| 1. |
- Faatz, B., et al.
(author)
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Simultaneous operation of two soft x-ray free-electron lasers driven by one linear accelerator
- 2016
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In: New Journal of Physics. - : IOP Publishing. - 1367-2630. ; 18
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Journal article (peer-reviewed)abstract
- Extreme-ultraviolet to x-ray free-electron lasers (FELs) in operation for scientific applications are up to now single-user facilities. While most FELs generate around 100 photon pulses per second, FLASH at DESY can deliver almost two orders of magnitude more pulses in this time span due to its superconducting accelerator technology. This makes the facility a prime candidate to realize the next step in FELs-dividing the electron pulse trains into several FEL lines and delivering photon pulses to several users at the same time. Hence, FLASH has been extended with a second undulator line and self-amplified spontaneous emission (SASE) is demonstrated in both FELs simultaneously. FLASH can now deliver MHz pulse trains to two user experiments in parallel with individually selected photon beam characteristics. First results of the capabilities of this extension are shown with emphasis on independent variation of wavelength, repetition rate, and photon pulse length.
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| 6. |
- Walker, Anthony P, et al.
(author)
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Horizon 2020 EuPRAXIA design study
- 2017
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In: Journal of Physics: Conference Series. - : IOP Publishing. - 1742-6588 .- 1742-6596. ; 874:1
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Journal article (peer-reviewed)abstract
- The Horizon 2020 Project EuPRAXIA ("European Plasma Research Accelerator with eXcellence In Applications") is preparing a conceptual design report of a highly compact and cost-effective European facility with multi-GeV electron beams using plasma as the acceleration medium. The accelerator facility will be based on a laser and/or a beam driven plasma acceleration approach and will be used for photon science, high-energy physics (HEP) detector tests, and other applications such as compact X-ray sources for medical imaging or material processing. EuPRAXIA started in November 2015 and will deliver the design report in October 2019. EuPRAXIA aims to be included on the ESFRI roadmap in 2020.
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| 7. |
- Battistoni, G, et al.
(author)
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FLUKA Monte Carlo calculations for hadrontherapy application
- 2013
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In: CERN-Proceedings-2012-002. ; , s. 461-467
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Conference paper (peer-reviewed)abstract
- Monte Carlo (MC) codes are increasingly spreading in the hadrontherapy community due to their detailed description of radiation transport and interaction with matter. The suitability of a MC code for application to hadrontherapy demands accurate and reliable physical models for the description of the transport and the interaction of all components of the expected radiation field (ions, hadrons, electrons, positrons and photons). This contribution will address the specific case of the general-purpose particle and interaction code FLUKA. In this work, an application of FLUKA will be presented, i.e. establishing CT (computed tomography)-based calculations of physical and RBE (relative biological effectiveness)-weighted dose distributions in scanned carbon ion beam therapy.
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| 11. |
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| 13. |
- Garte, S, et al.
(author)
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Metabolic gene polymorphism frequencies in control populations
- 2001
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In: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. - 1055-9965. ; 10:12, s. 1239-1248
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Journal article (peer-reviewed)
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| 14. |
- McKay, James D., et al.
(author)
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A Genome-Wide Association Study of Upper Aerodigestive Tract Cancers Conducted within the INHANCE Consortium
- 2011
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In: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 7:3
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p <= 5 x 10(-7)). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1 x 10(-8)) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p = 2 x 10(-8)) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 x 10(-8); rs1229984-ADH1B, p = 7 x 10(-9); and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
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| 15. |
- Smits, KM, et al.
(author)
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Association of metabolic gene polymorphisms with tobacco consumption in healthy controls
- 2004
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 110:2, s. 266-270
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Journal article (peer-reviewed)abstract
- Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case-control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20,938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYPIAI, GSTMI, GSTTI, NAT2 and GSTPI. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.
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| 16. |
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| 17. |
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| 18. |
- Beecham, Ashley H, et al.
(author)
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Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
- 2013
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In: Nature genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
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Journal article (peer-reviewed)abstract
- Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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| 22. |
- Chang, Yun Chien, et al.
