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| 2. |
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| 3. |
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| 4. |
- Aaltonen, T., et al.
(författare)
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Combination of Tevatron Searches for the Standard Model Higgs Boson in the W+W- Decay Mode
- 2010
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 104:6, s. 061802-
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Tidskriftsartikel (refereegranskat)abstract
- We combine searches by the CDF and D0 Collaborations for a Higgs boson decaying to W+W-. The data correspond to an integrated total luminosity of 4.8 (CDF) and 5.4 (D0) fb(-1) of p (p) over bar collisions at root s = 1.96 TeV at the Fermilab Tevatron collider. No excess is observed above background expectation, and resulting limits on Higgs boson production exclude a standard model Higgs boson in the mass range 162-166 GeV at the 95% C.L.
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| 5. |
- Aaltonen, T., et al.
(författare)
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Combination of CDF and D0 measurements of the W boson helicity in top quark decays
- 2012
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Ingår i: Physical Review D. - 1550-7998 .- 1550-2368. ; 85:7, s. 071106-
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Tidskriftsartikel (refereegranskat)abstract
- We report the combination of recent measurements of the helicity of the W boson from top quark decay by the CDF and D0 collaborations, based on data samples corresponding to integrated luminosities of 2.7-5.4 fb(-1) of p (p) over bar collisions collected during Run II of the Fermilab Tevatron collider. Combining measurements that simultaneously determine the fractions of W bosons with longitudinal (f(0)) and right-handed (f(+)) helicities, we find f(0) = 0.722 +/- 0.081[+/- 0.062(stat) +/- 0.052(syst)] and f(+) = -0.033 +/- 0.046[+/- 0.034(stat) +/- 0.031(syst)]. Combining measurements where one of the helicity fractions is fixed to the value expected in the standard model, we find f(0) = 0.682 +/- 0.057[+/- 0.035(stat) +/- 0.046(syst)] for fixed f(+) and f(+) = -0.015 +/- 0.035[+/- 0.018(stat) +/- 0.030(syst)] for fixed f(0). The results are consistent with standard model expectations.
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| 6. |
- Aaltonen, T., et al.
(författare)
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Evidence for a Particle Produced in Association with Weak Bosons and Decaying to a Bottom-Antibottom Quark Pair in Higgs Boson Searches at the Tevatron
- 2012
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 109:7, s. 071804-
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Tidskriftsartikel (refereegranskat)abstract
- We combine searches by the CDF and D0 Collaborations for the associated production of a Higgs boson with a W or Z boson and subsequent decay of the Higgs boson to a bottom-antibottom quark pair. The data, originating from Fermilab Tevatron p (p) over bar collisions at root s = 1.96 TeV, correspond to integrated luminosities of up to 9.7 fb(-1). The searches are conducted for a Higgs boson with mass in the range 100-150 GeV/c(2). We observe an excess of events in the data compared with the background predictions, which is most significant in the mass range between 120 and 135 GeV/c(2). The largest local significance is 3.3 standard deviations, corresponding to a global significance of 3.1 standard deviations. We interpret this as evidence for the presence of a new particle consistent with the standard model Higgs boson, which is produced in association with a weak vector boson and decays to a bottom-antibottom quark pair.
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| 7. |
- Aaltonen, T., et al.
(författare)
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Tevatron Run II combination of the effective leptonic electroweak mixing angle
- 2018
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Ingår i: Physical Review D. - : AMER PHYSICAL SOC. - 2470-0010 .- 2470-0029. ; 97:11
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Tidskriftsartikel (refereegranskat)abstract
- Drell-Yan lepton pairs produced in the process p (p) over bar -> l(+)l(-) + X through an intermediate gamma*/Z boson have an asymmetry in their angular distribution related to the spontaneous symmetry breaking of the electroweak force and the associated mixing of its neutral gauge bosons. The CDF and D0 experiments have measured the effective-leptonic electroweak mixing parameter sin(2) theta(lept)(eff) using electron and muon pairs selected from the full Tevatron proton-antiproton data sets collected in 2001-2011, corresponding to 9-10 fb(-1) of integrated luminosity. The combination of these measurements yields the most precise result from hadron colliders, sin(2)theta(lept)(eff) = 0.23148 +/- 0.00033. This result is consistent with, and approaches in precision, the best measurements from electron-positron colliders. The standard model inference of the on-shell electroweak mixing parameter sin(2) theta(W), or equivalently the W-boson mass M-W, using the ZFITTER software package yields sin(2) theta(W) = 0.22324 +/- 0.00033 or equivalently, M-W = 80.367 +/- 0.017 GeV/c(2).
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| 8. |
- Aaltonen, T., et al.
(författare)
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Combined Forward-Backward Asymmetry Measurements in Top-Antitop Quark Production at the Tevatron
- 2018
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Ingår i: Physical Review Letters. - : AMER PHYSICAL SOC. - 0031-9007 .- 1079-7114. ; 120:4
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Tidskriftsartikel (refereegranskat)abstract
- The CDF and D0 experiments at the Fermilab Tevatron have measured the asymmetry between yields of forward- and backward-produced top and antitop quarks based on their rapidity difference and the asymmetry between their decay leptons. These measurements use the full data sets collected in proton-antiproton collisions at a center-of-mass energy of root s = 1.96 TeV. We report the results of combinations of the inclusive asymmetries and their differential dependencies on relevant kinematic quantities. The combined inclusive asymmetry is A(FB)(t (t) over bar) = 0.128 +/- 0.025. The combined inclusive and differential asymmetries are consistent with recent standard model predictions.
