Balance Fluxes Research Articles

Laminated Cores in Inductive Power Transfer: A Viaduct Structure for Balanced Flux and Minimal Shielding Loss

Laminated Cores in Inductive Power Transfer: A Viaduct Structure for Balanced Flux and Minimal Shielding Loss

Metabolic modelling links Warburg effect to collagen formation, angiogenesis and inflammation in the tumoral stroma.

Cancer cells are known to express the Warburg effect-increased glycolysis and formation of lactic acid even in the presence of oxygen-as well as high glutamine uptake. In tumors, cancer cells are surrounded by collagen, immune cells, and neoangiogenesis. Whether collagen formation, neoangiogenesis, and inflammation in cancer are associated with the Warburg effect needs to be established. Metabolic modelling has proven to be a tool of choice to understand biological reality better and make in silico predictions. Elementary Flux Modes (EFMs) are essential for conducting an unbiased decomposition of a metabolic model into its minimal functional units. EFMs can be investigated using our tool, aspefm, an innovative approach based on logic programming where biological constraints can be incorporated. These constraints allow networks to be characterized regardless of their size. Using a metabolic model of the human cell containing collagen, neoangiogenesis, and inflammation markers, we derived a subset of EFMs of biological relevance to the Warburg effect. Within this model, EFMs analysis provided more adequate results than parsimonious flux balance analysis and flux sampling. Upon further inspection, the EFM with the best linear regression fit to cancer cell lines exometabolomics data was selected. The minimal pathway, presenting the Warburg effect, collagen synthesis, angiogenesis, and release of inflammation markers, showed that collagen production was possible directly de novo from glutamine uptake and without extracellular import of glycine and proline, collagen's main constituents.

Flux balance analysis and peptide mapping elucidate the impact of bioreactor pH on Chinese hamster ovary (CHO) cell metabolism and N-linked glycosylation in the fab and Fc regions of the produced IgG

Culture conditions have a profound impact on therapeutic protein production and glycosylation, a critical therapeutic-quality attribute, especially for monoclonal antibodies (mAbs). While the critical culture parameter of pH has been known since the early 1990s to affect protein glycosylation and production, detailed glycan and metabolic characterization and mechanistic understanding are critically lacking. Here, Chinese Hamster Ovary (CHO) cells were grown in bioreactors at pH 6.75, 7, and 7.25 (± 0.03) to examine how pH affects cell metabolism and site-specific N-linked glycosylation of the produced broadly neutralizing anti-HIV IgG1 mAb. VRC01 has N-linked glycosylation sites in both the Fc region and the Fab region, a situation not previously examined with respect to mAb glycosylation as affected by culture conditions. Using parsimonious Flux Balance Analysis (pFBA) and Flux Variability Analysis (FVA), we dissect and quantitate the impact of pH on cell growth, glucose/lactate metabolism, accumulation of the toxic metabolite ammonia, IgG production rates, and nonessential amino acid metabolism. pFBA revealed that beyond the established mechanism of glutamine conversion to glutamate, ammonia is also produced by the reaction converting serine to pyruvate, especially in the later phases of culture. pFBA also provided insights into the switch from ammonia production to consumption, notably due to depletion of glutamine, and consumption of glutamate and aspartate. We document that culture duration and pH alter the complex bimodal patterns (production/uptake) of several essential and non-essential amino acids. Site-specific N-linked glycan analysis using glycopeptide mapping demonstrated that pH significantly affects the glycosylation profiles of the two IgG1 sites. Fc region glycans were completely fucosylated but did not contain any sialylation. The Fab region glycans were not completely fucosylated but contained sialylated glycans. Bioreactor pH affected both the fucosylation and sialylation indexes in the Fab region and the galactosylation index of the Fc region. However, fucosylation in the Fc region was unaffected thus demonstrating that the effect of pH on site-specific N-linked glycosylation is complex.

