| 1. |
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| 2. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
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- 2019
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Journal article (peer-reviewed)
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| 4. |
- Akiyama, Kazunori, et al.
(author)
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First Sagittarius A* Event Horizon Telescope Results. II. EHT and Multiwavelength Observations, Data Processing, and Calibration
- 2022
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Journal article (peer-reviewed)abstract
- We present Event Horizon Telescope (EHT) 1.3 mm measurements of the radio source located at the position of the supermassive black hole Sagittarius A* (Sgr A*), collected during the 2017 April 5-11 campaign. The observations were carried out with eight facilities at six locations across the globe. Novel calibration methods are employed to account for Sgr A*'s flux variability. The majority of the 1.3 mm emission arises from horizon scales, where intrinsic structural source variability is detected on timescales of minutes to hours. The effects of interstellar scattering on the image and its variability are found to be subdominant to intrinsic source structure. The calibrated visibility amplitudes, particularly the locations of the visibility minima, are broadly consistent with a blurred ring with a diameter of similar to 50 mu as, as determined in later works in this series. Contemporaneous multiwavelength monitoring of Sgr A* was performed at 22, 43, and 86 GHz and at near-infrared and X-ray wavelengths. Several X-ray flares from Sgr A* are detected by Chandra, one at low significance jointly with Swift on 2017 April 7 and the other at higher significance jointly with NuSTAR on 2017 April 11. The brighter April 11 flare is not observed simultaneously by the EHT but is followed by a significant increase in millimeter flux variability immediately after the X-ray outburst, indicating a likely connection in the emission physics near the event horizon. We compare Sgr A*'s broadband flux during the EHT campaign to its historical spectral energy distribution and find that both the quiescent emission and flare emission are consistent with its long-term behavior.
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| 5. |
- Schunkert, Heribert, et al.
(author)
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
- 2011
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:4, s. 153-333
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Journal article (peer-reviewed)abstract
- We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 x 10(-8) and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
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| 6. |
- Shungin, Dmitry, et al.
(author)
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New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
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Journal article (peer-reviewed)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 7. |
- Zamora, Juan Carlos, et al.
(author)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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In: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Journal article (peer-reviewed)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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| 8. |
- Beal, Jacob, et al.
(author)
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Robust estimation of bacterial cell count from optical density
- 2020
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In: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 3:1
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Journal article (peer-reviewed)abstract
- Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data.
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| 9. |
- Berne, Olivier, et al.
(author)
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PDRs4All : A JWST Early Release Science Program on Radiative Feedback from Massive Stars
- 2022
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In: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 134:1035
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Journal article (peer-reviewed)abstract
- Massive stars disrupt their natal molecular cloud material through radiative and mechanical feedback processes. These processes have profound effects on the evolution of interstellar matter in our Galaxy and throughout the universe, from the era of vigorous star formation at redshifts of 1-3 to the present day. The dominant feedback processes can be probed by observations of the Photo-Dissociation Regions (PDRs) where the far-ultraviolet photons of massive stars create warm regions of gas and dust in the neutral atomic and molecular gas. PDR emission provides a unique tool to study in detail the physical and chemical processes that are relevant for most of the mass in inter- and circumstellar media including diffuse clouds, proto-planetary disks, and molecular cloud surfaces, globules, planetary nebulae, and star-forming regions. PDR emission dominates the infrared (IR) spectra of star-forming galaxies. Most of the Galactic and extragalactic observations obtained with the James Webb Space Telescope (JWST) will therefore arise in PDR emission. In this paper we present an Early Release Science program using the MIRI, NIRSpec, and NIRCam instruments dedicated to the observations of an emblematic and nearby PDR: the Orion Bar. These early JWST observations will provide template data sets designed to identify key PDR characteristics in JWST observations. These data will serve to benchmark PDR models and extend them into the JWST era. We also present the Science-Enabling products that we will provide to the community. These template data sets and Science-Enabling products will guide the preparation of future proposals on star-forming regions in our Galaxy and beyond and will facilitate data analysis and interpretation of forthcoming JWST observations.
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| 10. |
- Heid, Iris M, et al.
(author)
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
- 2010
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 949-960
-
Journal article (peer-reviewed)abstract
- Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
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| 11. |
- Kehoe, Laura, et al.
(author)
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Make EU trade with Brazil sustainable
- 2019
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Journal article (other academic/artistic)
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| 12. |
- Vasan, Ramachandran S, et al.
(author)
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Genetic variants associated with cardiac structure and function : a meta-analysis and replication of genome-wide association data
- 2009
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In: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 302:2, s. 168-178
-
Journal article (peer-reviewed)abstract
- CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
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| 13. |
- Akiyama, Kazunori, et al.