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| 9. |
- Aaltonen, T., et al.
(författare)
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Combination of CDF and D0 W-Boson mass measurements
- 2013
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Ingår i: Physical Review D. - 1550-7998 .- 1550-2368. ; 88:5, s. 052018-
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Tidskriftsartikel (refereegranskat)abstract
- We summarize and combine direct measurements of the mass of the W boson in root s = 1.96 TeV proton-antiproton collision data collected by CDF and D0 experiments at the Fermilab Tevatron Collider. Earlier measurements from CDF and D0 are combined with the two latest, more precise measurements: a CDF measurement in the electron and muon channels using data corresponding to 2.2 fb(-1) of integrated luminosity, and a D0 measurement in the electron channel using data corresponding to 4.3 fb(-1) of integrated luminosity. The resulting Tevatron average for the mass of the W boson is M-W = 80387 +/- 16 MeV. Including measurements obtained in electron-positron collisions at LEP yields the most precise value of M-W = 80385 +/- 15 MeV.
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| 10. |
- Aaltonen, T., et al.
(författare)
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Combination of measurements of the top-quark pair production cross section from the Tevatron Collider
- 2014
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Ingår i: Physical Review D. - 1550-7998 .- 1550-2368. ; 89:7
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Tidskriftsartikel (refereegranskat)abstract
- We combine six measurements of the inclusive top-quark pair (t(sic)) production cross section (sigma(t)(sic)) from data collected with the CDF and D0 detectors at the Fermilab Tevatron with proton-antiproton collisions at root s = 1.96 TeV. The data correspond to integrated luminosities of up to 8.8 fb(-1). We obtain a value of sigma tt = 7.60 +/- 0.41 pb for a top-quark mass of m(t) = 172.5 GeV. The contributions to the uncertainty are 0.20 pb from statistical sources, 0.29 pb from systematic sources, and 0.21 pb from the uncertainty on the integrated luminosity. The result is in good agreement with the standard model expectation of 7.35(-0.33)(+0.28) pb at next-to-next-to-leading order and next-to-next-to leading logarithms in perturbative QCD.
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| 11. |
- Aaltonen, T., et al.
(författare)
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Higgs boson studies at the Tevatron
- 2013
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Ingår i: Physical Review D. - 1550-7998 .- 1550-2368. ; 88:5, s. 052014-
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Tidskriftsartikel (refereegranskat)abstract
- We combine searches by the CDF and D0 Collaborations for the standard model Higgs boson with mass in the range 90-200 GeV/c(2) produced in the gluon-gluon fusion, WH, ZH, t (t) over barH, and vector boson fusion processes, and decaying in the H -> b (b) over bar, H -> W+W-, H -> ZZ, H -> tau(+)tau(-), and H -> gamma gamma modes. The data correspond to integrated luminosities of up to 10 fb(-1) and were collected at the Fermilab Tevatron in p (p) over bar collisions at root s = 1.96 TeV. The searches are also interpreted in the context of fermiophobic and fourth generation models. We observe a significant excess of events in the mass range between 115 and 140 GeV/c(2). The local significance corresponds to 3.0 standard deviations at m(H) = 125 GeV/c(2), consistent with the mass of the Higgs boson observed at the LHC, and we expect a local significance of 1.9 standard deviations. We separately combine searches for H -> b (b) over bar, H -> W+W-, H -> tau(+)tau(-), and H -> gamma gamma. The observed signal strengths in all channels are consistent with the presence of a standard model Higgs boson with a mass of 125 GeV/c(2).
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| 12. |
- Aaltonen, T., et al.
(författare)
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Observation of s-Channel Production of Single Top Quarks at the Tevatron
- 2014
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 112:23
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Tidskriftsartikel (refereegranskat)abstract
- We report the first observation of single-top-quark production in the s channel through the combination of the CDF and D0 measurements of the cross section in proton-antiproton collisions at a center-of-mass energy of 1.96 TeV. The data correspond to total integrated luminosities of up to 9.7 fb(-1) per experiment. The measured cross section is sigma(s) = 1.29(-0.24)(+0.26) pb. The probability of observing a statistical fluctuation of the background to a cross section of the observed size or larger is 1.8 x 10(-10), corresponding to a significance of 6.3 standard deviations for the presence of an s-channel contribution to the production of single-top quarks.
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| 13. |
- Aaltonen, T., et al.
