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1.
  • 2017
  • swepub:Mat__t
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2.
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3.
  • van Leeuwen, F., et al. (författare)
  • Gaia Data Release 1 : Open cluster astrometry: Performance, limitations, and future prospects
  • 2017
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 601
  • Tidskriftsartikel (refereegranskat)abstract
    • Context. The first Gaia Data Release contains the Tycho-Gaia Astrometric Solution (TGAS). This is a subset of about 2 million stars for which, besides the position and photometry, the proper motion and parallax are calculated using Hipparcos and Tycho-2 positions in 1991.25 as prior information. Aims. We investigate the scientific potential and limitations of the TGAS component by means of the astrometric data for open clusters. Methods. Mean cluster parallax and proper motion values are derived taking into account the error correlations within the astrometric solutions for individual stars, an estimate of the internal velocity dispersion in the cluster, and, where relevant, the effects of the depth of the cluster along the line of sight. Internal consistency of the TGAS data is assessed. Results. Values given for standard uncertainties are still inaccurate and may lead to unrealistic unit-weight standard deviations of least squares solutions for cluster parameters. Reconstructed mean cluster parallax and proper motion values are generally in very good agreement with earlier Hipparcos-based determination, although the Gaia mean parallax for the Pleiades is a significant exception. We have no current explanation for that discrepancy. Most clusters are observed to extend to nearly 15 pc from the cluster centre, and it will be up to future Gaia releases to establish whether those potential cluster-member stars are still dynamically bound to the clusters. Conclusions. The Gaia DR1 provides the means to examine open clusters far beyond their more easily visible cores, and can provide membership assessments based on proper motions and parallaxes. A combined HR diagram shows the same features as observed before using the Hipparcos data, with clearly increased luminosities for older A and F dwarfs.
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4.
  • 2019
  • Tidskriftsartikel (refereegranskat)
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5.
  • Klionsky, Daniel J., et al. (författare)
  • Guidelines for the use and interpretation of assays for monitoring autophagy
  • 2012
  • Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
  • 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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6.
  • Leleu, A., et al. (författare)
  • Six transiting planets and a chain of Laplace resonances in TOI-178
  • 2021
  • Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 649
  • Tidskriftsartikel (refereegranskat)abstract
    • Determining the architecture of multi-planetary systems is one of the cornerstones of understanding planet formation and evolution. Resonant systems are especially important as the fragility of their orbital configuration ensures that no significant scattering or collisional event has taken place since the earliest formation phase when the parent protoplanetary disc was still present. In this context, TOI-178 has been the subject of particular attention since the first TESS observations hinted at the possible presence of a near 2:3:3 resonant chain. Here we report the results of observations from CHEOPS, ESPRESSO, NGTS, and SPECULOOS with the aim of deciphering the peculiar orbital architecture of the system. We show that TOI-178 harbours at least six planets in the super-Earth to mini-Neptune regimes, with radii ranging from 1.152 to 2.87 Earth radii and periods of 1.91, 3.24, 6.56, 9.96, 15.23, and 20.71 days. All planets but the innermost one form a 2:4:6:9:12 chain of Laplace resonances, and the planetary densities show important variations from planet to planet, jumping from 1.02 to 0.177 times the Earth's density between planets c and d. Using Bayesian interior structure retrieval models, we show that the amount of gas in the planets does not vary in a monotonous way, contrary to what one would expect from simple formation and evolution models and unlike other known systems in a chain of Laplace resonances. The brightness of TOI-178 (H = 8.76 mag, J = 9.37 mag, V = 11.95 mag) allows for a precise characterisation of its orbital architecture as well as of the physical nature of the six presently known transiting planets it harbours. The peculiar orbital configuration and the diversity in average density among the planets in the system will enable the study of interior planetary structures and atmospheric evolution, providing important clues on the formation of super-Earths and mini-Neptunes. -0.070 -0.13 -0.23 -0.061 +0.073 +0.14 +0.28 +0.055
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7.
  • Jin, Shoko, et al. (författare)
  • The wide-field, multiplexed, spectroscopic facility WEAVE : Survey design, overview, and simulated implementation
  • 2024
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 530:3, s. 2688-2730
  • Tidskriftsartikel (refereegranskat)abstract
    • WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, saw first light in late 2022. WEAVE comprises a new 2-deg field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366-959nm at R similar to 5000, or two shorter ranges at . After summarizing the design and implementation of WEAVE and its data systems, we present the organization, science drivers, and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for similar to 3 million stars and detailed abundances for similar to 1.5 million brighter field and open-cluster stars; (ii) survey similar to 0.4 million Galactic-plane OBA stars, young stellar objects, and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey similar to 400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionized gas in z < 0.5 cluster galaxies; (vi) survey stellar populations and kinematics in field galaxies at 0.3 less than or similar to z less than or similar to 0.7; (vii) study the cosmic evolution of accretion and star formation using >1 million spectra of LOFAR-selected radio sources; and (viii) trace structures using intergalactic/circumgalactic gas at z > 2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.
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8.
  • The Seventeenth Data Release of the Sloan Digital Sky Surveys : Complete Release of MaNGA, MaStar, and APOGEE-2 Data
  • 2022
  • Ingår i: Astrophysical Journal Supplement Series. - : Institute of Physics (IOP). - 0067-0049 .- 1538-4365. ; 259:2
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper documents the seventeenth data release (DR17) from the Sloan Digital Sky Surveys; the fifth and final release from the fourth phase (SDSS-IV). DR17 contains the complete release of the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey, which reached its goal of surveying over 10,000 nearby galaxies. The complete release of the MaNGA Stellar Library accompanies this data, providing observations of almost 30,000 stars through the MaNGA instrument during bright time. DR17 also contains the complete release of the Apache Point Observatory Galactic Evolution Experiment 2 survey that publicly releases infrared spectra of over 650,000 stars. The main sample from the Extended Baryon Oscillation Spectroscopic Survey (eBOSS), as well as the subsurvey Time Domain Spectroscopic Survey data were fully released in DR16. New single-fiber optical spectroscopy released in DR17 is from the SPectroscipic IDentification of ERosita Survey subsurvey and the eBOSS-RM program. Along with the primary data sets, DR17 includes 25 new or updated value-added catalogs. This paper concludes the release of SDSS-IV survey data. SDSS continues into its fifth phase with observations already underway for the Milky Way Mapper, Local Volume Mapper, and Black Hole Mapper surveys.
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9.
  • Blanton, Michael R., et al. (författare)
  • Sloan Digital Sky Survey IV : Mapping the Milky Way, Nearby Galaxies, and the Distant Universe
  • 2017
  • Ingår i: Astronomical Journal. - : IOP Publishing Ltd. - 0004-6256 .- 1538-3881. ; 154:1
  • Tidskriftsartikel (refereegranskat)abstract
    • We describe the Sloan Digital Sky Survey IV (SDSS-IV), a project encompassing three major spectroscopic programs. The Apache Point Observatory Galactic Evolution Experiment 2 (APOGEE-2) is observing hundreds of thousands of Milky Way stars at high resolution and. high signal-to-noise ratios in the near-infrared. The Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey is obtaining spatially resolved spectroscopy for thousands of nearby galaxies (median z similar to 0.03). The extended Baryon Oscillation Spectroscopic Survey (eBOSS) is mapping the galaxy, quasar, and neutral gas distributions between z similar to 0.6 and 3.5 to constrain cosmology using baryon acoustic oscillations, redshift space distortions, and the shape of the power spectrum. Within eBOSS, we are conducting two major subprograms: the SPectroscopic IDentification of eROSITA Sources (SPIDERS), investigating X-ray AGNs. and galaxies in X-ray clusters, and the Time Domain Spectroscopic Survey (TDSS), obtaining spectra of variable sources. All programs use the 2.5 m Sloan Foundation Telescope at the. Apache Point Observatory; observations there began in Summer 2014. APOGEE-2 also operates a second near-infrared spectrograph at the 2.5 m du Pont Telescope at Las Campanas Observatory, with observations beginning in early 2017. Observations at both facilities are scheduled to continue through 2020. In keeping with previous SDSS policy, SDSS-IV provides regularly scheduled public data releases; the first one, Data Release 13, was made available in 2016 July.
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10.
  • Abolfathi, Bela, et al. (författare)
  • The Fourteenth Data Release of the Sloan Digital Sky Survey : First Spectroscopic Data from the Extended Baryon Oscillation Spectroscopic Survey and from the Second Phase of the Apache Point Observatory Galactic Evolution Experiment
  • 2018
  • Ingår i: Astrophysical Journal Supplement Series. - : IOP Publishing Ltd. - 0067-0049 .- 1538-4365. ; 235:2
  • Tidskriftsartikel (refereegranskat)abstract
    • The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014-2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as "The Cannon"; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release (N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site (www.sdss.org) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.
