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1.
  • Murari, A., et al. (författare)
  • A control oriented strategy of disruption prediction to avoid the configuration collapse of tokamak reactors
  • 2024
  • Ingår i: Nature Communications. - 2041-1723 .- 2041-1723. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The objective of thermonuclear fusion consists of producing electricity from the coalescence of light nuclei in high temperature plasmas. The most promising route to fusion envisages the confinement of such plasmas with magnetic fields, whose most studied configuration is the tokamak. Disruptions are catastrophic collapses affecting all tokamak devices and one of the main potential showstoppers on the route to a commercial reactor. In this work we report how, deploying innovative analysis methods on thousands of JET experiments covering the isotopic compositions from hydrogen to full tritium and including the major D-T campaign, the nature of the various forms of collapse is investigated in all phases of the discharges. An original approach to proximity detection has been developed, which allows determining both the probability of and the time interval remaining before an incoming disruption, with adaptive, from scratch, real time compatible techniques. The results indicate that physics based prediction and control tools can be developed, to deploy realistic strategies of disruption avoidance and prevention, meeting the requirements of the next generation of devices.
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  • Roberts, Jason D., et al. (författare)
  • Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
  • 2019
  • Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 129:8, s. 3171-3184
  • Tidskriftsartikel (refereegranskat)abstract
    • Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease.
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6.
  • Berg, Danielle A., et al. (författare)
  • The COS Legacy Archive Spectroscopy Survey (CLASSY) Treasury Atlas
  • 2022
  • Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 261:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Far-ultraviolet (FUV; ∼1200–2000 Å) spectra are fundamental to our understanding of star-forming galaxies, providing a unique window on massive stellar populations, chemical evolution, feedback processes, and reionization. The launch of the James Webb Space Telescope will soon usher in a new era, pushing the UV spectroscopic frontier to higher redshifts than ever before; however, its success hinges on a comprehensive understanding of the massive star populations and gas conditions that power the observed UV spectral features. This requires a level of detail that is only possible with a combination of ample wavelength coverage, signal-to-noise, spectral-resolution, and sample diversity that has not yet been achieved by any FUV spectral database. We present the Cosmic Origins Spectrograph Legacy Spectroscopic Survey (CLASSY) treasury and its first high-level science product, the CLASSY atlas. CLASSY builds on the Hubble Space Telescope (HST) archive to construct the first high-quality (S/N1500 Å ≳ 5/resel), high-resolution (R ∼ 15,000) FUV spectral database of 45 nearby (0.002 < z < 0.182) star-forming galaxies. The CLASSY atlas, available to the public via the CLASSY website, is the result of optimally extracting and coadding 170 archival+new spectra from 312 orbits of HST observations. The CLASSY sample covers a broad range of properties including stellar mass (6.2 < log M⋆(M⊙) < 10.1), star formation rate (−2.0 < log SFR (M⊙ yr−1) < +1.6), direct gas-phase metallicity (7.0 < 12+log(O/H) < 8.8), ionization (0.5 < O32 < 38.0), reddening (0.02 < E(B − V) < 0.67), and nebular density (10 < ne (cm−3) < 1120). CLASSY is biased to UV-bright star-forming galaxies, resulting in a sample that is consistent with the z ∼ 0 mass–metallicity relationship, but is offset to higher star formation rates by roughly 2 dex, similar to z ≳ 2 galaxies. This unique set of properties makes the CLASSY atlas the benchmark training set for star-forming galaxies across cosmic time.
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7.
