N
-methyladenosine (m
A) is an abundant internal RNA modification
that is catalysed predominantly by the METTL3-METTL14 methyltransferase complex
. The m
A methyltransferase METTL3 has been linked to ...the initiation and maintenance of acute myeloid leukaemia (AML), but the potential of therapeutic applications targeting this enzyme remains unknown
. Here we present the identification and characterization of STM2457, a highly potent and selective first-in-class catalytic inhibitor of METTL3, and a crystal structure of STM2457 in complex with METTL3-METTL14. Treatment of tumours with STM2457 leads to reduced AML growth and an increase in differentiation and apoptosis. These cellular effects are accompanied by selective reduction of m
A levels on known leukaemogenic mRNAs and a decrease in their expression consistent with a translational defect. We demonstrate that pharmacological inhibition of METTL3 in vivo leads to impaired engraftment and prolonged survival in various mouse models of AML, specifically targeting key stem cell subpopulations of AML. Collectively, these results reveal the inhibition of METTL3 as a potential therapeutic strategy against AML, and provide proof of concept that the targeting of RNA-modifying enzymes represents a promising avenue for anticancer therapy.
Streams and rivers are important conduits of terrestrially derived carbon (C) to atmospheric and marine reservoirs. Leaf litter breakdown rates are expected to increase as water temperatures rise in ...response to climate change. The magnitude of increase in breakdown rates is uncertain, given differences in litter quality and microbial and detritivore community responses to temperature, factors that can influence the apparent temperature sensitivity of breakdown and the relative proportion of C lost to the atmosphere vs. stored or transported downstream. Here, we synthesized 1025 records of litter breakdown in streams and rivers to quantify its temperature sensitivity, as measured by the activation energy (Ea, in eV). Temperature sensitivity of litter breakdown varied among twelve plant genera for which Ea could be calculated. Higher values of Ea were correlated with lower‐quality litter, but these correlations were influenced by a single, N‐fixing genus (Alnus). Ea values converged when genera were classified into three breakdown rate categories, potentially due to continual water availability in streams and rivers modulating the influence of leaf chemistry on breakdown. Across all data representing 85 plant genera, the Ea was 0.34 ± 0.04 eV, or approximately half the value (0.65 eV) predicted by metabolic theory. Our results indicate that average breakdown rates may increase by 5–21% with a 1–4 °C rise in water temperature, rather than a 10–45% increase expected, according to metabolic theory. Differential warming of tropical and temperate biomes could result in a similar proportional increase in breakdown rates, despite variation in Ea values for these regions (0.75 ± 0.13 eV and 0.27 ± 0.05 eV, respectively). The relative proportions of gaseous C loss and organic matter transport downstream should not change with rising temperature given that Ea values for breakdown mediated by microbes alone and microbes plus detritivores were similar at the global scale.
Warmer water enhances decomposition of organic matter in streams and rivers, but it is unclear if climate change will result in more carbon emitted to the atmosphere or transported to the ocean. We assembled over 1000 published data points on leaf litter breakdown in streams and rivers globally to assess how rates of breakdown will change with elevated temperature. Across 85 plant genera, we found that rates may increase only half as much as expected should water temperature rise by 1–4 °C. Among 12 plant genera for which temperature sensitivity could be calculated individually, higher sensitivity was correlated with lower quality litter. Similarity in the temperature sensitivity of breakdown mediated by microbes alone or microbes plus detritivores suggests the relative proportions of carbon converted to gas or transported as smaller particles will not change with elevated temperature.
To demonstrate that sensory and emotional states play an important role in moral processing, previous research has induced physical disgust in various sensory modalities (visual, tactile, gustatory, ...and olfactory modalities, among others) and measured its effects on moral judgment. To further assess the strength of the connection between embodied states and morality, we investigated whether the directionality of the effect could be reversed by exposing participants to different types of moral events prior to rating the same neutral tasting beverage. As expected, reading about moral transgressions, moral virtues, or control events resulted in inducing gustatory disgust, delight, or neutral taste experiences, respectively. Results are discussed in terms of the relation between embodied cognition and processing abstract conceptual representations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Evolutionary history and adaptation to climate shape plant traits. Some include leaf traits that influence litter quality. Thus, evolutionary history should affect litter decomposition, a crucial ...ecosystem process. In addition, litter decomposition is directly influenced by climate. We consequently expect plant phylogeny, adaptation and climate to jointly influence litter decomposition. These effects and their interactions have yet to be untangled at a global scale.