Design and Analysis of a Three-Phase High-Frequency Transformer for Three-Phase Bidirectional Isolated DC-DC Converter Using Superposition Theorem

Battery energy storage systems based on bidirectional isolated DC-DC converters (BIDCs) have been employed to level the output power of intermittent renewable energy generators and to supply power to electric vehicles. Moreover, BIDCs use high-frequency transformers (HFTs) to achieve voltage matching and galvanic isolation. Various studies have recently been conducted using soft magnetic materials, such as nanocrystalline, amorphous solids, and ferrite, to develop more compact and effective transformers with superior power densities. The HFTs in three-phase BIDCs are composed of three magnetic cores. However, this leads to low power density and high cost. Besides, the three-phase (3P) ferrite core has not been investigated for high-power converters such as 3P-BIDCs. This paper presents the design and development of a 3P-EE ferrite magnetic core for 3P-BIDCs. The area product design method was used to determine the core and winding design. The paper also proposes the use of the superposition theorem in conducting a magnetic circuit analysis to predict the flux density and magnetising inductance of the transformer core. Moreover, the use of the superposition theorem allowed the required air-gap length for balancing the distribution of flux density and magnetizing inductance in the transformer core to be determined. The balanced flux distribution and magnetizing inductance resulted in a uniform core loss and temperature in the transformer. This paper also presents the experimental results of the designed HFT operated in a 300-V, 3-kW 3P-BIDC. The experimental results showed that the proposed HFT achieved a balanced flux density and magnetizing inductance with a high power density and low cost. Moreover, the transformer performed at a maximum efficiency of 98.67%, with a decrease of 3.33 °C in the overall temperature of the transformer as compared to the transformer without air gaps.

On the factors and the degree of their effect on subglacial melt and changes in the state of Antarctic subglacial lakes

ABSTRACT This study presents the results of mathematical modeling of the degree of effects of various characteristics on basal conditions in Antarctica. The model is based on the numerical solution of the one-dimensional Stefan problem. Five factors determining the nature of subglacial processes have been studied: ice thickness, snow-firn thickness, surface mass balance, air temperature, and geothermal heat flux. It was found that on the Antarctic plateau, slope, and coast, the geothermal heat flux has the greatest influence on the basal conditions. It is the heat flux that is responsible for the transition of most Antarctic lakes from a stable state to an active one (except for the ice stream regions). In areas where the ice sheet is thinner than 1,500 m, air temperature is the second most important factor affecting subglacial conditions. In areas where the glacier is thicker, the ice thickness begins to have a greater effect. The snow-firn thickness and snow accumulation have little effect on subglacial melt in most parts of Antarctica. Calculations over a 100-year period show that if meltwater accumulates on the bedrock rather than being completely channeled, it leads to a decrease in the average rate of subglacial melting by approximately 10 times.

Assessing the impact of artificial geotextile covers on glacier mass balance and energy fluxes

As global warming accelerates, leading to the retreat of glaciers, the effectiveness of artificial coverings, in particular geotextiles, in reducing glacier ablation has emerged as a topic of increasing concern. Nevertheless, a critical gap in knowledge persists regarding the specific physical processes involved in the mitigation provided by these coverings. This study explores the underlying mechanisms that govern the interaction through field observations and COSIPY model simulations at Bailanghe Glacier No. 21 in the Qilian Mountains from 26 June to 17 September 2023. It compares covered and uncovered areas to evaluate differences in mass and energy balance fluxes. It was discovered that geotextiles could decrease ice melt by up to 1000 mm w.e. in comparison to the surface of glaciers without cover, primarily because of a 23% increase in albedo compared to ice, leading to a decrease in net short-wave radiation and available melt energy. The effect of covering the entire glacier with a geotextile, which has varying albedo properties, was also simulated. It was found that, with every 5% increase in the albedo of the geotextile, ablation was reduced by 10%‒25%, resulting in a decrease in ice volume loss of approximately 2.5 × 105 m3. While artificially covering glaciers can reduce ablation rates, it faces challenges such as high costs, environmental risks, and issues with replicability. Ultimately, this study aims to analyze the feasibility of glacier coverage from a mechanistic perspective for glacier management amidst ongoing climate change.