(author)
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First M87 Event Horizon Telescope Results. VII. Polarization of the Ring
- 2021
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 910:1
-
Journal article (peer-reviewed)abstract
- In 2017 April, the Event Horizon Telescope (EHT) observed the near-horizon region around the supermassive black hole at the core of the M87 galaxy. These 1.3 mm wavelength observations revealed a compact asymmetric ring-like source morphology. This structure originates from synchrotron emission produced by relativistic plasma located in the immediate vicinity of the black hole. Here we present the corresponding linear-polarimetric EHT images of the center of M87. We find that only a part of the ring is significantly polarized. The resolved fractional linear polarization has a maximum located in the southwest part of the ring, where it rises to the level of similar to 15%. The polarization position angles are arranged in a nearly azimuthal pattern. We perform quantitative measurements of relevant polarimetric properties of the compact emission and find evidence for the temporal evolution of the polarized source structure over one week of EHT observations. The details of the polarimetric data reduction and calibration methodology are provided. We carry out the data analysis using multiple independent imaging and modeling techniques, each of which is validated against a suite of synthetic data sets. The gross polarimetric structure and its apparent evolution with time are insensitive to the method used to reconstruct the image. These polarimetric images carry information about the structure of the magnetic fields responsible for the synchrotron emission. Their physical interpretation is discussed in an accompanying publication.
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| 14. |
- Akiyama, Kazunori, et al.
(author)
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First M87 Event Horizon Telescope Results. VIII. Magnetic Field Structure near The Event Horizon
- 2021
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 910:1
-
Journal article (peer-reviewed)abstract
- Event Horizon Telescope (EHT) observations at 230 GHz have now imaged polarized emission around the supermassive black hole in M87 on event-horizon scales. This polarized synchrotron radiation probes the structure of magnetic fields and the plasma properties near the black hole. Here we compare the resolved polarization structure observed by the EHT, along with simultaneous unresolved observations with the Atacama Large Millimeter/submillimeter Array, to expectations from theoretical models. The low fractional linear polarization in the resolved image suggests that the polarization is scrambled on scales smaller than the EHT beam, which we attribute to Faraday rotation internal to the emission region. We estimate the average density n(e) similar to 10(4-7) cm(-3), magnetic field strength B similar to 1-30 G, and electron temperature T-e similar to (1-12) x 10(10) K of the radiating plasma in a simple one-zone emission model. We show that the net azimuthal linear polarization pattern may result from organized, poloidal magnetic fields in the emission region. In a quantitative comparison with a large library of simulated polarimetric images from general relativistic magnetohydrodynamic (GRMHD) simulations, we identify a subset of physical models that can explain critical features of the polarimetric EHT observations while producing a relativistic jet of sufficient power. The consistent GRMHD models are all of magnetically arrested accretion disks, where near-horizon magnetic fields are dynamically important. We use the models to infer a mass accretion rate onto the black hole in M87 of (3-20) x 10(-4) M yr(-1).
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| 15. |
- Akiyama, Kazunori, et al.
(author)
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First Sagittarius A* Event Horizon Telescope Results. III. Imaging of the Galactic Center Supermassive Black Hole
- 2022
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Journal article (peer-reviewed)abstract
- We present the first event-horizon-scale images and spatiotemporal analysis of Sgr A* taken with the Event Horizon Telescope in 2017 April at a wavelength of 1.3 mm. Imaging of Sgr A* has been conducted through surveys over a wide range of imaging assumptions using the classical CLEAN algorithm, regularized maximum likelihood methods, and a Bayesian posterior sampling method. Different prescriptions have been used to account for scattering effects by the interstellar medium toward the Galactic center. Mitigation of the rapid intraday variability that characterizes Sgr A* has been carried out through the addition of a "variability noise budget" in the observed visibilities, facilitating the reconstruction of static full-track images. Our static reconstructions of Sgr A* can be clustered into four representative morphologies that correspond to ring images with three different azimuthal brightness distributions and a small cluster that contains diverse nonring morphologies. Based on our extensive analysis of the effects of sparse (u, v)-coverage, source variability, and interstellar scattering, as well as studies of simulated visibility data, we conclude that the Event Horizon Telescope Sgr A* data show compelling evidence for an image that is dominated by a bright ring of emission with a ring diameter of similar to 50 mu as, consistent with the expected "shadow" of a 4 x 10(6) M (circle dot) black hole in the Galactic center located at a distance of 8 kpc.
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| 16. |
- Akiyama, Kazunori, et al.
(author)
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First Sagittarius A* Event Horizon Telescope Results. IV. Variability, Morphology, and Black Hole Mass
- 2022
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Journal article (peer-reviewed)abstract
- In this paper we quantify the temporal variability and image morphology of the horizon-scale emission from Sgr A*, as observed by the EHT in 2017 April at a wavelength of 1.3 mm. We find that the Sgr A* data exhibit variability that exceeds what can be explained by the uncertainties in the data or by the effects of interstellar scattering. The magnitude of this variability can be a substantial fraction of the correlated flux density, reaching similar to 100% on some baselines. Through an exploration of simple geometric source models, we demonstrate that ring-like morphologies provide better fits to the Sgr A* data than do other morphologies with comparable complexity. We develop two strategies for fitting static geometric ring models to the time-variable Sgr A* data; one strategy fits models to short segments of data over which the source is static and averages these independent fits, while the other fits models to the full data set using a parametric model for the structural variability power spectrum around the average source structure. Both geometric modeling and image-domain feature extraction techniques determine the ring diameter to be 51.8 +/- 2.3 mu as (68% credible intervals), with the ring thickness constrained to have an FWHM between similar to 30% and 50% of the ring diameter. To bring the diameter measurements to a common physical scale, we calibrate them using synthetic data generated from GRMHD simulations. This calibration constrains the angular size of the gravitational radius to be 4.8(-0.7)(+1.4) mu as, which we combine with an independent distance measurement from maser parallaxes to determine the mass of Sgr A* to be 4.0(-0.6)(+1.1) x 10(6) M-circle dot.
