Mutagenic mechanisms of cancer-associated DNA polymerase ε alleles

A single amino acid residue change in the exonuclease domain of human DNA polymerase ε, P286R, is associated with the development of colorectal cancers, and has been shown to impart a mutagenic phenotype. The corresponding Pol ε allele in the yeast Saccharomyces cerevisiae ( pol2-P301R ), was found to drive greater mutagenesis than an entirely exonuclease-deficient Pol ε ( pol2-4 ), an unexpected phenotype of ultra -mutagenesis. By studying the impact on mutation frequency, type, replication-strand bias, and sequence context, we show that ultra -mutagenesis is commonly observed in yeast cells carrying a range of cancer-associated Pol ε exonuclease domain alleles. Similarities between mutations generated by these alleles and those generated in pol2-4 cells indicate a shared mechanism of mutagenesis that yields a mutation pattern similar to cancer Signature 14. Comparison of POL2 ultra -mutator with pol2-M644G , a mutant in the polymerase domain decreasing Pol ε fidelity, revealed unexpected analogies in the sequence context and strand bias of mutations. Analysis of mutational patterns unique to exonuclease domain mutant cells suggests that backtracking of the polymerase, when the mismatched primer end cannot be accommodated in the proofreading domain, results in the observed insertions and T>A mutations in specific sequence contexts.Swedish Research Counci

Radiopharmacokinetics and uptake of 99m Tc-cRGD in av B3 integrins for imaging angiogenesis in induced malignant tumors in athymic mice

The multistep process of angiogenesis offers several targets for therapeutic interventions. One molecular target structure is the alfa five beta three (av b3 ) integrin which is expressed on vascular endothelial cells and over-expressed in cancer tumor angiogenesis. To image neoangiogenesis in athymic mice with induced pancreatic, breast and prostate malignant tumors a new radiopharmaceutical was developed. The 99mTc-EDDA/HYNIC-cyclic-Arg-Gly- Asp-D-Phe-Lys (99mTc-cRGD) targets integrin receptors av b3 and was prepared with an average radiochemical purity > 95 %. 99mTc-cRGD shows high in vivo stability, fast blood clearance and rapid renal excretion in mice. There are statistical differences between tumor/muscle ratios for the 3 tumors studied. The highest tumor/non-target ratio was found in breast cancer (7.2 after 24 h) and a representative dorsal SPECT image was obtained where the tumor showed up very clearly over the background tissue. The high resolution of the image implies that 99mTc-cRGD will be of great value in nuclear medicine as a potential radiopharmaceutical for av b3 integrins receptor uptake and for imaging neoangiogenesis in neoplastic tissue and to follow up cancer tumor progression

Challenges and Opportunities for RISC-V Architectures towards Genomics-based Workloads

The use of large-scale supercomputing architectures is a hard requirement for scientific computing Big-Data applications. An example is genomics analytics, where millions of data transformations and tests per patient need to be done to find relevant clinical indicators. Therefore, to ensure open and broad access to high-performance technologies, governments, and academia are pushing toward the introduction of novel computing architectures in large-scale scientific environments. This is the case of RISC-V, an open-source and royalty-free instruction-set architecture. To evaluate such technologies, here we present the Variant-Interaction Analytics use case benchmarking suite and datasets. Through this use case, we search for possible genetic interactions using computational and statistical methods, providing a representative case for heavy ETL (Extract, Transform, Load) data processing. Current implementations are implemented in x86-based supercomputers (e.g. MareNostrum-IV at the Barcelona Supercomputing Center (BSC)), and future steps propose RISC-V as part of the next MareNostrum generations. Here we describe the Variant Interaction Use Case, highlighting the characteristics leveraging high-performance computing, indicating the caveats and challenges towards the next RISC-V developments and designs to come from a first comparison between x86 and RISC-V architectures on real Variant Interaction executions over real hardware implementations

Galaxy Pairs in the Sloan Digital Sky Survey - III: Evidence of Induced Star Formation from Optical Colours