Characterizing the seasonal relationships between urban heat island and surface energy balance fluxes considering the impact of three-dimensional urban morphology

Urbanization has disrupted the energy balance of natural surfaces, leading to the formation and intensification of urban heat island (UHI) phenomenon. Current research on the relationship between surface energy balance (SEB) and UHI mainly focuses on either a macro perspective of large-scale regions or a micro perspective based on numerical microclimate simulations. However, there are still relatively few studies conducted on the local scale of cities. Here, we investigated the relationships between seasonal SEB and land surface temperature (LST) based on local climate zones (LCZ) and explored the impact of three-dimensional (3D) urban morphology on SEB. Our results revealed that: (1) urban building spaces have relatively higher LST, sensible heat flux, and storage heat flux, but lower net radiation and latent heat flux, compared to urban blue and green spaces; (2) among LCZ built types, the compact and large low-rise buildings have high LST and heat-inducing energy fluxes, while the compact and open high-rise buildings exhibit the opposite situation; (3) the component proportions of SEB fluxes exhibit a more significant linear correlation with UHI intensity compared to the relative differences between SEB fluxes; and (4) 3D building morphology has a higher relative importance in influencing the variations of surface energy balance ratio (SEBR) components than 3D vegetation morphology. Specifically, building height has the greatest impact on the seasonal variations of SEBR components, while the 3D urban greening ratio has relatively high importance among vegetation morphology. These findings enable us to better consider local UHI effect from the perspective of SEB.

Congo Basin Water Balance and Terrestrial Fluxes Inferred From Satellite Observations of the Isotopic Composition of Water Vapor

AbstractLarge spatio‐temporal gradients in the Congo basin vegetation and rainfall are observed. However, its water‐balance (evapotranspiration minus precipitation, or ET − P) is typically measured at basin‐scales, limited primarily by river‐discharge data, spatial resolution of terrestrial water storage measurements, and poorly constrained ET. We use observations of the isotopic composition of water vapor to quantify the spatio‐temporal variability of net surface water fluxes across the Congo Basin between 2003 and 2018. These data are calibrated at basin scale using satellite gravity and total Congo river discharge measurements and then used to estimate time‐varying ET − P over four quadrants representing the Congo Basin, providing first estimates of this kind for the region. We find that the multi‐year record, seasonality, and interannual variability of ET − P from both the isotopes and the gravity/river discharge based estimates are consistent. Additionally, we use precipitation and gravity‐based estimates with our water vapor isotope‐based ET − P to calculate time and space averaged ET and net river discharge within the Congo Basin. These quadrant‐scale moisture flux estimates indicate (a) substantial recycling of moisture in the Congo Basin (temporally and spatially averaged ET/P > 70%), consistent with models and visible light‐based ET estimates, and (b) net river outflow is largest in the Western Congo where there are more rivers and higher flow rates. Our results confirm the importance of ET in modulating the Congo water cycle relative to other water sources.

Nonlinear gyrokinetic modelling of high confinement negative triangularity plasmas

Nonlinear gyrokinetic simulations correctly predict particle as well as ion and electron energy fluxes of high confinement plasmas with a negative triangularity cross sectional shape, showing that core transport in these plasmas is well described by standard gyrokinetic models. Experimentally inferred power balance fluxes are mostly reproduced within one standard deviation across a wide portion of the minor radius. Experimental conditions are reproduced by ion scale simulations, without the need to include density and temperature profile curvature effects. The experimental case is used as baseline to predict that the non-dimensional confinement scaling in negative triangularity plasmas increases strongly with plasma current while slightly degrading at increasing normalized pressure and decreasing collisionality. Recent experiments showed that low toroidal rotation negatively impacts confinement; consistent with the experiment, simulations predict that low rotational shear significantly affects confinement unless the plasma effective charge is maintained above a minimum level. Core confinement is predicted to significantly degrade in low aspect ratio devices.