  • James, Bethan L., et al. (författare)
  • CLASSY. II. A Technical Overview of the COS Legacy Archive Spectroscopic Survey
  • 2022
  • Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 262:2
  • Tidskriftsartikel (refereegranskat)abstract
    • The COS Legacy Archive Spectroscopic SurveY (CLASSY) is designed to provide the community with a spectral atlas of 45 nearby star-forming galaxies that were chosen to cover similar properties to those seen at high z (z > 6). The prime high-level science product of CLASSY is accurately coadded UV spectra, ranging from ∼1000 to 2000 Å, derived from a combination of archival and new data obtained with HST's Cosmic Origins Spectrograph (COS). This paper details the multistage technical processes of creating this prime data product and the methodologies involved in extracting, reducing, aligning, and coadding far-ultraviolet and near-ultraviolet (NUV) spectra. We provide guidelines on how to successfully utilize COS observations of extended sources, despite COS being optimized for point sources, and best-practice recommendations for the coaddition of UV spectra in general. Moreover, we discuss the effects of our reduction and coaddition techniques in the scientific application of the CLASSY data. In particular, we find that accurately accounting for flux calibration offsets can affect the derived properties of the stellar populations, while customized extractions of NUV spectra for extended sources are essential for correctly diagnosing the metallicity of galaxies via C iii] nebular emission. Despite changes in spectral resolution of up to ∼25% between individual data sets (due to changes in the COS line-spread function), no adverse affects were observed on the difference in velocity width and outflow velocities of isolated absorption lines when measured in the final combined data products, owing in part to our signal-to-noise regime of S/N < 20.
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8.
  • Sakornsakolpat, Phuwanat, et al. (författare)
  • Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations
  • 2019
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 51:3, s. 494-505
  • Tidskriftsartikel (refereegranskat)abstract
    • Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 x 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.
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9.
  • Turtelboom,, et al. (författare)
  • The TESS-Keck Survey. XI. Mass Measurements for Four Transiting Sub-Neptunes Orbiting K Dwarf TOI-1246
  • 2022
  • Ingår i: Astronomical Journal. - : American Astronomical Society. - 1538-3881 .- 0004-6256. ; 163:6
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiplanet systems are valuable arenas for investigating exoplanet architectures and comparing planetary siblings. TOI-1246 is one such system, with a moderately bright K dwarf (V = 11.6, K = 9.9) and four transiting sub-Neptunes identified by TESS with orbital periods of 4.31, 5.90, 18.66, and 37.92 days. We collected 130 radial velocity observations with Keck/HIRES and TNG/HARPS-N to measure planet masses. We refit the 14 sectors of TESS photometry to refine planet radii (2.97 +/- 0.06 R (circle plus), 2.47 +/- 0.08 R (circle plus), 3.46 +/- 0.09 R (circle plus), and 3.72 +/- 0.16 R (circle plus)) and confirm the four planets. We find that TOI-1246 e is substantially more massive than the three inner planets (8.1 +/- 1.1 M (circle plus), 8.8 +/- 1.2 M (circle plus), 5.3 +/- 1.7 M (circle plus), and 14.8 +/- 2.3 M (circle plus)). The two outer planets, TOI-1246 d and TOI-1246 e, lie near to the 2:1 resonance (P (e)/P ( d ) = 2.03) and exhibit transit-timing variations. TOI-1246 is one of the brightest four-planet systems, making it amenable for continued observations. It is one of only five systems with measured masses and radii for all four transiting planets. The planet densities range from 0.70 +/- 0.24 to 3.21 +/- 0.44 g cm(-3), implying a range of bulk and atmospheric compositions. We also report a fifth planet candidate found in the RV data with a minimum mass of 25.6 +/- 3.6 M (circle plus). This planet candidate is exterior to TOI-1246 e, with a candidate period of 93.8 days, and we discuss the implications if it is confirmed to be planetary in nature.
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10.
  • Arellano-Cordova, Karla Z., et al. (författare)
  • CLASSY V : The Impact of Aperture Effects on the Inferred Nebular Properties of Local Star-forming Galaxies
  • 2022
  • Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 935:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Strong nebular emission lines are an important diagnostic tool for tracing the evolution of star-forming galaxies across cosmic time. However, different observational setups can affect these lines, and the derivation of the physical nebular properties. We analyze 12 local star-forming galaxies from the COS Legacy Spectroscopy SurveY (CLASSY) to assess the impact of using different aperture combinations on the determination of the physical conditions and gas-phase metallicity. We compare optical spectra observed with the Sloan Digital Sky Survey Data Release aperture, which has a 3'' diameter similar to COS, IFU, and long-slit spectra, including new LBT/MODS observations of five CLASSY galaxies. We calculate the reddening, electron densities and temperatures, metallicities, star formation rates, and equivalent widths (EWs). We find that measurements of the electron densities and temperatures, and metallicity remained roughly constant with aperture size, indicating that the gas conditions are relatively uniform for this sample. However, using IFU observations of three galaxies, we find that the E(B − V) values derived from the Balmer ratios decrease (by up to 53%) with increasing aperture size. The values change most significantly in the center of the galaxies, and level out near the COS aperture diameter of 2 5. We examine the relative contributions from the gas and stars using the Hα and [O iii] λ5007 EWs as a function of aperture light fraction, but find little to no variations within a given galaxy. These results imply that the optical spectra provide nebular properties appropriate for the far-UV CLASSY spectra, even when narrow 1 0 long-slit observations are used.