(författare)
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Tevatron Combination of Single-Top-Quark Cross Sections and Determination of the Magnitude of the Cabibbo-Kobayashi-Maskawa Matrix Element V-tb
- 2015
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 115:15
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Tidskriftsartikel (refereegranskat)abstract
- We present the final combination of CDF and D0 measurements of cross sections for single-top-quark production in proton-antiproton collisions at a center-of-mass energy of 1.96 TeV. The data correspond to total integrated luminosities of up to 9.7 fb(-1) per experiment. The t-channel cross section is measured to be sigma(t) = 2.25(-0.31)(+0.29) pb. We also present the combinations of the two-dimensional measurements of the s- vs t-channel cross section. In addition, we give the combination of the s + t channel cross section measurement resulting in sigma(s+t) = 3.30(-0.40)(+0.52) pb, without assuming the standard model value for the ratio sigma(s)/sigma(t). The resulting value of the magnitude of the top-to-bottom quark coupling is vertical bar V-tb vertical bar = 1.02(-0.05)(+0.06), corresponding to vertical bar V-tb vertical bar > 0.92 at the 95% C. L.
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| 14. |
- Aaltonen, T., et al.
(författare)
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Tevatron Constraints on Models of the Higgs Boson with Exotic Spin and Parity Using Decays to Bottom-Antibottom Quark Pairs
- 2015
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Ingår i: Physical Review Letters. - 0031-9007 .- 1079-7114. ; 114:15
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Tidskriftsartikel (refereegranskat)abstract
- Combined constraints from the CDF and D0 Collaborations on models of the Higgs boson with exotic spin J and parity P are presented and compared with results obtained assuming the standard model value J(P) = 0(+). Both collaborations analyzed approximately 10 fb(-1) of proton-antiproton collisions with a center-of-mass energy of 1.96 TeV collected at the Fermilab Tevatron. Two models predicting exotic Higgs bosons with J(P) = 0(-) and J(P) = 2(+) are tested. The kinematic properties of exotic Higgs boson production in association with a vector boson differ from those predicted for the standard model Higgs boson. Upper limits at the 95% credibility level on the production rates of the exotic Higgs bosons, expressed as fractions of the standard model Higgs boson production rate, are set at 0.36 for both the J(P) = 0(-) hypothesis and the J(P) = 2(+) hypothesis. If the production rate times the branching ratio to a bottom-antibottom pair is the same as that predicted for the standard model Higgs boson, then the exotic bosons are excluded with significances of 5.0 standard deviations and 4.9 standard deviations for the J(P) = 0(-) and J(P) = 2(+) hypotheses, respectively.
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| 15. |
- Figlioli, G, et al.
(författare)
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The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer
- 2019
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Ingår i: NPJ breast cancer. - : Springer Science and Business Media LLC. - 2374-4677. ; 5, s. 38-
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors.
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| 16. |
- Georgiev, Boris, et al.
(författare)
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A Universal Power-law Prescription for Variability from Synthetic Images of Black Hole Accretion Flows
- 2022
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
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Tidskriftsartikel (refereegranskat)abstract
- We present a framework for characterizing the spatiotemporal power spectrum of the variability expected from the horizon-scale emission structure around supermassive black holes, and we apply this framework to a library of general relativistic magnetohydrodynamic (GRMHD) simulations and associated general relativistic ray-traced images relevant for Event Horizon Telescope (EHT) observations of Sgr A*. We find that the variability power spectrum is generically a red-noise process in both the temporal and spatial dimensions, with the peak in power occurring on the longest timescales and largest spatial scales. When both the time-averaged source structure and the spatially integrated light-curve variability are removed, the residual power spectrum exhibits a universal broken power-law behavior. On small spatial frequencies, the residual power spectrum rises as the square of the spatial frequency and is proportional to the variance in the centroid of emission. Beyond some peak in variability power, the residual power spectrum falls as that of the time-averaged source structure, which is similar across simulations; this behavior can be naturally explained if the variability arises from a multiplicative random field that has a steeper high-frequency power-law index than that of the time-averaged source structure. We briefly explore the ability of power spectral variability studies to constrain physical parameters relevant for the GRMHD simulations, which can be scaled to provide predictions for black holes in a range of systems in the optically thin regime. We present specific expectations for the behavior of the M87* and Sgr A* accretion flows as observed by the EHT.
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| 17. |
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| 18. |
- Paraschos, Georgios Filippos, et al.
(författare)
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Ordered magnetic fields around the 3C 84 central black hole
- 2024
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Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 682
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Tidskriftsartikel (refereegranskat)abstract
- Context . 3C 84 is a nearby radio source with a complex total intensity structure, showing linear polarisation and spectral patterns. A detailed investigation of the central engine region necessitates the use of very-long-baseline interferometry (VLBI) above the hitherto available maximum frequency of 86 GHz. Aims. Using ultrahigh resolution VLBI observations at the currently highest available frequency of 228 GHz, we aim to perform a direct detection of compact structures and understand the physical conditions in the compact region of 3C 84. Methods . We used Event Horizon Telescope (EHT) 228 GHz observations and, given the limited (u, v)-coverage, applied geometric model fitting to the data. Furthermore, we employed quasi-simultaneously observed, ancillary multi-frequency VLBI data for the source in order to carry out a comprehensive analysis of the core structure. Results . We report the detection of a highly ordered, strong magnetic field around the central, supermassive black hole of 3C 84. The brightness temperature analysis suggests that the system is in equipartition. We also determined a turnover frequency of νm = (113 ± 4) GHz, a corresponding synchrotron self-absorbed magnetic field of BSSA = (2.9 ± 1.6) G, and an equipartition magnetic field of Beq = (5.2 ± 0.6) G. Three components are resolved with the highest fractional polarisation detected for this object (mnet = (17.0 ± 3.9)%). The positions of the components are compatible with those seen in low-frequency VLBI observations since 2017-2018. We report a steeply negative slope of the spectrum at 228 GHz. We used these findings to test existing models of jet formation, propagation, and Faraday rotation in 3C 84. Conclusions . The findings of our investigation into different flow geometries and black hole spins support an advection-dominated accretion flow in a magnetically arrested state around a rapidly rotating supermassive black hole as a model of the jet-launching system in the core of 3C 84. However, systematic uncertainties due to the limited (u, v)-coverage, however, cannot be ignored. Our upcoming work using new EHT data, which offer full imaging capabilities, will shed more light on the compact region of 3C 84.