(author)
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Decrypting lysine deacetylase inhibitor action and protein modifications by dose-resolved proteomics
- 2024
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In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 43:6
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Journal article (peer-reviewed)abstract
- Lysine deacetylase inhibitors (KDACis) are approved drugs for cutaneous T cell lymphoma (CTCL), peripheral T cell lymphoma (PTCL), and multiple myeloma, but many aspects of their cellular mechanism of action (MoA) and substantial toxicity are not well understood. To shed more light on how KDACis elicit cellular responses, we systematically measured dose-dependent changes in acetylation, phosphorylation, and protein expression in response to 21 clinical and pre-clinical KDACis. The resulting 862,000 dose-response curves revealed, for instance, limited cellular specificity of histone deacetylase (HDAC) 1, 2, 3, and 6 inhibitors; strong cross-talk between acetylation and phosphorylation pathways; localization of most drug-responsive acetylation sites to intrinsically disordered regions (IDRs); an underappreciated role of acetylation in protein structure; and a shift in EP300 protein abundance between the cytoplasm and the nucleus. This comprehensive dataset serves as a resource for the investigation of the molecular mechanisms underlying KDACi action in cells and can be interactively explored online in ProteomicsDB.
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| 23. |
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| 24. |
- Englund, Elias, et al.
(author)
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Expanding Extender Substrate Selection for Unnatural Polyketide Biosynthesis by Acyltransferase Domain Exchange within a Modular Polyketide Synthase
- 2023
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In: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 145:16, s. 8822-8832
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Journal article (peer-reviewed)abstract
- Modular polyketide synthases (PKSs) are poly-merases that employ alpha-carboxyacyl-CoAs as extender substrates. This enzyme family contains several catalytic modules, where each module is responsible for a single round of polyketide chain extension. Although PKS modules typically use malonyl-CoA or methylmalonyl-CoA for chain elongation, many other malonyl-CoA analogues are used to diversify polyketide structures in nature. Previously, we developed a method to alter an extension substrate of a given module by exchanging an acyltransferase (AT) domain while maintaining protein folding. Here, we report in vitro polyketide biosynthesis by 13 PKSs (the wild-type PKS and 12 AT-exchanged PKSs with unusual ATs) and 14 extender substrates. Our similar to 200 in vitro reactions resulted in 13 structurally different polyketides, including several polyketides that have not been reported. In some cases, AT-exchanged PKSs produced target polyketides by >100-fold compared to the wild-type PKS. These data also indicate that most unusual AT domains do not incorporate malonyl-CoA and methylmalonyl-CoA but incorporate various rare extender substrates that are equal to in size or slightly larger than natural substrates. We developed a computational workflow to predict the approximate AT substrate range based on active site volumes to support the selection of ATs. These results greatly enhance our understanding of rare AT domains and demonstrate the benefit of using the proposed PKS engineering strategy to produce novel chemicals in vitro.
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| 29. |
- Hung, Rayjean J, et al.
(author)
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A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25
- 2008
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In: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 452:7187, s. 633-637
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Journal article (peer-reviewed)abstract
- Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.
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| 30. |
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| 31. |
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| 32. |
- Lechner, A., et al.
(author)
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Outcomes for Pressure Ulcer Trials (OUTPUTs) project : review and classification of outcomes reported in pressure ulcer prevention research
- 2021
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In: British Journal of Dermatology. - : Blackwell Science Ltd.. - 0007-0963 .- 1365-2133. ; 184:4, s. 617-626
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Research review (peer-reviewed)abstract
- BACKGROUND: In order to overcome inconsistencies in the reporting of outcomes in clinical trials, core outcome sets (COS) have been developed in many clinical areas and the awareness of this concept is growing steadily. The Outcomes for Pressure Ulcer Trials (OUTPUTs) project aims to improve the quality of evidence on pressure ulcer prevention trials by developing a COS.OBJECTIVES: As an initial step in the COS process we aimed to identify and classify outcomes as well as concepts that represent potential outcomes for future trials that have been reported in pressure ulcer prevention research.METHODS: A review was conducted in twelve major databases covering the literature indexed until 2016. Outcomes and relevant concepts reported in primary studies and/or reviews on pressure ulcer prevention in adult patients were extracted as presented in the articles, and afterwards inductively grouped into outcome domains. The domains were then categorized according to the outcome domain taxonomy recently proposed by the Core Outcome Measures in Effectiveness Trials Group.RESULTS: 332 studies were included and 68 outcome domains were identified, covering multiple aspects of pressure ulcer prevention. Pressure ulcer occurrence was reported in 71% of all included studies representing the most frequent outcome, followed by costs (22% of all studies), and acceptability of intervention and comfort (18% of all studies).CONCLUSION: A plethora of different outcomes is applied in pressure ulcer prevention research and substantial variations in definitions and reporting of similar outcomes were observed. A COS for pressure ulcer prevention trials is needed to overcome the non-comparability of outcomes.