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| 17. |
- Akiyama, Kazunori, et al.
(author)
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First Sagittarius A* Event Horizon Telescope Results. V. Testing Astrophysical Models of the Galactic Center Black Hole
- 2022
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Journal article (peer-reviewed)abstract
- In this paper we provide a first physical interpretation for the Event Horizon Telescope's (EHT) 2017 observations of Sgr A*. Our main approach is to compare resolved EHT data at 230 GHz and unresolved non-EHT observations from radio to X-ray wavelengths to predictions from a library of models based on time-dependent general relativistic magnetohydrodynamics simulations, including aligned, tilted, and stellar-wind-fed simulations; radiative transfer is performed assuming both thermal and nonthermal electron distribution functions. We test the models against 11 constraints drawn from EHT 230 GHz data and observations at 86 GHz, 2.2 mu m, and in the X-ray. All models fail at least one constraint. Light-curve variability provides a particularly severe constraint, failing nearly all strongly magnetized (magnetically arrested disk (MAD)) models and a large fraction of weakly magnetized models. A number of models fail only the variability constraints. We identify a promising cluster of these models, which are MAD and have inclination i <= 30 degrees. They have accretion rate (5.2-9.5) x 10(-9) M (circle dot) yr(-1), bolometric luminosity (6.8-9.2) x 10(35) erg s(-1), and outflow power (1.3-4.8) x 10(38) erg s(-1). We also find that all models with i >= 70 degrees fail at least two constraints, as do all models with equal ion and electron temperature; exploratory, nonthermal model sets tend to have higher 2.2 mu m flux density; and the population of cold electrons is limited by X-ray constraints due to the risk of bremsstrahlung overproduction. Finally, we discuss physical and numerical limitations of the models, highlighting the possible importance of kinetic effects and duration of the simulations.
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| 18. |
- Akiyama, Kazunori, et al.
(author)
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First Sagittarius A* Event Horizon Telescope Results. VI. Testing the Black Hole Metric
- 2022
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Journal article (peer-reviewed)abstract
- Astrophysical black holes are expected to be described by the Kerr metric. This is the only stationary, vacuum, axisymmetric metric, without electromagnetic charge, that satisfies Einstein's equations and does not have pathologies outside of the event horizon. We present new constraints on potential deviations from the Kerr prediction based on 2017 EHT observations of Sagittarius A* (Sgr A*). We calibrate the relationship between the geometrically defined black hole shadow and the observed size of the ring-like images using a library that includes both Kerr and non-Kerr simulations. We use the exquisite prior constraints on the mass-to-distance ratio for Sgr A* to show that the observed image size is within similar to 10% of the Kerr predictions. We use these bounds to constrain metrics that are parametrically different from Kerr, as well as the charges of several known spacetimes. To consider alternatives to the presence of an event horizon, we explore the possibility that Sgr A* is a compact object with a surface that either absorbs and thermally reemits incident radiation or partially reflects it. Using the observed image size and the broadband spectrum of Sgr A*, we conclude that a thermal surface can be ruled out and a fully reflective one is unlikely. We compare our results to the broader landscape of gravitational tests. Together with the bounds found for stellar-mass black holes and the M87 black hole, our observations provide further support that the external spacetimes of all black holes are described by the Kerr metric, independent of their mass.
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| 19. |
- Broderick, Avery E., et al.
(author)
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Characterizing and Mitigating Intraday Variability: Reconstructing Source Structure in Accreting Black Holes with mm-VLBI
- 2022
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Journal article (peer-reviewed)abstract
- The extraordinary physical resolution afforded by the Event Horizon Telescope has opened a window onto the astrophysical phenomena unfolding on horizon scales in two known black holes, M87* and Sgr A*. However, with this leap in resolution has come a new set of practical complications. Sgr A* exhibits intraday variability that violates the assumptions underlying Earth aperture synthesis, limiting traditional image reconstruction methods to short timescales and data sets with very sparse (u, v) coverage. We present a new set of tools to detect and mitigate this variability. We develop a data-driven, model-agnostic procedure to detect and characterize the spatial structure of intraday variability. This method is calibrated against a large set of mock data sets, producing an empirical estimator of the spatial power spectrum of the brightness fluctuations. We present a novel Bayesian noise modeling algorithm that simultaneously reconstructs an average image and statistical measure of the fluctuations about it using a parameterized form for the excess variance in the complex visibilities not otherwise explained by the statistical errors. These methods are validated using a variety of simulated data, including general relativistic magnetohydrodynamic simulations appropriate for Sgr A* and M87*. We find that the reconstructed source structure and variability are robust to changes in the underlying image model. We apply these methods to the 2017 EHT observations of M87*, finding evidence for variability across the EHT observing campaign. The variability mitigation strategies presented are widely applicable to very long baseline interferometry observations of variable sources generally, for which they provide a data-informed averaging procedure and natural characterization of inter-epoch image consistency.