Engineering and finetuning expression of SerC for balanced metabolic flux in vitamin B6 production

Vitamin B6 plays a crucial role in cellular metabolism and stress response, making it an essential component for growth in all known organisms. However, achieving efficient biosynthesis of vitamin B6 faces the challenge of maintaining a balanced distribution of metabolic flux between growth and production. In this study, our focus is on addressing this challenge through the engineering of phosphoserine aminotransferase (SerC) to resolve its redundancy and promiscuity. The enzyme SerC was semi-designed and screened based on sequences and predicted kcat values, respectively. Mutants and heterologous proteins showing potential were then fine-tuned to optimize the production of vitamin B6. The resulting strain enhances the production of vitamin B6, indicating that different fluxes are distributed to the biosynthesis pathway of serine and vitamin B6. This study presents a promising strategy to address the challenge posed by multifunctional enzymes, with significant implications for enhancing biochemical production through engineering processes.

Evaluation of a single-layer urban energy balance model using measured energy fluxes by scaled outdoor experiments in humid subtropical climate

Urban energy balance models can simulate the localized climate and fluxes in urban areas. They are often evaluated using real urban site observations. However, uncertainties in anthropogenic emission, geometry and materials can hinder interpretation. These uncertainties can be eliminated by scaled outdoor models. We assess the performance of a single-layer urban canopy model (SLUCM) offline in predicting surface energy balance (SEB) fluxes within a street canyon-like urban configuration using field measurements from a scaled outdoor setup in Guangzhou, China. We utilize observations of SEB fluxes and surface temperature from a homogenous scaled urban site characterized by street canyons. The scaled observations in June–December 2020 in a dense urban environment with a height-to-width ratio (H/W) of 2 are employed to assess seasonal variations in model performance. Additionally, the December data from two distinct urban scenarios (H/W = 2(2020) and 0.5(2019)) are utilized to compare model performance in deep and shallow street canyon settings. Results show that QS(R2 = ∼0.47, RMSE = ∼46.0) is the most challenging to predict, followed by QH (R2 = ∼0.92, RMSE = ∼65.5), Q*(R2 = ∼0.99, RMSE = ∼39.5), L↑(R2 = ∼0.95, RMSE = ∼33.7), and K↑(R2 = ∼0.99, RMSE = ∼6.2). SLUCM faces difficulties simulating L↑ particularly during nighttime and cloudy conditions. It also tends to underestimate daytime net radiation (Q*), especially during hot, humid months. Moreover, H/W ratio slightly affects SLUCM's performance in simulating SEB fluxes under dry cool conditions denser urban settings (H/W = 2) show better model performance in K↑, QH, and QS but worse performance in L↑ and Q*.

Aircraft-based mass balance estimate of methane emissions from offshore gas facilities in the southern North Sea

Abstract. Atmospheric methane (CH4) concentrations have more than doubled since the beginning of the industrial age, making CH4 the second most important anthropogenic greenhouse gas after carbon dioxide (CO2). The oil and gas sector represents one of the major anthropogenic CH4 emitters as it is estimated to account for 22 % of global anthropogenic CH4 emissions. An airborne field campaign was conducted in April–May 2019 to study CH4 emissions from offshore gas facilities in the southern North Sea with the aim of deriving emission estimates using a top-down (measurement-led) approach. We present CH4 fluxes for six UK and five Dutch offshore platforms or platform complexes using the well-established mass balance flux method. We identify specific gas production emissions and emission processes (venting and fugitive or flaring and combustion) using observations of co-emitted ethane (C2H6) and CO2. We compare our top-down estimated fluxes with a ship-based top-down study in the Dutch sector and with bottom-up estimates from a globally gridded annual inventory, UK national annual point-source inventories, and operator-based reporting for individual Dutch facilities. In this study, we find that all the inventories, except for the operator-based facility-level reporting, underestimate measured emissions, with the largest discrepancy observed with the globally gridded inventory. Individual facility reporting, as available for Dutch sites for the specific survey date, shows better agreement with our measurement-based estimates. For all the sampled Dutch installations together, we find that our estimated flux of (122.9 ± 36.8) kg h−1 deviates by a factor of 0.64 (0.33–12) from reported values (192.8 kg h−1). Comparisons with aircraft observations in two other offshore regions (the Norwegian Sea and the Gulf of Mexico) show that measured, absolute facility-level emission rates agree with the general distribution found in other offshore basins despite different production types (oil, gas) and gas production rates, which vary by 2 orders of magnitude. Therefore, mitigation is warranted equally across geographies.