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11.
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12.
  • ter Steege, Hans, et al. (författare)
  • Mapping density, diversity and species-richness of the Amazon tree flora
  • 2023
  • Ingår i: COMMUNICATIONS BIOLOGY. - 2399-3642. ; 6:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Using 2.046 botanically-inventoried tree plots across the largest tropical forest on Earth, we mapped tree species-diversity and tree species-richness at 0.1-degree resolution, and investigated drivers for diversity and richness. Using only location, stratified by forest type, as predictor, our spatial model, to the best of our knowledge, provides the most accurate map of tree diversity in Amazonia to date, explaining approximately 70% of the tree diversity and species-richness. Large soil-forest combinations determine a significant percentage of the variation in tree species-richness and tree alpha-diversity in Amazonian forest-plots. We suggest that the size and fragmentation of these systems drive their large-scale diversity patterns and hence local diversity. A model not using location but cumulative water deficit, tree density, and temperature seasonality explains 47% of the tree species-richness in the terra-firme forest in Amazonia. Over large areas across Amazonia, residuals of this relationship are small and poorly spatially structured, suggesting that much of the residual variation may be local. The Guyana Shield area has consistently negative residuals, showing that this area has lower tree species-richness than expected by our models. We provide extensive plot meta-data, including tree density, tree alpha-diversity and tree species-richness results and gridded maps at 0.1-degree resolution. A study mapping the tree species richness in Amazonian forests shows that soil type exerts a strong effect on species richness, probably caused by the areas of these forest types. Cumulative water deficit, tree density and temperature seasonality affect species richness at a regional scale.
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13.
  • Householder, John Ethan, et al. (författare)
  • One sixth of Amazonian tree diversity is dependent on river floodplains
  • 2024
  • Ingår i: NATURE ECOLOGY & EVOLUTION. - 2397-334X. ; 8, s. 901-911
  • Tidskriftsartikel (refereegranskat)abstract
    • Amazonia's floodplain system is the largest and most biodiverse on Earth. Although forests are crucial to the ecological integrity of floodplains, our understanding of their species composition and how this may differ from surrounding forest types is still far too limited, particularly as changing inundation regimes begin to reshape floodplain tree communities and the critical ecosystem functions they underpin. Here we address this gap by taking a spatially explicit look at Amazonia-wide patterns of tree-species turnover and ecological specialization of the region's floodplain forests. We show that the majority of Amazonian tree species can inhabit floodplains, and about a sixth of Amazonian tree diversity is ecologically specialized on floodplains. The degree of specialization in floodplain communities is driven by regional flood patterns, with the most compositionally differentiated floodplain forests located centrally within the fluvial network and contingent on the most extraordinary flood magnitudes regionally. Our results provide a spatially explicit view of ecological specialization of floodplain forest communities and expose the need for whole-basin hydrological integrity to protect the Amazon's tree diversity and its function.
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14.
  • Graco-Roza, Caio, et al. (författare)
  • Distance decay 2.0 – A global synthesis of taxonomic and functional turnover in ecological communities
  • 2022
  • Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 31:7, s. 1399-1421
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Understanding the variation in community composition and species abundances (i.e., beta-diversity) is at the heart of community ecology. A common approach to examine beta-diversity is to evaluate directional variation in community composition by measuring the decay in the similarity among pairs of communities along spatial or environmental distance. We provide the first global synthesis of taxonomic and functional distance decay along spatial and environmental distance by analysing 148 datasets comprising different types of organisms and environments.Location: Global.Time period: 1990 to present.Major taxa studied: From diatoms to mammals.Method: We measured the strength of the decay using ranked Mantel tests (Mantel r) and the rate of distance decay as the slope of an exponential fit using generalized linear models. We used null models to test whether functional similarity decays faster or slower than expected given the taxonomic decay along the spatial and environmental distance. We also unveiled the factors driving the rate of decay across the datasets, including latitude, spatial extent, realm and organismal features.Results: Taxonomic distance decay was stronger than functional distance decay along both spatial and environmental distance. Functional distance decay was random given the taxonomic distance decay. The rate of taxonomic and functional spatial distance decay was fastest in the datasets from mid-latitudes. Overall, datasets covering larger spatial extents showed a lower rate of decay along spatial distance but a higher rate of decay along environmental distance. Marine ecosystems had the slowest rate of decay along environmental distances.Main conclusions: In general, taxonomic distance decay is a useful tool for biogeographical research because it reflects dispersal-related factors in addition to species responses to climatic and environmental variables. Moreover, functional distance decay might be a cost-effective option for investigating community changes in heterogeneous environments.
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15.
  • Luize, Bruno Garcia, et al. (författare)
  • Geography and ecology shape the phylogenetic composition of Amazonian tree communities
  • 2024
  • Ingår i: JOURNAL OF BIOGEOGRAPHY. - 0305-0270 .- 1365-2699. ; 51:7, s. 1163-1184
  • Tidskriftsartikel (refereegranskat)abstract
    • Aim: Amazonia hosts more tree species from numerous evolutionary lineages, both young and ancient, than any other biogeographic region. Previous studies have shown that tree lineages colonized multiple edaphic environments and dispersed widely across Amazonia, leading to a hypothesis, which we test, that lineages should not be strongly associated with either geographic regions or edaphic forest types. Location: Amazonia. Taxon: Angiosperms (Magnoliids; Monocots; Eudicots). Methods: Data for the abundance of 5082 tree species in 1989 plots were combined with a mega-phylogeny. We applied evolutionary ordination to assess how phylogenetic composition varies across Amazonia. We used variation partitioning and Moran's eigenvector maps (MEM) to test and quantify the separate and joint contributions of spatial and environmental variables to explain the phylogenetic composition of plots. We tested the indicator value of lineages for geographic regions and edaphic forest types and mapped associations onto the phylogeny. Results: In the terra firme and v & aacute;rzea forest types, the phylogenetic composition varies by geographic region, but the igap & oacute; and white-sand forest types retain a unique evolutionary signature regardless of region. Overall, we find that soil chemistry, climate and topography explain 24% of the variation in phylogenetic composition, with 79% of that variation being spatially structured (R-2 = 19% overall for combined spatial/environmental effects). The phylogenetic composition also shows substantial spatial patterns not related to the environmental variables we quantified (R-2 = 28%). A greater number of lineages were significant indicators of geographic regions than forest types. Main Conclusion: Numerous tree lineages, including some ancient ones (>66 Ma), show strong associations with geographic regions and edaphic forest types of Amazonia. This shows that specialization in specific edaphic environments has played a long-standing role in the evolutionary assembly of Amazonian forests. Furthermore, many lineages, even those that have dispersed across Amazonia, dominate within a specific region, likely because of phylogenetically conserved niches for environmental conditions that are prevalent within regions.
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16.
  • Perez-Grijalba, V, et al. (författare)
  • Plasma Aβ42/40 ratio alone or combined with FDG-PET can accurately predict amyloid-PET positivity: a cross-sectional analysis from the AB255 Study
  • 2019
  • Ingår i: Alzheimer's research & therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 11:1, s. 96-
  • Tidskriftsartikel (refereegranskat)abstract
    • BackgroundTo facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers.MethodsWe included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification.ResultsEighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100).ConclusionsPlasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease.
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17.
  • Keller, Annika, et al. (författare)
  • Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice
  • 2013
  • Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:9, s. 1077-
  • Tidskriftsartikel (refereegranskat)abstract
    • Calcifications in the basal ganglia are a common incidental finding and are sometimes inherited as an autosomal dominant trait ( idiopathic basal ganglia calcification (IBGC)). Recently, mutations in the PDGFRB gene coding for the platelet-derived growth factor receptor beta (PDGF-R beta) were linked to IBGC. Here we identify six families of different ancestry with nonsense and missense mutations in the gene encoding PDGF-B, the main ligand for PDGF-R beta. We also show that mice carrying hypomorphic Pdgfb alleles develop brain calcifications that show age-related expansion. The occurrence of these calcium depositions depends on the loss of endothelial PDGF-B and correlates with the degree of pericyte and blood-brain barrier deficiency. Thus, our data present a clear link between Pdgfb mutations and brain calcifications in mice, as well as between PDGFB mutations and IBGC in humans.
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18.
  • Kostka, Kristin, et al. (författare)
  • Unraveling COVID-19: A Large-Scale Characterization of 4.5 Million COVID-19 Cases Using CHARYBDIS.