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| 20. |
- Farah, Joseph, et al.
(author)
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Selective Dynamical Imaging of Interferometric Data
- 2022
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Journal article (peer-reviewed)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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| 21. |
- Gaulton, Kyle J, et al.
(author)
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Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.
- 2015
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 47:12, s. 1415-1415
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Journal article (peer-reviewed)abstract
- We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease.
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| 22. |
- Goddi, Ciriaco, et al.
(author)
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Polarimetric Properties of Event Horizon Telescope Targets from ALMA
- 2021
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 910:1
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Journal article (peer-reviewed)abstract
- We present the results from a full polarization study carried out with the Atacama Large Millimeter/submillimeter Array (ALMA) during the first Very Long Baseline Interferometry (VLBI) campaign, which was conducted in 2017 April in the lambda 3 mm and lambda 1.3 mm bands, in concert with the Global mm-VLBI Array (GMVA) and the Event Horizon Telescope (EHT), respectively. We determine the polarization and Faraday properties of all VLBI targets, including Sgr A*, M87, and a dozen radio-loud active galactic nuclei (AGNs), in the two bands at several epochs in a time window of 10 days. We detect high linear polarization fractions (2%-15%) and large rotation measures (RM > 10(3.3)-10(5.5) rad m(-2)), confirming the trends of previous AGN studies at millimeter wavelengths. We find that blazars are more strongly polarized than other AGNs in the sample, while exhibiting (on average) order-of-magnitude lower RM values, consistent with the AGN viewing angle unification scheme. For Sgr A* we report a mean RM of (-4.2 0.3) x 10(5) rad m(-2) at 1.3 mm, consistent with measurements over the past decade and, for the first time, an RM of (-2.1 0.1) x 10(5) rad m(-2) at 3 mm, suggesting that about half of the Faraday rotation at 1.3 mm may occur between the 3 mm photosphere and the 1.3 mm source. We also report the first unambiguous measurement of RM toward the M87 nucleus at millimeter wavelengths, which undergoes significant changes in magnitude and sign reversals on a one year timescale, spanning the range from -1.2 to 0.3 x 10(5) rad m(-2) at 3 mm and -4.1 to 1.5 x 10(5) rad m(-2) at 1.3 mm. Given this time variability, we argue that, unlike the case of Sgr A*, the RM in M87 does not provide an accurate estimate of the mass accretion rate onto the black hole. We put forward a two-component model, comprised of a variable compact region and a static extended region, that can simultaneously explain the polarimetric properties observed by both the EHT (on horizon scales) and ALMA (which observes the combined emission from both components). These measurements provide critical constraints for the calibration, analysis, and interpretation of simultaneously obtained VLBI data with the EHT and GMVA.
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| 23. |
- Hudson, Thomas J., et al.
(author)
-
International network of cancer genome projects
- 2010
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
-
Journal article (peer-reviewed)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
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| 24. |
- Issaoun, Sara, et al.
(author)
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Resolving the Inner Parsec of the Blazar J1924-2914 with the Event Horizon Telescope
- 2022
-
In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 934:2
-
Journal article (peer-reviewed)abstract
- The blazar J1924-2914 is a primary Event Horizon Telescope (EHT) calibrator for the Galactic center's black hole Sagittarius A*. Here we present the first total and linearly polarized intensity images of this source obtained with the unprecedented 20 mu as resolution of the EHT. J1924-2914 is a very compact flat-spectrum radio source with strong optical variability and polarization. In April 2017 the source was observed quasi-simultaneously with the EHT (April 5-11), the Global Millimeter VLBI Array (April 3), and the Very Long Baseline Array (April 28), giving a novel view of the source at four observing frequencies, 230, 86, 8.7, and 2.3 GHz. These observations probe jet properties from the subparsec to 100 pc scales. We combine the multifrequency images of J1924-2914 to study the source morphology. We find that the jet exhibits a characteristic bending, with a gradual clockwise rotation of the jet projected position angle of about 90 degrees between 2.3 and 230 GHz. Linearly polarized intensity images of J1924-2914 with the extremely fine resolution of the EHT provide evidence for ordered toroidal magnetic fields in the blazar compact core.
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| 25. |
- Jones, Geraint H., et al.