Here we present an analysis of variation in litter decomposition rates in rivers and streams across 285 published studies for 239 species (from ferns to angiosperms) distributed at 494 locations world‐wide. We estimated the relative contributions of climatic conditions and phylogenetic heritage on litter decomposition rates, partitioning phylogenetic from climatic effects at the site and species levels using phylogenetic eigenvector analysis and phylogenetic linear mixed models. In addition, we modelled transitions in decomposition rates under a suite of multiple adaptive‐regime Ornstein–Uhlenbeck models to test the hypothesis that natural selection has shaped clade‐level litter decomposition rates.
Leaf litter decomposition rate exhibited a significant phylogenetic signal. Modelling decomposition rate as a function of location, climatic niche and phylogeny consistently recovered phylogeny alone as one of the top models in species‐level analyses. Since many previous studies have focused on the same species across many locations, we also conducted analyses at the species × site level. Both phylogenetic and climatic factors were favoured in models of this analysis, but the single most important predictor for angiosperms and for all taxa analysed together was phylogeny alone.
Synthesis. For plant species distributed globally at nearly 500 locations we found that plant phylogenetic history is a critically important predictor of litter decomposition rate in rivers and streams, explaining more of the variance in decomposition than site or climatic regime. Thus, our study demonstrates the influence of evolutionary history on suites of plant traits that shape a key ecosystem process.
Foreign Language Résumé
L’histoire évolutive et l'adaptation au climat façonnent les caractéristiques des plantes. Le contrôle des traits foliaires sur la qualité des litières végétales pourrait sous‐tendre l'existence de contraintes évolutives sur la décomposition des litières. Puisque ce processus écologique majeur est également directement modulé par le climat, il est important de mieux comprendre comment la phylogénie des plantes, leurs réponses adaptatives et le climat influencent ensemble la décomposition des litières à une échelle globale.
Nous présentons ici les résultats d'une analyses quantitatives des données de décomposition de litières dans des rivières et des ruisseaux, issues de 285 publications couvrant 239 espèces de plantes (des fougères aux angiospermes) dans 494 lieux à travers le monde. Nous avons quantifié la contribution des conditions climatiques et de l'héritage phylogénétique aux variations du taux de décomposition des litières entre les espèces et entre les sites, à l'aide de régressions sur les vecteurs propres phylogénétiques et de modèles phylogénétiques linéaires à effets mixtes. Le modèle de Ornstein‐Uhlenbeck a également été utilisé pour tenter de comprendre si et comment la sélection naturelle s'exerce sur la qualité des litières.
Un signal phylogénétique cohérent a été détecté au sein des données analysées dans notre étude. La construction de modèles utilisant les informations géographiques, climatiques et phylogénétiques disponibles a permis d’établir la phylogénie comme un des meilleurs prédicteurs des variations interspécifiques du taux de décomposition des litières. Les variations spatiales de la décomposition étaient expliquées par les contraintes climatiques et phylogénétiques. Néanmoins, seule la phylogénie était nécessaire pour prédire les variations du taux de décomposition chez les angiospermes seulement ou bien sur l'ensemble des espèces de litière.
Synthèses. En analysant les résultats d’études englobant un grand nombre d'espèces de plantes au sein de 500 sites environ, nous avons découvert que l'histoire évolutive des plantes prédisait mieux le taux de décomposition des litières dans les rivières et les ruisseaux que les données géographiques ou climatiques. Notre étude démontre comment les contraintes évolutives s'exerçant sur un ensemble de traits peuvent, de manière ultime, influencer un processus écologique majeur dans les écosystèmes.
