| 1. |
- Ruilope, LM, et al.
(author)
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Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
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In: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Journal article (peer-reviewed)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
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| 2. |
- Fenstermacher, M.E., et al.
(author)
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DIII-D research advancing the physics basis for optimizing the tokamak approach to fusion energy
- 2022
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In: Nuclear Fusion. - : IOP Publishing. - 0029-5515 .- 1741-4326. ; 62:4
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Journal article (peer-reviewed)abstract
- DIII-D physics research addresses critical challenges for the operation of ITER and the next generation of fusion energy devices. This is done through a focus on innovations to provide solutions for high performance long pulse operation, coupled with fundamental plasma physics understanding and model validation, to drive scenario development by integrating high performance core and boundary plasmas. Substantial increases in off-axis current drive efficiency from an innovative top launch system for EC power, and in pressure broadening for Alfven eigenmode control from a co-/counter-I p steerable off-axis neutral beam, all improve the prospects for optimization of future long pulse/steady state high performance tokamak operation. Fundamental studies into the modes that drive the evolution of the pedestal pressure profile and electron vs ion heat flux validate predictive models of pedestal recovery after ELMs. Understanding the physics mechanisms of ELM control and density pumpout by 3D magnetic perturbation fields leads to confident predictions for ITER and future devices. Validated modeling of high-Z shattered pellet injection for disruption mitigation, runaway electron dissipation, and techniques for disruption prediction and avoidance including machine learning, give confidence in handling disruptivity for future devices. For the non-nuclear phase of ITER, two actuators are identified to lower the L-H threshold power in hydrogen plasmas. With this physics understanding and suite of capabilities, a high poloidal beta optimized-core scenario with an internal transport barrier that projects nearly to Q = 10 in ITER at ∼8 MA was coupled to a detached divertor, and a near super H-mode optimized-pedestal scenario with co-I p beam injection was coupled to a radiative divertor. The hybrid core scenario was achieved directly, without the need for anomalous current diffusion, using off-axis current drive actuators. Also, a controller to assess proximity to stability limits and regulate β N in the ITER baseline scenario, based on plasma response to probing 3D fields, was demonstrated. Finally, innovative tokamak operation using a negative triangularity shape showed many attractive features for future pilot plant operation.
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| 3. |
- Abdo, A. A., et al.
(author)
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FERMI LARGE AREA TELESCOPE DETECTION OF PULSED gamma-RAYS FROM THE VELA-LIKE PULSARS PSR J1048-5832 AND PSR J2229+6114
- 2009
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 706:2, s. 1331-1340
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Journal article (peer-reviewed)abstract
- We report the detection of gamma-ray pulsations (>= 0.1GeV) from PSR J2229+ 6114 and PSR J1048-5832, the latter having been detected as a low-significance pulsar by EGRET. Data in the gamma-ray band were acquired by the Large Area Telescope (LAT) aboard the Fermi Gamma-ray Space Telescope, while the radio rotational ephemerides used to fold the gamma-ray light curves were obtained using the Green Bank Telescope, the Lovell telescope at Jodrell Bank, and the Parkes Telescope. The two young radio pulsars, located within the error circles of the previously unidentified EGRET sources 3EG J1048-5840 and 3EG J2227+6122, present spin-down characteristics similar to the Vela pulsar. PSR J1048-5832 shows two sharp peaks at phases 0.15 +/- 0.01 and 0.57 +/- 0.01 relative to the radio pulse confirming the EGRET light curve, while PSR J2229+ 6114 presents a very broad peak at phase 0.49 +/- 0.01. The gamma-ray spectra above 0.1 GeV of both pulsars are fit with power laws having exponential cutoffs near 3 GeV, leading to integral photon fluxes of (2.19 +/- 0.22 +/- 0.32) x 10(-7) cm(-2) s(-1) for PSR J1048-5832 and (3.77 +/- 0.22 +/- 0.44) x 10(-7) cm(-2) s(-1) for PSR J2229+6114. The first uncertainty is statistical and the second is systematic. PSR J1048-5832 is one of the two LAT sources whichwere entangled together as 3EG J1048-5840. These detections add to the growing number of young gamma-ray pulsars that make up the dominant population of GeV gamma-ray sources in the Galactic plane.
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| 4. |
- Abdo, A. A., et al.