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| 19. |
- Roelofs, F., et al.
(författare)
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Polarimetric Geometric Modeling for mm-VLBI Observations of Black Holes
- 2023
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Ingår i: Astrophysical Journal Letters. - 2041-8213 .- 2041-8205. ; 957:2
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Tidskriftsartikel (refereegranskat)abstract
- The Event Horizon Telescope (EHT) is a millimeter very long baseline interferometry (VLBI) array that has imaged the apparent shadows of the supermassive black holes M87* and Sagittarius A*. Polarimetric data from these observations contain a wealth of information on the black hole and accretion flow properties. In this work, we develop polarimetric geometric modeling methods for mm-VLBI data, focusing on approaches that fit data products with differing degrees of invariance to broad classes of calibration errors. We establish a fitting procedure using a polarimetric “m-ring” model to approximate the image structure near a black hole. By fitting this model to synthetic EHT data from general relativistic magnetohydrodynamic models, we show that the linear and circular polarization structure can be successfully approximated with relatively few model parameters. We then fit this model to EHT observations of M87* taken in 2017. In total intensity and linear polarization, the m-ring fits are consistent with previous results from imaging methods. In circular polarization, the m-ring fits indicate the presence of event-horizon-scale circular polarization structure, with a persistent dipolar asymmetry and orientation across several days. The same structure was recovered independently of observing band, used data products, and model assumptions. Despite this broad agreement, imaging methods do not produce similarly consistent results. Our circular polarization results, which imposed additional assumptions on the source structure, should thus be interpreted with some caution. Polarimetric geometric modeling provides a useful and powerful method to constrain the properties of horizon-scale polarized emission, particularly for sparse arrays like the EHT.
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| 20. |
- Akiyama, Kazunori, et al.
(författare)
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First M87 Event Horizon Telescope Results. IX. Detection of Near-horizon Circular Polarization
- 2023
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Ingår i: Astrophysical Journal Letters. - 2041-8213 .- 2041-8205. ; 957:2
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Tidskriftsartikel (refereegranskat)abstract
- Event Horizon Telescope (EHT) observations have revealed a bright ring of emission around the supermassive black hole at the center of the M87 galaxy. EHT images in linear polarization have further identified a coherent spiral pattern around the black hole, produced from ordered magnetic fields threading the emitting plasma. Here we present the first analysis of circular polarization using EHT data, acquired in 2017, which can potentially provide additional insights into the magnetic fields and plasma composition near the black hole. Interferometric closure quantities provide convincing evidence for the presence of circularly polarized emission on event-horizon scales. We produce images of the circular polarization using both traditional and newly developed methods. All methods find a moderate level of resolved circular polarization across the image (〈|v|〉 < 3.7%), consistent with the low image-integrated circular polarization fraction measured by the Atacama Large Millimeter/submillimeter Array (|vint| < 1%). Despite this broad agreement, the methods show substantial variation in the morphology of the circularly polarized emission, indicating that our conclusions are strongly dependent on the imaging assumptions because of the limited baseline coverage, uncertain telescope gain calibration, and weakly polarized signal. We include this upper limit in an updated comparison to general relativistic magnetohydrodynamic simulation models. This analysis reinforces the previously reported preference for magnetically arrested accretion flow models. We find that most simulations naturally produce a low level of circular polarization consistent with our upper limit and that Faraday conversion is likely the dominant production mechanism for circular polarization at 230 GHz in M87*
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| 21. |
- Akiyama, Kazunori, et al.
(författare)
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First Sagittarius A∗ Event Horizon Telescope Results. VII. Polarization of the Ring
- 2024
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Ingår i: Astrophysical Journal Letters. - 2041-8213 .- 2041-8205. ; 964:2
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Tidskriftsartikel (refereegranskat)abstract
- The Event Horizon Telescope observed the horizon-scale synchrotron emission region around the Galactic center supermassive black hole, Sagittarius A∗ (Sgr A∗), in 2017. These observations revealed a bright, thick ring morphology with a diameter of 51.8 ± 2.3 μas and modest azimuthal brightness asymmetry, consistent with the expected appearance of a black hole with mass M≈ 4 × 106 M⊙. From these observations, we present the first resolved linear and circular polarimetric images of Sgr A∗. The linear polarization images demonstrate that the emission ring is highly polarized, exhibiting a prominent spiral electric vector polarization angle pattern with a peak fractional polarization of ∼40% in the western portion of the ring. The circular polarization images feature a modestly (∼5%°-10%) polarized dipole structure along the emission ring, with negative circular polarization in the western region and positive circular polarization in the eastern region, although our methods exhibit stronger disagreement than for linear polarization. We analyze the data using multiple independent imaging and modeling methods, each of which is validated using a standardized suite of synthetic data sets. While the detailed spatial distribution of the linear polarization along the ring remains uncertain owing to the intrinsic variability of the source, the spiraling polarization structure is robust to methodological choices. The degree and orientation of the linear polarization provide stringent constraints for the black hole and its surrounding magnetic fields, which we discuss in an accompanying publication.
