| 41. |
- Farah, Joseph, et al.
(författare)
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Selective Dynamical Imaging of Interferometric Data
- 2022
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Ingår i: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Tidskriftsartikel (refereegranskat)abstract
- Recent developments in very long baseline interferometry (VLBI) have made it possible for the Event Horizon Telescope (EHT) to resolve the innermost accretion flows of the largest supermassive black holes on the sky. The sparse nature of the EHT's (u, v)-coverage presents a challenge when attempting to resolve highly time-variable sources. We demonstrate that the changing (u, v)-coverage of the EHT can contain regions of time over the course of a single observation that facilitate dynamical imaging. These optimal time regions typically have projected baseline distributions that are approximately angularly isotropic and radially homogeneous. We derive a metric of coverage quality based on baseline isotropy and density that is capable of ranking array configurations by their ability to produce accurate dynamical reconstructions. We compare this metric to existing metrics in the literature and investigate their utility by performing dynamical reconstructions on synthetic data from simulated EHT observations of sources with simple orbital variability. We then use these results to make recommendations for imaging the 2017 EHT Sgr A* data set.
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| 42. |
- Mahajan, Anubha, et al.
(författare)
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Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus.
- 2015
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
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| 43. |
- Narayan, Ramesh, et al.
(författare)
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The Polarized Image of a Synchrotron-emitting Ring of Gas Orbiting a Black Hole
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 912:1
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Tidskriftsartikel (refereegranskat)abstract
- Synchrotron radiation from hot gas near a black hole results in a polarized image. The image polarization is determined by effects including the orientation of the magnetic field in the emitting region, relativistic motion of the gas, strong gravitational lensing by the black hole, and parallel transport in the curved spacetime. We explore these effects using a simple model of an axisymmetric, equatorial accretion disk around a Schwarzschild black hole. By using an approximate expression for the null geodesics derived by Beloborodov and conservation of the Walker-Penrose constant, we provide analytic estimates for the image polarization. We test this model using currently favored general relativistic magnetohydrodynamic simulations of M87*, using ring parameters given by the simulations. For a subset of these with modest Faraday effects, we show that the ring model broadly reproduces the polarimetric image morphology. Our model also predicts the polarization evolution for compact flaring regions, such as those observed from Sgr A* with GRAVITY. With suitably chosen parameters, our simple model can reproduce the EVPA pattern and relative polarized intensity in Event Horizon Telescope images of M87*. Under the physically motivated assumption that the magnetic field trails the fluid velocity, this comparison is consistent with the clockwise rotation inferred from total intensity images.
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| 44. |
- Porth, Oliver, et al.
(författare)
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The Event Horizon General Relativistic Magnetohydrodynamic Code Comparison Project
- 2019
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Ingår i: Astrophysical Journal, Supplement Series. - : American Astronomical Society. - 1538-4365 .- 0067-0049. ; 243:2
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Tidskriftsartikel (refereegranskat)abstract
- Recent developments in compact object astrophysics, especially the discovery of merging neutron stars by LIGO, the imaging of the black hole in M87 by the Event Horizon Telescope, and high- precision astrometry of the Galactic Center at close to the event horizon scale by the GRAVITY experiment motivate the development of numerical source models that solve the equations of general relativistic magnetohydrodynamics (GRMHD). Here we compare GRMHD solutions for the evolution of a magnetized accretion flow where turbulence is promoted by the magnetorotational instability from a set of nine GRMHD codes: Athena++, BHAC, Cosmos++, ECHO, H-AMR, iharm3D, HARM-Noble, IllinoisGRMHD, and KORAL. Agreement among the codes improves as resolution increases, as measured by a consistently applied, specially developed set of code performance metrics. We conclude that the community of GRMHD codes is mature, capable, and consistent on these test problems.
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| 45. |
- Erlinge, David, et al.