(author)
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Fermi Large Area Telescope Detection of Pulsed γ-rays from the Vela-like Pulsars PSR J1048–5832 and PSR J2229+6114
- 2009
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 706:2, s. 1331-1340
-
Journal article (peer-reviewed)abstract
- We report the detection of γ-ray pulsations (>=0.1 GeV) from PSR J2229+6114 and PSR J1048–5832, the latter having been detected as a low-significance pulsar by EGRET. Data in the γ-ray band were acquired by the Large Area Telescope (LAT) aboard the Fermi Gamma-ray Space Telescope, while the radio rotational ephemerides used to fold the γ-ray light curves were obtained using the Green Bank Telescope, the Lovell telescope at Jodrell Bank, and the Parkes Telescope. The two young radio pulsars, located within the error circles of the previously unidentified EGRET sources 3EG J1048–5840 and 3EG J2227+6122, present spin-down characteristics similar to the Vela pulsar. PSR J1048–5832 shows two sharp peaks at phases 0.15 ± 0.01 and 0.57 ± 0.01 relative to the radio pulse confirming the EGRET light curve, while PSR J2229+6114 presents a very broad peak at phase 0.49 ± 0.01. The γ-ray spectra above 0.1 GeV of both pulsars are fit with power laws having exponential cutoffs near 3 GeV, leading to integral photon fluxes of (2.19 ± 0.22 ± 0.32) × 10–7 cm–2 s–1 for PSR J1048–5832 and (3.77 ± 0.22 ± 0.44) × 10–7 cm–2 s–1 for PSR J2229+6114. The first uncertainty is statistical and the second is systematic. PSR J1048–5832 is one of the two LAT sources which were entangled together as 3EG J1048–5840. These detections add to the growing number of young γ-ray pulsars that make up the dominant population of GeV γ-ray sources in the Galactic plane.
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| 5. |
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| 6. |
- Ogishi, M, et al.
(author)
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Impaired IL-23-dependent induction of IFN-γ underlies mycobacterial disease in patients with inherited TYK2 deficiency
- 2022
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 219:10
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Journal article (peer-reviewed)abstract
- Human cells homozygous for rare loss-of-expression (LOE) TYK2 alleles have impaired, but not abolished, cellular responses to IFN-α/β (underlying viral diseases in the patients) and to IL-12 and IL-23 (underlying mycobacterial diseases). Cells homozygous for the common P1104A TYK2 allele have selectively impaired responses to IL-23 (underlying isolated mycobacterial disease). We report three new forms of TYK2 deficiency in six patients from five families homozygous for rare TYK2 alleles (R864C, G996R, G634E, or G1010D) or compound heterozygous for P1104A and a rare allele (A928V). All these missense alleles encode detectable proteins. The R864C and G1010D alleles are hypomorphic and loss-of-function (LOF), respectively, across signaling pathways. By contrast, hypomorphic G996R, G634E, and A928V mutations selectively impair responses to IL-23, like P1104A. Impairment of the IL-23–dependent induction of IFN-γ is the only mechanism of mycobacterial disease common to patients with complete TYK2 deficiency with or without TYK2 expression, partial TYK2 deficiency across signaling pathways, or rare or common partial TYK2 deficiency specific for IL-23 signaling.
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| 7. |
- Clark, Andrew G., et al.
(author)
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Evolution of genes and genomes on the Drosophila phylogeny
- 2007
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 450:7167, s. 203-218
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Journal article (peer-reviewed)abstract
- Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.
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| 8. |
- Archambault, S., et al.
(author)
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Discovery of a New TeV Gamma-Ray Source : VER J0521+211
- 2013
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In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 776:2
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Journal article (peer-reviewed)abstract
- We report the detection of a new TeV gamma-ray source, VER J0521+211, based on observations made with the VERITAS imaging atmospheric Cherenkov Telescope Array. These observations were motivated by the discovery of a cluster of >30 GeV photons in the first year of Fermi Large Area Telescope observations. VER J0521+211 is relatively bright at TeV energies, with a mean photon flux of (1.93 ± 0.13stat ± 0.78sys) × 10–11 cm–2 s–1 above 0.2 TeV during the period of the VERITAS observations. The source is strongly variable on a daily timescale across all wavebands, from optical to TeV, with a peak flux corresponding to ~0.3 times the steady Crab Nebula flux at TeV energies. Follow-up observations in the optical and X-ray bands classify the newly discovered TeV source as a BL Lac-type blazar with uncertain redshift, although recent measurements suggest z = 0.108. VER J0521+211 exhibits all the defining properties of blazars in radio, optical, X-ray, and gamma-ray wavelengths.
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