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| 22. |
- Akiyama, Kazunori, et al.
(författare)
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First Sagittarius A∗ Event Horizon Telescope Results. VIII. Physical Interpretation of the Polarized Ring
- 2024
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Ingår i: Astrophysical Journal Letters. - 2041-8213 .- 2041-8205. ; 964:2
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Tidskriftsartikel (refereegranskat)abstract
- In a companion paper, we present the first spatially resolved polarized image of Sagittarius A∗ on event horizon scales, captured using the Event Horizon Telescope, a global very long baseline interferometric array operating at a wavelength of 1.3 mm. Here we interpret this image using both simple analytic models and numerical general relativistic magnetohydrodynamic (GRMHD) simulations. The large spatially resolved linear polarization fraction (24%-28%, peaking at ∼40%) is the most stringent constraint on parameter space, disfavoring models that are too Faraday depolarized. Similar to our studies of M87∗, polarimetric constraints reinforce a preference for GRMHD models with dynamically important magnetic fields. Although the spiral morphology of the polarization pattern is known to constrain the spin and inclination angle, the time-variable rotation measure (RM) of Sgr A∗ (equivalent to ≈ 46° ± 12° rotation at 228 GHz) limits its present utility as a constraint. If we attribute the RM to internal Faraday rotation, then the motion of accreting material is inferred to be counterclockwise, contrary to inferences based on historical polarized flares, and no model satisfies all polarimetric and total intensity constraints. On the other hand, if we attribute the mean RM to an external Faraday screen, then the motion of accreting material is inferred to be clockwise, and one model passes all applied total intensity and polarimetric constraints: a model with strong magnetic fields, a spin parameter of 0.94, and an inclination of 150°. We discuss how future 345 GHz and dynamical imaging will mitigate our present uncertainties and provide additional constraints on the black hole and its accretion flow.
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| 23. |
- Mueller, Stefanie H., et al.
(författare)
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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
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Ingår i: Genome Medicine. - : BioMed Central (BMC). - 1756-994X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
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| 24. |
- Akiyama, Kazunori, et al.
(författare)
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First Sagittarius A * Event Horizon Telescope Results. I. The Shadow of the Supermassive Black Hole in the Center of the Milky Way
- 2022
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
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Tidskriftsartikel (refereegranskat)abstract
- We present the first Event Horizon Telescope (EHT) observations of Sagittarius A* (Sgr A*), the Galactic center source associated with a supermassive black hole. These observations were conducted in 2017 using a global interferometric array of eight telescopes operating at a wavelength of λ = 1.3 mm. The EHT data resolve a compact emission region with intrahour variability. A variety of imaging and modeling analyses all support an image that is dominated by a bright, thick ring with a diameter of 51.8 ± 2.3 μas (68% credible interval). The ring has modest azimuthal brightness asymmetry and a comparatively dim interior. Using a large suite of numerical simulations, we demonstrate that the EHT images of Sgr A* are consistent with the expected appearance of a Kerr black hole with mass ∼4 × 106 M☉, which is inferred to exist at this location based on previous infrared observations of individual stellar orbits, as well as maser proper-motion studies. Our model comparisons disfavor scenarios where the black hole is viewed at high inclination (i > 50°), as well as nonspinning black holes and those with retrograde accretion disks. Our results provide direct evidence for the presence of a supermassive black hole at the center of the Milky Way, and for the first time we connect the predictions from dynamical measurements of stellar orbits on scales of 103-105 gravitational radii to event-horizon-scale images and variability. Furthermore, a comparison with the EHT results for the supermassive black hole M87* shows consistency with the predictions of general relativity spanning over three orders of magnitude in central mass.
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| 25. |
- Akiyama, Kazunori, et al.