(författare)
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Clopidogrel metaboliser status based on point-of-care CYP2C19 genetic testing in patients with coronary artery disease
- 2014
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 111:5, s. 943-950
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Tidskriftsartikel (refereegranskat)abstract
- We compared results obtained with the Nanosphere Verigene (R) System, a novel point-of-care (POC) genetic test capable of analysing 11, CYP2C19 variants within 3 hours, to an established, validated genotyping method (Affymetrix (TM) DMET+; reference assay) for identifying extensive and reduced metabolisers of clopidogrel. Based on genotyping, patients (N=82) with stable coronary artery disease on clopidogrel 75 mg daily were defined as extensive metabolisers (*1/*1, *1/*17,*17/*17), reduced metabolisers (*1/*2,*1/*8,*2/*2,*2/*3), or of indeterminate metaboliser status (*2/*17). Pharmacokinetic exposure to clopidogrel's active metabolite and pharmacodynamic measures with P2Y12 reaction units (PRU) (VerifyNow (R) P2Y12 assay), and VASP PRI (PRI) were also assessed. There was a 99.9% overall; concordance of marker-level data between the Nanosphere Verigene and DMET+ systems in identifying the CYP2C19 variants and 100% agreement in classifying the patients as extensive (n=59) or reduced metabolisers (n=15). Extensive metabolisers had significantly higher active metabolite exposure than reduced metabolisers (LS means 12.6 ng*h/ml vs 7.7 ng*h/ml; p<0.001). Extensive metabolisers also had lower PRU (LS means 158 vs 212; p=0.003) and VASP PRI (LS means 48% vs 63%, p=0.01) compared to reduced metabolisers. Rates of high on-treatment platelet reactivity were higher in reduced metabolisers compared to extensive metabolisers (VASP PRI >= 50%: 79% vs 47%; PRU >235: 33% vs 16%). The Nanosphere Verigene CBS system identified 11 CYP2C19 alleles in less than 3 hours with a high degree of accuracy when compared to a conventional method, and was further validated against pharmacokinetic and pharmacodynamic phenotypes.
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| 46. |
- Erlinge, David, et al.
(författare)
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Prasugrel 5-mg in the very elderly attenuates platelet inhibition but maintains non-inferiority to prasugrel 10-mg in non-elderly patients: The GENERATIONS trial, a pharmacodynamic and pharmacokinetic study in stable coronary artery disease patients.
- 2013
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 62:7, s. 577-583
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: We assessed pharmacodynamic (PD) response for the reduced prasugrel 5-mg maintenance dose in very elderly (≥75y; VE) patients. BACKGROUND: In TRITON-TIMI 38, prasugrel 10-mg reduced ischemic events versus clopidogrel 75-mg, but increased bleeding in VE patients. METHODS: We examined PD and active-metabolite pharmacokinetics with prasugrel 5-mg and 10-mg and clopidogrel 75-mg in a three-period (12 days each), blinded, cross-over study in VE (n=73, mean 79±3y) or non-elderly (≥45-<65y, NE) (n=82, 56±5y) stable coronary artery disease (CAD) patients on background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow(®) P2Y12 (VN-P2Y12), and VASP. The primary comparison was non-inferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5-mg in VE versus the 75th percentile for prasugrel 10-mg in NE, using a prespecified one-sided 97.5% confidence interval for the difference <15%. RESULTS: Prasugrel 5-mg in VE met the primary pharmacodynamic non-inferiority criterion versus prasugrel 10-mg in NE. For prasugrel 5-mg, MPA was significantly lower (mean±SD, 57±14%) than clopidogrel (63±14%) (p<0.001) in VE, but higher than prasugrel 10-mg in NE (46±12%) (p<0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5-mg resulted in fewer VE poor responders versus clopidogrel. Rates of mild bleeding were higher with prasugrel 10-mg, but similar for prasugrel 5-mg versus clopidogrel 75-mg. CONCLUSIONS: In aspirin-treated stable CAD patients, prasugrel 5-mg in VE attenuated platelet inhibition while meeting prespecified non-inferiority criterion versus prasugrel 10-mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75-mg in VE.
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| 47. |
- Erlinge, David, et al.