(author)
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The Comet Interceptor Mission
- 2024
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In: Space Science Reviews. - : Springer Nature. - 0038-6308 .- 1572-9672. ; 220:1
-
Journal article (peer-reviewed)abstract
- Here we describe the novel, multi-point Comet Interceptor mission. It is dedicated to the exploration of a little-processed long-period comet, possibly entering the inner Solar System for the first time, or to encounter an interstellar object originating at another star. The objectives of the mission are to address the following questions: What are the surface composition, shape, morphology, and structure of the target object? What is the composition of the gas and dust in the coma, its connection to the nucleus, and the nature of its interaction with the solar wind? The mission was proposed to the European Space Agency in 2018, and formally adopted by the agency in June 2022, for launch in 2029 together with the Ariel mission. Comet Interceptor will take advantage of the opportunity presented by ESA’s F-Class call for fast, flexible, low-cost missions to which it was proposed. The call required a launch to a halo orbit around the Sun-Earth L2 point. The mission can take advantage of this placement to wait for the discovery of a suitable comet reachable with its minimum Δ V capability of 600 ms − 1 . Comet Interceptor will be unique in encountering and studying, at a nominal closest approach distance of 1000 km, a comet that represents a near-pristine sample of material from the formation of the Solar System. It will also add a capability that no previous cometary mission has had, which is to deploy two sub-probes – B1, provided by the Japanese space agency, JAXA, and B2 – that will follow different trajectories through the coma. While the main probe passes at a nominal 1000 km distance, probes B1 and B2 will follow different chords through the coma at distances of 850 km and 400 km, respectively. The result will be unique, simultaneous, spatially resolved information of the 3-dimensional properties of the target comet and its interaction with the space environment. We present the mission’s science background leading to these objectives, as well as an overview of the scientific instruments, mission design, and schedule.
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| 26. |
- Jorstad, S.G., et al.
(author)
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The Event Horizon Telescope Image of the Quasar NRAO 530
- 2023
-
In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 943:2
-
Journal article (peer-reviewed)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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| 27. |
- Locke, Adam E, et al.
(author)
-
Genetic studies of body mass index yield new insights for obesity biology.
- 2015
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
-
Journal article (peer-reviewed)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 28. |
- Mahdavi, Jafar, et al.
(author)
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Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation
- 2002
-
In: Science. - : American Association for the Advancement of Science. - 0036-8075 .- 1095-9203. ; 297:5581, s. 573-578
-
Journal article (peer-reviewed)abstract
- Helicobacter pylori adherence in the human gastric mucosa involves specific bacterial adhesins and cognate host receptors. Here, we identify sialyl-dimeric-Lewis x glycosphingolipid as a receptor for H. pylori and show that H. pylori infection induced formation of sialyl-Lewis x antigens in gastric epithelium in humans and in a Rhesus monkey. The corresponding sialic acid-binding adhesin (SabA) was isolated with the "retagging" method, and the underlying sabA gene (JHP662/HP0725) was identified. The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might thus contribute to virulence and the extraordinary chronicity of H. pylori infection.
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| 29. |
- Narayan, Ramesh, et al.
(author)
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The Polarized Image of a Synchrotron-emitting Ring of Gas Orbiting a Black Hole
- 2021
-
In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 912:1
-
Journal article (peer-reviewed)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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| 30. |
- Richards, Stephen, et al.
(author)
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Genome Sequence of the Pea Aphid Acyrthosiphon pisum
- 2010
-
In: PLoS biology. - : Public Library of Science (PLoS). - 1544-9173 .- 1545-7885. ; 8:2, s. e1000313-
-
Journal article (peer-reviewed)abstract
- Aphids are important agricultural pests and also biological models for studies of insect-plant interactions, symbiosis, virus vectoring, and the developmental causes of extreme phenotypic plasticity. Here we present the 464 Mb draft genome assembly of the pea aphid Acyrthosiphon pisum. This first published whole genome sequence of a basal hemimetabolous insect provides an outgroup to the multiple published genomes of holometabolous insects. Pea aphids are host-plant specialists, they can reproduce both sexually and asexually, and they have coevolved with an obligate bacterial symbiont. Here we highlight findings from whole genome analysis that may be related to these unusual biological features. These findings include discovery of extensive gene duplication in more than 2000 gene families as well as loss of evolutionarily conserved genes. Gene family expansions relative to other published genomes include genes involved in chromatin modification, miRNA synthesis, and sugar transport. Gene losses include genes central to the IMD immune pathway, selenoprotein utilization, purine salvage, and the entire urea cycle. The pea aphid genome reveals that only a limited number of genes have been acquired from bacteria; thus the reduced gene count of Buchnera does not reflect gene transfer to the host genome. The inventory of metabolic genes in the pea aphid genome suggests that there is extensive metabolite exchange between the aphid and Buchnera, including sharing of amino acid biosynthesis between the aphid and Buchnera. The pea aphid genome provides a foundation for post-genomic studies of fundamental biological questions and applied agricultural problems.
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| 31. |
- Satapathy, Kaushik, et al.
