While remdesivir has garnered much hope for its moderate anti-Covid-19 effects, its parent nucleoside, GS-441524, has been overlooked. Pharmacokinetic analysis of remdesivir evidences premature serum ...hydrolysis to GS-441524; GS-441524 is the predominant metabolite reaching the lungs. With its synthetic simplicity and in vivo efficacy in the veterinary setting, we contend that GS-441524 is superior to remdesivir for Covid-19 treatment.
Key message
Pollen heat acclimation.
As a consequence of global warming, plants have to face more severe and more frequently occurring periods of high temperature stress. While this affects the whole ...plant, development of the male gametophyte, the pollen, seems to be the most sensitive process. Given the great importance of functioning pollen for the plant life cycle and for agricultural production, it is necessary to understand this sensitivity. While changes in temperature affect different components of all cells and require a cellular response and acclimation, high temperature effects and responses in developing pollen are distinct from vegetative tissues at several points. This could be related to specific physiological characteristics of developing pollen and supporting tissues which make them vulnerable to high temperature, or its derived effects such as ROS accumulation and carbohydrate starvation. But also expression of heat stress-responsive genes shows unique patterns in developing pollen when compared to vegetative tissues that might explain the failure to withstand high temperatures. As an alternative to viewing pollen failure under high temperature as a result of inherent sensitivity of a specific developmental process, we end by discussing whether it might actually be an adaptation.
Remdesivir is a nucleoside monophosphoramidate prodrug that has been FDA approved for coronavirus disease 2019 (COVID-19). However, the clinical efficacy of remdesivir for COVID-19 remains ...contentious, as several trials have not found statistically significant differences in either time to clinical improvement or mortality between remdesivir-treated and control groups. Similarly, the inability of remdesivir to provide a clinically significant benefit above other investigational agents in patients with Ebola contrasts with strong, curative preclinical data generated in rhesus macaque models. For both COVID-19 and Ebola, significant discordance between the robust preclinical data and remdesivir’s lackluster clinical performance have left many puzzled. Here, we critically evaluate the assumptions of the models underlying remdesivir’s promising preclinical data and show that such assumptions overpredict efficacy and minimize toxicity of remdesivir in humans. Had the limitations of in vitro drug efficacy testing and species differences in drug metabolism been considered, the underwhelming clinical performance of remdesivir for both COVID-19 and Ebola would have been fully anticipated.
To foster the green energy transition, local acceptance of wind energy is highly relevant. Since simple solutions like setback distances do not reflect the issue complexity, we incorporated ...acceptance factors from social science and interdisciplinary research in an Integrated Acceptance Model (IAM). To capture impact differences of the acceptance factors, in Study 1, residents of three operating wind farms in Germany (N = 158) were surveyed. Five most relevant acceptance factors were derived by a regression analysis: economic effects, impacts on residents and nature, attitudes towards the energy transition, trust in local actors and the planning process as well as social norms substantially explained local acceptance (R2 = 0.76). Next, in Study 2 the IAM was validated in an early stage, informal planning process in a Bavarian region (N = 92). In accord with Study 1, the IAM explained the variance in local acceptance comprehensively (R2 = 0.78). Moreover, a consistent impact of economic effects, attitudes towards the energy transition, expected effects on residents and nature as well as social norms was observed. While social norms played a pronounced role in Study 2, trust only related to the acceptance in Study 1. The IAM seems to capture the overall relevant acceptance categories, which can be used as guidance to create a sustainable green energy transition.
•Integrated model on the social acceptance of wind energy is presented.•Integrated model explains local acceptance substantially.•The model is validated in an operating and an early informal planning stage.•Five significant predictors cover categories for best practice recommendations.
Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized. Histone methyltransferase KMT2D (a COMPASS-like enzyme, ...also called MLL4) is among the most highly inactivated epigenetic modifiers in lung cancer. Here, we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, including glycolysis. Pharmacological inhibition of glycolysis preferentially impedes tumorigenicity of human lung cancer cells bearing KMT2D-inactivating mutations. Mechanistically, Kmt2d loss widely impairs epigenomic signals for super-enhancers/enhancers, including the super-enhancer for the circadian rhythm repressor Per2. Loss of Kmt2d decreases expression of PER2, which regulates multiple glycolytic genes. These findings indicate that KMT2D is a lung tumor suppressor and that KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors.