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| 33. |
- Lechner, C., et al.
(author)
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First direct seeding at 38 nm
- 2012
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In: FEL 2012 - 34th International Free Electron Laser Conference. - 9783954501236 ; , s. 197-199
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Conference paper (other academic/artistic)abstract
- The sFLASH project at DESY is an experiment to study direct seeding using a source based on the high-harmonic generation (HHG) process. In contrast to SASE, a seeded FEL exhibits greatly improved longitudinal coherence and higher shot-to-shot stability (both spectral and energetic). In addition, the output of the seeded FEL is intrinsically synchronized to the HHG drive laser, thus enabling pump-probe experiments with a resolution of the order of 10 fs. The installation and successful commissioning of the sFLASH components in 2010/2011 has been followed by a planned upgrade in autumn 2011. As a result of these improvements, in spring 2012 direct HHG seeding at 38 nm has been successfully demonstrated. In this contribution, we describe the experimental layout and announce the first seeding at 38 nm.
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| 34. |
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| 35. |
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| 36. |
- Porro, M., et al.
(author)
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The MiniSDD-Based 1-Mpixel Camera of the DSSC Project for the European XFEL
- 2021
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In: IEEE Transactions on Nuclear Science. - : Institute of Electrical and Electronics Engineers Inc.. - 0018-9499 .- 1558-1578. ; 68:6, s. 1334-1350
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Journal article (peer-reviewed)abstract
- The first DSSC 1-Mpixel camera became available at the European XFEL (EuXFEL) in the Hamburg area in February 2019. It was successfully tested, installed, and commissioned at the Spectroscopy and Coherent Scattering Instrument. DSSC is a high-speed, large-area, 2-D imaging detector system optimized for photon science applications in the energy range between 0.25 and 6 keV. The camera is based on direct conversion Si sensors and is composed of 1024 × 1024 pixels of hexagonal shape with a side length of 136∼μm. The 256 application-specific integrated circuits (ASICs) provide full parallel readout, comprising analog filtering, digitization, and in-pixel data storage. In order to cope with the demanding X-ray pulse time structure of the EuXFEL, the DSSC provides a peak frame rate of 4.5 MHz. The first Mpixel camera is equipped with miniaturized silicon drift detector (MiniSDD) pixel arrays. The intrinsic response of the pixels and the linear readout limit the dynamic range but allow one to achieve noise values of about 60 electrons r.m.s. at the highest frame rate. The challenge of providing high-dynamic range (104 photons/pixel/pulse) and single-photon detection simultaneously requires a nonlinear system front end, which will be obtained with the DEPFET active pixel technology foreseen for the advanced version of the camera. This technology will provide lower noise and a nonlinear response at the sensor level. This article describes the architecture of the whole detector system together with the main experimental results achieved up to now. © 1963-2012 IEEE.
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| 37. |
- Purdue, Mark P, et al.
(author)
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Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3
- 2011
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:1, s. 60-65
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Journal article (peer-reviewed)abstract
- We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and 11q13.3 were associated with RCC susceptibility below genome-wide significance. Two correlated variants (r² = 0.99 in controls), rs11894252 (P = 1.8 × 10⁻⁸) and rs7579899 (P = 2.3 × 10⁻⁹), map to EPAS1 on 2p21, which encodes hypoxia-inducible-factor-2 alpha, a transcription factor previously implicated in RCC. The second locus, rs7105934, at 11q13.3, contains no characterized genes (P = 7.8 × 10⁻¹⁴). In addition, we observed a promising association on 12q24.31 for rs4765623, which maps to SCARB1, the scavenger receptor class B, member 1 gene (P = 2.6 × 10⁻⁸). Our study reports previously unidentified genomic regions associated with RCC risk that may lead to new etiological insights.
