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Träfflista för sökning "WFRF:(Forster Michael) "

Sökning: WFRF:(Forster Michael)

  • Resultat 1-10 av 26
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1.
  • Tidskriftsartikel (refereegranskat)
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2.
  • Ellinghaus, David, et al. (författare)
  • Association between variants of PRDM1 and NDP52 and Crohn's disease, based on exome sequencing and functional studies
  • 2013
  • Ingår i: Gastroenterology. - 0016-5085 .- 1528-0012. ; 145:2, s. 339-347
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND & AIMS: Genome-wide association studies (GWAS) have identified 140 Crohn's disease (CD) susceptibility loci. For most loci, the variants that cause disease are not known and the genes affected by these variants have not been identified. We aimed to identify variants that cause CD through detailed sequencing, genetic association, expression, and functional studies.METHODS: We sequenced whole exomes of 42 unrelated subjects with CD and 5 healthy subjects (controls) and then filtered single nucleotide variants by incorporating association results from meta-analyses of CD GWAS and in silico mutation effect prediction algorithms. We then genotyped 9348 subjects with CD, 2868 subjects with ulcerative colitis, and 14,567 control subjects and associated variants analyzed in functional studies using materials from subjects and controls and in vitro model systems.RESULTS: We identified rare missense mutations in PR domain-containing 1 (PRDM1) and associated these with CD. These mutations increased proliferation of T cells and secretion of cytokines on activation and increased expression of the adhesion molecule L-selectin. A common CD risk allele, identified in GWAS, correlated with reduced expression of PRDM1 in ileal biopsy specimens and peripheral blood mononuclear cells (combined P = 1.6 x 10(-8)). We identified an association between CD and a common missense variant, Val248Ala, in nuclear domain 10 protein 52 (NDP52) (P = 4.83 x 10(-9)). We found that this variant impairs the regulatory functions of NDP52 to inhibit nuclear factor kappa B activation of genes that regulate inflammation and affect the stability of proteins in Toll-like receptor pathways.CONCLUSIONS: We have extended the results of GWAS and provide evidence that variants in PRDM1 and NDP52 determine susceptibility to CD. PRDM1 maps adjacent to a CD interval identified in GWAS and encodes a transcription factor expressed by T and B cells. NDP52 is an adaptor protein that functions in selective autophagy of intracellular bacteria and signaling molecules, supporting the role of autophagy in the pathogenesis of CD.
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4.
  • Forster, Michael, et al. (författare)
  • Genetic control of antibody production during collagen-induced arthritis development in heterogeneous stock mice
  • 2012
  • Ingår i: Arthritis and Rheumatism. - : John Wiley and Sons Inc.. - 1529-0131. ; 64:11, s. 3594-3603
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. To identify genetic factors driving pathogenic autoantibody formation in collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (RA), in order to better understand the etiology of RA and identify possible new avenues for therapeutic intervention. Methods. We performed a genome-wide analysis of quantitative trait loci controlling autoantibody to type II collagen (anti-CII), anti-citrullinated protein antibody (ACPA), and rheumatoid factor (RF). To identify loci controlling autoantibody production, we induced CIA in a heterogeneous stock-derived mouse cohort, with contribution of 8 inbred mouse strains backcrossed to C57BL/10. Q. Serum samples were collected from 1,640 mice before arthritis onset and at the peak of the disease. Antibody concentrations were measured by standard enzyme-linked immunosorbent assay, and linkage analysis was performed using a linear regression-based method. Results. We identified loci controlling formation of anti-CII of different IgG isotypes (IgG1, IgG3), antibodies to major CII epitopes (C1, J1, U1), antibodies to a citrullinated CII peptide (citC1), and RF. The anti-CII, ACPA, and RF responses were all found to be controlled by distinct genes, one of the most important loci being the immunoglobulin heavy chain locus. Conclusion. This comprehensive genetic analysis of autoantibody formation in CIA demonstrates an association not only of anti-CII, but interestingly also of ACPA and RF, with arthritis development in mice. These results underscore the importance of non-major histocompatibility complex genes in controlling the formation of clinically relevant autoantibodies.
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5.