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•Lung-specific Kmt2d loss in mice promotes lung tumorigenesis•Kmt2d loss impairs enhancers, including a super-enhancer for the tumor suppressor Per2•KMT2D activates Per2 expression and thereby represses glycolytic genes•Glycolysis inhibition impedes the growth of KMT2D-mutant lung cancer
Histone methyltransferase KMT2D is frequently mutated in lung tumors, and Alam et al. identify KMT2D as a lung tumor suppressor. KMT2D deficiency induces aberrant metabolic reprogramming via super-enhancer impairment, conferring sensitivity to glycolytic inhibitors in lung cancer with KMT2D-inactivating mutations.
The analysis of fuel rod bundle flows constitutes a key element of Pressurized-Water Reactors (PWR) safety studies. The present work aims at improving our understanding of nefarious reorganisation ...phenomena observed by numerous studies in the flow large-scale structures. 3D simulations allowed identifying two distinct reorganisations consisting in a sign change for either a transverse velocity in rod-to-rod gaps or for a subchannel vortex. A Taylor “frozen turbulence” hypothesis was adopted to model the evolution of large-scale 3D structures as transported-2D. A statistical method was applied to the 2D field to determine its thermodynamically stable states through an optimization problem. Similarities were obtained between the PWR coherent structures and the stable states in a simplified 2D geometry. Further, 2D simulations allowed identifying two possible flow bifurcations, each related to one of the reorganisations observed in 3D simulations, laying the foundations for a physical explanation of this phenomenon.
The early observations on the rate-of-living theory by Max Rubner and the report by Gershman that oxygen free radicals exist in vivo culminated in the seminal proposal in the 1950s by Denham Harman ...that reactive oxygen species are a cause of aging (free radical theory of aging). The goal of this review is to analyze recent findings relevant in evaluating Harman’s theory using experimental results as grouped by model organisms (i.e., invertebrate models and mice). In this regard, we have focused primarily on recent work involving genetic manipulations. Because the free radical theory of aging is not the only theorem proposed to explain the mechanism(s) involved in aging at the molecular level, we also discuss how this theory is related to other areas of research in biogerontology, specifically, telomere/cell senescence, genomic instability, and the mitochondrial hypothesis of aging. We also discuss where we think the free radical theory is headed. It is now possible to give at least a partial answer to the question
whether oxidative stress determines life span as Harman posed so long ago. Based on studies to date, we argue that a tentative case for oxidative stress as a life-span determinant can be made in
Drosophila melanogaster. Studies in mice argue for a role of oxidative stress in age-related disease, especially cancer; however, with regard to aging per se, the data either do not support or remain inconclusive on whether oxidative stress determines life span.
Mechanisms of mitochondrial superoxide formation remain poorly understood despite considerable medical interest in oxidative
stress. Superoxide is produced from both Complexes I and III of the ...electron transport chain, and once in its anionic form
it is too strongly charged to readily cross the inner mitochondrial membrane. Thus, superoxide production exhibits a distinct
membrane sidedness or âtopology.â In the present work, using measurements of hydrogen peroxide (Amplex red) as well as superoxide
(modified Cypridina luciferin analog and aconitase), we demonstrate that Complex I-dependent superoxide is exclusively released into the matrix
and that no detectable levels escape from intact mitochondria. This finding fits well with the proposed site of electron leak
at Complex I, namely the iron-sulfur clusters of the (matrix-protruding) hydrophilic arm. Our data on Complex III show direct
extramitochondrial release of superoxide, but measurements of hydrogen peroxide production revealed that this could only account
for â¼50% of the total electron leak even in mitochondria lacking CuZn-superoxide dismutase. We posit that the remaining â¼50%
of the electron leak must be due to superoxide released to the matrix. Measurements of (mitochondrial matrix) aconitase inhibition,
performed in the presence of exogenous superoxide dismutase and catalase, confirmed this hypothesis. Our data indicate that
Complex III can release superoxide to both sides of the inner mitochondrial membrane. The locus of superoxide production in
Complex III, the ubiquinol oxidation site, is situated immediately next to the intermembrane space. This explains extramitochondrial
release of superoxide but raises the question of how superoxide could reach the matrix. We discuss two models explaining this
result.
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