  • 2022
  • Ingår i: Clinical epidemiology. - 1179-1349. ; 14, s. 369-384
  • Tidskriftsartikel (refereegranskat)abstract
    • Routinely collected real world data (RWD) have great utility in aiding the novel coronavirus disease (COVID-19) pandemic response. Here we present the international Observational Health Data Sciences and Informatics (OHDSI) Characterizing Health Associated Risks and Your Baseline Disease In SARS-COV-2 (CHARYBDIS) framework for standardisation and analysis of COVID-19 RWD.We conducted a descriptive retrospective database study using a federated network of data partners in the United States, Europe (the Netherlands, Spain, the UK, Germany, France and Italy) and Asia (South Korea and China). The study protocol and analytical package were released on 11th June 2020 and are iteratively updated via GitHub. We identified three non-mutually exclusive cohorts of 4,537,153 individuals with a clinical COVID-19 diagnosis or positive test, 886,193 hospitalized with COVID-19, and 113,627 hospitalized with COVID-19 requiring intensive services.We aggregated over 22,000 unique characteristics describing patients with COVID-19. All comorbidities, symptoms, medications, and outcomes are described by cohort in aggregate counts and are readily available online. Globally, we observed similarities in the USA and Europe: more women diagnosed than men but more men hospitalized than women, most diagnosed cases between 25 and 60 years of age versus most hospitalized cases between 60 and 80 years of age. South Korea differed with more women than men hospitalized. Common comorbidities included type 2 diabetes, hypertension, chronic kidney disease and heart disease. Common presenting symptoms were dyspnea, cough and fever. Symptom data availability was more common in hospitalized cohorts than diagnosed.We constructed a global, multi-centre view to describe trends in COVID-19 progression, management and evolution over time. By characterising baseline variability in patients and geography, our work provides critical context that may otherwise be misconstrued as data quality issues. This is important as we perform studies on adverse events of special interest in COVID-19 vaccine surveillance.
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19.
  • Lluis, Nuria, et al. (författare)
  • Intraductal papillary neoplasms of the bile duct: a European retrospective multicenter observational study (EUR-IPNB study)
  • 2023
  • Ingår i: International Journal of Surgery. - : LIPPINCOTT WILLIAMS & WILKINS. - 1743-9191 .- 1743-9159. ; 109:4, s. 760-771
  • Tidskriftsartikel (refereegranskat)abstract
    • Background/Purpose:Intraductal papillary neoplasm of the bile duct (IPNB) is a rare disease in Western countries. The main aim of this study was to characterize current surgical strategies and outcomes in the mainly European participating centers. Methods:A multi-institutional retrospective series of patients with a diagnosis of IPNB undergoing surgery between 1 January 2010 and 31 December 2020 was gathered under the auspices of the European-African Hepato-Pancreato-Biliary Association. The textbook outcome (TO) was defined as a non-prolonged length of hospital stay plus the absence of any Clavien-Dindo grade at least III complications, readmission, or mortality within 90 postoperative days. Results:A total of 28 centers contributed 85 patients who underwent surgery for IPNB. The median age was 66 years (55-72), 49.4% were women, and 87.1% were Caucasian. Open surgery was performed in 72 patients (84.7%) and laparoscopic in 13 (15.3%). TO was achieved in 54.1% of patients, reaching 63.8% after liver resection and 32.0% after pancreas resection. Median overall survival was 5.72 years, with 5-year overall survival of 63% (95% CI: 50-82). Overall survival was better in patients with Charlson comorbidity score 4 or less versus more than 4 (P=0.016), intrahepatic versus extrahepatic tumor (P=0.027), single versus multiple tumors (P=0.007), those who underwent hepatic versus pancreatic resection (P=0.017), or achieved versus failed TO (P=0.029). Multivariable Cox regression analysis showed that not achieving TO (HR: 4.20; 95% CI: 1.11-15.94; P=0.03) was an independent prognostic factor of poor overall survival. Conclusions:Patients undergoing liver resection for IPNB were more likely to achieve a TO outcome than those requiring a pancreatic resection. Comorbidity, tumor location, and tumor multiplicity influenced overall survival. TO was an independent prognostic factor of overall survival.
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20.
  • Lluís, Núria, et al. (författare)
  • Intraductal papillary neoplasms of the bile ducts : a comparative study of a rare disease in Europe and Nagoya, Japan
  • 2024
  • Ingår i: HPB. - : ELSEVIER SCI LTD. - 1365-182X .- 1477-2574. ; 26:4, s. 565-575
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Intraductal papillary neoplasm of the bile ducts (IPNB) is a rare disease in Western countries. The aim of this study was to compare tumor characteristics, management strategies, and outcomes between Western and Eastern patients who underwent surgical resection for IPNB. Methods: A multi-institutional retrospective series of patients with IPNB undergoing surgery between January 2010 and December 2020 was gathered under the auspices of the European-African Hepato-Pancreato-Biliary Association (E-AHPBA), and at Nagoya University Hospital, Japan. Results: A total of 85 patients (51% male; median age 66 years) from 28 E-AHPBA centers were compared to 91 patients (64% male; median age 71 years) from Nagoya. Patients in Europe had more multiple lesions (23% vs 2%, P < .001), less invasive carcinoma (42% vs 85%, P < .001), and more intrahepatic tumors (52% vs 24%, P < .001) than in Nagoya. Patients in Europe experienced less 90-day grade >3 Clavien-Dindo complications (33% vs 68%, P < .001), but higher 90-day mortality rate (7.0% vs 0%, P = .03). R0 resections (81% vs 82%) were similar. Overall survival, excluding 90-day postoperative deaths, was similar in both regions. Discussion: Despite performing more extensive resections, the low perioperative mortality rate observed in Nagoya was probably influenced by a combination of patient-, tumor-, and surgery-related factors.
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21.
  • Muscarella, Robert, et al. (författare)
  • The global abundance of tree palms
  • 2020
  • Ingår i: Global Ecology and Biogeography. - : Wiley. - 1466-822X .- 1466-8238. ; 29:9, s. 1495-1514
  • Tidskriftsartikel (refereegranskat)abstract
    • AimPalms are an iconic, diverse and often abundant component of tropical ecosystems that provide many ecosystem services. Being monocots, tree palms are evolutionarily, morphologically and physiologically distinct from other trees, and these differences have important consequences for ecosystem services (e.g., carbon sequestration and storage) and in terms of responses to climate change. We quantified global patterns of tree palm relative abundance to help improve understanding of tropical forests and reduce uncertainty about these ecosystems under climate change.LocationTropical and subtropical moist forests.Time periodCurrent.Major taxa studiedPalms (Arecaceae).MethodsWe assembled a pantropical dataset of 2,548 forest plots (covering 1,191 ha) and quantified tree palm (i.e., ≥10 cm diameter at breast height) abundance relative to co‐occurring non‐palm trees. We compared the relative abundance of tree palms across biogeographical realms and tested for associations with palaeoclimate stability, current climate, edaphic conditions and metrics of forest structure.ResultsOn average, the relative abundance of tree palms was more than five times larger between Neotropical locations and other biogeographical realms. Tree palms were absent in most locations outside the Neotropics but present in >80% of Neotropical locations. The relative abundance of tree palms was more strongly associated with local conditions (e.g., higher mean annual precipitation, lower soil fertility, shallower water table and lower plot mean wood density) than metrics of long‐term climate stability. Life‐form diversity also influenced the patterns; palm assemblages outside the Neotropics comprise many non‐tree (e.g., climbing) palms. Finally, we show that tree palms can influence estimates of above‐ground biomass, but the magnitude and direction of the effect require additional work.ConclusionsTree palms are not only quintessentially tropical, but they are also overwhelmingly Neotropical. Future work to understand the contributions of tree palms to biomass estimates and carbon cycling will be particularly crucial in Neotropical forests.
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22.
  • Velilla Prieto, Luis, 1981, et al. (författare)
  • Circumstellar chemistry of Si-C bearing molecules in the C-rich AGB star IRC+10216
  • 2018
  • Ingår i: Proceedings of the International Astronomical Union. - 1743-9213 .- 1743-9221. ; 14, s. 535-537
  • Konferensbidrag (refereegranskat)abstract
    • Silicon carbide together with amorphous carbon are the main components of dust grains in the atmospheres of C-rich AGB stars. Small gaseous Si-C bearing molecules (such as SiC, SiCSi, and SiC2) are efficiently formed close to the stellar photosphere. They likely condense onto dust seeds owing to their highly refractory nature at the lower temperatures (i.e., below about 2500 K) in the dust growth zone which extends a few stellar radii from the photosphere. Beyond this region, the abundances of Si-C bearing molecules are expected to decrease until they are eventually reformed in the outer shells of the circumstellar envelope, owing to the interaction between the gas and the interstellar UV radiation field. Our goal is to understand the time-dependent chemical evolution of Si-C bond carriers probed by molecular spectral line emission in the circumstellar envelope of IRC+10216 at millimeter wavelengths.
