p-medicine: a medical informatics platform for integrated large scale heterogeneous patient data

Secure access to patient data is becoming of increasing importance, as medical informatics grows in significance, to both assist with population health studies, and patient specific medicine in support of treatment. However, assembling the many different types of data emanating from the clinic is in itself a difficulty, and doing so across national borders compounds the problem. In this paper we present our solution: an easy to use distributed informatics platform embedding a state of the art data warehouse incorporating a secure pseudonymisation system protecting access to personal healthcare data. Using this system, a whole range of patient derived data, from genomics to imaging to clinical records, can be assembled and linked, and then connected with analytics tools that help us to understand the data. Research performed in this environment will have immediate clinical impact for personalised patient healthcare.

Heterogeneous architecture for the optimization of large-scale graph processing data centres

Con el auge del Cloud Computing, las aplicaciones de proceso de datos han sufrido un incremento de demanda, y por ello ha cobrado importancia lograr m�ás eficiencia en los Centros de Proceso de datos. El objetivo de este trabajo es la obtenci�ón de herramientas que permitan analizar la viabilidad y rentabilidad de diseñar Centros de Datos especializados para procesamiento de datos, con una arquitectura, sistemas de refrigeraci�ón, etc. adaptados. Algunas aplicaciones de procesamiento de datos se benefician de las arquitecturas software, mientras que en otras puede ser m�ás eficiente un procesamiento con arquitectura hardware. Debido a que ya hay software con muy buenos resultados en el procesamiento de grafos, como el sistema XPregel, en este proyecto se realizará una arquitectura hardware en VHDL, implementando el algoritmo PageRank de Google de forma escalable. Se ha escogido este algoritmo ya que podr��á ser m�ás eficiente en arquitectura hardware, debido a sus características concretas que se indicaráan m�ás adelante. PageRank sirve para ordenar las p�áginas por su relevancia en la web, utilizando para ello la teorí��a de grafos, siendo cada página web un vértice de un grafo; y los enlaces entre páginas, las aristas del citado grafo. En este proyecto, primero se realizará un an�álisis del estado de la técnica. Se supone que la implementaci�ón en XPregel, un sistema de procesamiento de grafos, es una de las m�ás eficientes. Por ello se estudiará esta �ultima implementaci�ón. Sin embargo, debido a que Xpregel procesa, en general, algoritmos que trabajan con grafos; no tiene en cuenta ciertas caracterí��sticas del algoritmo PageRank, por lo que la implementaci�on no es �optima. Esto es debido a que en PageRank, almacenar todos los datos que manda un mismo v�értice es un gasto innecesario de memoria ya que todos los mensajes que manda un vértice son iguales entre sí e iguales a su PageRank. Se realizará el diseño en VHDL teniendo en cuenta esta caracter��ística del citado algoritmo,evitando almacenar varias veces los mensajes que son iguales. Se ha elegido implementar PageRank en VHDL porque actualmente las arquitecturas de los sistemas operativos no escalan adecuadamente. Se busca evaluar si con otra arquitectura se obtienen mejores resultados. Se realizará un diseño partiendo de cero, utilizando la memoria ROM de IPcore de Xillinx (Software de desarrollo en VHDL), generada autom�áticamente. Se considera hacer cuatro tipos de módulos para que as�� el procesamiento se pueda hacer en paralelo. Se simplificar�á la estructura de XPregel con el fin de intentar aprovechar la particularidad de PageRank mencionada, que hace que XPregel no le saque el m�aximo partido. Despu�és se escribirá el c�ódigo, realizando una estructura escalable, ya que en la computación intervienen millones de páginas web. A continuación, se sintetizar�á y se probará el código en una FPGA. El �ultimo paso será una evaluaci�ón de la implementaci�ón, y de posibles mejoras en cuanto al consumo.

A local electrostatic change is the cause of the large-scale protein conformation shift in bacteriorhodopsin

During light-driven proton transport bacteriorhodopsin shuttles between two protein conformations. A large-scale structural change similar to that in the photochemical cycle is produced in the D85N mutant upon raising the pH, even without illumination. We report here that (i) the pKa values for the change in crystallographic parameters and for deprotonation of the retinal Schiff base are the same, (ii) the retinal isomeric configuration is nearly unaffected by the protein conformation, and (iii) preventing rotation of the C13—C14 double bond by replacing the retinal with an all-trans locked analogue makes little difference to the Schiff base pKa. We conclude that the direct cause of the conformational shift is destabilization of the structure upon loss of interaction of the positively charged Schiff base with anionic residues that form its counter-ion.