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11.
  • Gazagnes, Simon, et al. (författare)
  • Interpreting the Si ii and C ii Line Spectra from the COS Legacy Archive Spectroscopic SurveY Using a Virtual Galaxy from a High-resolution Radiation-hydrodynamic Simulation
  • 2023
  • Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 952:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Observations of low-ionization state metal lines provide crucial insights into the interstellar medium (ISM) of galaxies, yet, disentangling the physical processes responsible for the emerging line profiles is difficult. This work investigates how mock spectra generated using a single galaxy in a radiation-hydrodynamical simulation can help us interpret observations of a real galaxy. We create 22,500 C ii and Si ii spectra from the virtual galaxy at different times and through multiple lines of sight and compare them with the 45 observations of low-redshift star-forming galaxies from the COS Legacy Spectroscopic SurveY (classy). We find that the mock profiles provide accurate replicates of the observations of 38 galaxies with a broad range of stellar masses (106–109M⊙) and metallicities (0.02–0.55 Z⊙). Additionally, we highlight that aperture losses explain the weakness of the fluorescent emission in several classy spectra and must be accounted for when comparing simulations to observations. Overall, we show that the evolution of a single simulated galaxy can produce a large diversity of spectra whose properties are representative of galaxies of comparable or smaller masses. Building upon these results, we explore the origin of the continuum, residual flux, and fluorescent emission in the simulation. We find that these different spectral features all emerge from distinct regions in the galaxy's ISM, and their characteristics can vary as a function of the viewing angle. While these outcomes challenge simplified interpretations of down-the-barrel spectra, our results indicate that high-resolution simulations provide an optimal framework to interpret these observations.
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12.
  • Hu, Weida, et al. (författare)
  • CLASSY VII Lyα Profiles : The Structure and Kinematics of Neutral Gas and Implications for LyC Escape in Reionization-era Analogs
  • 2023
  • Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 956:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Lyα line profiles are a powerful probe of interstellar medium (ISM) structure, outflow speed, and Lyman-continuum escape fraction. In this paper, we present the Lyα line profiles of the Cosmic Origins Spectrograph (COS) Legacy Archive Spectroscopic SurveY, a sample rich in spectroscopic analogs of reionization-era galaxies. A large fraction of the spectra show a complex profile, consisting of a double-peaked Lyα emission profile in the bottom of a damped, Lyα absorption trough. Such profiles reveal an inhomogeneous ISM. We successfully fit the damped Lyα absorption and the Lyα emission profiles separately, but with complementary covering factors, a surprising result because this approach requires no Lyα exchange between high-NH i and low-NH i paths. The combined distribution of column densities is qualitatively similar to the bimodal distributions observed in numerical simulations. We find an inverse relation between Lyα peak separation and the [O iii]/[O ii] flux ratio, confirming that the covering fraction of Lyman-continuum-thin sightlines increases as the Lyα peak separation decreases. We combine measurements of Lyα peak separation and Lyα red peak asymmetry in a diagnostic diagram, which identifies six Lyman-continuum leakers in the COS Legacy Archive Spectrocopy SurveY (CLASSY) sample. We find a strong correlation between the Lyα trough velocity and the outflow velocity measured from interstellar absorption lines. We argue that greater vignetting of the blueshifted Lyα peak, relative to the redshifted peak, is the source of the well-known discrepancy between shell-model parameters and directly measured outflow properties. The CLASSY sample illustrates how scattering of Lyα photons outside the spectroscopic aperture reshapes Lyα profiles because the distances to these compact starbursts span a large range.
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13.
  • Lakens, Daniel, et al. (författare)
  • Justify your alpha
  • 2018
  • Ingår i: Nature Human Behaviour. - : Nature Publishing Group. - 2397-3374. ; 2:3, s. 168-171
  • Tidskriftsartikel (refereegranskat)abstract
    • In response to recommendations to redefine statistical significance to P ≤ 0.005, we propose that researchers should transparently report and justify all choices they make when designing a study, including the alpha level.