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23.
  • Blösch, Günter, et al. (författare)
  • Twenty-three unsolved problems in hydrology (UPH) - a community perspective
  • 2019
  • Ingår i: Hydrological Sciences Journal. - : Informa UK Limited. - 0262-6667 .- 2150-3435. ; 64:10, s. 1141-1158
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper is the outcome of a community initiative to identify major unsolved scientific problems in hydrology motivated by a need for stronger harmonisation of research efforts. The procedure involved a public consultation through online media, followed by two workshops through which a large number of potential science questions were collated, prioritised, and synthesised. In spite of the diversity of the participants (230 scientists in total), the process revealed much about community priorities and the state of our science: a preference for continuity in research questions rather than radical departures or redirections from past and current work. Questions remain focused on the process-based understanding of hydrological variability and causality at all space and time scales. Increased attention to environmental change drives a new emphasis on understanding how change propagates across interfaces within the hydrological system and across disciplinary boundaries. In particular, the expansion of the human footprint raises a new set of questions related to human interactions with nature and water cycle feedbacks in the context of complex water management problems. We hope that this reflection and synthesis of the 23 unsolved problems in hydrology will help guide research efforts for some years to come.
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24.
  • Bose, Subhash, et al. (författare)
  • ASASSN-18am/SN 2018gk : an overluminous Type IIb supernova from a massive progenitor
  • 2021
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 503:3, s. 3472-3491
  • Tidskriftsartikel (refereegranskat)abstract
    • ASASSN-18am/SN 2018gk is a newly discovered member of the rare group of luminous, hydrogen-rich supernovae (SNe) with a peak absolute magnitude of M-V approximate to -20 mag that is in between normal core-collapse SNe and superluminous SNe. These SNe show no prominent spectroscopic signatures of ejecta interacting with circumstellar material (CSM), and their powering mechanism is debated. ASASSN-18am declines extremely rapidly for a Type II SN, with a photospheric-phase decline rate of similar to 6.0 mag (100 d)(-1). Owing to the weakening of H I and the appearance of He I in its later phases, ASASSN-18am is spectroscopically a Type IIb SN with a partially stripped envelope. However, its photometric and spectroscopic evolution shows significant differences from typical SNe IIb. Using a radiative diffusion model, we find that the light curve requires a high synthesized Ni-56 mass M-Ni similar to 0.4 M-circle dot and ejecta with high kinetic energy E-kin = (7-10) x 10(51) erg. Introducing a magnetar central engine still requires M-Ni similar to 0.3 M-circle dot and E-kin = 3 x 10(51) erg. The high Ni-56 mass is consistent with strong iron-group nebular lines in its spectra, which are also similar to several SNe Ic-BL with high Ni-56 yields. The earliest spectrum shows 'flash ionization' features, from which we estimate a mass-loss rate of (M) over dot approximate to 2 x 10(-4 )M(circle dot) yr(-1). This wind density is too low to power the luminous light curve by ejecta-CSM interaction. We measure expansion velocities as high as 17 000 km s(-1) for H alpha, which is remarkably high compared to other SNe II. We estimate an oxygen core mass of 1.8-3.4 M-circle dot using the [O I] luminosity measured from a nebular-phase spectrum, implying a progenitor with a zero-age main-sequence mass of 19-26 M-circle dot.
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25.
  • Duarte-Salles, Talita, et al. (författare)
  • Thirty-Day Outcomes of Children and Adolescents With COVID-19: An International Experience.
  • 2021
  • Ingår i: Pediatrics. - : American Academy of Pediatrics (AAP). - 1098-4275 .- 0031-4005. ; 148:3
  • Tidskriftsartikel (refereegranskat)abstract
    • To characterize the demographics, comorbidities, symptoms, in-hospital treatments, and health outcomes among children and adolescents diagnosed or hospitalized with coronavirus disease 2019 (COVID-19) and to compare them in secondary analyses with patients diagnosed with previous seasonal influenza in 2017-2018.International network cohort using real-world data from European primary care records (France, Germany, and Spain), South Korean claims and US claims, and hospital databases. We included children and adolescents diagnosed and/or hospitalized with COVID-19 at age <18 between January and June 2020. We described baseline demographics, comorbidities, symptoms, 30-day in-hospital treatments, and outcomes including hospitalization, pneumonia, acute respiratory distress syndrome, multisystem inflammatory syndrome in children, and death.A total of 242158 children and adolescents diagnosed and 9769 hospitalized with COVID-19 and 2084180 diagnosed with influenza were studied. Comorbidities including neurodevelopmental disorders, heart disease, and cancer were more common among those hospitalized with versus diagnosed with COVID-19. Dyspnea, bronchiolitis, anosmia, and gastrointestinal symptoms were more common in COVID-19 than influenza. In-hospital prevalent treatments for COVID-19 included repurposed medications (<10%) and adjunctive therapies: systemic corticosteroids (6.8%-7.6%), famotidine (9.0%-28.1%), and antithrombotics such as aspirin (2.0%-21.4%), heparin (2.2%-18.1%), and enoxaparin (2.8%-14.8%). Hospitalization was observed in 0.3% to 1.3% of the cohort diagnosed with COVID-19, with undetectable (n < 5 per database) 30-day fatality. Thirty-day outcomes including pneumonia and hypoxemia were more frequent in COVID-19 than influenza.Despite negligible fatality, complications including hospitalization, hypoxemia, and pneumonia were more frequent in children and adolescents with COVID-19 than with influenza. Dyspnea, anosmia, and gastrointestinal symptoms could help differentiate diagnoses. A wide range of medications was used for the inpatient management of pediatric COVID-19.
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26.
  • Kessler, Richard, et al. (författare)
  • First-Year Sloan Digital Sky Survey-II Supernova Results : Hubble Diagram and Cosmological Parameters
  • 2009
  • Ingår i: Astrophysical Journal Supplement Series. - : American Astronomical Society. - 0067-0049 .- 1538-4365. ; 185:1, s. 32-84
  • Tidskriftsartikel (refereegranskat)abstract
    • We present measurements of the Hubble diagram for 103 Type Ia supernovae (SNe) with redshifts 0.04 < z < 0.42, discovered during the first season (Fall 2005) of the Sloan Digital Sky Survey-II (SDSS-II) Supernova Survey. These data fill in the redshift "desert" between low- and high-redshift SN Ia surveys. Within the framework of the MLCS2K2 light-curve fitting method, we use the SDSS-II SN sample to infer the mean reddening parameter for host galaxies, RV = 2.18 ± 0.14stat ± 0.48syst, and find that the intrinsic distribution of host-galaxy extinction is well fitted by an exponential function, P(AV ) = exp(-AV /τV), with τV = 0.334 ± 0.088 mag. We combine the SDSS-II measurements with new distance estimates for published SN data from the ESSENCE survey, the Supernova Legacy Survey (SNLS), the Hubble Space Telescope (HST), and a compilation of Nearby SN Ia measurements. A new feature in our analysis is the use of detailed Monte Carlo simulations of all surveys to account for selection biases, including those from spectroscopic targeting. Combining the SN Hubble diagram with measurements of baryon acoustic oscillations from the SDSS Luminous Red Galaxy sample and with cosmic microwave background temperature anisotropy measurements from the Wilkinson Microwave Anisotropy Probe, we estimate the cosmological parameters w and ΩM, assuming a spatially flat cosmological model (FwCDM) with constant dark energy equation of state parameter, w. We also consider constraints upon ΩM and ΩΛ for a cosmological constant model (ΛCDM) with w = -1 and non-zero spatial curvature. For the FwCDM model and the combined sample of 288 SNe Ia, we find w = -0.76 ± 0.07(stat) ± 0.11(syst), ΩM = 0.307 ± 0.019(stat) ± 0.023(syst) using MLCS2K2 and w = -0.96 ± 0.06(stat) ± 0.12(syst), ΩM = 0.265 ± 0.016(stat) ± 0.025(syst) using the SALT-II fitter. We trace the discrepancy between these results to a difference in the rest-frame UV model combined with a different luminosity correction from color variations; these differences mostly affect the distance estimates for the SNLS and HST SNe. We present detailed discussions of systematic errors for both light-curve methods and find that they both show data-model discrepancies in rest-frame U band. For the SALT-II approach, we also see strong evidence for redshift-dependence of the color-luminosity parameter (β). Restricting the analysis to the 136 SNe Ia in the Nearby+SDSS-II samples, we find much better agreement between the two analysis methods but with larger uncertainties: w = -0.92 ± 0.13(stat)+0.10 -0.33(syst) for MLCS2K2 and w = -0.92 ± 0.11(stat)+0.07 -0.15 (syst) for SALT-II.