We have assembled a large, high quality catalogue of galaxy colours from the Sloan Digital Sky Survey Data Release 7, and have identified 21,347 galaxies in pairs spanning a range of projected separations (r_p < 80 h_{70}^{-1} kpc), relative velocities (\Delta v < 10,000 km/s, which includes projected pairs that are essential for quality control), and stellar mass ratios (from 1:10 to 10:1). We find that the red fraction of galaxies in pairs is higher than that of a control sample matched in stellar mass and redshift, and demonstrate that this difference is likely due to the fact that galaxy pairs reside in higher density environments than non-paired galaxies. We detect clear signs of interaction-induced star formation within the blue galaxies in pairs, as evidenced by a higher fraction of extremely blue galaxies, along with blueward offsets between the colours of paired versus control galaxies. These signs are strongest in close pairs (r_p < 30 h_{70}^{-1} kpc and \Delta v < 200 km/s), diminish for more widely separated pairs (r_p > 60 h_{70}^{-1} kpc and \Delta v < 200 km/s) and disappear for close projected pairs (r_p < 30 h_{70}^{-1} kpc and \Delta v > 3000 km/s). These effects are also stronger in central (fibre) colours than in global colours, and are found primarily in low- to medium-density environments. Conversely, no such trends are seen in red galaxies, apart from a small reddening at small separations which may result from residual errors with photometry in crowded fields. When interpreted in conjunction with a simple model of induced starbursts, these results are consistent with a scenario in which close peri-centre passages trigger induced star formation in the centres of galaxies which are sufficiently gas rich, after which time the galaxies gradually redden as they separate and their starbursts age.Comment: 17 pages. Accepted for publication in MNRA

Analysis of the suitability of existing medical ontologies for building a scalable semantic interoperability solution supporting multi-site collaboration in oncology

Semantic interoperability is essential to facilitate efficient collaboration in heterogeneous multi-site healthcare environments. The deployment of a semantic interoperability solution has the potential to enable a wide range of informatics supported applications in clinical care and research both within as ingle healthcare organization and in a network of organizations. At the same time, building and deploying a semantic interoperability solution may require significant effort to carryout data transformation and to harmonize the semantics of the information in the different systems. Our approach to semantic interoperability leverages existing healthcare standards and ontologies, focusing first on specific clinical domains and key applications, and gradually expanding the solution when needed. An important objective of this work is to create a semantic link between clinical research and care environments to enable applications such as streamlining the execution of multi-centric clinical trials, including the identification of eligible patients for the trials. This paper presents an analysis of the suitability of several widely-used medical ontologies in the clinical domain: SNOMED-CT, LOINC, MedDRA, to capture the semantics of the clinical trial eligibility criteria, of the clinical trial data (e.g., Clinical Report Forms), and of the corresponding patient record data that would enable the automatic identification of eligible patients. Next to the coverage provided by the ontologies we evaluate and compare the sizes of the sets of relevant concepts and their relative frequency to estimate the cost of data transformation, of building the necessary semantic mappings, and of extending the solution to new domains. This analysis shows that our approach is both feasible and scalable

Galaxy Pairs in the Sloan Digital Sky Survey - II: The Effect of Environment on Interactions

We use a sample of close galaxy pairs selected from the Sloan Digital Sky Survey Data Release 4 (SDSS DR4) to investigate in what environments galaxy mergers occur and how the results of these mergers depend on differences in local galaxy density. The galaxies are quantified morphologically using two-dimensional bulge-plus-disk decompositions and compared to a control sample matched in stellar mass, redshift and local projected density. Lower density environments have fractionally more galaxy pairs with small projected separations (r_p) and relative velocities (Delta v), but even high density environments contain significant populations of pairs with parameters that should be conducive to interactions. Metrics of asymmetry and colour are used to identify merger activity and triggered star formation. The location of star formation is inferred by distinguishing bulge and disk colours and calculating bulge fractions from the SDSS images. Galaxies in the lowest density environments show the largest changes in star formation rate, asymmetry and bulge-total fractions at small separations, accompanied by bluer bulge colours. At the highest local densities, the only galaxy property to show an enhancement in the closest pairs is asymmetry. We interpret these results as evidence that whilst interactions (leading to tidal distortions) occur at all densities, triggered star formation is seen only in low-to-intermediate density environments. We suggest that this is likely due to the typically higher gas fractions of galaxies in low density environments. Finally, by cross-correlating our sample of galaxy pairs with a cluster catalogue, we investigate the dependence of interactions on clustercentric distance. It is found that for close pairs the fraction of asymmetric galaxies is highest in the cluster centres.Comment: Accepted by MNRAS, 15 page

Adaptive Task Migration Policies for Thermal control in MPSoCs

In deep submicron circuits, high temperatures have created critical issues in reliability, timing, performance, coolings costs and leakage power. Task migration techniques have been proposed to manage efficiently the thermal distribution in multi-processor systems but at the cost of important performance penalties. While traditional techniques have focused on reducing the average temperature of the chip, they have not considered the effect that temperature gradients have in system reliability. In this work, we explore the benefits of thermal-aware task migration techniques for embedded multi-processor systems. We propose several policies that are able to reduce the average temperature of the chip and the thermal gradients with a negligible performance overhead. With our techniques, hot spots and temperature gradients are decreased up to 30% with respect to state-of-the-art thermal management approache

