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| 2. |
- Namkoong, H, et al.
(författare)
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DOCK2 is involved in the host genetics and biology of severe COVID-19
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 609:7928, s. 754-
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Tidskriftsartikel (refereegranskat)abstract
- Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
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| 4. |
- Ruilope, LM, et al.
(författare)
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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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Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
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Tidskriftsartikel (refereegranskat)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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| 6. |
- Mizuki, T., et al.
(författare)
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Orbital Characterization of GJ1108A System, and Comparison of Dynamical Mass with Model-derived Mass for Resolved Binaries
- 2018
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 865:2
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Tidskriftsartikel (refereegranskat)abstract
- We report an orbital characterization of GJ1108Aab that is a low-mass binary system in the pre-main-sequence phase. Via the combination of astrometry using adaptive optics and radial velocity measurements, an eccentric orbital solution of e = 0.63 is obtained, which might be induced by the Kozai-Lidov mechanism with a widely separated GJ1108B system. Combined with several observed properties, we confirm that the system is indeed young. Columba is the most probable moving group, to which the GJ1108A system belongs, although its membership to the group has not been established. If the age of Columba is assumed for GJ1108A, the dynamical masses of both GJ1108Aa and GJ1108Ab (M-dynamical,M-GJ1108Aa= 0.72 +/- 0.04 M-circle dot and M-dynamical,M-GJ1108Ab = 0.30 +/- 0.03 M-circle dot) are more massive than what an evolutionary model predicts based on the age and luminosities. We consider that the discrepancy in mass comparison can be attributed to an age uncertainty; the system is likely older than stars in Columba, and effects that are not implemented in classical models such as accretion history and magnetic activity are not preferred to explain the mass discrepancy. We also discuss the performance of the evolutionary model by compiling similar low-mass objects in the evolutionary state based on the literature. Consequently, it is suggested that the current model on average reproduces the mass of resolved low-mass binaries without any significant offsets.
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| 7. |
- Akiyama, E., et al.
(författare)
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DISCOVERY OF A DISK GAP CANDIDATE AT 20 AU IN TW HYDRAE
- 2015
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Ingår i: Astrophysical Journal Letters. - 2041-8205 .- 2041-8213. ; 802:2
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Tidskriftsartikel (refereegranskat)abstract
- We present a new Subaru/HiCIAO high-contrast H-band polarized intensity (PI) image of a nearby transitional disk associated with TW Hydrae. The scattered light from the disk was detected from 0 ''.2 to 1 ''.5 (11-81 AU) and the PI image shows a clear axisymmetric depression in PI at similar to 0 ''.4 (similar to 20 AU) from the central star, similar to the similar to 80 AU gap previously reported from Hubble Space Telescope images. The azimuthal PI profile also shows that the disk beyond 0 ''.2 is almost axisymmetric. We discuss two possible scenarios explaining the origin of the PI depression: (1) a gap structure may exist at similar to 20 AU from the central star because of a shallow slope seen in the PI profile, and (2) grain growth may be occurring in the inner region of the disk. Multi-band observations at near-infrared and millimeter/submillimeter wavelengths play a complementary role in investigating dust opacity and may help reveal the origin of the gap more precisely.
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| 8. |
- Grady, C., et al.
(författare)
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The outer disks of Herbig stars from the UV to NIR
- 2015
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Ingår i: Astrophysics and Space Science. - : Springer Science and Business Media LLC. - 0004-640X .- 1572-946X. ; 355:2, s. 253-266
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Forskningsöversikt (refereegranskat)abstract
- Spatially-resolved imaging of Herbig stars and related objects began with HST, but intensified with commissioning of high-contrast imagers on 8-m class telescopes. The bulk of the data taken from the ground have been polarized intensity imagery at H-band, with the majority of the sources observed as part of the Strategic Exploration of Exoplanets and Disks with Subaru (SEEDS) survey. Sufficiently many systems have been imaged that we discuss disk properties in scattered, polarized light in terms of groups defined by the IR spectral energy distribution. We find novel phenomena in many of the disks, including spiral density waves, and discuss the disks in terms of clearing mechanisms. Some of the disks have sufficient data to map the dust and gas components, including water ice dissociation products.
