481 research outputs found

    The ATF6-Met [67] Val substitution is associated with increased plasma cholesterol levels

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    Objective— Activating transcription factor 6 (ATF6) is a sensor of the endoplasmic reticulum stress response and regulates expression of several key lipogenic genes. We used a 2-stage design to investigate whether ATF6 polymorphisms are associated with lipids in subjects at increased risk for cardiovascular disease (CVD). Methods and Results— In stage 1, 13 tag-SNPs were tested for association in Dutch samples ascertained for familial combined hyperlipidemia (FCHL) or increased risk for CVD (CVR). In stage 2, we further investigated the SNP with the strongest association from stage 1, a Methionine/Valine substitution at amino-acid 67, in Finnish FCHL families and in subjects with CVR from METSIM, a Finnish population-based cohort. The combined analysis of both stages reached region-wide significance (P=9x10–4), but this association was not seen in the entire METSIM cohort. Our functional analysis demonstrated that Valine at position 67 augments ATF6 protein and its targets Grp78 and Grp94 as well as increases luciferase expression through Grp78 promoter. Conclusions— A common nonsynonymous variant in ATF6 increases ATF6 protein levels and is associated with cholesterol levels in subjects at increased risk for CVD, but this association was not seen in a population-based cohort. Further replication is needed to confirm the role of this variant in lipids. We report the association of the ATF6-methionine [67]valine amino-acid substitution with plasma cholesterol levels. Association analyses in 2674 subjects and functional data suggest that the ATF6 gene may influence cholesterol levels in subjects at increased risk to develop cardiovascular disease

    Parallel programming systems for scalable scientific computing

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    High-performance computing (HPC) systems are more powerful than ever before. However, this rise in performance brings with it greater complexity, presenting significant challenges for researchers who wish to use these systems for their scientific work. This dissertation explores the development of scalable programming solutions for scientific computing. These solutions aim to be effective across a diverse range of computing platforms, from personal desktops to advanced supercomputers.To better understand HPC systems, this dissertation begins with a literature review on exascale supercomputers, massive systems capable of performing 10¹⁸ floating-point operations per second. This review combines both manual and data-driven analyses, revealing that while traditional challenges of exascale computing have largely been addressed, issues like software complexity and data volume remain. Additionally, the dissertation introduces the open-source software tool (called LitStudy) developed for this research.Next, this dissertation introduces two novel programming systems. The first system (called Rocket) is designed to scale all-versus-all algorithms to massive datasets. It features a multi-level software-based cache, a divide-and-conquer approach, hierarchical work-stealing, and asynchronous processing to maximize data reuse, exploit data locality, dynamically balance workloads, and optimize resource utilization. The second system (called Lightning) aims to scale existing single-GPU kernel functions across multiple GPUs, even on different nodes, with minimal code adjustments. Results across eight benchmarks on up to 32 GPUs show excellent scalability.The dissertation concludes by proposing a set of design principles for developing parallel programming systems for scalable scientific computing. These principles, based on lessons from this PhD research, represent significant steps forward in enabling researchers to efficiently utilize HPC systems

    Parallel programming systems for scalable scientific computing

    Get PDF
    High-performance computing (HPC) systems are more powerful than ever before. However, this rise in performance brings with it greater complexity, presenting significant challenges for researchers who wish to use these systems for their scientific work. This dissertation explores the development of scalable programming solutions for scientific computing. These solutions aim to be effective across a diverse range of computing platforms, from personal desktops to advanced supercomputers.To better understand HPC systems, this dissertation begins with a literature review on exascale supercomputers, massive systems capable of performing 10¹⁸ floating-point operations per second. This review combines both manual and data-driven analyses, revealing that while traditional challenges of exascale computing have largely been addressed, issues like software complexity and data volume remain. Additionally, the dissertation introduces the open-source software tool (called LitStudy) developed for this research.Next, this dissertation introduces two novel programming systems. The first system (called Rocket) is designed to scale all-versus-all algorithms to massive datasets. It features a multi-level software-based cache, a divide-and-conquer approach, hierarchical work-stealing, and asynchronous processing to maximize data reuse, exploit data locality, dynamically balance workloads, and optimize resource utilization. The second system (called Lightning) aims to scale existing single-GPU kernel functions across multiple GPUs, even on different nodes, with minimal code adjustments. Results across eight benchmarks on up to 32 GPUs show excellent scalability.The dissertation concludes by proposing a set of design principles for developing parallel programming systems for scalable scientific computing. These principles, based on lessons from this PhD research, represent significant steps forward in enabling researchers to efficiently utilize HPC systems

