RESUMEN
Methane emissions from oil and gas (O&G) production and transmission represent a considerable contribution to climate change. These emissions comprise sporadic releases of large amounts of methane during maintenance operations or equipment failures not accounted for in current inventory estimates. We collected and analyzed hundreds of very large releases from atmospheric methane images sampled by the TROPOspheric Monitoring Instrument (TROPOMI) between 2019 and 2020. Ultra-emitters are primarily detected over the largest O&G basins throughout the world. With a total contribution equivalent to 8 to 12% (~8 million metric tons of methane per year) of the global O&G production methane emissions, mitigation of ultra-emitters is largely achievable at low costs and would lead to robust net benefits in billions of US dollars for the six major O&G-producing countries when considering societal costs of methane.
RESUMEN
Acute myeloid leukemias (AMLs) are a heterogeneous group of diseases that are sustained by relatively rare leukemia-initiating cells (LICs) that exhibit diverse genetic and phenotypic properties. AML heterogeneity presents a major challenge to development of targeted therapies, and effective treatment will require targeting of common molecular drivers of AML maintenance. The orphan nuclear receptors NR4A1 and NR4A3 are potent tumor suppressors of AML. They are silenced in all human AML LICs, irrespective of patient cytogenetics, and their deletion in mice leads to postnatal AML development. In the current report, we address the tumor-suppressive mechanisms and therapeutic potential of NR4As for AML intervention. We show that rescue of either NR4A1 or NR4A3 inhibits the leukemogenicity of AML cells in vivo and reprograms a subset of gene signatures that distinguish primary human LICs from normal hematopoietic stem cells (HSCs), irrespective of subtype. Central to NR4A reprogramming is the acute suppression of an LIC submodule that includes the transcriptional repression of MYC. Additionally, we show that upregulation of MYC is an acute preleukemic consequence of NR4A deletion and that MYC suppression functionally contributes to NR4A antileukemic effects. Collectively, these results identify NR4As as novel targets for AML therapeutic intervention and reveal molecular targets of NR4A tumor suppression, including the suppression of MYC.
RESUMEN
In order to understand the substrate behaviour of several 7-alkoxycoumarins and 7-alkoxy-4-alkylcoumarins towards the liver microsomal monooxygenase system, their lipophilic properties have been examined. As a model for the lipophilicity the reversed-phase liquid chromatographic retention parameter log kw has been used. In a system with methanol-water as the mobile phase and RP-18 (octadecylsilica) as the stationary phase, we found a quadratic relationship between the volume fraction of the organic solvent and the logarithm of the capacity factor (log k'). The extrapolation to a pure aqueous phase reveals a linear relationship of the theoretical capacity factor log kw with the chain length. This holds for 1-12 carbon atoms in the alkoxy chain and for zero to three carbon atoms in the alkyl chain. Moreover, the incremental effect of the methylene residues on the lipophilicity of the compounds (delta log kw/delta CH2) is found to be 0.60 +/- 0.01. If the coumarin derivatives are used as substates for the liver microsomal monooxygenase system, no systematic dependence of the enzymic data (Michaelis-Menten constant Km) on the lipophilic data (log kw) can be demonstrated. The metabolism of these compounds by the microsomal monooxygenase system seems not to be limited by the partition between the membrane and the aqueous phase. Whether other factors, e.g. the lateral diffusion of the substrates versus the membrane-bound enzyme system or enzyme active-site characteristics, govern the metabolism remains to be investigated.