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| 9. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)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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| 10. |
- Helminiak, K. G., et al.
(författare)
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SEEDS DIRECT IMAGING OF THE RV-DETECTED COMPANION TO V450 ANDROMEDAE, AND CHARACTERIZATION OF THE SYSTEM
- 2016
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Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 832:1
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Tidskriftsartikel (refereegranskat)abstract
- We report the direct imaging detection of a low-mass companion to a young, moderately active star V450. And, that was previously identified with the radial velocity (RV) method. The companion was found in high-contrast images obtained with the Subaru Telescope equipped with the HiCIAO camera and AO188 adaptive optics system. From the public ELODIE and SOPHIE archives we extracted available high-resolution spectra and RV measurements, along with RVs from the Lick planet search program. We combined our multi-epoch astrometry with these archival, partially unpublished RVs, and found that the companion is a low-mass star, not a brown dwarf, as previously suggested. We found the best-fitting dynamical masses to be m(1) = 1.141(-0.091)(+0.037)and m(2) = 0.279(-0.020)(+0.023) M-circle dot. We also performed spectral analysis of the SOPHIE spectra with the iSpec code. Hipparcos time-series photometry shows a periodicity of P = 5.743 day, which is also seen in the SOPHIE spectra as an RV modulation of the star A. We interpret it as being caused by spots on the stellar surface, and the star to be rotating with the given period. From the rotation and level of activity, we found that the system is 380(-100)(+220) Myr old, consistent with an isochrone analysis (220(-90)(+2120) Myr). This work may serve as a test case for future studies of low-mass stars, brown dwarfs, and exoplanets by combination of RV and direct imaging data.
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| 11. |
- Asensio-Torres, Ruben, et al.
(författare)
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Polarimetry and flux distribution in the debris disk around HD 32297
- 2016
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 593
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Tidskriftsartikel (refereegranskat)abstract
- We present high-contrast angular differential imaging (ADI) observations of the debris disk around HD32297 in H-band, as well as the first polarimetric images for this system in polarized differential imaging (PDI) mode with Subaru/HICIAO. In ADI, we detect the nearly edge-on disk at > 5 sigma levels from similar to 0.45 '' to similar to 1.7 '' (50-192AU) from the star and recover the spine deviation from the midplane already found in previous works. We also find for the first time imaging and surface brightness (SB) indications for the presence of a gapped structure on both sides of the disk at distances of similar to 0.75 '' (NE side) and similar to 0.65 '' (SW side). Global forward-modelling work delivers a best-fit model disk and well-fitting parameter intervals that essentially match previous results, with high-forward scattering grains and a ring located at 110AU. However, this single ring model cannot account for the gapped structure seen in our SB profiles. We create simple double ring models and achieve a satisfactory fit with two rings located at 60 and 95AU, respectively, low-forward scattering grains and very sharp inner slopes. In polarized light we retrieve the disk extending from similar to 0.25-1.6 '', although the central region is quite noisy and high S/N are only found in the range similar to 0.75-1.2 ''. The disk is polarized in the azimuthal direction, as expected, and the departure from the midplane is also clearly observed. Evidence for a gapped scenario is not found in the PDI data. We obtain a linear polarization degree of the grains that increases from similar to 10% at 0.55 '' to similar to 25% at 1.6 ''. The maximum is found at scattering angles of similar to 90 degrees, either from the main components of the disk or from dust grains blown out to larger radii.
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| 12. |
- Garcia, E. Victor, et al.