(author)
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The Variability of the Black Hole Image in M87 at the Dynamical Timescale
- 2022
-
In: Astrophysical Journal. - : American Astronomical Society. - 1538-4357 .- 0004-637X. ; 925:1
-
Journal article (peer-reviewed)abstract
- The black hole images obtained with the Event Horizon Telescope (EHT) are expected to be variable at the dynamical timescale near their horizons. For the black hole at the center of the M87 galaxy, this timescale (5-61 days) is comparable to the 6 day extent of the 2017 EHT observations. Closure phases along baseline triangles are robust interferometric observables that are sensitive to the expected structural changes of the images but are free of station-based atmospheric and instrumental errors. We explored the day-to-day variability in closure-phase measurements on all six linearly independent nontrivial baseline triangles that can be formed from the 2017 observations. We showed that three triangles exhibit very low day-to-day variability, with a dispersion of similar to 3 degrees-5 degrees. The only triangles that exhibit substantially higher variability (similar to 90 degrees-180 degrees) are the ones with baselines that cross the visibility amplitude minima on the u-v plane, as expected from theoretical modeling. We used two sets of general relativistic magnetohydrodynamic simulations to explore the dependence of the predicted variability on various black hole and accretion-flow parameters. We found that changing the magnetic field configuration, electron temperature model, or black hole spin has a marginal effect on the model consistency with the observed level of variability. On the other hand, the most discriminating image characteristic of models is the fractional width of the bright ring of emission. Models that best reproduce the observed small level of variability are characterized by thin ring-like images with structures dominated by gravitational lensing effects and thus least affected by turbulence in the accreting plasmas.
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| 32. |
- Scott, Robert A., et al.
(author)
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An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans
- 2017
-
In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 66:11, s. 2888-2902
-
Journal article (peer-reviewed)abstract
- To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 x 10(-8)), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
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| 33. |
- Stitziel, Nathan O., et al.
(author)
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Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease
- 2016
-
In: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 374:12, s. 1134-1144
-
Journal article (peer-reviewed)abstract
- BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we tested 54,003 coding-sequence variants covering 13,715 human genes in up to 72,868 patients with coronary artery disease and 120,770 controls who did not have coronary artery disease. Through DNA sequencing, we studied the effects of loss-of-function mutations in selected genes. RESULTS We confirmed previously observed significant associations between coronary artery disease and low-frequency missense variants in the genes LPA and PCSK9. We also found significant associations between coronary artery disease and low-frequency missense variants in the genes SVEP1 (p.D2702G; minor-allele frequency, 3.60%; odds ratio for disease, 1.14; P = 4.2x10(-10)) and ANGPTL4 (p.E40K; minor-allele frequency, 2.01%; odds ratio, 0.86; P = 4.0x10(-8)), which encodes angiopoietin-like 4. Through sequencing of ANGPTL4, we identified 9 carriers of loss-of-function mutations among 6924 patients with myocardial infarction, as compared with 19 carriers among 6834 controls (odds ratio, 0.47; P = 0.04); carriers of ANGPTL4 loss-of-function alleles had triglyceride levels that were 35% lower than the levels among persons who did not carry a loss-of-function allele (P = 0.003). ANGPTL4 inhibits lipoprotein lipase; we therefore searched for mutations in LPL and identified a loss-of-function variant that was associated with an increased risk of coronary artery disease (p.D36N; minor-allele frequency, 1.9%; odds ratio, 1.13; P = 2.0x10(-4)) and a gain-of-function variant that was associated with protection from coronary artery disease (p.S447*; minor-allele frequency, 9.9%; odds ratio, 0.94; P = 2.5x10(-7)). CONCLUSIONS We found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
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| 34. |
- Torne, Pablo, et al.
(author)
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A Search for Pulsars around Sgr A* in the First Event Horizon Telescope Data Set
- 2023
-
In: Astrophysical Journal. - 1538-4357 .- 0004-637X. ; 959:1
-
Journal article (peer-reviewed)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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| 35. |
- Webb, Thomas R., et al.
(author)
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Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
- 2017
-
In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097 .- 1558-3597. ; 69:7, s. 823-836
-
Journal article (peer-reviewed)abstract
- BACKGROUND Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits.OBJECTIVES This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci.METHODS In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs.RESULTS We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 x 10(-4) with a range of other diseases/traits.CONCLUSIONS We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk.
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| 36. |
- Wielgus, Maciek, et al.
(author)
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Millimeter Light Curves of Sagittarius A* Observed during the 2017 Event Horizon Telescope Campaign
- 2022
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 930:2
-
Journal article (peer-reviewed)abstract
- The Event Horizon Telescope (EHT) observed the compact radio source, Sagittarius A* (Sgr A*), in the Galactic Center on 2017 April 5-11 in the 1.3 mm wavelength band. At the same time, interferometric array data from the Atacama Large Millimeter/submillimeter Array and the Submillimeter Array were collected, providing Sgr A* light curves simultaneous with the EHT observations. These data sets, complementing the EHT very long baseline interferometry, are characterized by a cadence and signal-to-noise ratio previously unattainable for Sgr A* at millimeter wavelengths, and they allow for the investigation of source variability on timescales as short as a minute. While most of the light curves correspond to a low variability state of Sgr A*, the April 11 observations follow an X-ray flare and exhibit strongly enhanced variability. All of the light curves are consistent with a red-noise process, with a power spectral density (PSD) slope measured to be between -2 and -3 on timescales between 1 minute and several hours. Our results indicate a steepening of the PSD slope for timescales shorter than 0.3 hr. The spectral energy distribution is flat at 220 GHz, and there are no time lags between the 213 and 229 GHz frequency bands, suggesting low optical depth for the event horizon scale source. We characterize Sgr A*'s variability, highlighting the different behavior observed just after the X-ray flare, and use Gaussian process modeling to extract a decorrelation timescale and a PSD slope. We also investigate the systematic calibration uncertainties by analyzing data from independent data reduction pipelines.
