69 research outputs found

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

    Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

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    Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

    Whole-genome sequencing reveals host factors underlying critical COVID-19

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    Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

    New Saurorhynchus (Actinopterygii: Saurichthyidae) material from the Early Jurassic of Alberta, Canada

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    Saurichthyidae are a family of elongate, piscivorous actinopterygian fishes with a stratigraphic range extending from the late Permian to the Middle Jurassic. There are four recognized Early Jurassic species, all from Europe and all referred to the genus Saurorhynchus. Only a single non-European Jurassic occurrence has been reported, a partial Saurorhynchus skull from the Fernie Formation of western Alberta, Canada. Here, we evaluate the Saurorhynchus material from Canada, including a new skull from Ya Ha Tinda, Alberta, and a fragmentary mandible from Canyon Creek, Alberta. All diagnostic Canadian Saurorhynchus specimens are consistent with the European species Saurorhynchus acutus, on the basis of external narial morphology and reduced dermal ornamentation. S. acutus was present in the Toarcian of western North America from the tenuicostatum Zone to the late serpentinum/early bifrons Zone, similar to the stratigraphic range documented in Europe. The absence of divergence between eastern Panthalassan and western Tethyan saurichthyids is surprising, given that divergence has been well-documented in coeval invertebrates. Saurorhynchus may have had slower rates of morphological evolution than contemporaneous marine invertebrates; alternatively greater mobility, broader environmental tolerance, or both in these fish may have allowed ongoing gene flow between the two oceanic basins in the early Toarcian.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

    Crustose coralline algae increased framework and diversity on ancient coral reefs

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    <div><p>Crustose coralline algae (CCA) are key producers of carbonate sediment on reefs today. Despite their importance in modern reef ecosystems, the long-term relationship of CCA with reef development has not been quantitatively assessed in the fossil record. This study includes data from 128 Cenozoic coral reefs collected from the Paleobiology Database, the Paleoreefs Database, as well as the original literature and assesses the correlation of CCA abundance with taxonomic diversity (both corals and reef dwellers) and framework of fossil coral reefs. Chi-squared tests show reef type is significantly correlated with CCA abundance and post-hoc tests indicate higher involvement of CCA is associated with stronger reef structure. Additionally, general linear models show coral reefs with higher amounts of CCA had a higher diversity of reef-dwelling organisms. These data have important implications for paleoecology as they demonstrate that CCA increased building capacity, structural integrity, and diversity of ancient coral reefs. The analyses presented here demonstrate that the function of CCA on modern coral reefs is similar to their function on Cenozoic reefs; thus, studies of ancient coral reef collapse are even more meaningful as modern analogues.</p></div

    "Taphonomy: Dead and Fossilized" board game and associated educational material tested in 2018/2019

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    This is the Print-and-Play version of "Taphonomy: Dead and Fossilized" that was used for testing the game's efficacy in an undergraduate classroom. This site also contains the associated educational material and instructions to play the game during the assessment

    "Taphonomy: Dead and Fossilized" board game. Most recent game version (print and play)

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    This is the most up-to-date version of the "Taphonomy: Dead and Fossilized" board game (Print-and-Play). This site also contains the associated educational material and instructions to play the game

    Supplemental Data S1-S3 and S26-S37

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    Supplemental Data for Weiss and Martindale paper. Student and Professor Survey Questions and Results as well as statistical analyses of the data

    Data from: New records of the late Pliensbachian to early Toarcian (Early Jurassic) gladius-bearing coleoid cephalopods from the Ya Ha Tinda Lagerstätte, Canada

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    The Ya Ha Tinda Lagerstätte from Alberta, Canada, is the first Jurassic marine Konservat-Lagerstätte from North America and hosts a substantial collection of exceptionally preserved fossil Vampyropoda specimens. Vampyropods are soft-bodied cephalopods (coleoids) characterized by eight arms and an internalized chitinous shell (gladius). Due to their lack of hard parts, Vampyropoda have a fragmentary fossil record, largely limited to exceptional Lagerstätten deposits. Excavations at Ya Ha Tinda have uncovered sixteen vampyropod fossils from Pliensbachian and Toarcian strata, making it the largest deposit of Vampyropoda found outside of the Tethys Ocean (Europe and the Middle East) for the Jurassic. Here, we present a taxonomic analysis of the Ya Ha Tinda Vampyropoda specimens and the first comprehensive study of Early Jurassic vampyropods from North America. In total, fourteen specimens have sufficient morphological details preserved on the gladius for taxonomic descriptions. Two specimens are identifiable only to the suborder Loligosepiina (one to the family Geopeltidae), while the remaining twelve specimens are identified to the genus level; six Paraplesioteuthis, three Loligosepia, one Geopeltis, one Parabelopeltis, and one Jeletzkyteuthis. The discovery of Loligosepia cf. aalensis within Pliensbachian strata pushes back the earliest occurrence of this taxon from the early Toarcian to the late Pliensbachian. With the exception of Paraplesioteuthis, this is the first time these genera have been found outside of Europe for the Jurassic; therefore, this study significantly expands their palaeogeographic range. Furthermore, with established high-resolution bio and chemostratigraphy, specimens can be assigned to ammonite zones and placed in context of the global Toarcian Oceanic Anoxic Event
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