  • Lincoff, A. Michael, et al. (författare)
  • Inhibition of delta-protein kinase C by delcasertib as an adjunct to primary percutaneous coronary intervention for acute anterior ST-segment elevation myocardial infarction: results of the PROTECTION AMI Randomized Controlled Trial
  • 2014
  • Ingår i: European Heart Journal. - : Oxford University Press. - 1522-9645. ; 35:37, s. 2516-2523
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims Delcasertib is a selective inhibitor of delta-protein kinase C (delta-PKC), which reduced infarct size during ischaemia/reperfusion in animal models and diminished myocardial necrosis and improved reperfusion in a pilot study during primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI). Methods and results A multicentre, double-blind trial was performed in patients presenting within 6 h and undergoing primary PCI for anterior (the primary analysis cohort, n = 1010 patients) or inferior (an exploratory cohort, capped at 166 patients) STEMI. Patients with anterior STEMI were randomized to placebo or one of three doses of delcasertib (50,150, or 450 mg/h) by intravenous infusion initiated before PCI and continued for similar to 2.5 h. There were no differences between treatment groups in the primary efficacy endpoint of infarct size measured by creatine kinase MB fraction area under the curve (AUC) (median 5156, 5043, 4419, and 5253 ng h/mL in the placebo, delcasertib 50, 150, and 450 mg/mL groups, respectively) in the anterior STEMI cohort. No treatment-related differences were seen in secondary endpoints of infarct size, electrocardiographic ST-segment recovery AUC or time to stable ST recovery, or left ventricular ejection fraction at 3 months. No differences in rates of adjudicated clinical endpoints (death, heart failure, or serious ventricular arrhythmias) were observed. Conclusions Selective inhibition of delta-PKC with intravenous infusion of delcasertib during PCI for acute STEMI in a population of patients treated according to contemporary standard of care did not reduce biomarkers of myocardial injury.
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6.
  • McGinn, Steven, et al. (författare)
  • New Technologies for DNA analysis-A review of the READNA Project.
  • Ingår i: New Biotechnology. - : Elsevier. - 1876-4347 .- 1871-6784. ; 33:3, s. 311-330
  • Forskningsöversikt (refereegranskat)abstract
    • The REvolutionary Approaches and Devices for Nucleic Acid analysis (READNA) project received funding from the European Commission for 4 1/2 years. The objectives of the project revolved around technological developments in nucleic acid analysis. The project partners have discovered, created and developed a huge body of insights into nucleic acid analysis, ranging from improvements and implementation of current technologies to the most promising sequencing technologies that constitute a 3(rd) and 4(th) generation of sequencing methods with nanopores and in situ sequencing, respectively.
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7.
  • Petroff, E., et al. (författare)
  • A polarized fast radio burst at low Galactic latitude
  • 2017
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 469:4, s. 4465-4482
  • Tidskriftsartikel (refereegranskat)abstract
    • We report on the discovery of a new fast radio burst (FRB), FRB 150215, with the Parkes radio telescope on 2015 February 15. The burst was detected in real time with a dispersion measure (DM) of 1105.6 +/- 0.8 pc cm(-3), a pulse duration of 2.8(-0.5)(+1.2) ms, and a measured peak flux density assuming that the burst was at beam centre of 0.7(-0.1)(+0.2) Jy. The FRB originated at a Galactic longitude and latitude of 24.66 degrees, 5.28 degrees and 25 degrees away from the Galactic Center. The burst was found to be 43 +/- 5 per cent linearly polarized with a rotation measure (RM) in the range -9 < RM < 12 rad m(-2) (95 per cent confidence level), consistent with zero. The burst was followed up with 11 telescopes to search for radio, optical, X-ray, gamma-ray and neutrino emission. Neither transient nor variable emission was found to be associated with the burst and no repeat pulses have been observed in 17.25 h of observing. The sightline to the burst is close to the Galactic plane and the observed physical properties of FRB 150215 demonstrate the existence of sight lines of anomalously low RM for a given electron column density. The Galactic RM foreground may approach a null value due to magnetic field reversals along the line of sight, a decreased total electron column density from the Milky Way, or some combination of these effects. A lower Galactic DM contribution might explain why this burst was detectable whereas previous searches at low latitude have had lower detection rates than those out of the plane.
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8.