(författare)
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The persistent shadow of the supermassive black hole of M 87: I. Observations, calibration, imaging, and analysis*
- 2024
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Ingår i: Astronomy and Astrophysics. - 0004-6361 .- 1432-0746. ; 681
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Tidskriftsartikel (refereegranskat)abstract
- In April 2019, the Event Horizon Telescope (EHT) Collaboration reported the first-ever event-horizon-scale images of a black hole, resolving the central compact radio source in the giant elliptical galaxy M 87. These images reveal a ring with a southerly brightness distribution and a diameter of ∼42 μas, consistent with the predicted size and shape of a shadow produced by the gravitationally lensed emission around a supermassive black hole. These results were obtained as part of the April 2017 EHT observation campaign, using a global very long baseline interferometric radio array operating at a wavelength of 1.3 mm. Here, we present results based on the second EHT observing campaign, taking place in April 2018 with an improved array, wider frequency coverage, and increased bandwidth. In particular, the additional baselines provided by the Greenland telescope improved the coverage of the array. Multiyear EHT observations provide independent snapshots of the horizon-scale emission, allowing us to confirm the persistence, size, and shape of the black hole shadow, and constrain the intrinsic structural variability of the accretion flow. We have confirmed the presence of an asymmetric ring structure, brighter in the southwest, with a median diameter of 43.3-3.1+1.5 μas. The diameter of the 2018 ring is remarkably consistent with the diameter obtained from the previous 2017 observations. On the other hand, the position angle of the brightness asymmetry in 2018 is shifted by about 30 relative to 2017. The perennial persistence of the ring and its diameter robustly support the interpretation that the ring is formed by lensed emission surrounding a Kerr black hole with a mass ∼6.5× 109M. The significant change in the ring brightness asymmetry implies a spin axis that is more consistent with the position angle of the large-scale jet.
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| 26. |
- Eatough, Ralph P., et al.
(författare)
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Verification of Radiative Transfer Schemes for the EHT
- 2020
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 897:2
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Tidskriftsartikel (refereegranskat)abstract
- The Event Horizon Telescope (EHT) Collaboration has recently produced the first resolved images of the central supermassive black hole in the giant elliptical galaxy M87. Here we report on tests of the consistency and accuracy of the general relativistic radiative transfer codes used within the collaboration to model M87∗ and Sgr A∗. We compare and evaluate (1) deflection angles for equatorial null geodesics in a Kerr spacetime; (2) images calculated from a series of simple, parameterized matter distributions in the Kerr metric using simplified emissivities and absorptivities; (3) for a subset of codes, images calculated from general relativistic magnetohydrodynamics simulations using different realistic synchrotron emissivities and absorptivities; (4) observables for the 2017 configuration of EHT, including visibility amplitudes and closure phases. The error in total flux is of order 1% when the codes are run with production numerical parameters. The dominant source of discrepancies for small camera distances is the location and detailed setup of the software "camera"that each code uses to produce synthetic images. We find that when numerical parameters are suitably chosen and the camera is sufficiently far away the images converge and that for given transfer coefficients, numerical uncertainties are unlikely to limit parameter estimation for the current generation of EHT observations. The purpose of this paper is to describe a verification and comparison of EHT radiative transfer codes. It is not to verify EHT models more generally.
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| 27. |
- Holmqvist, Fredrik, et al.
(författare)
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Heart rate is associated with progression of atrial fibrillation, independent of rhythm
- 2015
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Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 101:11, s. 894-899
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Tidskriftsartikel (refereegranskat)abstract
- Objective Atrial fibrillation (AF) often progresses from paroxysmal or persistent to more sustained forms, but the rate and predictors of AF progression in clinical practice are not well described. Methods Using the Outcomes Registry for Better Informed Treatment of AF, we analysed the incidence and predictors of progression and tested the discrimination and calibration of the HATCH (hypertension, age, TIA/stroke, chronic obstructive pulmonary disease, heart failure) and CHA(2)DS(2)VASc scores for identifying AF progression. Results Among 6235 patients with paroxysmal or persistent AF at baseline, 1479 progressed, during follow-up (median 18 (IQR 12-24) months). These patients were older and had more comorbidities than patients who did not progress (CHADS(2) 2.3 +/- 1.3 vs 2.1 +/- 1.3, p<0.0001). At baseline, patients with AF progression were more often on a rate control as opposed to a rhythm control strategy (66 vs 56%, p<0.0001) and had higher heart rate (72(64-80) vs 68 (60-76) bpm, p<0.0001). The strongest predictors of AF progression were AF on the baseline ECG (OR 2.30, 95% CI 1.95 to 2.73, p<0.0001) and increasing age (OR 1.16, 95% CI1.09 to 1.24, p<0.0001, per 10 increase), while patients with lower heart rate (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001, per 10 decrease <= 80) were less likely to progress. There was no significant interaction between rhythm on baseline ECG and heart rate (p=0.71). The HATCH and CHA(2)DS(2)VASc scores had modest discriminatory power for AF progression (C-indices 0.55 (95% CI 0.53 to 0.58) and 0.55 (95% CI 0.52 to 0.57)). Conclusions Within 1.5 years, almost a quarter of the patients with paroxysmal or persistent AF progress to a more sustained form. Progression is strongly associated with heart rate, and age.
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| 28. |
- Jorstad, S.G., et al.