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| 37. |
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| 38. |
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| 39. |
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| 40. |
- Akiyama, Kazunori, et al.
(author)
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First M87 Event Horizon Telescope Results. IV. Imaging the Central Supermassive Black Hole
- 2019
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 875:1
-
Journal article (peer-reviewed)abstract
- We present the first Event Horizon Telescope (EHT) images of M87, using observations from April 2017 at 1.3 mm wavelength. These images show a prominent ring with a diameter of similar to 40 mu as, consistent with the size and shape of the lensed photon orbit encircling the "shadow" of a supermassive black hole. The ring is persistent across four observing nights and shows enhanced brightness in the south. To assess the reliability of these results, we implemented a two-stage imaging procedure. In the first stage, four teams, each blind to the others' work, produced images of M87 using both an established method (CLEAN) and a newer technique (regularized maximum likelihood). This stage allowed us to avoid shared human bias and to assess common features among independent reconstructions. In the second stage, we reconstructed synthetic data from a large survey of imaging parameters and then compared the results with the corresponding ground truth images. This stage allowed us to select parameters objectively to use when reconstructing images of M87. Across all tests in both stages, the ring diameter and asymmetry remained stable, insensitive to the choice of imaging technique. We describe the EHT imaging procedures, the primary image features in M87, and the dependence of these features on imaging assumptions.
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| 41. |
- Akiyama, Kazunori, et al.
(author)
-
First M87 Event Horizon Telescope Results. V. Physical Origin of the Asymmetric Ring
- 2019
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 875:1
-
Journal article (peer-reviewed)abstract
- The Event Horizon Telescope (EHT) has mapped the central compact radio source of the elliptical galaxy M87 at 1.3 mm with unprecedented angular resolution. Here we consider the physical implications of the asymmetric ring seen in the 2017 EHT data. To this end, we construct a large library of models based on general relativistic magnetohydrodynamic (GRMHD) simulations and synthetic images produced by general relativistic ray tracing. We compare the observed visibilities with this library and confirm that the asymmetric ring is consistent with earlier predictions of strong gravitational lensing of synchrotron emission from a hot plasma orbiting near the black hole event horizon. The ring radius and ring asymmetry depend on black hole mass and spin, respectively, and both are therefore expected to be stable when observed in future EHT campaigns. Overall, the observed image is consistent with expectations for the shadow of a spinning Kerr black hole as predicted by general relativity. If the black hole spin and M87's large scale jet are aligned, then the black hole spin vector is pointed away from Earth. Models in our library of non-spinning black holes are inconsistent with the observations as they do not produce sufficiently powerful jets. At the same time, in those models that produce a sufficiently powerful jet, the latter is powered by extraction of black hole spin energy through mechanisms akin to the Blandford-Znajek process. We briefly consider alternatives to a black hole for the central compact object. Analysis of existing EHT polarization data and data taken simultaneously at other wavelengths will soon enable new tests of the GRMHD models, as will future EHT campaigns at 230 and 345 GHz.
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| 42. |
- Akiyama, Kazunori, et al.
(author)
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First M87 Event Horizon Telescope Results. VI. The Shadow and Mass of the Central Black Hole
- 2019
-
In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8213 .- 2041-8205. ; 875:1
-
Journal article (peer-reviewed)abstract
- We present measurements of the properties of the central radio source in M87 using Event Horizon Telescope data obtained during the 2017 campaign. We develop and fit geometric crescent models (asymmetric rings with interior brightness depressions) using two independent sampling algorithms that consider distinct representations of the visibility data. We show that the crescent family of models is statistically preferred over other comparably complex geometric models that we explore. We calibrate the geometric model parameters using general relativistic magnetohydrodynamic (GRMHD) models of the emission region and estimate physical properties of the source. We further fit images generated from GRMHD models directly to the data. We compare the derived emission region and black hole parameters from these analyses with those recovered from reconstructed images. There is a remarkable consistency among all methods and data sets. We find that >50% of the total flux at arcsecond scales comes from near the horizon, and that the emission is dramatically suppressed interior to this region by a factor >10, providing direct evidence of the predicted shadow of a black hole. Across all methods, we measure a crescent diameter of 42 +/- 3 mu as and constrain its fractional width to be
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| 43. |
- Assimes, Themistocles L., et al.
(author)
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Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies
- 2010
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In: Journal of the American College of Cardiology. - : Elsevier BV. - 0735-1097. ; 56:19, s. 1552-1563
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Journal article (peer-reviewed)abstract
- Objectives We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD). Background Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers. Methods The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports. Results A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of >= 2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups. Conclusions The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study. (J Am Coll Cardiol 2010;56:1552-63) (C) 2010 by the American College of Cardiology Foundation
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| 44. |
- Berndt, Sonja I., et al.
(author)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
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Journal article (peer-reviewed)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 45. |
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| 46. |
- Mauritsen, Thorsten, et al.
