Anabolic metabolism mediated by aberrant growth factor signalling fuels tumour growth and progression. The first biochemical descriptions of the altered metabolic nature of solid tumours were ...reported by Otto Warburg almost a century ago. Now, the study of tumour metabolism is being redefined by the development of new molecular tools, tumour modelling systems and precise instrumentation together with important advances in genetics, cell biology and spectroscopy. In contrast to Warburg's original hypothesis, accumulating evidence demonstrates a critical role for mitochondrial metabolism and substantial variation in the way in which different tumours metabolize nutrients to generate biomass. Furthermore, computational and experimental approaches suggest a dominant influence of the tissue-of-origin in shaping the metabolic reprogramming that enables tumour growth. For example, the unique metabolic properties of prostate adenocarcinoma are likely to stem from the distinct metabolism of the prostatic epithelium from which it emerges. Normal prostatic epithelium employs comparatively glycolytic metabolism to sustain physiological citrate secretion, whereas prostate adenocarcinoma consumes citrate to power oxidative phosphorylation and fuel lipogenesis, enabling tumour progression through metabolic reprogramming. Current data suggest that the distinct metabolic aberrations in prostate adenocarcinoma are driven by the androgen receptor, providing opportunities for functional metabolic imaging and novel therapeutic interventions that will be complementary to existing diagnostic and treatment options.
The progression of tau pathology in Alzheimer's disease follows a stereotyped pattern, and recent evidence suggests a role of synaptic connections in this process. Astrocytes are well positioned at ...the neuronal synapse to capture and degrade extracellular tau as it transits the synapse and hence could potentially have the ability to inhibit tau spreading and delay disease progression. Our study shows increased expression and activity of Transcription Factor EB (TFEB), a master regulator of lysosomal biogenesis, in response to tau pathology in both human brains with dementia and transgenic mouse models. Exogenous TFEB expression in primary astrocytes enhances tau fibril uptake and lysosomal activity, while TFEB knockout has the reverse effect. In vivo, induced TFEB expression in astrocytes reduces pathology in the hippocampus of PS19 tauopathy mice, as well as prominently attenuates tau spreading from the ipsilateral to the contralateral hippocampus in a mouse model of tau spreading. Our study suggests that astrocytic TFEB plays a functional role in modulating extracellular tau and the propagation of neuronal tau pathology in tauopathies such as Alzheimer's disease.
Supported by the U.S. Department of Energy (DOE), the Energy Exascale Earth System Model (E3SM) project aims to optimize the use of DOE resources to address the grand challenge of actionable ...predictions of Earth system variability and change. This requires sustained advancement to (1) integrate model development with leading‐edge computational advances toward ultra‐high‐resolution modeling; (2) represent the coupled human‐Earth system to address energy sector vulnerability to variability and change; and (3) address uncertainty in model simulations and projections. Scientific development of the E3SM modeling system is driven by the simulation requirements in three overarching science areas centering on understanding the Earth's water cycle, biogeochemistry, and cryosphere systems and their future changes. This paper serves as an introduction to the E3SM special collection, which includes 50 papers published in several AGU journals. It provides an overview of the E3SM project, including its goals and science drivers. It also provides a brief history of the development of E3SM version 1 and highlights some key findings from papers included in the special collection.
Plain Language Summary
Earth system models are important tools for predicting future changes in the Earth system. Supported by the U.S. Department of Energy (DOE), the Energy Exascale Earth System Model (E3SM) project aims to improve predictions of Earth system variability and change. The latter has a particular focus on predicting changes in the water cycle that influences precipitation and storms, biogeochemistry that influences greenhouse gases and future warming, and cryosphere systems that influence sea‐level rise that threatens coastal communities. This paper serves as an introduction to the E3SM special collection, which includes 50 papers published in several AGU journals. It provides an overview of the E3SM project, including its goals and science drivers. It also provides a brief history of the development of E3SM version 1 and highlights some key findings from papers included in the special collection.