(författare)
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The Event Horizon Telescope Image of the Quasar NRAO 530
- 2023
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 943:2
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Tidskriftsartikel (refereegranskat)abstract
- We report on the observations of the quasar NRAO 530 with the Event Horizon Telescope (EHT) on 2017 April 5-7, when NRAO 530 was used as a calibrator for the EHT observations of Sagittarius A*. At z = 0.902, this is the most distant object imaged by the EHT so far. We reconstruct the first images of the source at 230 GHz, at an unprecedented angular resolution of similar to 20 mu as, both in total intensity and in linear polarization (LP). We do not detect source variability, allowing us to represent the whole data set with static images. The images reveal a bright feature located on the southern end of the jet, which we associate with the core. The feature is linearly polarized, with a fractional polarization of similar to 5%-8%, and it has a substructure consisting of two components. Their observed brightness temperature suggests that the energy density of the jet is dominated by the magnetic field. The jet extends over 60 mu as along a position angle similar to -28 degrees. It includes two features with orthogonal directions of polarization (electric vector position angle), parallel and perpendicular to the jet axis, consistent with a helical structure of the magnetic field in the jet. The outermost feature has a particularly high degree of LP, suggestive of a nearly uniform magnetic field. Future EHT observations will probe the variability of the jet structure on microarcsecond scales, while simultaneous multiwavelength monitoring will provide insight into the high-energy emission origin.
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| 29. |
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| 30. |
- Torne, Pablo, et al.
(författare)
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A Search for Pulsars around Sgr A* in the First Event Horizon Telescope Data Set
- 2023
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Ingår i: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 959:1
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Tidskriftsartikel (refereegranskat)abstract
- In 2017 the Event Horizon Telescope (EHT) observed the supermassive black hole at the center of the Milky Way, Sagittarius A* (Sgr A*), at a frequency of 228.1 GHz (lambda = 1.3 mm). The fundamental physics tests that even a single pulsar orbiting Sgr A* would enable motivate searching for pulsars in EHT data sets. The high observing frequency means that pulsars-which typically exhibit steep emission spectra-are expected to be very faint. However, it also negates pulse scattering, an effect that could hinder pulsar detections in the Galactic center. Additionally, magnetars or a secondary inverse Compton emission could be stronger at millimeter wavelengths than at lower frequencies. We present a search for pulsars close to Sgr A* using the data from the three most sensitive stations in the EHT 2017 campaign: the Atacama Large Millimeter/submillimeter Array, the Large Millimeter Telescope, and the IRAM 30 m Telescope. We apply three detection methods based on Fourier-domain analysis, the fast folding algorithm, and single-pulse searches targeting both pulsars and burst-like transient emission. We use the simultaneity of the observations to confirm potential candidates. No new pulsars or significant bursts were found. Being the first pulsar search ever carried out at such high radio frequencies, we detail our analysis methods and give a detailed estimation of the sensitivity of the search. We conclude that the EHT 2017 observations are only sensitive to a small fraction (less than or similar to 2.2%) of the pulsars that may exist close to Sgr A*, motivating further searches for fainter pulsars in the region.
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| 31. |
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| 32. |
- Wang, Anqi, et al.
(författare)
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Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants
- 2023
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 55:12, s. 2065-2074
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Tidskriftsartikel (refereegranskat)abstract
- The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.
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| 33. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 34. |
- Akiyama, Kazunori, et al.
(författare)
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First M87 Event Horizon Telescope Results. I. the Shadow of the Supermassive Black Hole
- 2019
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 875:1
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Tidskriftsartikel (refereegranskat)abstract
- When surrounded by a transparent emission region, black holes are expected to reveal a dark shadow caused by gravitational light bending and photon capture at the event horizon. To image and study this phenomenon, we have assembled the Event Horizon Telescope, a global very long baseline interferometry array observing at a wavelength of 1.3 mm. This allows us to reconstruct event-horizon-scale images of the supermassive black hole candidate in the center of the giant elliptical galaxy M87. We have resolved the central compact radio source as an asymmetric bright emission ring with a diameter of 42 ±3 μas, which is circular and encompasses a central depression in brightness with a flux ratio ≈10:1. The emission ring is recovered using different calibration and imaging schemes, with its diameter and width remaining stable over four different observations carried out in different days. Overall, the observed image is consistent with expectations for the shadow of a Kerr black hole as predicted by general relativity. The asymmetry in brightness in the ring can be explained in terms of relativistic beaming of the emission from a plasma rotating close to the speed of light around a black hole. We compare our images to an extensive library of ray-traced general-relativistic magnetohydrodynamic simulations of black holes and derive a central mass of M =(6.5 ±0.7) ×10 9 M o . Our radio-wave observations thus provide powerful evidence for the presence of supermassive black holes in centers of galaxies and as the central engines of active galactic nuclei. They also present a new tool to explore gravity in its most extreme limit and on a mass scale that was so far not accessible.
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| 35. |
- Conti, David, V, et al.
(författare)
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Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
- 2021
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
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Tidskriftsartikel (refereegranskat)abstract
- Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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| 36. |
- Dixon-Suen, Suzanne C, et al.
(författare)
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Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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| 37. |
- Jung, Audrey Y, et al.