Revolutionizing agriculture: Exploring the potential of digital technologies and controlled environmental agriculture

The agricultural sector has experienced remarkable transformations fueled by technological advancements over the past 50 years, which have enhanced productivity and sustainability. Presently, agriculture is transitioning into a new era, driven by connectivity and data, known as Agriculture 4.0. This transition holds promise for further enhancing yield, optimizing resource utilization, and promoting sustainability and resilience. However, challenges such as population growth, resource scarcity, environmental degradation, and food waste persist and necessitate innovative solutions. Controlled Environment Agriculture (CEA) has emerged as a pivotal domain in urban agriculture, offering solutions to address these challenges. Several Controlled Environment Agriculture (CEA) facilities, such as greenhouses, plant factories, and rooftop gardens, employ sophisticated methods to enhance plant growth and quality while reducing resource usage. Achieving optimal growth conditions within CEA facilities remains a challenge, necessitating the effective management of microclimates and root zone environments. Recent research has emphasized the role of intelligent systems, particularly artificial intelligence and deep learning, in addressing these challenges. Moreover, optimizing indoor growing environments requires careful consideration of factors, such as temperature, humidity, chemical balance, and photosynthetic photon flux. Despite these advancements, the global food supply chain faces significant inefficiencies and wastage, exacerbated by factors such as the COVID-19 pandemic and climate change. Climate-smart agriculture, which leverages technologies such as AI and genomic tools, offers promising avenues for enhancing crop resilience and productivity in the face of changing climatic conditions. The integration of information technologies has further revolutionized agriculture and offers potential solutions to mitigate the impact of climate.

A guide to cell death pathways.

Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.

Efficient property-oriented optimization of magnetic high-entropy metallic glasses via a multi-stage design strategy

High-entropy metallic glasses (HE-MGs) have drawn much attention as promising multifunctional materials combining the excellent soft magnetic properties of traditional metallic glasses and impressive mechanical properties, thermal stability, corrosion resistance, etc., of solid solution high entropy alloys. Property optimization of HE-MGs is of great significance for promoting their engineering applications. However, various constituent elements and the high chemical complexity make the possible alloying composition space extremely massive, which is very challenging for the rational design of HE-MGs. In this work, we proposed a multi-stage optimization strategy based on machine learning (ML) to accelerate the rational design of magnetic HE-MGs with desired properties. The huge composition search space was significantly narrowed by the ML-based phase prediction model and constraints from user preferences. Utility functions based on the exploitation and exploration strategy were designed to find the global optimization solutions, i.e., alloying compositions. Experiments were conducted as concept validation, and new Fe-Co-Ni-Si-B HE-MGs with balanced saturation magnetic flux density and mixing entropy were developed.

Overexpression of the LAT1 in primary human trophoblast cells increases the uptake of essential amino acids and activates mTOR signaling.

The System L amino acid transporter, particularly the isoform Large Neutral Amino Acid Transporter Small Subunit 1 (LAT1) encoded by SLC7A5, is believed to mediate the transfer of essential amino acids in the human placenta. Placental System L amino acid transporter expression and activity is decreased in pregnancies complicated by IUGR and increased in fetal overgrowth. However, it remains unknown if changes in the expression of LAT1 are mechanistically linked to System L amino acid transport activity. Here, we combined overexpression approaches with protein analysis and functional studies in cultured primary human trophoblast (PHT) cells to test the hypothesis that SLC7A5 overexpression increases the uptake of essential amino acids and activates mTOR signaling in PHT cells. Overexpression of SLC7A5 resulted in a marked increase in protein expression of LAT1 in the PHT cells microvillous plasma membrane and System L amino acid transporter activity. Moreover, mTOR signaling was activated, and System A amino acid transporter activity increased following SLC7A5 overexpression, suggesting coordination of trophoblast amino transporter expression and activity to ensure balanced nutrient flux to the fetus. This is the first report showing that overexpression of LAT1 is sufficient to increase the uptake of essential amino acids in PHT cells, which activates mTOR, a master regulator of placental function. The decreased placental System L activity in human IUGR and the increased placental activity of this transporter system in some cases of fetal overgrowth may directly contribute to changes in fetal amino acid availability and altered fetal growth in these pregnancy complications.