(author)
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Developments in the MPI-M Earth System Model version 1.2 (MPI-ESM1.2) and Its Response to Increasing CO2
- 2019
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In: Journal of Advances in Modeling Earth Systems. - 1942-2466. ; 11:4, s. 998-1038
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Journal article (peer-reviewed)abstract
- A new release of the Max Planck Institute for Meteorology Earth System Model version 1.2 (MPI-ESM1.2) is presented. The development focused on correcting errors in and improving the physical processes representation, as well as improving the computational performance, versatility, and overall user friendliness. In addition to new radiation and aerosol parameterizations of the atmosphere, several relatively large, but partly compensating, coding errors in the model's cloud, convection, and turbulence parameterizations were corrected. The representation of land processes was refined by introducing a multilayer soil hydrology scheme, extending the land biogeochemistry to include the nitrogen cycle, replacing the soil and litter decomposition model and improving the representation of wildfires. The ocean biogeochemistry now represents cyanobacteria prognostically in order to capture the response of nitrogen fixation to changing climate conditions and further includes improved detritus settling and numerous other refinements. As something new, in addition to limiting drift and minimizing certain biases, the instrumental record warming was explicitly taken into account during the tuning process. To this end, a very high climate sensitivity of around 7 K caused by low-level clouds in the tropics as found in an intermediate model version was addressed, as it was not deemed possible to match observed warming otherwise. As a result, the model has a climate sensitivity to a doubling of CO2 over preindustrial conditions of 2.77 K, maintaining the previously identified highly nonlinear global mean response to increasing CO2 forcing, which nonetheless can be represented by a simple two-layer model.
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| 47. |
- Porth, Oliver, et al.
(author)
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The Event Horizon General Relativistic Magnetohydrodynamic Code Comparison Project
- 2019
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In: Astrophysical Journal, Supplement Series. - : American Astronomical Society. - 1538-4365 .- 0067-0049. ; 243:2
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Journal article (peer-reviewed)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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| 48. |
- Schnabel, Renate B, et al.
(author)
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Early diagnosis and better rhythm management to improve outcomes in patients with atrial fibrillation : the 8th AFNET/EHRA consensus conference
- 2023
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In: Europace. - : Oxford University Press. - 1099-5129 .- 1532-2092. ; 25:1, s. 6-27
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Journal article (peer-reviewed)abstract
- Despite marked progress in the management of atrial fibrillation (AF), detecting AF remains difficult and AF-related complications cause unacceptable morbidity and mortality even on optimal current therapy. This document summarizes the key outcomes of the 8th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Eighty-three international experts met in Hamburg for 2 days in October 2021. Results of the interdisciplinary, hybrid discussions in breakout groups and the plenary based on recently published and unpublished observations are summarized in this consensus paper to support improved care for patients with AF by guiding prevention, individualized management, and research strategies. The main outcomes are (i) new evidence supports a simple, scalable, and pragmatic population-based AF screening pathway; (ii) rhythm management is evolving from therapy aimed at improving symptoms to an integrated domain in the prevention of AF-related outcomes, especially in patients with recently diagnosed AF; (iii) improved characterization of atrial cardiomyopathy may help to identify patients in need for therapy; (iv) standardized assessment of cognitive function in patients with AF could lead to improvement in patient outcomes; and (v) artificial intelligence (AI) can support all of the above aims, but requires advanced interdisciplinary knowledge and collaboration as well as a better medico-legal framework. Implementation of new evidence-based approaches to AF screening and rhythm management can improve outcomes in patients with AF. Additional benefits are possible with further efforts to identify and target atrial cardiomyopathy and cognitive impairment, which can be facilitated by AI.
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| 49. |
- Schosserer, Markus, et al.
(author)
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Methylation of ribosomal RNA by NSUN5 is a conserved mechanism modulating organismal lifespan
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6:1
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Journal article (peer-reviewed)abstract
- Several pathways modulating longevity and stress resistance converge on translation by targeting ribosomal proteins or initiation factors, but whether this involves modifications of ribosomal RNA is unclear. Here, we show that reduced levels of the conserved RNA methyltransferase NSUN5 increase the lifespan and stress resistance in yeast, worms and flies. Rcm1, the yeast homologue of NSUN5, methylates C2278 within a conserved region of 25S rRNA. Loss of Rcm1 alters the structural conformation of the ribosome in close proximity to C2278, as well as translational fidelity, and favours recruitment of a distinct subset of oxidative stress-responsive mRNAs into polysomes. Thus, rather than merely being a static molecular machine executing translation, the ribosome exhibits functional diversity by modification of just a single rRNA nucleotide, resulting in an alteration of organismal physiological behaviour, and linking rRNA-mediated translational regulation to modulation of lifespan, and differential stress response.
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| 50. |
- Scutelnic, Adrian, et al.
(author)
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Management of Cerebral Venous Thrombosis Due to Adenoviral COVID-19 Vaccination.
- 2022
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In: Annals of neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 92:4, s. 562-573
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Journal article (peer-reviewed)abstract
- Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality.We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis.Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p<0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR]=0.43, 95% confidence interval [CI]=0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR=0.19, 95% CI=0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR=0.70, 95% CI=0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR=2.19, 95% CI=0.74-6.54).In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573.
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