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27.
  • Ravikumar, Sadhana, et al. (författare)
  • Ex vivo MRI atlas of the human medial temporal lobe : characterizing neurodegeneration due to tau pathology
  • 2021
  • Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 9:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Tau neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s disease (AD). To elucidate patterns of structural change in the MTL specifically associated with tau pathology, we compared high-resolution ex vivo MRI scans of human postmortem MTL specimens with histology-based pathological assessments of the MTL. MTL specimens were obtained from twenty-nine brain donors, including patients with AD, other dementias, and individuals with no known history of neurological disease. Ex vivo MRI scans were combined using a customized groupwise diffeomorphic registration approach to construct a 3D probabilistic atlas that captures the anatomical variability of the MTL. Using serial histology imaging in eleven specimens, we labelled the MTL subregions in the atlas based on cytoarchitecture. Leveraging the atlas and neuropathological ratings of tau and TAR DNA-binding protein 43 (TDP-43) pathology severity, morphometric analysis was performed to correlate regional MTL thickness with the severity of tau pathology, after correcting for age and TDP-43 pathology. We found significant correlations between tau pathology and thickness in the entorhinal cortex (ERC) and stratum radiatum lacunosum moleculare (SRLM). When focusing on cases with low levels of TDP-43 pathology, we found strong associations between tau pathology and thickness in the ERC, SRLM and the subiculum/cornu ammonis 1 (CA1) subfields of the hippocampus, consistent with early Braak stages.
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28.
  • Ravikumar, Sadhana, et al. (författare)
  • Improved Segmentation of Deep Sulci in Cortical Gray Matter Using a Deep Learning Framework Incorporating Laplace’s Equation
  • 2023
  • Ingår i: Information Processing in Medical Imaging - 28th International Conference, IPMI 2023, Proceedings. - 0302-9743 .- 1611-3349. - 9783031340475 ; 13939 LNCS, s. 692-704
  • Konferensbidrag (refereegranskat)abstract
    • When developing tools for automated cortical segmentation, the ability to produce topologically correct segmentations is important in order to compute geometrically valid morphometry measures. In practice, accurate cortical segmentation is challenged by image artifacts and the highly convoluted anatomy of the cortex itself. To address this, we propose a novel deep learning-based cortical segmentation method in which prior knowledge about the geometry of the cortex is incorporated into the network during the training process. We design a loss function which uses the theory of Laplace’s equation applied to the cortex to locally penalize unresolved boundaries between tightly folded sulci. Using an ex vivo MRI dataset of human medial temporal lobe specimens, we demonstrate that our approach outperforms baseline segmentation networks, both quantitatively and qualitatively.
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29.
  • Ravikumar, Sadhana, et al. (författare)
  • Postmortem imaging reveals patterns of medial temporal lobe vulnerability to tau pathology in Alzheimer’s disease
  • 2024
  • Ingår i: Nature Communications. - 2041-1723. ; 15:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Our current understanding of the spread and neurodegenerative effects of tau neurofibrillary tangles (NFTs) within the medial temporal lobe (MTL) during the early stages of Alzheimer’s Disease (AD) is limited by the presence of confounding non-AD pathologies and the two-dimensional (2-D) nature of conventional histology studies. Here, we combine ex vivo MRI and serial histological imaging from 25 human MTL specimens to present a detailed, 3-D characterization of quantitative NFT burden measures in the space of a high-resolution, ex vivo atlas with cytoarchitecturally-defined subregion labels, that can be used to inform future in vivo neuroimaging studies. Average maps show a clear anterior to poster gradient in NFT distribution and a precise, spatial pattern with highest levels of NFTs found not just within the transentorhinal region but also the cornu ammonis (CA1) subfield. Additionally, we identify granular MTL regions where measures of neurodegeneration are likely to be linked to NFTs specifically, and thus potentially more sensitive as early AD biomarkers.
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30.
  • Roel, Elena, et al. (författare)
  • Characteristics and Outcomes of Over 300,000 Patients with COVID-19 and History of Cancer in the United States and Spain.
  • 2021
  • Ingår i: Cancer epidemiology, biomarkers & prevention. - 1538-7755. ; 30:10, s. 1884-1894
  • Tidskriftsartikel (refereegranskat)abstract
    • We described the demographics, cancer subtypes, comorbidities, and outcomes of patients with a history of cancer and coronavirus disease 2019 (COVID-19). Second, we compared patients hospitalized with COVID-19 to patients diagnosed with COVID-19 and patients hospitalized with influenza.We conducted a cohort study using eight routinely collected health care databases from Spain and the United States, standardized to the Observational Medical Outcome Partnership common data model. Three cohorts of patients with a history of cancer were included: (i) diagnosed with COVID-19, (ii) hospitalized with COVID-19, and (iii) hospitalized with influenza in 2017 to 2018. Patients were followed from index date to 30 days or death. We reported demographics, cancer subtypes, comorbidities, and 30-day outcomes.We included 366,050 and 119,597 patients diagnosed and hospitalized with COVID-19, respectively. Prostate and breast cancers were the most frequent cancers (range: 5%-18% and 1%-14% in the diagnosed cohort, respectively). Hematologic malignancies were also frequent, with non-Hodgkin's lymphoma being among the five most common cancer subtypes in the diagnosed cohort. Overall, patients were aged above 65 years and had multiple comorbidities. Occurrence of death ranged from 2% to 14% and from 6% to 26% in the diagnosed and hospitalized COVID-19 cohorts, respectively. Patients hospitalized with influenza (n = 67,743) had a similar distribution of cancer subtypes, sex, age, and comorbidities but lower occurrence of adverse events.Patients with a history of cancer and COVID-19 had multiple comorbidities and a high occurrence of COVID-19-related events. Hematologic malignancies were frequent.This study provides epidemiologic characteristics that can inform clinical care and etiologic studies.
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31.
  • Smets, Benoît, et al. (författare)
  • Detailed multidisciplinary monitoring reveals pre- and co-eruptive signals at Nyamulagira volcano (North Kivu, Democratic Republic of Congo)
  • 2014
  • Ingår i: Bulletin of Volcanology. - : Springer Science and Business Media LLC. - 0258-8900 .- 1432-0819. ; 76:787, s. 1-35
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper presents a thorough description of Nyamulagira’s January 2010 volcanic eruption (North Kivu, Democratic Republic of Congo), based on a combination of field observation and ground-based and space-borne data. It is the first eruption in the Virunga Volcanic Province that has been described by a combination of several modern monitoring techniques. The 2010 eruption lasted 26 days and emitted ∼45.5 × 106 m3 of lava. Field observations divided the event into four eruptive stages delimited by major changes in effusive activity. These stages are consistent with those described by Pouclet (1976) for historical eruptions of Nyamulagira. Co-eruptive signals from ground deformation, seismicity, SO2 emission and thermal flux correlate with the eruptive stages. Unambiguous pre-eruptive ground deformation was observed 3 weeks before the lava outburst, coinciding with a small but clear increase in the short period seismicity and SO2 emission. The 3 weeks of precursors contrasts with the only precursory signal previously recognized in the Virunga Volcanic Province, the short-term increase of tremor and long period seismicity, which, for example, were only detected less than 2 h prior to the 2010 eruption. The present paper is the most detailed picture of a typical flank eruption of this volcano. It provides valuable tools for re-examining former—mostly qualitative—descriptions of historical Nyamulagira eruptions that occurred during the colonial period.
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32.
  • Tan, Eng Hooi, et al. (författare)
  • COVID-19 in patients with autoimmune diseases: characteristics and outcomes in a multinational network of cohorts across three countries.
  • 2021
  • Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 60:SI
  • Tidskriftsartikel (refereegranskat)abstract
    • Patients with autoimmune diseases were advised to shield to avoid coronavirus disease 2019 (COVID-19), but information on their prognosis is lacking. We characterized 30-day outcomes and mortality after hospitalization with COVID-19 among patients with prevalent autoimmune diseases, and compared outcomes after hospital admissions among similar patients with seasonal influenza.A multinational network cohort study was conducted using electronic health records data from Columbia University Irving Medical Center [USA, Optum (USA), Department of Veterans Affairs (USA), Information System for Research in Primary Care-Hospitalization Linked Data (Spain) and claims data from IQVIA Open Claims (USA) and Health Insurance and Review Assessment (South Korea). All patients with prevalent autoimmune diseases, diagnosed and/or hospitalized between January and June 2020 with COVID-19, and similar patients hospitalized with influenza in 2017-18 were included. Outcomes were death and complications within 30days of hospitalization.We studied 133589 patients diagnosed and 48418 hospitalized with COVID-19 with prevalent autoimmune diseases. Most patients were female, aged ≥50years with previous comorbidities. The prevalence of hypertension (45.5-93.2%), chronic kidney disease (14.0-52.7%) and heart disease (29.0-83.8%) was higher in hospitalized vs diagnosed patients with COVID-19. Compared with 70660 hospitalized with influenza, those admitted with COVID-19 had more respiratory complications including pneumonia and acute respiratory distress syndrome, and higher 30-day mortality (2.2-4.3% vs 6.32-24.6%).Compared with influenza, COVID-19 is a more severe disease, leading to more complications and higher mortality.