Surface energy balance fluxes in a suburban area of Beijing: energy partitioning variability

Abstract. Measurements of radiative and turbulent heat fluxes for 16 months in suburban Miyun with a mix of buildings and agriculture allows the changing role of these fluxes to be assessed. Daytime turbulent latent heat fluxes (QE) are largest in summer and smaller in winter, consistent with the net all-wave radiation (Q*), whereas the daytime sensible heat flux (QH) is greatest in spring but smallest in summer rather than in winter, as commonly observed in suburban areas. The results have larger seasonal variability in energy partitioning compared to previous suburban studies. Daytime energy partitioning is between 0.15–0.57 for QH/Q* (mean summer = 0.16; winter = 0.46), 0.06–0.56 for QE/Q* (mean summer = 0.52; winter = 0.10), and 0.26–7.40 for QH/QE (mean summer = 0.32; winter = 4.60). Compared to the literature for suburban areas, these are amongst the lowest and highest values. Results indicate that precipitation, irrigation, vegetation growth activity, and land use and land cover all play critical roles in the energy partitioning. These results will help to enhance our understanding of surface–atmosphere energy exchanges over cities and are critical to improving and evaluating urban canopy models needed to support integrated urban services that include urban planning to mitigate the adverse effects of urban climate change.

Influence of the biochar application on the thermal properties of soddy-podzolic soil and on the energy balance fluxes of spring wheat in the Leningrad region under various soil moisture conditions

The article presents the results of a field experiment to assess the effect of pre-sowing application of the biochar on the thermal properties of the arable horizon of soddy-podzolic sandy loam soil, on the energy balance components, on the crop surface temperature and on the leaves temperature of spring wheat (variety “Daria”) under various conditions of soil moisture in 2022. The experiment took place at the Menkovo Experimental Station of the Agrophysical Research Institute, located in the Gatchinsky District of the Leningrad Region. The experiment included the plot with the biochar application at the dose of 21.9 t ha-1 and the control plot. The soil thermal properties were measured by the heat pulse method. The components of the energy balance were determined using agrometeorological measurements, radiation balance measurements, crop surface temperature, and phenological measurements. The crop surface temperature was measured by a non-contact method using pyrometers. The soil moisture conditions and available water for wheat were characterized by volumetric soil moisture and evapotranspiration. The volumetric soil moisture was measured using a capacitive soil moisture sensor. The evapotranspiration was determined using the residual term of the energy balance equation through the latent heat flux. According to the results of field experiments, a significant effect (p < 0.05) of the biochar application on the soil thermal properties was found, however, under different moisture conditions, the effect was multidirectional. At zero soil moisture, the biochar application reduced thermal conductivity by 29.7%, reduced volumetric heat capacity by 18.5%, reduced diffusivity by 13.7%, and reduced thermal inertia by 24.3%. Under the conditions of field capacity, the biochar application increased thermal conductivity by 9.4%, reduced volumetric heat capacity by 2.6%, increased diffusivity by 12.3%, and increased thermal inertia by 3.2%. The biochar application significantly (p < 0.05) increased the turbulent heat flux – by 35.5%, which is due to an increase in the crop surface temperature (by 6.4%). Resulting from the decrease in soil evaporation, the biochar application reduced the latent heat flux by 17.0%, and the evapotranspiration by 13.9%. Leaf temperature is related to transpiration. Transpiration can increase when biochar is applied on light-textured soils due to an increase in soil water capacity. The biochar application did not result in significant changes of leaf temperature. The study results are confirmed by numerous articles of both foreign and Russian researchers.