Multiple-complete-digest restriction fragment mapping: Generating sequence-ready maps for large-scale DNA sequencing

Multiple-complete-digest mapping is a DNA mapping technique based on complete-restriction-digest fingerprints of a set of clones that provides highly redundant coverage of the mapping target. The maps assembled from these fingerprints order both the clones and the restriction fragments. Maps are coordinated across three enzymes in the examples presented. Starting with yeast artificial chromosome contigs from the 7q31.3 and 7p14 regions of the human genome, we have produced cosmid-based maps spanning more than one million base pairs. Each yeast artificial chromosome is first subcloned into cosmids at a redundancy of ×15–30. Complete-digest fragments are electrophoresed on agarose gels, poststained, and imaged on a fluorescent scanner. Aberrant clones that are not representative of the underlying genome are rejected in the map construction process. Almost every restriction fragment is ordered, allowing selection of minimal tiling paths with clone-to-clone overlaps of only a few thousand base pairs. These maps demonstrate the practicality of applying the experimental and software-based steps in multiple-complete-digest mapping to a target of significant size and complexity. We present evidence that the maps are sufficiently accurate to validate both the clones selected for sequencing and the sequence assemblies obtained once these clones have been sequenced by a “shotgun” method.

Large-scale protein structure modeling of the Saccharomyces cerevisiae genome

The function of a protein generally is determined by its three-dimensional (3D) structure. Thus, it would be useful to know the 3D structure of the thousands of protein sequences that are emerging from the many genome projects. To this end, fold assignment, comparative protein structure modeling, and model evaluation were automated completely. As an illustration, the method was applied to the proteins in the Saccharomyces cerevisiae (baker’s yeast) genome. It resulted in all-atom 3D models for substantial segments of 1,071 (17%) of the yeast proteins, only 40 of which have had their 3D structure determined experimentally. Of the 1,071 modeled yeast proteins, 236 were related clearly to a protein of known structure for the first time; 41 of these previously have not been characterized at all.

Linking genome and proteome by mass spectrometry: Large-scale identification of yeast proteins from two dimensional gels

The function of many of the uncharacterized open reading frames discovered by genomic sequencing can be determined at the level of expressed gene products, the proteome. However, identifying the cognate gene from minute amounts of protein has been one of the major problems in molecular biology. Using yeast as an example, we demonstrate here that mass spectrometric protein identification is a general solution to this problem given a completely sequenced genome. As a first screen, our strategy uses automated laser desorption ionization mass spectrometry of the peptide mixtures produced by in-gel tryptic digestion of a protein. Up to 90% of proteins are identified by searching sequence data bases by lists of peptide masses obtained with high accuracy. The remaining proteins are identified by partially sequencing several peptides of the unseparated mixture by nanoelectrospray tandem mass spectrometry followed by data base searching with multiple peptide sequence tags. In blind trials, the method led to unambiguous identification in all cases. In the largest individual protein identification project to date, a total of 150 gel spots—many of them at subpicomole amounts—were successfully analyzed, greatly enlarging a yeast two-dimensional gel data base. More than 32 proteins were novel and matched to previously uncharacterized open reading frames in the yeast genome. This study establishes that mass spectrometry provides the required throughput, the certainty of identification, and the general applicability to serve as the method of choice to connect genome and proteome.

A large-scale overexpression screen in Saccharomyces cerevisiae identifies previously uncharacterized cell cycle genes

We have undertaken an extensive screen to identify Saccharomyces cerevisiae genes whose products are involved in cell cycle progression. We report the identification of 113 genes, including 19 hypothetical ORFs, which confer arrest or delay in specific compartments of the cell cycle when overexpressed. The collection of genes identified by this screen overlaps with those identified in loss-of-function cdc screens but also includes genes whose products have not previously been implicated in cell cycle control. Through analysis of strains lacking these hypothetical ORFs, we have identified a variety of new CDC and checkpoint genes.

Real or virtual large-scale structure?

Modeling the development of structure in the universe on galactic and larger scales is the challenge that drives the field of computational cosmology. Here, photorealism is used as a simple, yet expert, means of assessing the degree to which virtual worlds succeed in replicating our own.

Galaxies and large scale structure at high redshifts

It is now straightforward to assemble large samples of very high redshift (z ∼ 3) field galaxies selected by their pronounced spectral discontinuity at the rest frame Lyman limit of hydrogen (at 912 Å). This makes possible both statistical analyses of the properties of the galaxies and the first direct glimpse of the progression of the growth of their large-scale distribution at such an early epoch. Here I present a summary of the progress made in these areas to date and some preliminary results of and future plans for a targeted redshift survey at z = 2.7–3.4. Also discussed is how the same discovery method may be used to obtain a “census” of star formation in the high redshift Universe, and the current implications for the history of galaxy formation as a function of cosmic epoch.

Large-scale isolation of candidate virulence genes of Pseudomonas aeruginosa by in vivo selection.

