated with applications of multi-criteria analysis to the sustainability of agriculture. I wrap up by pointing out the crucial difference between "integrated assessment" and "integrated analysis". An integrated analysis is a set of indicators and analytical models generating an analytical output. An integrated assessment is much more than that. It is about finding an effective way to deal with three key issues: (i) legitimacy – how to handle the unavoidable existence of legitimate but contrasting points of view about different meanings given by social actors to the word "development"; (ii) pertinence – how to handle in a coherent way scientific analyses referring to different scales and dimensions; and (iii) credibility – how to handle the unavoidable existence of uncertainty and genuine ignorance, when dealing with the analysis of future scenarios.

Dynamic graphics of parametrically linked multivariate methods used in compositional data analysis

Many multivariate methods that are apparently distinct can be linked by introducing oneor more parameters in their definition. Methods that can be linked in this way arecorrespondence analysis, unweighted or weighted logratio analysis (the latter alsoknown as "spectral mapping"), nonsymmetric correspondence analysis, principalcomponent analysis (with and without logarithmic transformation of the data) andmultidimensional scaling. In this presentation I will show how several of thesemethods, which are frequently used in compositional data analysis, may be linkedthrough parametrizations such as power transformations, linear transformations andconvex linear combinations. Since the methods of interest here all lead to visual mapsof data, a "movie" can be made where where the linking parameter is allowed to vary insmall steps: the results are recalculated "frame by frame" and one can see the smoothchange from one method to another. Several of these "movies" will be shown, giving adeeper insight into the similarities and differences between these methods

A compositional approach to stable isotope data analysis

Isotopic data are currently becoming an important source of information regardingsources, evolution and mixing processes of water in hydrogeologic systems. However, itis not clear how to treat with statistics the geochemical data and the isotopic datatogether. We propose to introduce the isotopic information as new parts, and applycompositional data analysis with the resulting increased composition. Results areequivalent to downscale the classical isotopic delta variables, because they are alreadyrelative (as needed in the compositional framework) and isotopic variations are almostalways very small. This methodology is illustrated and tested with the study of theLlobregat River Basin (Barcelona, NE Spain), where it is shown that, though verysmall, isotopic variations comp lement geochemical principal components, and help inthe better identification of pollution sources

Natural abundance of stable isotopes (15N and 13C) and isotopic fractionation of sea bream muscle as markers of food and culture conditions and its relationship with metabolic and proteomic analyses

Els isòtops estables com a traçadors de la cadena alimentària, s'han utilitzat per caracteritzar la relació entre els consumidors i els seus aliments, ja que el fraccionament isotòpic implica una discriminació en contra de certs isòtops. Però les anàlisis d'isòtops estables (SIA), també es poden dur a terme en peixos cultivats amb dietes artificials, com la orada (Sparus aurata), la especie más cultivada en el Mediterráneo. Canvis en l'abundància natural d'isòtops estables (13C i 15N) en els teixits i les seves reserves poden reflectir els canvis en l'ús i reciclatge dels nutrients ja que els enzims catabòlics implicats en els processos de descarboxilació i desaminació mostren una preferència pels isòtops més lleugers. Per tant, aquestes anàlisis ens poden proporcionar informació útil sobre l'estat nutricional i metabòlic dels peixos. L'objectiu d'aquest projecte va ser determinar la capacitat dels isòtops estables per ser utilitzats com a marcadors potencials de la capacitat de creixement i condicions de cria de l'orada. En aquest sentit, les anàlisis d'isòtops estables s'han combinat amb altres metabòlics (activitats citocrom-c-oxidasa, COX, i citrat sintasa, CS) i els paràmetres de creixement (ARN/ADN). El conjunt de resultats obtinguts en els diferents estudis realitzats en aquest projecte demostra que el SIA, en combinació amb altres paràmetres metabòlics, pot servir com una eina eficaç per discriminar els peixos amb millor potencial de creixement, així com a marcador sensible de l'estat nutricional i d'engreix. D'altra banda, la combinació de l'anàlisi d'isòtops estables amb les eines emergents, com ara tècniques de proteòmica (2D-PAGE), ens proporciona nous coneixements sobre els canvis metabòlics que ocorren en els músculs dels peixos durant l‟increment del creixement muscular induït per l'exercici.