    Breaking new ground in mapping human settlements from space -The Global Urban Footprint-

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    Today 7.2 billion people inhabit the Earth and by 2050 this number will have risen to around nine billion, of which about 70 percent will be living in cities. Hence, it is essential to understand drivers, dynamics, and impacts of the human settlements development. A key component in this context is the availability of an up-to-date and spatially consistent map of the location and distribution of human settlements. It is here that the Global Urban Footprint (GUF) raster map can make a valuable contribution. The new global GUF binary settlement mask shows a so far unprecedented spatial resolution of 0.4 arcsec (12m\sim12 m) that provides - for the first time - a complete picture of the entirety of urban and rural settlements. The GUF has been derived by means of a fully automated processing framework - the Urban Footprint Processor (UFP) - that was used to analyze a global coverage of more than 180,000 TanDEM-X and TerraSAR-X radar images with 3m ground resolution collected in 2011-2012. Various quality assessment studies to determine the absolute GUF accuracy based on ground truth data on the one hand and the relative accuracies compared to established settlements maps on the other hand, clearly indicate the added value of the new global GUF layer, in particular with respect to the representation of rural settlement patterns. Generally, the GUF layer achieves an overall absolute accuracy of about 85\%, with observed minima around 65\% and maxima around 98 \%. The GUF will be provided open and free for any scientific use in the full resolution and for any non-profit (but also non-scientific) use in a generalized version of 2.8 arcsec (84m\sim84m). Therewith, the new GUF layer can be expected to break new ground with respect to the analysis of global urbanization and peri-urbanization patterns, population estimation or vulnerability assessment

    Molecular genetics of the Spodoptera exigua multicapsid nucleopolyhedrovirus genome