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14.
  • Mingozzi, Matilde, et al. (författare)
  • CLASSY IV. Exploring UV Diagnostics of the Interstellar Medium in Local High-z Analogs at the Dawn of the JWST Era
  • 2022
  • Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 939:2
  • Tidskriftsartikel (refereegranskat)abstract
    • The Cosmic Origins Spectrograph (COS) Legacy Archive Spectroscopic SurveY (CLASSY) provides the first high-resolution spectral catalog of 45 local high-z analogs in the ultraviolet (UV; 1200–2000 Å) to investigate their stellar and gas properties. Here we present a toolkit of UV interstellar medium (ISM) diagnostics, analyzing the main emission lines of CLASSY spectra (N iv] λλ1483,87, C iv λλ1548,51, He iiλ1640, O iii]λλ1661,6, Si iii] λλ1883,92, C iii] λ1907,9). Specifically, our aim is to provide accurate diagnostics for the reddening E(B − V), electron density ne, electron temperature Te, metallicity 12+log(O/H), and ionization parameter log(U), taking the different ISM ionization zones into account. We calibrate our UV toolkit using well-known optical diagnostics, analyzing archival optical spectra for all CLASSY targets. We find that UV density diagnostics estimate ne values that are ∼1–2 dex higher (e.g., ne(C iii]λλ1907,9) ∼ 104 cm−3) than those inferred from their optical counterparts (e.g., ne([S ii]λλ6717,31) ∼ 102 cm−3; ne([Ar iv]λλ4714,41) ∼ 103 cm−3). Te derived from the hybrid ratio [O iii] λ1666/λ5007 proves to be reliable, implying differences in determining 12+log(O/H) compared to the optical counterpart O iii] λ4363/[O iii] λ5007 within ∼ ±0.3 dex. We also investigate the relation between the stellar and gas E(B − V), finding consistent values at high specific star formation rates (sSFRs; log(sSFR)  ≳ -8 yr−1), while at low sSFRs we confirmed an excess of dust attenuation in the gas. Finally, we investigate UV line ratios and equivalent widths to provide correlations with 12+log(O/H) and log(U), but note that there are degeneracies between the two. With this suite of UV-based diagnostics, we illustrate the pivotal role CLASSY plays in understanding the chemical and physical properties of high-z systems that JWST can observe in the rest-frame UV.
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15.
  • Mingozzi, Matilde, et al. (författare)
  • CLASSY. VIII. Exploring the Source of Ionization with UV Interstellar Medium Diagnostics in Local High-z Analogs
  • 2024
  • Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 962:1
  • Tidskriftsartikel (refereegranskat)abstract
    • In the current JWST era, rest-frame UV spectra play a crucial role in enhancing our understanding of the interstellar medium (ISM) and stellar properties of the first galaxies in the epoch of reionization (z > 6). Here, we compare well-known and reliable optical diagrams sensitive to the main ionization source (i.e., star formation, SF; active galactic nuclei, AGN; and shocks) to UV counterparts proposed in the literature—the so-called "UV–BPT diagrams"—using the HST COS Legacy Archive Spectroscopic SurveY (CLASSY), which is the largest high-quality, high-resolution, and broad-wavelength range atlas of far-UV spectra for 45 local star-forming galaxies. In particular, we explore where CLASSY UV line ratios are located in the different UV diagnostic plots, taking into account state-of-the-art photoionization and shock models, and, for the first time, the measured ISM and stellar properties (e.g., gas-phase metallicity, ionization parameter, carbon abundance, and stellar age). We find that the combination of C iii] λλ1907,9 He iiλ1640 and O iii] λ1666 can be a powerful tool to separate between SF, shocks, and AGN at subsolar metallicities. We also confirm that alternative diagrams without O iii] λ1666 still allow us to define an SF-locus, with some caveats. Diagrams including C ivλλ1548,51 should be taken with caution given the complexity of this doublet profile. Finally, we present a discussion detailing the ISM conditions required to detect UV emission lines, visible only in low gas-phase metallicity (12 + log(O/H) ≲ 8.3) and high ionization parameter (log(U) ≳ −2.5) environments. Overall, CLASSY and our UV toolkit will be crucial in interpreting the spectra of the earliest galaxies that JWST is currently revealing.
