| 1. |
- Schael, S., et al.
(author)
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Electroweak measurements in electron positron collisions at W-boson-pair energies at LEP
- 2013
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In: Physics Reports. - : Elsevier BV. - 0370-1573 .- 1873-6270. ; 532:4, s. 119-244
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Research review (peer-reviewed)abstract
- Electroweak measurements performed with data taken at the electron positron collider LEP at CERN from 1995 to 2000 are reported. The combined data set considered in this report corresponds to a total luminosity of about 3 fb(-1) collected by the four LEP experiments ALEPH, DELPHI, 13 and OPAL, at centre-of-mass energies ranging from 130 GeV to 209 GeV. Combining the published results of the four LEP experiments, the measurements include total and differential cross-sections in photon-pair, fermion-pair and four-fermion production, the latter resulting from both double-resonant WW and ZZ production as well as singly resonant production. Total and differential cross-sections are measured precisely, providing a stringent test of the Standard Model at centre-of-mass energies never explored before in electron positron collisions. Final-state interaction effects in four-fermion production, such as those arising from colour reconnection and Bose Einstein correlations between the two W decay systems arising in WW production, are searched for and upper limits on the strength of possible effects are obtained. The data are used to determine fundamental properties of the W boson and the electroweak theory. Among others, the mass and width of the W boson, m(w) and Gamma(w), the branching fraction of W decays to hadrons, B(W -> had), and the trilinear gauge-boson self-couplings g(1)(Z), K-gamma and lambda(gamma), are determined to be: m(w) = 80.376 +/- 0.033 GeV Gamma(w) = 2.195 +/- 0.083 GeV B(W -> had) = 67.41 +/- 0.27% g(1)(Z) = 0.984(-0.020)(+0.018) K-gamma - 0.982 +/- 0.042 lambda(gamma) = 0.022 +/- 0.019. (C) 2013 Elsevier B.V. All rights reserved.
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| 2. |
- Fernandez, J. L. Abelleira, et al.
(author)
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A Large Hadron Electron Collider at CERN
- 2012
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In: Journal of Physics G. - : IOP Publishing. - 0954-3899 .- 1361-6471. ; 39:7
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Journal article (peer-reviewed)
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| 3. |
- Godoy, Patricio, et al.
(author)
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Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME
- 2013
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In: Archives of Toxicology. - : Springer Science and Business Media LLC. - 0340-5761 .- 1432-0738. ; 87:8, s. 1315-1530
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Research review (peer-reviewed)abstract
- This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4 alpha, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4 alpha), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.
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| 4. |
- Alexandrov, Ludmil B., et al.
(author)
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Signatures of mutational processes in human cancer
- 2013
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 500:7463, s. 415-421
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Journal article (peer-reviewed)abstract
- All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
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| 5. |
- Adermark, Louise, 1974, et al.
(author)
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Brain region specific modulation of ethanol-induced depression of GABAergic neurons in the brain reward system by the nicotine receptor antagonist mecamylamine
- 2014
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In: Alcohol. - : Elsevier BV. - 0741-8329. ; 48:5, s. 455-461
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Journal article (peer-reviewed)abstract
- The mechanisms underlying ethanol-induced activation of the mesolimbic dopamine system are not fully understood, but increased extracellular dopamine in the nucleus accumbens (nAc) has been shown to involve nicotinic acetylcholine receptors (nAChRs). Basal activity of dopaminergic neurons in the ventral tegmental area (VTA) is under the influence of GABAergic neurotransmission, and the aim of this study was to characterize the involvement of nAChRs in mediating acute ethanol effects on GABAergic activity in subregions of the brain reward system. Multi-electrode in vivo recordings were made in the VTA and nAc of awake and behaving C57BL6/J mice receiving intraperitoneal injections of saline or ethanol (2.0 g/kg), combined with, or without, pre-injection of the non-competitive nAChR antagonist mecamylamine (1.0 mg/kg). Ethanol significantly decreased the activity of quinpirole-insensitive slow-spiking and fast-spiking units in both the VTA and the nAc as compared to saline injection. Pre-treatment with mecamylamine inhibited the rate-inhibiting properties of ethanol in the VTA, but not in the nAc. The data presented here show that ethanol depresses the activity of quinpirole-insensitive, putative GABAergic neurons, in the mesolimbic dopamine system of mice, and that nAChRs contribute to this modulation. This finding, taken together with previous microdialysis studies, supports an involvement of GABAergic neurons and nAChRs in ethanol's interaction with the mesolimbic dopamine system. (C) 2014 The Authors. Published by Elsevier Inc. All rights reserved.
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| 6. |
- Apel, Maria, et al.