Simulation of High-Performance Memory Allocators

This study presents a single-core and a multi-core processor architecture for health monitoring systems where slow biosignal events and highly parallel computations exist. The single-core architecture is composed of a processing core (PC), an instruction memory (IM) and a data memory (DM), while the multi-core architecture consists of PCs, individual IMs for each core, a shared DM and an interconnection crossbar between the cores and the DM. These architectures are compared with respect to power vs. performance trade-offs for a multi-lead electrocardiogram signal conditioning application exploiting near threshold computing. The results show that the multi-core solution consumes 66%less power for high computation requirements (50.1 MOps/s), whereas 10.4% more power for low computation needs (681 kOps/s)

Simulation of High-Performance Memory Allocators

Current general-purpose memory allocators do not provide sufficient speed or flexibility for modern highperformance applications. To optimize metrics like performance, memory usage and energy consumption, software engineers often write custom allocators from scratch, which is a difficult and error-prone process. In this paper, we present a flexible and efficient simulator to study Dynamic Memory Managers (DMMs), a composition of one or more memory allocators. This novel approach allows programmers to simulate custom and general DMMs, which can be composed without incurring any additional runtime overhead or additional programming cost. We show that this infrastructure simplifies DMM construction, mainly because the target application does not need to be compiled every time a new DMM must be evaluated. Within a search procedure, the system designer can choose the "best" allocator by simulation for a particular target application. In our evaluation, we show that our scheme will deliver better performance, less memory usage and less energy consumption than single memory allocators

Posicionamiento de la sociedad Española de infectología pediátrica sobre la implementación, ejecución y monitorización de los programas de optimización de uso de antimicrobianos (PROA) en pediatría hospitalaria

Pediatría; Resistencia antibióticaPaediatrics; Antimicrobial resistancePediatria; Resistència antibiòticaIn the past few years, antimicrobial resistance has increased, becoming a serious public health problem. The irrational use of antimicrobials is one of the main contributors to antimicrobial resistance. The paediatric population is not free from this problem, as antimicrobials are widely prescribed in this age group, often inappropriately. The introduction of antimicrobial stewardship programmes (ASPs) has proven crucial in curbing the emergence of antimicrobial resistance. At the international level, the need to develop specific paediatric ASPs has been recognised on account of the differences between adult and paediatric patients as concerns infection and approaches to diagnosis and treatment. For this reason, paediatric ASPs should be multidisciplinary programmes led by paediatric infectious disease specialists and use specific paediatric indicators (such as days of treatment, antimicrobial susceptibility patterns in the paediatric population, or clinical indicators) to help identify areas of improvement and develop effective targeted interventions. On the other hand, the support and leadership of the pertinent scientific societies are also essential. The purpose of this document is to present the position of the Sociedad Española de Infectología Pediátrica (SEIP, Spanish Society of Paediatric Infectious Diseases) concerning the implementation of paediatric ASPs in hospitals in Spain and to provide tools to facilitate their application in hospitals throughout the regional health care systems in the country.Durante los últimos años ha habido un aumento en la aparición de resistencias antimicrobianas, lo cual supone un grave problema de salud pública. El mal uso de antimicrobianos es un factor determinante en su desarrollo. La población pediátrica no queda exenta de dicha problemática ya que la prescripción de antibióticos en pediatría es elevada y en muchas ocasiones inadecuada. La incorporación de los programas de optimización de uso de antimicrobianos (PROA) ha resultado ser una medida crucial para disminuir el riesgo en la aparición de resistencias antibióticas. A nivel internacional se reconoce la necesidad de crear PROAs específicos en pediatría (PROA-P) debido a las diferencias existentes entre pacientes adultos y pediátricos en referencia a las infecciones, así como al abordaje tanto diagnóstico como terapéutico de las mismas. Por esta misma razón, los PROA-P deben ser programas multidisciplinares liderados por especialistas en infecciones pediátricas y trabajar con indicadores específicos pediátricos (DOT, patrones de sensibilidad antibiótica de población pediátrica, indicadores clínicos…) que permitan detectar puntos de mejora y establecer estrategias dirigidas eficaces. Por otro lado, es imprescindible el apoyo y liderazgo por parte de las distintas sociedades científicas implicadas. El objetivo de este documento es dar a conocer el posicionamiento de la Sociedad Española de Infectología Pediátrica (SEIP) sobre la implementación de los PROA pediátricos hospitalarios en nuestro territorio así como aportar herramientas que ayuden en la aplicación de dichos programas en los diferentes hospitales de las distintas regiones sanitarias del país