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33.
  • Yushkevich, Paul A., et al. (författare)
  • Three-dimensional mapping of neurofibrillary tangle burden in the human medial temporal lobe
  • 2021
  • Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 144:9, s. 2784-2797
  • Tidskriftsartikel (refereegranskat)abstract
    • Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.
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34.
  • Finzell, Thomas, et al. (författare)
  • A Detailed Observational Analysis of V1324 Sco, the Most Gamma-Ray-luminous Classical Nova to Date
  • 2018
  • Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 852:2
  • Tidskriftsartikel (refereegranskat)abstract
    • It has recently been discovered that some, if not all, classical novae emit GeV gamma-rays during outburst, but the mechanisms involved in the production ofgamma-rays are still not well understood. We present here a comprehensive multiwavelength data set - from radio to X-rays - for the most gamma-ray-luminous classical nova to date, V1324 Sco. Using this data set, we show that V1324 Sco is a canonical dusty Fe ii-type nova, with a maximum ejecta velocity of 2600 km s-1 and an ejecta mass of a few × 10-5 M⊙. There is also evidence for complex shock interactions, including a double-peaked radio light curve which shows high brightness temperatures at early times. To explore why V1324 Sco was so gamma-ray luminous, we present a model of the nova ejecta featuring strong internal shocks and find that higher gamma-ray luminosities result from higher ejecta velocities and/or mass-loss rates. Comparison of V1324 Sco with other gamma-ray-detected novae does not show clear signatures of either, and we conclude that a larger sample of similarly well-observed novae is needed to understand the origin and variation of gamma-rays in novae.
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35.
  • Insausti, Ricardo, et al. (författare)
  • Ex vivo, in situ perfusion protocol for human brain fixation compatible with microscopy, MRI techniques, and anatomical studies
  • 2023
  • Ingår i: Frontiers in Neuroanatomy. - : Frontiers Media SA. - 1662-5129. ; 17
  • Tidskriftsartikel (refereegranskat)abstract
    • We present a method for human brain fixation based on simultaneous perfusion of 4% paraformaldehyde through carotids after a flush with saline. The left carotid cannula is used to perfuse the body with 10% formalin, to allow further use of the body for anatomical research or teaching. The aim of our method is to develop a vascular fixation protocol for the human brain, by adapting protocols that are commonly used in experimental animal studies. We show that a variety of histological procedures can be carried out (cyto- and myeloarchitectonics, histochemistry, immunohistochemistry, intracellular cell injection, and electron microscopy). In addition, ex vivo, ex situ high-resolution MRI (9.4T) can be obtained in the same specimens. This procedure resulted in similar morphological features to those obtained by intravascular perfusion in experimental animals, provided that the postmortem interval was under 10 h for several of the techniques used and under 4 h in the case of intracellular injections and electron microscopy. The use of intravascular fixation of the brain inside the skull provides a fixed whole human brain, perfectly fitted to the skull, with negligible deformation compared to conventional techniques. Given this characteristic of ex vivo, in situ fixation, this procedure can probably be considered the most suitable one available for ex vivo MRI scans of the brain. We describe the compatibility of the method proposed for intravascular fixation of the human brain and fixation of the donor’s body for anatomical purposes. Thus, body donor programs can provide human brain tissue, while the remainder of the body can also be fixed for anatomical studies. Therefore, this method of human brain fixation through the carotid system optimizes the procurement of human brain tissue, allowing a greater understanding of human neurological diseases, while benefiting anatomy departments by making the remainder of the body available for teaching purposes.
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36.
  • Krisciunas, Kevin, et al. (författare)
  • The Type Ia supernova 2004s, a clone of SN 2001el, and the optimal photometric bands for extinction estimation
  • 2007
  • Ingår i: Astronomical Journal. - : American Astronomical Society. - 0004-6256 .- 1538-3881. ; 133:1, s. 58-72
  • Tidskriftsartikel (refereegranskat)abstract
    • We present optical (UBVRI) and near-IR (YJHK) photometry of the normal Type Ia supernova (SN) 2004S. We also present eight optical spectra and one near-IR spectrum of SN 2004S. The light curves and spectra are nearly identical to those of SN 2001el. This is the first time we have seen optical and IR light curves of two Type Ia SNe match so closely. Within the one parameter family of light curves for normal Type Ia SNe, that two objects should have such similar light curves implies that they had identical intrinsic colors and produced similar amounts of Ni-56. From the similarities of the light-curve shapes we obtain a set of extinctions as a function of wavelength that allows a simultaneous solution for the distance modulus difference of the two objects, the difference of the host galaxy extinctions, and RV. Since SN 2001el had roughly an order of magnitude more host galaxy extinction than SN 2004S, the value of R-V = 2.15(-0.22)(+0.24) pertains primarily to dust in the host galaxy of SN 2001el. We have also shown via Monte Carlo simulations that adding rest-frame J-band photometry to the complement of BVRI photometry of Type Ia SNe decreases the uncertainty in the distance modulus by a factor of 2.7. A combination of rest-frame optical and near-IR photometry clearly gives more accurate distances than using rest-frame optical photometry alone.
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37.
  • Miranda-Pastoriza, Dario, et al. (författare)
  • Exploring Non-orthosteric Interactions with a Series of Potent and Selective A(3) Antagonists
  • 2022
  • Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 13:2, s. 243-249
  • Tidskriftsartikel (refereegranskat)abstract
    • : A library of potent and highly A3AR selective pyrimidinebased compounds was designed to explore non-orthosteric interactions within this receptor. Starting from a prototypical orthosteric A3AR antagonist (ISVY130), the structure-based design explored functionalized residues at the exocyclic amide L1 region and aimed to provide additional interactions outside the A3AR orthosteric site. The novel ligands were assembled through an efficient and succinct synthetic approach, resulting in compounds that retain the A3AR potent and selective profile while improving the solubility of the original scaffold. The experimentally demonstrated tolerability of the L1 region to structural functionalization was further assessed by molecular dynamics simulations, giving hints of the non-orthosteric interactions explored by these series. The results pave the way to explore newly functionalized A3AR ligands, including covalent drugs and molecular probes for diagnostic and delivery purposes.
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38.
  • Moreno-Martos, David, et al. (författare)
  • Characteristics and outcomes of COVID-19 patients with COPD from the United States, South Korea, and Europe
  • 2023
  • Ingår i: Wellcome Open Research. - : F1000 Research Ltd. - 2398-502X. ; 7
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Characterization studies of COVID-19 patients with chronic obstructive pulmonary disease (COPD) are limited in size and scope. The aim of the study is to provide a large-scale characterization of COVID-19 patients with COPD. Methods: We included thirteen databases contributing data from January-June 2020 from North America (US), Europe and Asia. We defined two cohorts of patients with COVID-19 namely a ‘diagnosed’ and ‘hospitalized’ cohort. We followed patients from COVID-19 index date to 30 days or death. We performed descriptive analysis and reported the frequency of characteristics and outcomes among COPD patients with COVID-19. Results: The study included 934,778 patients in the diagnosed COVID-19 cohort and 177,201 in the hospitalized COVID-19 cohort. Observed COPD prevalence in the diagnosed cohort ranged from 3.8% (95%CI 3.5-4.1%) in French data to 22.7% (95%CI 22.4-23.0) in US data, and from 1.9% (95%CI 1.6-2.2) in South Korean to 44.0% (95%CI 43.1-45.0) in US data, in the hospitalized cohorts. COPD patients in the hospitalized cohort had greater comorbidity than those in the diagnosed cohort, including hypertension, heart disease, diabetes and obesity. Mortality was higher in COPD patients in the hospitalized cohort and ranged from 7.6% (95%CI 6.9-8.4) to 32.2% (95%CI 28.0-36.7) across databases. ARDS, acute renal failure, cardiac arrhythmia and sepsis were the most common outcomes among hospitalized COPD patients. Conclusion: COPD patients with COVID-19 have high levels of COVID-19-associated comorbidities and poor COVID-19 outcomes. Further research is required to identify patients with COPD at high risk of worse outcomes.
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39.