  • Abdalla, H., et al. (författare)
  • Gamma-ray blazar spectra with HESS II mono analysis : The case of PKS2155-304 and PG1553+113
  • 2017
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 600
  • Tidskriftsartikel (refereegranskat)abstract
    • Context. The addition of a 28 m Cherenkov telescope (CT5) to the H.E.S.S. array extended the experiment's sensitivity to lower energies. The lowest energy threshold is obtained using monoscopic analysis of data taken with CT5, providing access to gamma-ray energies below 100 GeV for small zenith angle observations. Such an extension of the instrument's energy range is particularly beneficial for studies of active galactic nuclei with soft spectra, as expected for those at a redshift >= 0.5. The high-frequency peaked BL Lac objects PKS 2155-304 (z = 0.116) and PG 1553 + 113 (0.43 < z < 0.58) are among the brightest objects in the gamma-ray sky, both showing clear signatures of gamma-ray absorption at E > 100 GeV interpreted as being due to interactions with the extragalactic background light (EBL). Aims. The aims of this work are twofold: to demonstrate the monoscopic analysis of CT5 data with a low energy threshold, and to obtain accurate measurements of the spectral energy distributions (SED) of PKS 2155-304 and PG 1553 + 113 near their SED peaks at energies approximate to 100 GeV. Methods. Multiple observational campaigns of PKS 2155 304 and PG 1553 + 113 were conducted during 2013 and 2014 using the full H.E.S.S. II instrument (CT1-5). A monoscopic analysis of the data taken with the new CT5 telescope was developed along with an investigation into the systematic uncertainties on the spectral parameters which are derived from this analysis. Results. Using the data from CT5, the energy spectra of PKS 2155 304 and PG 1553 + 113 were reconstructed down to conservative threshold energies of 80 GeV for PKS 2155 304, which transits near zenith, and 110 GeV for the more northern PG 1553 + 113. The measured spectra, well fitted in both cases by a log-parabola spectral model ( with a 5.0 similar to statistical preference for non-zero curvature for PKS 2155 304 and 4.5 sigma for PG 1553+113), were found consistent with spectra derived from contemporaneous Fermi-LAT data, indicating a sharp break in the observed spectra of both sources at E approximate to 100 GeV. When corrected for EBL absorption, the intrinsic H.E.S.S. II mono and Fermi-LAT spectrum of PKS 2155 304 was found to show significant curvature. For PG 1553+113, however, no significant detection of curvature in the intrinsic spectrum could be found within statistical and systematic uncertainties.
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9.
  • Abdalla, H., et al. (författare)
  • HESS discovery of very high energy gamma-ray emission from PKS 0625-354
  • 2018
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 476:3, s. 4187-4198
  • Tidskriftsartikel (refereegranskat)abstract
    • PKS 0625-354 (z = 0.055) was observed with the four High Energy Stereoscopic System (H.E.S.S.) telescopes in 2012 during 5.5 h. The source was detected above an energy threshold of 200 GeV at a significance level of 6.1 sigma. No significant variability is found in these observations. The source is well described with a power-law spectrum with photon index Gamma = 2.84 +/- 0.50(stat) +/- 0.10(syst) and normalization (at E-0 = 1.0 TeV) N-0(E-0)=(0.58 +/- 0.22(stat) +/- 0.12(syst)) x 10(-12) TeV-1 cm(-2) s(-1). Multiwavelength data collected with Fermi-LAT, Swift-XRT, Swift-UVOT, ATOM and WISE are also analysed. Significant variability is observed only in the Fermi-LAT gamma-ray and Swift-XRT X-ray energy bands. Having a good multiwavelength coverage from radio to very high energy, we performed a broad-band modelling from two types of emission scenarios. The results from a one zone lepto-hadronic and a multizone leptonic models are compared and discussed. On the grounds of energetics, our analysis favours a leptonic multizone model. Models associated to the X-ray variability constraint support previous results, suggesting a BL Lac nature of PKS 0625-354 with, however, a large-scale jet structure typical of a radio galaxy.
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10.
  • Abdalla, H., et al. (författare)
  • Simultaneous observations of the blazar PKS 2155-304 from ultra-violet to TeV energies
  • 2020
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 639, s. 1-13
  • Tidskriftsartikel (refereegranskat)abstract
    • Here we report the results of the first ever contemporaneous multi-wavelength observation campaign on the BL Lac object PKS 2155-304 involving Swift, NuSTAR, Fermi-LAT, and H.E.S.S. The use of these instruments allows us to cover a broad energy range, which is important for disentangling the different radiative mechanisms. The source, observed from June 2013 to October 2013, was found in a low flux state with respect to previous observations but exhibited highly significant flux variability in the X-rays. The high-energy end of the synchrotron spectrum can be traced up to 40 keV without significant contamination by high-energy emission. A one-zone synchrotron self-Compton model was used to reproduce the broadband flux of the source for all the observations presented here but failed for previous observations made in April 2013. A lepto-hadronic solution was then explored to explain these earlier observational results.
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