Cycle Flux Research Articles

Metabolic Control During Macrophage Polarization by a Citrate-Functionalized Scaffold for Maintaining Bone Homeostasis.

Metabolites, as markers of phenotype at the molecular level, can regulate the function of DNA, RNA, and proteins through chemical modifications or interactions with large molecules. Citrate is an important metabolite that affects macrophage polarization and osteoporotic bone function. Therefore, a better understanding of the precise effect of citrate on macrophage polarization may provide an effective alternative strategy to reverse osteoporotic bone metabolism. In this study, a citrate functional scaffold to control the metabolic pathway during macrophage polarization based on the metabolic differences between pro-inflammatory and anti-inflammatory phenotypes for maintaining bone homeostasis, is fabricated. Mechanistically, only outside M1 macrophages are accumulated high concentrations of citrate, in contrast, M2 macrophages consume massive citrate. Therefore, citrate-functionalized scaffolds exert more sensitive inhibitory effects on metabolic enzyme activity during M1 macrophage polarization than M2 macrophage polarization. Citrate can block glycolysis-related enzymes by occupying the binding-site and ensure sufficient metabolic flux in the TCA cycle, so as to turn the metabolism of macrophages to oxidative phosphorylation of M2 macrophage, largely maintaining bone homeostasis. These studies indicate that exogenous citrate can realize metabolic control of macrophage polarization for maintaining bone homeostasis in osteoporosis.

Pharmacological SERCA activation limits diet-induced steatohepatitis and restores liver metabolic function in mice

Metabolic dysfunction-associated steatotic liver disease is the most common form of liver disease and poses significant health risks to patients who progress to metabolic dysfunction-associated steatohepatitis. Fatty acid overload alters endoplasmic reticulum (ER) calcium stores and induces mitochondrial oxidative stress in hepatocytes, leading to hepatocellular inflammation and apoptosis. Obese mice have impaired liver sarco/ER Ca2+-ATPase (SERCA) function, which normally maintains intracellular calcium homeostasis by transporting Ca2+ ions from the cytoplasm to the ER. We hypothesized that restoration of SERCA activity would improve diet-induced steatohepatitis in mice by limiting ER stress and mitochondrial dysfunction. WT and melanocortin-4 receptor KO (Mc4r−/−) mice were placed on either chow or Western diet (WD) for 8 weeks. Half of the WD-fed mice were administered CDN1163 to activate SERCA, which reduced liver fibrosis and inflammation. SERCA activation also restored glucose tolerance and insulin sensitivity, improved histological markers of metabolic dysfunction-associated steatohepatitis, increased expression of antioxidant enzymes, and decreased expression of oxidative stress and ER stress genes. CDN1163 decreased hepatic citric acid cycle flux and liver pyruvate cycling, enhanced expression of mitochondrial respiratory genes, and shifted hepatocellular [NADH]/[NAD+] and [NADPH]/[NADP+] ratios to a less oxidized state, which was associated with elevated PUFA content of liver lipids. In sum, the data demonstrate that pharmacological SERCA activation limits metabolic dysfunction-associated steatotic liver disease progression and prevents metabolic dysfunction induced by WD feeding in mice.

Endurance training and essential amino acid intervention synergize to ameliorate fructose-induced metabolic dysfunction in mice