Estimating arterial blood gases with the EABC® System (“Earlobe Arterialized Blood Collector”) in critically ill patients. A validation study.

The Earlobe Arterialized Blood Collector® is a minimally invasive system able to perform arterialized capillary blood gas analysis from the earlobe (EL). A prospective validation study was performed in 55 critical ill patients. Sampling failure rate was high (53.6%). Risk factors were age > 65 years, diabetes, vasoactive drug therapy and noradrenaline (NA) doses above 0.22 μg / kg / min. Multivariate analysis showed age > 65 years was the only factor independently associated with failure. Concordance analysis with arterial blood gases and Bland-Altman agreement evaluation were insufficient for validating the new system for all gasometrical variables.

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.

Characterization and evolution of the novel gene family FAM90A in primates originated by multiple duplication and rearrangement events

Genomic plasticity of human chromosome 8p23.1 region is highly influenced by two groups of complex segmental duplications (SDs), termed REPD and REPP, that mediate different kinds of rearrangements. Part of the difficulty to explain the wide range of phenotypes associated with 8p23.1 rearrangements is that REPP and REPD are not yet well characterized, probably due to their polymorphic status. Here, we describe a novel primate-specific gene family, named FAM90A (family with sequence similarity 90), found within these SDs. According to the current human reference sequence assembly, the FAM90A family includes 24 members along 8p23.1 region plus a single member on chromosome 12p13.31, showing copy number variation (CNV) between individuals. These genes can be classified into subfamilies I and II, which differ in their upstream and 5′-untranslated region sequences, but both share the same open reading frame and are ubiquitously expressed. Sequence analysis and comparative fluorescence in situ hybridization studies showed that FAM90A subfamily II suffered a big expansion in the hominoid lineage, whereas subfamily I members were likely generated sometime around the divergence of orangutan and African great apes by a fusion process. In addition, the analysis of the Ka/Ks ratios provides evidence of functional constraint of some FAM90A genes in all species. The characterization of the FAM90A gene family contributes to a better understanding of the structural polymorphism of the human 8p23.1 region and constitutes a good example of how SDs, CNVs and rearrangements within themselves can promote the formation of new gene sequences with potential functional consequences.

A general definition and nomenclature for alternative splicing events

Understanding the molecular mechanisms responsible for the regulation of the transcriptome present in eukaryotic cells isone of the most challenging tasks in the postgenomic era. In this regard, alternative splicing (AS) is a key phenomenoncontributing to the production of different mature transcripts from the same primary RNA sequence. As a plethora ofdifferent transcript forms is available in databases, a first step to uncover the biology that drives AS is to identify thedifferent types of reflected splicing variation. In this work, we present a general definition of the AS event along with anotation system that involves the relative positions of the splice sites. This nomenclature univocally and dynamically assignsa specific ‘‘AS code’’ to every possible pattern of splicing variation. On the basis of this definition and the correspondingcodes, we have developed a computational tool (AStalavista) that automatically characterizes the complete landscape of ASevents in a given transcript annotation of a genome, thus providing a platform to investigate the transcriptome diversityacross genes, chromosomes, and species. Our analysis reveals that a substantial part—in human more than a quarter—ofthe observed splicing variations are ignored in common classification pipelines. We have used AStalavista to investigate andto compare the AS landscape of different reference annotation sets in human and in other metazoan species and found thatproportions of AS events change substantially depending on the annotation protocol, species-specific attributes, andcoding constraints acting on the transcripts. The AStalavista system therefore provides a general framework to conductspecific studies investigating the occurrence, impact, and regulation of AS.