(författare)
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Distinct reproductive risk profiles for intrinsic-like breast cancer subtypes : pooled analysis of population-based studies
- 2022
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press. - 0027-8874 .- 1460-2105. ; 114:12, s. 1706-1719
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Reproductive factors have been shown to be differentially associated with risk of estrogen receptor (ER) positive and ER-negative breast cancer. However, their associations with intrinsic-like subtypes are less clear.METHODS: Analyses included up to 23,353 cases, and 71,072 controls pooled from 31 population-based case-control or cohort studies in the Breast Cancer Association Consortium across 16 countries on 4 continents. Polytomous logistic regression was used to estimate the association between reproductive factors and risk of breast cancer by intrinsic-like subtypes (luminal A-like, luminal B-like, luminal B-HER2-like, HER2-enriched-like, and triple-negative) and by invasiveness. All statistical tests were 2-sided.RESULTS: Compared to nulliparous women, parous women had a lower risk of luminal A-like, luminal B-like, luminal B-HER2-like and HER2-enriched-like disease. This association was apparent only after approximately 10 years since last birth and became stronger with increasing time (odds ratio [OR] = 0.59, 95% confidence interval [CI] = 0.49 to 0.71; and OR = 0.36, 95% CI = 0.28 to 0.46; for multiparous women with luminal A-like tumors 20-<25 years after last birth and 45-<50 years after last birth, respectively). In contrast, parous women had a higher risk of triple-negative breast cancer right after their last birth (for multiparous women: OR = 3.12, 95%CI = 2.02 to 4.83) that was attenuated with time but persisted for decades (OR = 1.03, 95%CI = 0.79 to 1.34, for multiparous women 25 to < 30 years after last birth). Older age at first birth (P-heterogeneity<.001 for triple-negative compared to luminal-A like) and breastfeeding (P-heterogeneity<.001 for triple-negative compared to luminal-A like) were associated with lower risk of triple-negative but not with other disease subtypes. Younger age at menarche was associated with higher risk of all subtypes; older age at menopause was associated with higher risk of luminal A-like but not triple-negative breast cancer. Associations for in situ tumors were similar to luminal A-like.CONCLUSION: This large and comprehensive study demonstrates a distinct reproductive risk factor profile for triple-negative breast cancer compared to other subtypes, with implications for the understanding of disease etiology and risk prediction.
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| 38. |
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| 39. |
- Middha, Pooja K., et al.
(författare)
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A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry
- 2023
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Ingår i: Breast Cancer Research. - : BioMed Central (BMC). - 1465-5411 .- 1465-542X. ; 25:1
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Tidskriftsartikel (refereegranskat)abstract
- Background Genome-wide studies of gene-environment interactions (GxE) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide GxE analysis of similar to 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene-environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 x 10(-5) prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92-0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88-0.94). Conclusions Overall, the contribution of GxE interactions to the heritability of breast cancer is very small. At the population level, multiplicative GxE interactions do not make an important contribution to risk prediction in breast cancer.
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| 40. |
- Prather, Ben, et al.
(författare)
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Comparison of Polarized Radiative Transfer Codes Used by the EHT Collaboration
- 2023
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Ingår i: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 950:1
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Tidskriftsartikel (refereegranskat)abstract
- Interpretation of resolved polarized images of black holes by the Event Horizon Telescope (EHT) requires predictions of the polarized emission observable by an Earth-based instrument for a particular model of the black hole accretion system. Such predictions are generated by general relativistic radiative transfer (GRRT) codes, which integrate the equations of polarized radiative transfer in curved spacetime. A selection of ray-tracing GRRT codes used within the EHT Collaboration is evaluated for accuracy and consistency in producing a selection of test images, demonstrating that the various methods and implementations of radiative transfer calculations are highly consistent. When imaging an analytic accretion model, we find that all codes produce images similar within a pixel-wise normalized mean squared error (NMSE) of 0.012 in the worst case. When imaging a snapshot from a cell-based magnetohydrodynamic simulation, we find all test images to be similar within NMSEs of 0.02, 0.04, 0.04, and 0.12 in Stokes I, Q, U, and V, respectively. We additionally find the values of several image metrics relevant to published EHT results to be in agreement to much better precision than measurement uncertainties.
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| 41. |
- Prudencio, Mercedes, et al.
(författare)
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Toward allele-specific targeting therapy and pharmacodynamic marker for spinocerebellar ataxia type 3
- 2020
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6242 .- 1946-6234. ; 12:566
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Tidskriftsartikel (refereegranskat)abstract
- Spinocerebellar ataxia type 3 (SCA3), caused by a CAG repeat expansion in the ataxin-3 gene (ATXN3), is characterized by neuronal polyglutamine (polyQ) ATXN3 protein aggregates. Although there is no cure for SCA3, gene-silencing approaches to reduce toxic polyQ ATXN3 showed promise in preclinical models. However, a major limitation in translating putative treatments for this rare disease to the clinic is the lack of pharmacodynamic markers for use in clinical trials. Here, we developed an immunoassay that readily detects polyQ ATXN3 proteins in human biological fluids and discriminates patients with SCA3 from healthy controls and individuals with other ataxias. We show that polyQ ATXN3 serves as a marker of target engagement in human fibroblasts, which may bode well for its use in clinical trials. Last, we identified a single-nucleotide polymorphism that strongly associates with the expanded allele, thus providing an exciting drug target to abrogate detrimental events initiated by mutant ATXN3. Gene-silencing strategies for several repeat diseases are well under way, and our results are expected to improve clinical trial preparedness for SCA3 therapies.
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| 42. |
- Van Deerlin, Vivian M, et al.
(författare)
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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:3, s. 234-239
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Tidskriftsartikel (refereegranskat)abstract
- Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.
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| 43. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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