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    Spodoptera exigua multicapsid nucleopolyhedrovirus (SeMNPV) is an attractive biological control agent for the beet army worm S. exigua . This baculovirus has a narrow host range and is relatively, compared to other baculoviruses, virulent for beet army worm larvae. The molecular principles that specify the host range and virulence of SeMNPV are unknown. This thesis describes studies aimed at the unravelling of the molecular genetics of this baculovirus and the key steps in the infection and genome replication process.As a first step SeMNPV was multiplied in an established cell line of S. exigua to obtain a better understanding of the replication process. Polyhedra derived from cell culture were unable to infect S. exigua larvae, although the hemolymph isolated from these larvae did contain budded virus able to infect insect cell lines (Chapter 2). This suggested the generation of a genetic defect in the SeMNPV genome during replication and/or maintenance in cell culture. A partial plasmid library and complete cosmid library were made to construct a physical map of the SeMNPV genome and locate the genetic defect(s). The position of the polyhedrin gene and the transcriptional direction of the p10 gene allowed the pin-pointing of the zero point and orientation of the circular SeMNPV genome. A large deletion (20-25 kilobase pairs), turned out to be the genetic defect, arising upon limited passaging of the virus in cell culture. This deletion was located between map unit 12.9 and 31.3 in the SeMNPV genome. The occurrence of this deletion implied that the construction of SeMNPV recombinant viruses still virulent in vivo cannot be achieved via conventional techniques, i.e. homologous recombination in cell culture (Chapter 2). Alternative recombinationstrategies involving yeast artificial chromosomes and in vivo cloning were considered and partially tested (Chapter 7).In Chapters 3 and 4 the identification and characterization of cis -acting elements in SeMNPV DNA replication are described. Transient DNA replication assays, sequence analyses and hybridization experiments identified one non- hr ( hr homologous region) and six hr origins of DNA replication. SeMNPV hr s contained one ( hr 4) up to nine ( hr 1) repeated, near-identical 68-bp long palindromes. The SeMNPV hr s, located in non-coding regions, were found dispersed in the viral genome as observed in the genomes of two other baculoviruses, Autographa californica MNPV and Orgyia pseudotsugata MNPV. Transient DNA replication assays in AcMNPV-infected insect cells revealed no replication of SeMNPV- hr s and, in SeMNPV-infected insect cells no replication of AcMNPV- hr s could be observed, suggesting that these elements display specificity (Chapter 3). In the SeMNPV- Xba I library one additional genomic fragment unrelated to hr s and reminiscent of AcMNPV and OpMNPV non- hr origins of DNA replication that underwent SeMNPV dependent DNA replication was identified. By deletion analysis the core of this non- hr origin was mapped within a 800 bp region of non-coding sequence. This sequence contained also several motifs such as multiple palindromes, direct repeats, putative transcriptional factor binding sites and multiple polyadenylation signals, characteristic for baculovirus non- hr and other eukaryotic origins of DNA replication. In contrast to the hr s, the SeMNPV non- hr origin could be replicated by the replication machinery of the heterologous AcMNPV (Chapter 4).The putative helicase is the most intriguing trans -acting DNA replication factor of baculoviruses, since it may be involved in both DNA replication and host range determination. An open reading frame (ORF) potentially encoding a polypeptide of 143 kDa (p143) with considerable amino acid identity to the putative helicases of AcMNPV, BmNPV and OpMNPV was identified in SeMNPV. Sequence alignment of the SeMNPV p143 indicated that it is somewhat diverged from its AcMNPV, BmNPV and OpMNPV homologs. Whether the protein is also involved in the host range of SeMNPV determination remained unsolved. The ORF is expressed as a 4 kb transcript between 4 and 24 h p.i., starting from an unusual transcriptional initiation site present eleven nucleotides upstream of the translational start. Transient plasmid dependent DNA replication assays showed that not only helicase plays a crucial role in SeMNPV and AcMNPV replication specificity, but also one or more of the other previously mentioned essential trans -acting DNA replication factors. Apparently the interaction between the origins of DNA replication and/or the assembly of the replisome is a highly virus specific process (Chapter 5).Complete sequence and transcriptional analysis of the 11.3 kb SeMNPV- Xbal-C fragment containing the p143 gene revealed twelve ORFs that all showed high amino acid identity to AcMNPV and OpMNPV homologs. The genetic organization of the SeMNPV- Xba I-C fragment was identical to the AcMNPV and OpMNPV helicase region, although in an antigenomic orientation. In line with recent observations in herpes- and poxvirus genomes, which contain conserved central parts of their genomes and more diverged termini, it is hypothesized that baculoviruses genomes could also contain a highly conserved gene block centered around the p143 gene and a more diverged region at the polyhedrin - p10 loci. This hypothesis is further supported by partial sequence and hybridization data from other baculovirus genomes. The organization of the less conserved polyhedrin-p10 region could be a marker for the genetic relatedness of baculoviruses (Chapter 6). The state of the art on the sequence analysis of the complete SeMNPV genome is described in Chapter 7.The availability of a physical map, the insght in the genetic organization of the SeMNPV genome and the occurence of the spontaneous deletion mutants in cell culture prompted the development of alternative recombination strategies to bypass the use of the insect cell lines (Chapter 7). To this end a recombination strategy using yeast genetics was employed. Deletion of the yeast autonomous replicating sequences prior to the application of the recombinant baculoviruses in the field is recommended and can be achieved for SeMNPV using a direct in vivo recombination and selection protocol. The strategy proposed is based on the occurrence of homologous recombination of baculoviruses in the insect (Chapter 7).The research on SeMNPV described in this thesis, has created a good starting point to study the molecular basis of virulence and host range. The development of the recombination system described in chapter 7 could offer a tool for the insertion and deletion of specific (viral) genes for this purpose. Moreover exploiting the proposed recombination system, the improvement of the insecticidal properties of SeMNPV can be pursued.</p
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