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16.
  • Xu, Xinfeng, et al. (författare)
  • CLASSY III. The Properties of Starburst-driven Warm Ionized Outflows
  • 2022
  • Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 933:2
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the results of analyses of galactic outflows in a sample of 45 low-redshift starburst galaxies in the COS Legacy Archive Spectroscopic SurveY (CLASSY), augmented by five additional similar starbursts with Cosmic Origins Spectrograph (COS) data. The outflows are traced by blueshifted absorption lines of metals spanning a wide range of ionization potential. The high quality and broad spectral coverage of CLASSY data enable us to disentangle the absorption due to the static interstellar medium (ISM) from that due to outflows. We further use different line multiplets and doublets to determine the covering fraction, column density, and ionization state as a function of velocity for each outflow. We measure the outflow's mean velocity and velocity width, and find that both correlate in a highly significant way with the star formation rate, galaxy mass, and circular velocity over ranges of four orders of magnitude for the first two properties. We also estimate outflow rates of metals, mass, momentum, and kinetic energy. We find that, at most, only about 20% of silicon created and ejected by supernovae in the starburst is carried out in the warm phase we observe. The outflows' mass-loading factor increases steeply and inversely with both circular and outflow velocity (log–log slope ∼−1.6), and reaches ∼10 for dwarf galaxies. We find that the outflows typically carry about 10%–100% of the momentum injected by massive stars and about 1%–20% of the kinetic energy. We show that these results place interesting constraints on, and new insights into, models and simulations of galactic winds.
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17.
  • Xu, Xinfeng, et al. (författare)
  • CLASSY. VI. The Density, Structure, and Size of Absorption-line Outflows in Starburst Galaxies
  • 2023
  • Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 948:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Galaxy formation and evolution are regulated by the feedback from galactic winds. Absorption lines provide the most widely available probe of winds. However, since most data only provide information integrated along the line of sight, they do not directly constrain the radial structure of the outflows. In this paper, we present a method to directly measure the gas electron density in outflows (n ( e )), which in turn yields estimates of outflow cloud properties (e.g., density, volume filling factor, and sizes/masses). We also estimate the distance (r ( n )) from the starburst at which the observed densities are found. We focus on 22 local star-forming galaxies primarily from the COS Legacy Archive Spectroscopic SurveY (CLASSY). In half of them, we detect absorption lines from fine-structure excited transitions of Si ii (i.e., Si ii*). We determine n ( e ) from relative column densities of Si ii and Si ii*, given Si ii* originates from collisional excitation by free electrons. We find that the derived n ( e ) correlates well with the galaxy's star formation rate per unit area. From photoionization models or assuming the outflow is in pressure equilibrium with the wind fluid, we get r ( n ) similar to 1-2r (*) or similar to 5r (*), respectively, where r (*) is the starburst radius. Based on comparisons to theoretical models of multiphase outflows, nearly all of the outflows have cloud sizes large enough for the clouds to survive their interaction with the hot wind fluid. Most of these measurements are the first ever for galactic winds detected in absorption lines and, thus, will provide important constraints for future models of galactic winds.
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18.
  • Bagley, Micaela B., et al. (författare)
  • A High Space Density of Luminous Ly alpha Emitters at z similar to 6.5
  • 2017
  • Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 837:1
  • Tidskriftsartikel (refereegranskat)abstract
    • We present the results of a systematic search for Ly alpha emitters (LAEs) at 6 less than or similar to z less than or similar to 7.6 using the HST WFC3 Infrared Spectroscopic Parallel (WISP) Survey. Our total volume over this redshift range is similar to 8 x 10(5) Mpc(3), comparable to many of the narrowband surveys despite their larger area coverage. We find two LAEs at z = 6.38 and 6.44 with line luminosities of L-Lya similar to 4.7 x 10(43) erg s(-1), putting them among the brightest LAEs discovered at these redshifts. Taking advantage of the broad spectral coverage of WISP, we are able to rule out almost all lower-redshift contaminants. The WISP LAEs have a high number density of 7.7 x 10(-6) Mpc (3). We argue that the LAEs reside in megaparsec-scale ionized bubbles that allow the Ly alpha photons to redshift out of resonance before encountering the neutral intergalactic medium. We discuss possible ionizing sources and conclude that the observed LAEs alone are not sufficient to ionize the bubbles.