(författare)
-
Prasugrel 5 mg in the Very Elderly Attenuates Platelet Inhibition But Maintains Noninferiority to Prasugrel 10 mg in Nonelderly Patients
- 2013
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:7, s. 577-583
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives This study assessed pharmacodynamic (PD) response to the reduced prasugrel maintenance dose of 5 mg in very elderly (VE) patients (andgt;= 75 years of age). less thanbrgreater than less thanbrgreater thanBackground In the TRITON-TIMI 38 (TRial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet InhibitioN with Prasugrel-Thrombolysis In Myocardial Infarction 38) study prasugrel 10 mg reduced ischemic events versus clopidogrel 75 mg, but increased bleeding in VE patients. less thanbrgreater than less thanbrgreater thanMethods We examined PD and active metabolite pharmacokinetics (PKs) with prasugrel 5 and 10 mg and clopidogrel 75 mg in a 3-period (12 days each) blinded, crossover study in VE (n = 73; mean: 79 +/- 3 years of age) or (n 82) nonelderly (NE) (andgt;= 45 to andlt;65 years of age; mean: 56 +/- 5 years of age) stable coronary artery disease (CAD) patients receiving background aspirin. Assays included light transmission aggregometry (LTA), VerifyNow P2Y12 (VN-P2Y12), and vasodilator-associated stimulated phosphoprotein (VASP). The primary comparison was noninferiority of maximum platelet aggregation (MPA) comparing the median for prasugrel 5 mg in VE versus the 75th percentile for prasugrel 10 mg in NE, using a pre-specified 1-sided 97.5% confidence interval for the difference andlt;15%. less thanbrgreater than less thanbrgreater thanResults Prasugrel 5 mg in VE met the primary PD noninferiority criterion versus prasugrel 10 mg in NE. For prasugrel 5 mg, MPA was significantly lower (57 +/- 14%) than clopidogrel (63 +/- 14%; p andlt; 0.001) in VE but higher than prasugrel 10 mg in NE (46 +/- 12%; p andlt; 0.001). PD response by LTA, VN-P2Y12, and VASP during all treatments appeared similar between age cohorts. Prasugrel 5 mg resulted in fewer VE poor responders than clopidogrel. Rates of mild bleeding were higher with prasugrel 10 mg but similar for prasugrel 5 mg versus clopidogrel 75 mg. less thanbrgreater than less thanbrgreater thanConclusions In aspirin-treated stable CAD patients, prasugrel 5 mg in VE attenuated platelet inhibition while meeting pre-specified noninferiority criterion versus prasugrel 10 mg in NE, with significantly better PD response and fewer poor responders compared to clopidogrel 75 mg in VE. (Comparison of Prasugrel and Clopidogrel in Very Elderly and Non-Elderly Patients With Stable Coronary Artery Disease [GENERATIONS]; NCT01107912)
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| 48. |
- Kooner, Jaspal S, et al.
(författare)
-
Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci.
- 2011
-
Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:10
-
Tidskriftsartikel (refereegranskat)abstract
- We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10(-4) for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10(-8) to P = 1.9 × 10(-11)). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10(-4)), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D.
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| 49. |
- McCarthy, Shane, et al.
(författare)
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A reference panel of 64,976 haplotypes for genotype imputation
- 2016
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1279-1283
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Tidskriftsartikel (refereegranskat)abstract
- We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
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| 50. |
- Grundberg, Elin, et al.
(författare)
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Mapping cis- and trans-regulatory effects across multiple tissues in twins.
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:10
-
Tidskriftsartikel (refereegranskat)abstract
- Sequence-based variation in gene expression is a key driver of disease risk. Common variants regulating expression in cis have been mapped in many expression quantitative trait locus (eQTL) studies, typically in single tissues from unrelated individuals. Here, we present a comprehensive analysis of gene expression across multiple tissues conducted in a large set of mono- and dizygotic twins that allows systematic dissection of genetic (cis and trans) and non-genetic effects on gene expression. Using identity-by-descent estimates, we show that at least 40% of the total heritable cis effect on expression cannot be accounted for by common cis variants, a finding that reveals the contribution of low-frequency and rare regulatory variants with respect to both transcriptional regulation and complex trait susceptibility. We show that a substantial proportion of gene expression heritability is trans to the structural gene, and we identify several replicating trans variants that act predominantly in a tissue-restricted manner and may regulate the transcription of many genes.
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