(författare)
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SCExAO AND GPI Y JH BAND PHOTOMETRY AND INTEGRAL FIELD SPECTROSCOPY OF THE YOUNG BROWN DWARF COMPANION TO HD 1160
- 2017
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 834:2
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Tidskriftsartikel (refereegranskat)abstract
- We present high signal-to-noise ratio, precise Y JH photometry and Y band (0.957-1.120 mu m) spectroscopy of HD 1160 B, a young substellar companion discovered from the Gemini NICI Planet Finding Campaign using the Subaru Coronagraphic Extreme Adaptive Optics instrument and the Gemini Planet Imager. HD 1160 B has typical mid-M dwarf-like infrared colors and a spectral type of M5.5(-0.5)(+1.0), where the blue edge of our Y band spectrum rules out earlier spectral types. Atmospheric modeling suggests HD 1160 B has an effective temperature of 3000-3100 K, a surface gravity of log g - 4-4.5, a radius of. 1.55 +/- 0.10 R-J, and a luminosity of log L/L circle dot - 2.76 +/- 0.05. Neither the primary's Hertzspring-Russell diagram position nor atmospheric modeling of HD 1160 B show evidence for a subsolar metallicity. Interpretation of the HD 1160 B spectroscopy depends on which stellar system components are used to estimate the age. Considering HD 1160 A, B and C jointly, we derive an age of 80-125 Myr, implying that HD 1160 B straddles the hydrogen-burning limit (70-90 M-J) If we consider HD 1160 A alone, younger ages (20-125 Myr) and a brown dwarf-like mass (35-90 M-J) are possible. Interferometric measurements of the primary, a precise Gaia parallax, and moderate-resolution spectroscopy can better constrain the system's age and how HD 1160 B fits within the context of (sub) stellar evolution.
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| 21. |
- Lawrenson, Kate, et al.
(författare)
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Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
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| 23. |
- Sumpter, N. A., et al.
(författare)
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Association of Gout Polygenic Risk Score With Age at Disease Onset and Tophaceous Disease in European and Polynesian Men With Gout
- 2023
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 75:5, s. 816-825
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To determine whether a gout polygenic risk score (PRS) is associated with age at gout onset and tophaceous disease in European, East Polynesian, and West Polynesian men and women with gout. Methods. A 19-variant gout PRS was produced in 7 European gout cohorts (N = 4,016), 2 East Polynesian gout cohorts (N = 682), and 1 West Polynesian gout cohort (N = 490). Sex-stratified regression models were used to estimate the relationship between the PRS and age at gout onset and tophaceous disease. Results. The PRS was associated with earlier age at gout onset in men (beta = -3.61 in years per unit PRS [95% confidence interval (95% CI) -4.32, -2.90] in European men; beta = -6.35 [95% CI -8.91, -3.80] in East Polynesian men; beta = -3.51 [95% CI -5.46, -1.57] in West Polynesian men) but not in women (beta = 0.07 [95% CI -2.32, 2.45] in European women; beta = 0.20 [95% CI -7.21, 7.62] in East Polynesian women; beta -3.33 [95% CI -9.28, 2.62] in West Polynesian women). The PRS showed a positive association with tophaceous disease in men (odds ratio [OR] for the association 1.15 [95% CI 1.00, 1.31] in European men; OR 2.60 [95% CI 1.66, 4.06] in East Polynesian men; OR 1.53 [95% CI 1.07, 2.19] in West Polynesian men) but not in women (OR for the association 0.68 [95% CI 0.42, 1.10] in European women; OR 1.45 [95% CI 0.39, 5.36] in East Polynesian women). The PRS association with age at gout onset was robust to the removal of ABCG2 variants from the PRS in European and East Polynesian men (beta = -2.42 [95% CI -3.37, -1.46] and beta = -6.80 [95% CI -10.06, -3.55], respectively) but not in West Polynesian men (beta = -1.79 [95% CI -4.74, 1.16]). Conclusion. Genetic risk variants for gout also harbor risk for earlier age at gout onset and tophaceous disease in European and Polynesian men. Our findings suggest that earlier gout onset involves the accumulation of gout risk alleles in men but perhaps not in women, and that this genetic risk is shared across multiple ancestral groups.
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