Key Points
The Energy Exascale Earth System Model (E3SM) project aims to improve actionable predictions of Earth system variability and change
Water cycle, biogeochemistry, and cryosphere systems are the three key science drivers of model development and numerical experiments
This paper provides an overview of the E3SM project and introduces the E3SM special collection of papers published in AGU journals
This paper presents results from a 40 year Weather Research and Forecasting (WRF) based dynamical downscaling experiment performed at 12 km horizontal grid spacing, centered on the state of ...California, and forced by a 1° x 1.25° finite-volume current-climate Community Climate System Model ver. 3 (CCSM3) simulation. In-depth comparisons between modeled and observed regional-average precipitation, 2 m temperature, and snowpack are performed. The regional model reproduces the spatial distribution of precipitation quite well, but substantially overestimates rainfall along windward slopes. This is due to strong overprediction of precipitation intensity; precipitation frequency is actually underpredicted by the model. Moisture fluxes impinging on the coast seem to be well-represented over California, implying that precipitation bias is caused by processes internal to WRF. Positive-definite moisture advection and use of the Grell cumulus parameterization result in some decrease in precipitation bias, but other sources are needed to explain the full bias magnitude. Surface temperature is well simulated in all seasons except summer, when overly-dry soil moisture results in a several degree warm bias in both CCSM3 and WRF. Additionally, coastal temperatures appear to be too warm due to a coastal sea surface temperature bias inherited from CCSM3. Modeled snowfall/snowmelt agrees quite well with observations, but snow water equivalent is found to be much too low due to monthly reinitialization of all regional model fields from CCSM3 values.
The intestinal microbiome is a unique ecosystem and an essential mediator of metabolism and obesity in mammals. However, studies investigating the impact of the diet on the establishment of the gut ...microbiome early in life are generally lacking, and most notably so in primate models. Here we report that a high-fat maternal or postnatal diet, but not obesity per se, structures the offspring's intestinal microbiome in Macaca fuscata (Japanese macaque). The resultant microbial dysbiosis is only partially corrected by a low-fat, control diet after weaning. Unexpectedly, early exposure to a high-fat diet diminished the abundance of non-pathogenic Campylobacter in the juvenile gut, suggesting a potential role for dietary fat in shaping commensal microbial communities in primates. Our data challenge the concept of an obesity-causing gut microbiome and rather provide evidence for a contribution of the maternal diet in establishing the microbiota, which in turn affects intestinal maintenance of metabolic health.
Clouds represent a key uncertainty in future climate projection. While explicit cloud resolution remains beyond our computational grasp for global climate, we can incorporate important cloud effects ...through a computational middle ground called the Multi-scale Modeling Framework (MMF), also known as Super Parameterization. This algorithmic approach embeds high-resolution Cloud Resolving Models (CRMs) to represent moist convective processes within each grid column in a Global Climate Model (GCM). The MMF code requires no parallel data transfers and provides a self-contained target for acceleration. This study investigates the performance of the Energy Exascale Earth System Model-MMF (E3SM-MMF) code on the OLCF Summit supercomputer at an unprecedented scale of simulation. Hundreds of kernels in the roughly 10K lines of code in the E3SM-MMF CRM were ported to GPUs with OpenACC directives. A high-resolution benchmark using 4600 nodes on Summit demonstrates the computational capability of the GPU-enabled E3SM-MMF code in a full physics climate simulation.
Low-grade, sustained inflammation in white adipose tissue (WAT) characterizes obesity and coincides with type 2 diabetes mellitus (T2DM). However, pharmacological targeting of inflammation lacks ...durable therapeutic effects in insulin-resistant conditions. Through a computational screen, we discovered that the FDA-approved rheumatoid arthritis drug auranofin improved insulin sensitivity and normalized obesity-associated abnormalities, including hepatic steatosis and hyperinsulinemia in mouse models of T2DM. We also discovered that auranofin accumulation in WAT depleted inflammatory responses to a high-fat diet without altering body composition in obese wild-type mice. Surprisingly, elevated leptin levels and blunted beta-adrenergic receptor activity achieved by leptin receptor deletion abolished the antidiabetic effects of auranofin. These experiments also revealed that the metabolic benefits of leptin reduction were superior to immune impacts of auranofin in WAT. Our studies uncover important metabolic properties of anti-inflammatory treatments and contribute to the notion that leptin reduction in the periphery can be accomplished to treat obesity and T2DM.
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•The rheumatoid arthritis drug auranofin improves insulin sensitivity in obese mice•Auranofin accumulation in epididymal white fat drives whole-body glucose disposal•Metabolic benefits of auranofin require an intact leptin axis•Auranofin couples lipolytic competence to inhibition of leptin secretion
The FDA-approved rheumatoid arthritis drug auranofin accumulates in white adipose tissue, improves insulin sensitivity, and normalizes fatty-liver disease in obesity. Beta-adrenergic receptor regulation of leptin secretion generates metabolic benefits superior to anti-inflammatory effects. Consequently, studies of auranofin reinforce that partial leptin reduction represents a relevant method for treating obesity.
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