  • Nidever, David L., et al. (författare)
  • The Lazy Giants : APOGEE Abundances Reveal Low Star Formation Efficiencies in the Magellanic Clouds
  • 2020
  • Ingår i: Astrophysical Journal. - : Institute of Physics (IOP). - 0004-637X .- 1538-4357. ; 895:2
  • Tidskriftsartikel (refereegranskat)abstract
    • We report the first APOGEE metallicities and alpha-element abundances measured for 3600 red giant stars spanning a large radial range of both the Large (LMC) and Small Magellanic Clouds, the largest Milky Way (MW) dwarf galaxies. Our sample is an order of magnitude larger than that of previous studies and extends to much larger radial distances. These are the first results presented that make use of the newly installed southern APOGEE instrument on the du Pont telescope at Las Campanas Observatory. Our unbiased sample of the LMC spans a large range in metallicity, from [Fe/H] = -0.2 to very metal-poor stars with [Fe/H] -2.5, the most metal-poor Magellanic Cloud (MC) stars detected to date. The LMC [alpha/Fe]-[Fe/H] distribution is very flat over a large metallicity range but rises by similar to 0.1 dex at -1.0 < [Fe/H] less than or similar to -0.5. We interpret this as a sign of the known recent increase in MC star formation activity and are able to reproduce the pattern with a chemical evolution model that includes a recent "starburst." At the metal-poor end, we capture the increase of [alpha/Fe] with decreasing [Fe/H] and constrain the "alpha-knee" to [Fe/H] less than or similar to -2.2 in both MCs, implying a low star formation efficiency of similar to 0.01 Gyr(-1). The MC knees are more metal-poor than those of less massive MW dwarf galaxies such as Fornax, Sculptor, or Sagittarius. One possible interpretation is that the MCs formed in a lower-density environment than the MW, a hypothesis that is consistent with the paradigm that the MCs fell into the MW's gravitational potential only recently.
  •  
40.
  • Prieto-Diaz, Ruben, et al. (författare)
  • Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists : Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents
  • 2024
  • Ingår i: Biomedicine and Pharmacotherapy. - : Elsevier. - 0753-3322 .- 1950-6007. ; 173
  • Tidskriftsartikel (refereegranskat)abstract
    • Antagonists of the A2B adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyclic derivatives, as A2BAR antagonists. We conducted a comprehensive examination of the adenosinergic profile (both binding and functional) of a large compound library consisting of 168 compounds. This approach unveiled original lead compounds and enabled the identification of novel structure-activity relationship (SAR) trends, which were supported by extensive computational studies, including quantum mechanical calculations and free energy perturbation (FEP) analysis. In total, 25 molecules showed attractive affinity (Ki < 100 nM) and outstanding selectivity for A2BAR. From these, five molecules corresponding to the new benzothiazole scaffold were below the Ki < 10 nM threshold, in addition to a novel dual A2A/A2B antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A2BAR. Two A2BAR selective antagonists and the dual A2AAR/A2BAR antagonist reported in this study were assessed for their impact on colorectal cancer cell lines. The results revealed a significant and dose-dependent reduction in cell proliferation. Notably, the A2BAR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A2BAR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A2AAR antagonism in the context of immune checkpoint inhibition.
  •  
41.
  • Prieto-Díaz, Rubén, et al. (författare)
  • Exploring the Effect of Halogenation in a Series of Potent and Selective A2B Adenosine Receptor Antagonists
  • 2023
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 66:1, s. 890-912
  • Tidskriftsartikel (refereegranskat)abstract
    • The modulation of the A2B adenosine receptor is a promising strategy in cancer (immuno) therapy, with A2BAR antagonists emerging as immune checkpoint inhibitors. Herein, we report a systematic assessment of the impact of (di- and mono-)halogenation at positions 7 and/or 8 on both A2BAR affinity and pharmacokinetic properties of a collection of A2BAR antagonists and its study with structure-based free energy perturbation simulations. Monohalogenation at position 8 produced potent A2BAR ligands irrespective of the nature of the halogen. In contrast, halogenation at position 7 and dihalogenation produced a halogen-size-dependent decay in affinity. Eight novel A2BAR ligands exhibited remarkable affinity (Ki < 10 nM), exquisite subtype selectivity, and enantioselective recognition, with some eutomers eliciting sub-nanomolar affinity. The pharmacokinetic profile of representative derivatives showed enhanced solubility and microsomal stability. Finally, two compounds showed the capacity of reversing the antiproliferative effect of adenosine in activated primary human peripheral blood mononuclear cells.
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42.
  • Ravikumar, Sadhana, et al. (författare)
  • Unfolding the Medial Temporal Lobe Cortex to Characterize Neurodegeneration Due to Alzheimer’s Disease Pathology Using Ex vivo Imaging
  • 2021
  • Ingår i: Machine Learning in Clinical Neuroimaging - 4th International Workshop, MLCN 2021, Held in Conjunction with MICCAI 2021, Proceedings. - Cham : Springer International Publishing. - 1611-3349 .- 0302-9743. - 9783030875855 ; 13001 LNCS, s. 3-12
  • Konferensbidrag (refereegranskat)abstract
    • Neurofibrillary tangle (NFT) pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is the early pathological change associated with Alzheimer’s Disease (AD). In this work, we investigate the relationship between MTL morphometry features derived from high-resolution ex vivo imaging and histology-based measures of NFT pathology using a topological unfolding framework applied to a dataset of 18 human postmortem MTL specimens. The MTL has a complex 3D topography and exhibits a high degree of inter-subject variability in cortical folding patterns which poses a significant challenge for volumetric registration methods typically used during MRI template construction. By unfolding the MTL cortex, the proposed framework explicitly accounts for the sheet-like geometry of the MTL cortex and provides a two-dimensional reference coordinate space which can be used to implicitly register cortical folding patterns across specimens based on distance along the cortex despite large anatomical variability. Leveraging this framework in a subset of 15 specimens, we characterize the associations between NFTs and morphological features such as cortical thickness and surface curvature and identify regions in the MTL where patterns of atrophy are strongly correlated with NFT pathology.
  •  
43.
  • Roederer, Ian U., et al. (författare)
  • The discovery space of ELT-ANDES. Stars and stellar populations
  • 2024
  • Ingår i: Experimental Astronomy. - : Springer. - 0922-6435 .- 1572-9508. ; 57:2
  • Tidskriftsartikel (refereegranskat)abstract
    • The ArmazoNes high Dispersion Echelle Spectrograph (ANDES) is the optical and near-infrared high-resolution echelle spectrograph envisioned for the Extremely Large Telescope (ELT). We present a selection of science cases, supported by new calculations and simulations, where ANDES could enable major advances in the fields of stars and stellar populations. We focus on three key areas, including the physics of stellar atmospheres, structure, and evolution; stars of the Milky Way, Local Group, and beyond; and the star-planet connection. The key features of ANDES are its wide wavelength coverage at high spectral resolution and its access to the large collecting area of the ELT. These features position ANDES to address the most compelling questions and potentially transformative advances in stellar astrophysics of the decades ahead, including questions which cannot be anticipated today.
  •  
44.
  • Roh, Hyung S., et al. (författare)
  • Integrating Color Deconvolution Thresholding and Weakly Supervised Learning for Automated Segmentation of Neurofibrillary Tangle and Neuropil Threads
  • 2023
  • Ingår i: Medical Imaging 2023 : Digital and Computational Pathology - Digital and Computational Pathology. - 1605-7422. - 9781510660472 ; 12471
  • Konferensbidrag (refereegranskat)abstract
    • Abnormally phosphorylated tau proteins are known to be a major indicator of Alzheimer's Disease (AD) with strong association with memory loss and cognitive decline. Automated generation of pixel-wise accurate neurofibrillary tangles (NFTs) and neuropil threads (NTs) segmentation is a challenging task, due to lack of ground truth segmentation data of these abnormal tau pathology. This problem is most prominent in the case of segmenting NTs, where the small threadlike morphology makes pixel-wise labeling a laborious task and unrealistic for large-scale studies. Lack of ground truth data poses a significant limitation for many learning-based methods to generate accurate segmentations of NFTs and NTs. This work presents an automated pipeline for pixel level segmentation of NFTs and NTs that does not rely on ground truth segmentation data. The pipeline is composed of four main steps: (1) color deconvolution is used to separate histopathology images into staining channels (DAB, Hematoxylin, and Eosin), (2) Otsu's thresholding is used on the DAB stain channel to generate pixel level segmentation of abnormal tau proteins staining, (3) a weakly-supervised learning paradigm (WildCat), using only global descriptors of images, is used to generate density maps of potential regions of NFTs and NTs, and (4) density maps and segmentations are then integrated using connected component analysis to localize NFTs and NTs in the detected tau segmentations. Our results show high global classification accuracy for NFTs (Acc:0.96) and NTs (Acc:0.91), and statistically significant distinctions when evaluating the percent area occupied of the detected NTs relative to expert ratings of NTs severity. Qualitative assessment of the NFTs and NTs results showed accurate pixel-level segmentations of the NFTs, while modest performance for NTs.