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19.
  • Benson, Tyler W., et al. (författare)
  • Gut Microbiota-Derived Trimethylamine N-Oxide Contributes to Abdominal Aortic Aneurysm Through Inflammatory and Apoptotic Mechanisms
  • 2023
  • Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 0009-7322 .- 1524-4539. ; 147:14, s. 1079-1096
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:Large-scale human and mechanistic mouse studies indicate a strong relationship between the microbiome-dependent metabolite trimethylamine N-oxide (TMAO) and several cardiometabolic diseases. This study aims to investigate the role of TMAO in the pathogenesis of abdominal aortic aneurysm (AAA) and target its parent microbes as a potential pharmacological intervention.Methods:TMAO and choline metabolites were examined in plasma samples, with associated clinical data, from 2 independent patient cohorts (N=2129 total). Mice were fed a high-choline diet and underwent 2 murine AAA models, angiotensin II infusion in low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice or topical porcine pancreatic elastase in C57BL/6J mice. Gut microbial production of TMAO was inhibited through broad-spectrum antibiotics, targeted inhibition of the gut microbial choline TMA lyase (CutC/D) with fluoromethylcholine, or the use of mice genetically deficient in flavin monooxygenase 3 (Fmo3(-/-)). Finally, RNA sequencing of in vitro human vascular smooth muscle cells and in vivo mouse aortas was used to investigate how TMAO affects AAA.Results:Elevated TMAO was associated with increased AAA incidence and growth in both patient cohorts studied. Dietary choline supplementation augmented plasma TMAO and aortic diameter in both mouse models of AAA, which was suppressed with poorly absorbed oral broad-spectrum antibiotics. Treatment with fluoromethylcholine ablated TMAO production, attenuated choline-augmented aneurysm initiation, and halted progression of an established aneurysm model. In addition, Fmo3(-/-) mice had reduced plasma TMAO and aortic diameters and were protected from AAA rupture compared with wild-type mice. RNA sequencing and functional analyses revealed choline supplementation in mice or TMAO treatment of human vascular smooth muscle cells-augmented gene pathways associated with the endoplasmic reticulum stress response, specifically the endoplasmic reticulum stress kinase PERK.Conclusions:These results define a role for gut microbiota-generated TMAO in AAA formation through upregulation of endoplasmic reticulum stress-related pathways in the aortic wall. In addition, inhibition of microbiome-derived TMAO may serve as a novel therapeutic approach for AAA treatment where none currently exist.
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20.
  • Moshontz, Hannah, et al. (författare)
  • The Psychological Science Accelerator: Advancing Psychology Through a Distributed Collaborative Network
  • 2018
  • Ingår i: Advances in Methods and Practices in Psychological Science. - : SAGE Publications. - 2515-2459 .- 2515-2467. ; 1:4, s. 501-515
  • Tidskriftsartikel (refereegranskat)abstract
    • Concerns about the veracity of psychological research have been growing. Many findings in psychological science are based on studies with insufficient statistical power and nonrepresentative samples, or may otherwise be limited to specific, ungeneralizable settings or populations. Crowdsourced research, a type of large-scale collaboration in which one or more research projects are conducted across multiple lab sites, offers a pragmatic solution to these and other current methodological challenges. The Psychological Science Accelerator (PSA) is a distributed network of laboratories designed to enable and support crowdsourced research projects. These projects can focus on novel research questions or replicate prior research in large, diverse samples. The PSA’s mission is to accelerate the accumulation of reliable and generalizable evidence in psychological science. Here, we describe the background, structure, principles, procedures, benefits, and challenges of the PSA. In contrast to other crowdsourced research networks, the PSA is ongoing (as opposed to time limited), efficient (in that structures and principles are reused for different projects), decentralized, diverse (in both subjects and researchers), and inclusive (of proposals, contributions, and other relevant input from anyone inside or outside the network). The PSA and other approaches to crowdsourced psychological science will advance understanding of mental processes and behaviors by enabling rigorous research and systematic examination of its generalizability.
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