Influence of collisions on the validation of global gyrokinetic simulations in the edge and scrape-off layer of TCV

Understanding and predicting turbulent transport in the edge and scrape-off-layer (SOL) of magnetic confinement fusion devices is crucial for developing feasible fusion power plants. In this work, we present the latest improvements to the gyrokinetic turbulence code GENE-X and validate the extended model against experimental results in the TCV tokamak (“TCV-X21”). GENE-X features a full-f electromagnetic gyrokinetic model and is specifically targeted for edge and SOL simulations in diverted geometries. GENE-X can model the effect of collisions using either a basic Bhatnagar–Gross–Krook (BGK) or more sophisticated Lenard–Bernstein/Dougherty (LBD) collision operator. We present the results of a series of GENE-X simulations using the BGK or LBD collision models, contrasting them to collisionless simulations. We validate the resulting plasma profiles, power balance, and SOL heat flux against experimental measurements. The match to the experiment significantly improves with the fidelity of the collision model chosen. We analyze the characteristics of the turbulence and find that in almost all cases in the confined region the turbulence is driven by trapped electron modes (TEM). Both the simulations without collisions and those with the BGK collision operator do not accurately describe turbulence driven by TEMs. The more sophisticated LBD collision operator presents a minimum requirement for accurate gyrokinetic edge turbulence simulations.

NR3C1/Glucocorticoid receptor activation promotes pancreatic β-cell autophagy overload in response to glucolipotoxicity

ABSTRACT Diabetes is a complex and heterogeneous disorder characterized by chronic hyperglycemia. Its core cause is progressively impaired insulin secretion by pancreatic β-cell failures, usually upon a background of preexisting insulin resistance. Recent studies demonstrate that macroautophagy/autophagy is essential to maintain architecture and function of β-cells, whereas excessive autophagy is also involved in β-cell dysfunction and death. It has been poorly understood whether autophagy plays a protective or harmful role in β-cells, while we report here that it is dependent on NR3C1/glucocorticoid receptor activation. We proved that deleterious hyperactive autophagy happened only upon NR3C1 activation in β-cells under glucolipotoxic conditions, which eventually promoted diabetes. The transcriptome and the N6-methyladenosine (m6A) methylome revealed that NR3C1-enhancement upregulated the RNA demethylase FTO (fat mass and obesity associated) protein in β-cells, which caused diminished m6A modifications on mRNAs of four core Atg (autophagy related) genes (Atg12, Atg5, Atg16l2, Atg9a) and, hence, hyperactive autophagy and defective insulin output; by contrast, FTO inhibition, achieved by the specific FTO inhibitor Dac51, prevented NR3C1-instigated excessive autophagy activation. Importantly, Dac51 effectively alleviated impaired insulin secretion and glucose intolerance in hyperglycemic β-cell specific NR3C1 overexpression mice. Our results determine that the NR3C1-FTO-m6A modifications-Atg genes axis acts as a key mediator of balanced autophagic flux in pancreatic β-cells, which offers a novel therapeutic target for the treatment of diabetes. Abbreviations: 3-MA: 3-methyladenine; AAV: adeno-associated virus; Ac: acetylation; Ad: adenovirus; AL: autolysosome; ATG: autophagy related; AUC: area under curve; Baf A1: bafilomycin A1; βNR3C1 mice: pancreatic β-cell-specific NR3C1 overexpression mice; cFBS: charcoal-stripped FBS; Ctrl: control; ER: endoplasmic reticulum; FTO: fat mass and obesity associated; GC: glucocorticoid; GRE: glucocorticoid response element; GSIS: glucose-stimulated insulin secretion assay; HFD: high-fat diet; HG: high glucose; HsND: non-diabetic human; HsT2D: type 2 diabetic human; i.p.: intraperitoneal injected; KSIS: potassium-stimulated insulin secretion assay; m6A: N6-methyladenosine; MeRIP-seq: methylated RNA immunoprecipitation sequencing; NR3C1/GR: nuclear receptor subfamily 3, group C, member 1; NR3C1-Enhc.: NR3C1-enhancement; NC: negative control; Palm.: palmitate; RNA-seq: RNA sequencing; T2D: type 2 diabetes; TEM: transmission electron microscopy; UTR: untranslated region; WT: wild-type.