(author)
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Variants in RUNX3 Contribute to Susceptibility to Psoriatic Arthritis, Exhibiting Further Common Ground With Ankylosing Spondylitis
- 2013
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In: Arthritis and Rheumatism. - : Wiley. - 0004-3591 .- 1529-0131. ; 65:5, s. 1224-1231
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Journal article (peer-reviewed)abstract
- Objective Psoriatic arthritis (PsA) is a common inflammatory joint disease distinct from other chronic arthritides and frequently accompanied by psoriasis vulgaris. In a first genome-wide association study (GWAS), we were able to identify several genetic risk factors. However, even combined with previously identified factors, the genetic contribution to disease was not fully explained. Therefore, we undertook this study to investigate further 17 loci from our GWAS that did not reach genome-wide significance levels of association in the initial analysis. Methods Twenty-one of 22 single-nucleotide polymorphisms were successfully genotyped in independent cohorts of 1,398 PsA patients and 6,389 controls and in a group of 964 German patients with psoriasis vulgaris. Results Association with a RUNX3 variant, rs4649038, was replicated in independent patients and controls and resulted in a combined P value of 1.40 x 108 by Cochran-Mantel-Haenszel test and an odds ratio (OR) of 1.24 (95% confidence interval [95% CI] 1.151.33). Further analyses based on linkage disequilibrium (LD) at RUNX3 refined the most significant association to an LD block located in the first intron of one isoform. Weaker evidence for association was detected in German patients with psoriasis vulgaris (P = 5.89 x 102; OR 1.13 [95% CI 1.001.28]), indicating a role in the skin manifestations of psoriasis. Conclusion Our analyses identified variants in RUNX3 as susceptibility factors for PsA. RUNX3 has already been implicated in susceptibility to ankylosing spondylitis, another spondyloarthritis, although its risk allele is independent from the one for PsA. RUNX-3 is involved in CD8+ T lymphocyte differentiation and is therefore a good candidate for involvement in PsA and psoriasis vulgaris as T cellmediated diseases.
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| 7. |
- Burkhardt, H., et al.
(author)
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Commissioning and Operation at beta = 1000 m in the LHC
- 2013
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In: IPAC'13. ; , s. 1983-1984
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Conference paper (other academic/artistic)abstract
- We have developed a special optics with aβ∗ of 1000m for two interaction regions (IR1 and IR5) in the LHC, to produce very low divergence beams required for elastic proton-proton scattering. We describe the design, commissioning and operation of this optics in the LHC. Theβ∗ of 1000 m was reached by de-squeezing the beams using 17 intermediate steps beyond the β∗ of 90 m, which had been the previous highest β∗ value reached in the LHC. The optics was measured and the β-beating globally corrected toa level of 10%.
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| 8. |
- Burkhardt, J. M., et al.
(author)
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Locus of onset and subpopulation specificity of in vivo ethanol effect in the reciprocal ventral tegmental area-nucleus accumbens circuit
- 2014
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In: Neurochemistry International. - : Elsevier BV. - 0197-0186. ; 76, s. 122-130
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Journal article (peer-reviewed)abstract
- Elevated levels of dopamine in the nucleus accumbens (nAc) as a consequence of increased activation of dopaminergic neurons in the VTA are associated with the reinforcing properties of ethanol consumption, but whether the initiation of drug-response is connected to a direct activation of dopaminergic cell bodies in the VTA region or involves GABAergic neurons in VTA and/or the nAc is unclear. To this end, neuronal firing rate was recorded simultaneously in the VTA and nAc of awake and freely-moving C57BL6/J mice receiving an intraperitoneal (i.p.) injection of ethanol (0.75, 2.0, or 3.5 g/kg) or saline. Recorded units were classified based on electrophysiological properties and the pharmacological response to the dopamine D-2 receptor agonist quinpirole into putative dopaminergic (DA) neurons and fast-spiking or slow-spiking putative GABAergic neurons. Our data show that ethanol acutely decreases the firing frequency of GABAergic units in both the VTA and nAc in a dose-dependent manner, and enhances the firing rate of DA neurons. In order to define the onset of ethanol-induced rate changes normalized population vectors describing the collective firing rate of classes of neurons over time were generated and compared with saline-treatment. Population vectors of DA neurons in the VTA and GABAergic units in the nAc showed a significant deviation from the saline condition within 40 s following ethanol-administration (2.0 g/kg), while inhibition of GABAergic units in the VTA had a slower onset. In conclusion, the data presented here suggests that EtOH exerts a direct effect on DA firing frequency, but that decreased firing frequency of inhibitory neurons in VTA and nAc contributes to the dopamine-elevating properties of ethanol. (C) 2014 Elsevier Ltd. All rights reserved.
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| 9. |
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| 10. |
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| 11. |
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| 12. |
- Hüffmeier, Ulrike, et al.
(author)
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Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 996-999
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Journal article (peer-reviewed)abstract
- Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.
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| 13. |
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| 14. |
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| 15. |
- Paeth, Heiko, et al.
(author)
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Progress in regional downscaling of west African precipitation
- 2011
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In: Atmospheric Science Letters. - : Wiley. - 1530-261X. ; 12:1, s. 75-82
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Journal article (peer-reviewed)abstract
- We review the recent progress in dynamical and statistical downscaling approaches for west African precipitation and perform a regional climate model (RCM) intercomparison using the novel multi-model RCM data set from the Ensembles-based Predictions of Climate Changes and Their Impacts (ENSEMBLES) and African Monsoon Multidisciplinary Analyses (AMMA) projects. Present RCMs have distinct systematic errors in terms of west African precipitation varying in amplitude and pattern across models. This is also reflected in a relatively large spread in projected future precipitation trends. Altogether, the ENSEMBLES RCMs indicate a prevailing drying tendency in sub-Saharan Africa. Statistical post-processing of simulated precipitation is a promising tool to reduce systematic model errors before application in impact studies.
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| 16. |
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