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| 38. |
- Rodriguez, L. , V, et al.
(author)
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Doubly-magic character of Sn-132 studied via electromagnetic moments of( 13)(3)Sn
- 2020
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In: Physical Review C. - : American Physical Society. - 2469-9985 .- 2469-9993. ; 102:5
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Journal article (peer-reviewed)abstract
- We report the first measurement of the magnetic dipole and electric quadrupole moment of the exotic nucleus Sn-133 by high-resolution laser spectroscopy at ISOLDE/CERN. These, in combination with state-of-the-art shell-model calculations, demonstrate the single-particle character of the ground state of this short-lived isotope and, hence, the doubly-magic character of its immediate neighbor Sn-132. The trend of the electromagnetic moments along the N = 83 isotonic chain, now enriched with the values of tin, are discussed on the basis of realistic shell-model calculations.
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| 39. |
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| 40. |
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| 41. |
- Smits, KM, et al.
(author)
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Interaction between smoking, GSTM1 deletion and colorectal cancer: results from the GSEC study
- 2003
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In: Biomarkers. - : Informa UK Limited. - 1366-5804 .- 1354-750X. ; 8:3-4, s. 299-310
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Journal article (peer-reviewed)abstract
- Cigarette smoking has inconsistently been associated with an increased risk of colorectal cancer. One of the enzymes responsible for the detoxification of the carcinogenic compounds present in tobacco smoke is glutathione S-transferase-mu (GST-mu). The gene that codes for this enzyme is GSTM1. In this study, we evaluated the associations and interaction between GSTM1 deletion, smoking behaviour and the development of colorectal cancer. We performed a pooled analysis within the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens (GSEC). We selected six studies on colorectal cancer, including 1130 cases and 2519 controls, and restricted our analyses to Caucasians because the number of patients from other races was too limited. In addition we performed a meta-analysis including the studies from the GSEC database and other studies identified on MEDLINE on the same subject. The prevalence of the GSTM1 null genotype was within the range reported in other studies: 51.8% of the cases had the GSTM1 null genotype versus 56.6% of the controls. No significant association between the GSTM1 null genotype and colorectal cancer was found (odds ratio 0.92, 95% confidence interval 0.73-1.14). Our results suggest a possible positive association between lack of the GST-mu enzyme and colorectal cancer for non-smoking women (odds ratio 1.47, 95% confidence interval 0.80-2.70). There was no interaction between the effects of smoking and GSTM1 genotype on colorectal cancer risk in men and women (chi(2) = 0.007, p = 0.97). Our findings do not support an association between the GSTM1 null genotype and colorectal cancer. In addition, we did not find any modification of the smoking-induced colorectal cancer risk by GSTM1 genotype.
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| 42. |
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| 44. |
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| 45. |
- Tsapatsaris, Nikolaos, et al.
(author)
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From BASIS to MIRACLES: Benchmarking and perspectives for high-resolution neutron spectroscopy at the ESS
- 2015
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In: QENS/WINS 2014 - 11th International Conference on Quasielastic Neutron Scattering and 6th International Workshopon Inelastic Neutron Spectrometers. - : EDP Sciences. - 2101-6275 .- 2100-014X. ; 83, s. 03015-03015
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Conference paper (peer-reviewed)abstract
- Results based on virtual instrument models for the first high-flux, high-resolution, spallation based, backscattering spectrometer, BASIS are presented in this paper. These were verified using the Monte Carlo instrument simulation packages McStas and VITESS. Excellent agreement of the neutron count rate at the sample position between the virtual instrument simulation and experiments was found, in both time and energy distributions. This achievement was only possible after a new component for a bent single crystal analyser in McStas, using a Gaussian approximation, was developed. These findings are pivotal to the conceptual design of the next generation backscattering spectrometer, MIRACLES at the European Spallation Source.
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