33 research outputs found

    Genetics of rheumatoid arthritis contributes to biology and drug discovery

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    A major challenge in human genetics is to devise a systematic strategy to integrate disease-associated variants with diverse genomic and biological datasets to provide insight into disease pathogenesis and guide drug discovery for complex traits such as rheumatoid arthritis (RA)1. Here, we performed a genome-wide association study (GWAS) meta-analysis in a total of >100,000 subjects of European and Asian ancestries (29,880 RA cases and 73,758 controls), by evaluating ~10 million single nucleotide polymorphisms (SNPs). We discovered 42 novel RA risk loci at a genome-wide level of significance, bringing the total to 1012–4. We devised an in-silico pipeline using established bioinformatics methods based on functional annotation5, cis-acting expression quantitative trait loci (cis-eQTL)6, and pathway analyses7–9 – as well as novel methods based on genetic overlap with human primary immunodeficiency (PID), hematological cancer somatic mutations and knock-out mouse phenotypes – to identify 98 biological candidate genes at these 101 risk loci. We demonstrate that these genes are the targets of approved therapies for RA, and further suggest that drugs approved for other indications may be repurposed for the treatment of RA. Together, this comprehensive genetic study sheds light on fundamental genes, pathways and cell types that contribute to RA pathogenesis, and provides empirical evidence that the genetics of RA can provide important information for drug discovery

    Measuring the heat of interaction between lignocellulosic materials and water

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    Research Highlights: When investigating the sorption of water on lignocellulosic materials, the sorption or mixing enthalpy is an interesting parameter that, together with the sorption isotherms commonly measured, can be used to characterize and understand the sorption process. We have compared different methods to assess these enthalpies. Additionally, we propose a sorption nomenclature. Background and Objectives: Sorption enthalpies are non-trivial to measure. We have, for the first time, measured sorption enthalpies on the same materials with four different methods, to be able to compare the method's strengths and weaknesses. Materials and Methods: The following four methods were used on beech and Scots pine wood: isosteric heat, solution calorimetry, sorption calorimetry, and RH perfusion calorimetry. Results: The results for beech and pine were similar, and were in general agreement with the literature. We do not recommend one of the methods over the others, as they are quite different, and they can therefore be used to elucidate different aspects of the interactions between water and, for example, novel biobased materials (modified woods, cellulose derivatives, and regenerated cellulose)

    Autonomous production cell for mym- and nm-processing

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    Shorter life time cycles of products, increasing workpiece variety and declining lot sizes demand for a closed processing chain which enables the economic production of variable products in the future. A new type of manufacturing concept for the production of the 21st century is lined out by the design of an "Autonomous Production Cell." Applied to and designed for manufacturing with laser radiation this concept shows completely new ways in comparison to former manufacturing procedures. The manufacturing processes in the Autonomous Production Cell start with a production oriented design and planning of the manufacturing procedure is including sensor controlled processing of the workpieces with integrated quality management. The quality management detects failures in the manufacturing procedure and allows back-coupling to any preceding step by means of a multistage cascaded production controller. In comparison to former concepts the user is at all times integrated into the manufacturing procedure. The user can add his own competence and creativity. At the same time he is being relieved by routine work and gets adequate help by the system in corresponding situations. The design of the components of the Autonomous Production Cell (design and planning tools, networking of sensors and actuators, user interface, etc.) has been performed as general as possible. This offers the possibility to transfer this concept with countable efforts to all the manufacturing with laser radiation such as welding, cutting, surface treatment, freeforming, rapid prototyping, etc

    Characterization of the Archaeal Thermophile Sulfolobus Turreted Icosahedral Virus Validates an Evolutionary Link among Double-Stranded DNA Viruses from All Domains of Life

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    Icosahedral nontailed double-stranded DNA (dsDNA) viruses are present in all three domains of life, leading to speculation about a common viral ancestor that predates the divergence of Eukarya, Bacteria, and Archaea. This suggestion is supported by the shared general architecture of this group of viruses and the common fold of their major capsid protein. However, limited information on the diversity and replication of archaeal viruses, in general, has hampered further analysis. Sulfolobus turreted icosahedral virus (STIV), isolated from a hot spring in Yellowstone National Park, was the first icosahedral virus with an archaeal host to be described. Here we present a detailed characterization of the components forming this unusual virus. Using a proteomics-based approach, we identified nine viral and two host proteins from purified STIV particles. Interestingly, one of the viral proteins originates from a reading frame lacking a consensus start site. The major capsid protein (B345) was found to be glycosylated, implying a strong similarity to proteins from other dsDNA viruses. Sequence analysis and structural predication of virion-associated viral proteins suggest that they may have roles in DNA packaging, penton formation, and protein-protein interaction. The presence of an internal lipid layer containing acidic tetraether lipids has also been confirmed. The previously presented structural models in conjunction with the protein, lipid, and carbohydrate information reported here reveal that STIV is strikingly similar to viruses associated with the Bacteria and Eukarya domains of life, further strengthening the hypothesis for a common ancestor of this group of dsDNA viruses from all domains of life

    An In Vitro Model Using TRIS-Buffered Plasma-Activated Water to Reduce Pathogenic Microorganisms Involved in Digital Dermatitis Infection in Cattle

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    Bovine digital dermatitis is an important infectious claw disease caused by multimicrobial infections with bacteria such as Fusobacterium (F.) necrophorum or Porphyromonas (P.) levii. To analyze the antibacterial effects of a TRIS-buffered plasma-activated water (Tb-PAW) on the bacterial number of F. necrophorum, P. levii, Escherichia (E.) coli, Staphylococcus (S.) aureus and Clostridium (C.) sporogenes 1 mL of each bacterial solution (106–108 CFU/mL) was incubated with 9 mL Tb-PAW up to 15 min. E. coli, F. necrophorum and P. levii were significantly reduced by 5.0 log after 1 min of treatment, while S. aureus and C. sporogenes required 15 min to reach a 3.0 log reduction. The addition of bovine serum albumin did not negatively affect the bactericidal effect. Tb-PAW storage at 7 °C and 21 °C is possible for up to 24 h without any change in the bactericidal effect, while Tb-PAW stored at 30 °C can only be used for a period of 12 h. The present data indicate that Tb-PAW can be used to reduce various bacteria even under the influence of different parameters. However, due to the complexity of Tb-PAW, further studies are required to ensure its microbicidal activity before practical application
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