Pseudomonas aeruginosa, an opportunistic human pathogen, is a major causative agent of mortality and morbidity in immunocompromised patients and those with cystic fibrosis genetic disease. To identify new virulence genes of P. aeruginosa, a selection system was developed based on the in vivo expression technology (IVET) that was first reported in Salmonella system. An adenine-requiring auxotrophic mutant strain of P. aeruginosa was isolated and found avirulent on neutropenic mice. A DNA fragment that can complement the mutant strain, containing purEK operon that is required for de novo biosynthesis of purine, was sequenced and used in the IVET vector construction. By applying the IVET selection system to a neutropenic mouse infection model, genetic loci that are specifically induced in vivo were identified. Twenty-two such loci were partially sequenced and analyzed. One of them was a well-studied virulence factor, pyochelin receptor (FptA), that is involved in iron acquisition. Fifteen showed significant homology to reported sequences in GenBank, while the remaining six did not. One locus, designated np20, encodes an open reading frame that shares amino acid sequence homology to transcriptional regulators, especially to the ferric uptake regulator (Fur) proteins of other bacteria. An insertional np20 null mutant strain of P. aeruginosa did not show a growth defect on laboratory media; however, its virulence on neutropenic mice was significantly reduced compared with that of a wild-type parent strain, demonstrating the importance of the np20 locus in the bacterial virulence. The successful isolation of genetic loci that affect bacterial virulence demonstrates the utility of the IVET system in identification of new virulence genes of P. aeruginosa.

A rat genetic map constructed by representational difference analysis markers with suitability for large-scale typing.

Representational difference analysis (RDA) was applied to isolate chromosomal markers in the rat. Four series of RDA [restriction enzymes, BamHI and HindIII; subtraction of ACI/N (ACI) amplicon from BUF/Nac (BUF) amplicon and vice versa] yielded 131 polymorphic markers; 125 of these markers were mapped to all chromosomes except for chromosome X. This was done by using a mapping panel of 105 ACI x BUF F2 rats. To complement the relative paucity of chromosomal markers in the rat, genetically directed RDA, which allows isolation of polymorphic markers in the specific chromosomal region, was performed. By changing the F2 driver-DNA allele frequency around the region, four markers were isolated from the D1Ncc1 locus. Twenty-five of 27 RDA markers were informative regarding the dot blot analysis of amplicons, hybridizing only with tester amplicons. Dot blot analysis at a high density per unit of area made it possible to process a large number of samples. Quantitative trait loci can now be mapped in the rat genome by processing a large number of samples with RDA markers and then by isolating markers close to the loci of interest by genetically directed RDA.

Unification and large-scale structure.

The hypothesis of relativistic flow on parsec scales, coupled with the symmetrical (and therefore subrelativistic) outer structure of extended radio sources, requires that jets decelerate on scales observable with the Very Large Array. The consequences of this idea for the appearances of FRI and FRII radio sources are explored.

Large-scale clustering measurements with photometric redshifts: comparing the dark matter haloes of X-ray AGN, star-forming and passive galaxies at z ≈ 1

We combine multi-wavelength data in the AEGIS-XD and C-COSMOS surveys to measure the typical dark matter halo mass of X-ray selected active galactic nuclei (AGN) [L_X(2–10 keV) > 10^42 erg s^− 1] in comparison with far-infrared selected star-forming galaxies detected in the Herschel/PEP survey (PACS Evolutionary Probe; L_IR > 10^11 L_⊙) and quiescent systems at z ≈ 1. We develop a novel method to measure the clustering of extragalactic populations that uses photometric redshift probability distribution functions in addition to any spectroscopy. This is advantageous in that all sources in the sample are used in the clustering analysis, not just the subset with secure spectroscopy. The method works best for large samples. The loss of accuracy because of the lack of spectroscopy is balanced by increasing the number of sources used to measure the clustering. We find that X-ray AGN, far-infrared selected star-forming galaxies and passive systems in the redshift interval 0.6 < z < 1.4 are found in haloes of similar mass, log M_DMH/(M_⊙ h^−1) ≈ 13.0. We argue that this is because the galaxies in all three samples (AGN, star-forming, passive) have similar stellar mass distributions, approximated by the J-band luminosity. Therefore, all galaxies that can potentially host X-ray AGN, because they have stellar masses in the appropriate range, live in dark matter haloes of log M_DMH/(M_⊙ h^−1) ≈ 13.0 independent of their star formation rates. This suggests that the stellar mass of X-ray AGN hosts is driving the observed clustering properties of this population. We also speculate that trends between AGN properties (e.g. luminosity, level of obscuration) and large-scale environment may be related to differences in the stellar mass of the host galaxies.

The effect of the geomagnetic field on cosmic ray energy estimates and large scale anisotropy searches on data from the Pierre Auger Observatory

We present a comprehensive study of the influence of the geomagnetic field on the energy estimation of extensive air showers with a zenith angle smaller than 60 degrees, detected at the Pierre Auger Observatory. the geomagnetic field induces an azimuthal modulation of the estimated energy of cosmic rays up to the similar to 2% level at large zenith angles. We present a method to account for this modulation of the reconstructed energy. We analyse the effect of the modulation on large scale anisotropy searches in the arrival direction distributions of cosmic rays. At a given energy, the geomagnetic effect is shown to induce a pseudo-dipolar pattern at the percent level in the declination distribution that needs to be accounted for.