A global synthesis finds that plant phylogenetic history better predicts aquatic litter decomposition than climatic factors. This demonstrates the influence of evolutionary history on suites of plant traits that influence a key ecosystem process. New findings will improve models of carbon cycling rates through geological time by identifying the characteristics of dominant lineages in different habitats over deep time.
SINEUPs are a novel class of natural and synthetic non-coding antisense RNA molecules able to increase the translation of a target mRNA. They present a modular organization comprising an unstructured ...antisense target-specific domain, which sets the specificity of each individual SINEUP, and a structured effector domain, which is responsible for the translation enhancement. In order to design a fully functional in vitro transcribed SINEUP for therapeutics applications, SINEUP RNAs were synthesized in vitro with a variety of chemical modifications and screened for their activity on endogenous target mRNA upon transfection. Three combinations of modified ribonucleotides—2′O methyl-ATP (Am), N6 methyl-ATP (m6A), and pseudo-UTP (ψ)—conferred SINEUP activity to naked RNA. The best combination tested in this study was fully modified with m6A and ψ. Aside from functionality, this combination conferred improved stability upon transfection and higher thermal stability. Common structural determinants of activity were identified by circular dichroisms, defining a core functional structure that is achieved with different combinations of modifications.
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SINEUP RNAs are a new platform for therapeutics to increase endogenous protein expression within a physiological range. We identified a combination of modified chemical modifications to confer SINEUP activity to an in vitro transcribed RNA. Common structural determinants of activity were identified by circular dichroisms.
Herein we describe the identification of 4-{1,2,4triazolo1,5-apyridin-5-yl}benzonitrile-based inhibitors of the hypoxia-inducible factor prolylhydroxylase domain-1 (PHD-1) enzyme. These ...inhibitors were shown to possess a novel binding mode by X-ray crystallography, in which the triazolo N1 atom coordinates in a hitherto unreported monodentate interaction with the active site Fe2+ ion, while the benzonitrile group accepts a hydrogen-bonding interaction from the side chain residue of Asn315. Further optimization led to potent PHD-1 inhibitors with good physicochemical and pharmacokinetic properties.
Studies of trophic-level material and energy transfers are central to ecology. The use of isotopic tracers has now made it possible to measure trophic transfer efficiencies of important nutrients and ...to better understand how these materials move through food webs. We analyzed data from thirteen 15N-ammonium tracer addition experiments to quantify N transfer from basal resources to animals in headwater streams with varying physical, chemical, and biological features. N transfer efficiencies from primary uptake compartments (PUCs; heterotrophic microorganisms and primary producers) to primary consumers was lower (mean 11.5%, range <1% to 43%) than N transfer efficiencies from primary consumers to predators (mean 80%, range 5% to >100%). Total N transferred (as a rate) was greater in streams with open compared to closed canopies and overall N transfer efficiency generally followed a similar pattern, although was not statistically significant. We used principal component analysis to condense a suite of site characteristics into two environmental components. Total N uptake rates among trophic levels were best predicted by the component that was correlated with latitude, DIN:SRP, GPP:ER, and percent canopy cover. N transfer efficiency did not respond consistently to environmental variables. Our results suggest that canopy cover influences N movement through stream food webs because light availability and primary production facilitate N transfer to higher trophic levels.
Rivers and streams contribute to global carbon cycling by decomposing immense quantities of terrestrial plant matter. However, decomposition rates are highly variable and large-scale patterns and ...drivers of this process remain poorly understood. Using a cellulose-based assay to reflect the primary constituent of plant detritus, we generated a predictive model (81% variance explained) for cellulose decomposition rates across 514 globally distributed streams. A large number of variables were important for predicting decomposition, highlighting the complexity of this process at the global scale. Predicted cellulose decomposition rates, when combined with genus-level litter quality attributes, explain published leaf-litter-decomposition rates with impressive accuracy (70% variance explained). Our global map provides estimates of rates across vast understudied areas of Earth, and reveals rapid decomposition across continental-scale areas dominated by human activities.
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