  •  
45.
  • Sako, Masao, et al. (författare)
  • The Data Release of the Sloan Digital Sky Survey-II Supernova Survey
  • 2018
  • Ingår i: Publications of the Astronomical Society of the Pacific. - : IOP Publishing. - 0004-6280 .- 1538-3873. ; 130:988
  • Tidskriftsartikel (refereegranskat)abstract
    • This paper describes the data release of the Sloan Digital Sky Survey-II (SDSS-II) Supernova Survey conducted between 2005 and 2007. Light curves, spectra, classifications, and ancillary data are presented for 10,258 variable and transient sources discovered through repeat ugriz imaging of SDSS Stripe 82, a 300 deg(2) area along the celestial equator. This data release is comprised of all transient sources brighter than r similar or equal to 22.5 mag with no history of variability prior to 2004. Dedicated spectroscopic observations were performed on a subset of 889 transients, as well as spectra for thousands of transient host galaxies using the SDSS-III BOSS spectrographs. Photometric classifications are provided for the candidates with good multi-color light curves that were not observed spectroscopically, using host galaxy redshift information when available. From these observations, 4607 transients are either spectroscopically confirmed, or likely to be, supernovae, making this the largest sample of supernova candidates ever compiled. We present a new method for SN host-galaxy identification and derive host-galaxy properties including stellar masses, star formation rates, and the average stellar population ages from our SDSS multi-band photometry. We derive SALT2 distance moduli for a total of 1364 SN. Ia with spectroscopic redshifts as well as photometric redshifts for a further 624 purely photometric SN. Ia candidates. Using the spectroscopically confirmed subset of the three-year SDSS-II SN. Ia sample and assuming a flat.CDM cosmology, we determine Omega(M) = 0.315 +/- 0.093 (statistical error only) and detect a non-zero cosmological constant at 5.7 sigma.
  •  
46.
  • Schiavon, Ricardo P., et al. (författare)
  • The APOGEE value-added catalogue of Galactic globular cluster stars
  • 2024
  • Ingår i: Monthly notices of the Royal Astronomical Society. - : Oxford University Press. - 0035-8711 .- 1365-2966. ; 528:2, s. 1393-1407
  • Tidskriftsartikel (refereegranskat)abstract
    • We introduce the Sloan Digital Sky Survey (SDSS)/ Apache Point Observatory Galactic Evolution Experiment (APOGEE) value-added catalogue of Galactic globular cluster (GC) stars. The catalogue is the result of a critical search of the APOGEE Data Release 17 (DR17) catalogue for candidate members of all known Galactic GCs. Candidate members are assigned to various GCs on the basis of position in the sky, proper motion, and radial velocity. The catalogue contains a total of 7737 entries for 6422 unique stars associated with 72 Galactic GCs. Full APOGEE DR17 information is provided, including radial velocities and abundances for up to 20 elements. Membership probabilities estimated on the basis of precision radial velocities are made available. Comparisons with chemical compositions derived from the GALactic Archaeology with HERMES (GALAH) survey, as well as optical values from the literature, show good agreement. This catalogue represents a significant increase in the public data base of GC star chemical compositions and kinematics, providing a massive homogeneous data set that will enable a variety of studies. The catalogue in fits format is available for public download from the SDSS-IV DR17 value-added catalogue website.
  •  
47.
  • Tarroc Gil, Sergi, et al. (författare)
  • Zonal Model Based Aircraft Passenger Thermal Comfort Comparative Study
  • 2022
  • Ingår i: 33rd Congress of the International Council of the Aeronautical Sciences, ICAS 2022. - : International Council of the Aeronautical Sciences (ICAS). - 9781713871163 ; , s. 312-322
  • Konferensbidrag (refereegranskat)abstract
    • Computational simulations have become during the last decades an essential tool to be used every day sooner in the design chain within the aerospace industry, leading to better decision making and more efficient concepts. However, in the aircraft design field, the thermal comfort of the passengers is not assessed until late design stages due to the complexity and high computational cost of simulating the flow inside it. The present work has the aim to show the Zonal Model approach as a solid early design simulation alternative to conventional CFD. A complete Fractional Step based Zonal Model solver is proposed, able to provide first estimations to the two-dimensional fluid solution, for a given cabin concept, with a low computational cost associated. This solver has also integrated its own automatized mesh generation algorithm along with a Radial Basis Functionsmorphing tool. With this method, a set of comparative studies have been performed for comparing several cabin design parameters attending to the thermal comfort of passengers and crew, giving a demonstration of the capabilities that this Zonal Model approach has for early aircraft design optimization and decision making.
  •  
48.
  • Tay, Apple Hui Min, et al. (författare)
  • A(2B) adenosine receptor antagonists rescue lymphocyte activity in adenosine-producing patient-derived cancer models
  • 2022
  • Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:5, s. e004592-
  • Tidskriftsartikel (refereegranskat)abstract
    • Background Adenosine is a metabolite that suppresses antitumor immune response of T and NK cells via extracellular binding to the two subtypes of adenosine-2 receptors, A(2)ARs. While blockade of the A(2A)ARs subtype effectively rescues lymphocyte activity, with four A(2A)AR antagonists currently in anticancer clinical trials, less is known for the therapeutic potential of the other A(2B)AR blockade within cancer immunotherapy. Recent studies suggest the formation of A(2A)AR/A(2B)AR dimers in tissues that coexpress the two receptor subtypes, where the A(2B)AR plays a dominant role, suggesting it as a promising target for cancer immunotherapy. Methods We report the synthesis and functional evaluation of five potent A(2B)AR antagonists and a dual A(2A)AR/A(2B)AR antagonist. The compounds were designed using previous pharmacological data assisted by modeling studies. Synthesis was developed using multicomponent approaches. Flow cytometry was used to evaluate the phenotype of T and NK cells on A(2B)AR antagonist treatment. Functional activity of T and NK cells was tested in patient-derived tumor spheroid models. Results We provide data for six novel small molecules: five A(2B)AR selective antagonists and a dual A(2A)AR/A(2B)AR antagonist. The growth of patient-derived breast cancer spheroids is prevented when treated with A(2B)AR antagonists. To elucidate if this depends on increased lymphocyte activity, immune cells proliferation, and cytokine production, lymphocyte infiltration was evaluated and compared with the potent A(2A)AR antagonist AZD-4635. We find that A(2B)AR antagonists rescue T and NK cell proliferation, IFN gamma and perforin production, and increase tumor infiltrating lymphocytes infiltration into tumor spheroids without altering the expression of adhesion molecules. Conclusions Our results demonstrate that A(2B)AR is a promising target in immunotherapy, identifying ISAM-R56A as the most potent candidate for A(2B)AR blockade. Inhibition of A(2B)AR signaling restores T cell function and proliferation. Furthermore, A(2B)AR and dual A(2A)AR/A(2B)AR antagonists showed similar or better results than A(2A)AR antagonist AZD-4635 reinforcing the idea of dominant role of the A(2B)AR in the regulation of the immune system.
  •  
49.
  • Tricoci, Pierluigi, et al. (författare)
  • Thrombin-receptor antagonist vorapaxar in acute coronary syndromes
  • 2012
  • Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 366:1, s. 20-33
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND:Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.METHODS:In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.RESULTS:Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups.CONCLUSIONS:In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).
  •  
50.
  • Val, Cristina, et al. (författare)
  • Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A(1) Antagonists
  • 2022
  • Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:3, s. 2091-2106
  • Tidskriftsartikel (refereegranskat)abstract
    • We herein document a large collection of 108 2-amino-4,6-disubstituted-pyrimidine derivatives as potent, structurally simple, and highly selective A(1)AR ligands. The most attractive ligands were confirmed as antagonists of the canonical cyclic adenosine monophosphate pathway, and some pharmacokinetic parameters were preliminarily evaluated. The library, built through a reliable and efficient three-component reaction, comprehensively explored the chemical space allowing the identification of the most prominent features of the structure-activity and structure-selectivity relationships around this scaffold. These included the influence on the selectivity profile of the aromatic residues at positions R-4 and R-6 of the pyrimidine core but most importantly the prominent role to the unprecedented A(1)AR selectivity profile exerted by the methyl group introduced at the exocyclic amino group. The structure-activity relationship trends on both A(1) and A(2A)ARs were conveniently interpreted with rigorous free energy perturbation simulations, which started from the receptor-driven docking model that guided the design of these series.
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