Purpose: Excessive fructose (FRU) consumption can rapidly produce multiple features of metabolic syndrome, including dysregulation of systemic metabolism, insulin resistance, and diabetes. Essential amino acids (EAAs) and endurance exercise training (ET) improve abnormal metabolism in various disease conditions, yet their combined effect and metabolic mechanism remain unclear. Thus, the current study aimed to investigate metabolic kinetic mechanism and the combined effect of EAA and ET on fructose-induced metabolic dysfunction. Materials and methods: Mice were randomly divided into 5 groups with an 8-week intervention: normal chow (CON), FRU, FRU+ET, FRU+EAA or FRU+ET+ EAA, followed by stable isotope tracer infusions ([U-13C16]palmitate, [D2]glucose, and [D5]glycerol) or D2O administration to determine substrate metabolic flux rates and their contribution to TCA cycle flux and protein synthesis rates of various organs, respectively. Summary of results: FRU-induced adverse changes in body weight and physical function were reversed by ET, EAA, or ET+EAA. In stable isotope tracing analysis, ET and ET+EAA alleviated hyperglycemia by suppressing hepatic glucose production rate, while EAA and ET+EAA normalized palmitate turnover and contribution to TCA cycle in various organs. Additionally, the altered protein synthesis measured using a D2O labeling method was normalized by ET and ET+EAA. Conclusion:These findings suggest that the combined treatment of dietary EAAs and ET more effectively mitigates fructose-induced metabolic dysfunction by normalizing hepatic glucose production rate, protein synthesis rates, and fatty acid metabolism. This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI22C2208), and the National Research Foundation of Korea (NRF), funded by the Korea government (MSIT) (No. 2021R1A2C3005801), and partially funded by MYOCARE INC. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effects of drought on ecosystem evapotranspiration and gross primary productivity in the Haihe River Basin

Evapotranspiration is a crucial component of the hydrological cycle and Gross Primary Productivity (GPP) is the largest flux in the global carbon cycle. However, both evapotranspiration and GPP are significantly affected by climate disasters, especially extreme drought events. Therefore, in this study, MODIS product data from 2002 to 2021 was used to analyze the spatiotemporal variations of actual evapotranspiration (ET), potential evapotranspiration (PET) and GPP within the Haihe River Basin. Then extreme drought events were identified by using EDDI drought index. A statistical analysis was performed to assess the impact of extreme drought on ecosystem evapotranspiration and GPP. The results showed that: (1) the annual evapotranspiration in the Haihe River Basin fluctuated greatly, ET showed a general increasing trend which was higher in the eastern region and lower in the central and western regions, PET showed an overall decreasing trend which was higher in the central and western regions and lower in the eastern region; (2) the annual GPP in the Haihe River Basin from 2002 to 2021 was 646.88 g C/m2/a and the increase rate was 14.75 g C/m2/a, which exhibited a decreasing trend from the northern to the southern and central-western regions; (3) under extreme drought conditions, ET decreased compared with the mean value, while PET increased, the Zhangweihe and the Tuhaimajiahe sub-basins were the most affected, with ET decreasing by 16.36% and PET increasing by 7.00% compared to the reference year. Additionally, extreme drought led to a decrease in GPP, with a reduction ranging from 7% to 18%.

Review of the Influence of Climate Change on the Hydrologic Cycling and Gaseous Fluxes of Mercury in Boreal Peatlands: Implications for Restoration

Review of the Influence of Climate Change on the Hydrologic Cycling and Gaseous Fluxes of Mercury in Boreal Peatlands: Implications for Restoration

Methane sink of subterranean space in an integrated atmosphere-soil-cave system

CH4 serves as an important greenhouse gas, yet limited knowledge is available in global and regional CH4 cycling, particularly in widely distributed karst terrain. In this study, we investigated an upland in Puding Karst Ecosystem Research Station, and explored CH4 concentration and/or flux in atmosphere, soil and cave using a closed static chamber method and an eddy covariance system. Meanwhile, we monitored atmospheric temperature, precipitation, temperature and wind velocity in the cave entrance. The results demonstrated that atmospheric CH4 and actual soil CH4 fluxes in the source area of eddy covariance system were −0.19 ± 8.64 nmols−1m−2 and -0.16 nmols−1m−2 respectively. The CH4 concentrations in Shawan Cave exhibited 10 ∼ 100-fold lower than that of the external atmosphere. CH4 oxidation rate dominated by methane-oxidizing bacteria was 1.98 nmols−1m−2 in Shawan Cave when it combined with temperature difference between cave and external atmosphere. Therefore, CH4 sink in global karst subterranean spaces was estimated at 106.2 Tg CH4 yr−1. We supplemented an understanding of CH4 cycling paths and fluxes in karst terrain, as well as CH4 sinks in karst subterranean space. Further works require to establish a karst ecosystem observation network to conduct long-term integrated studies on CH4 fluxes regarding atmosphere, soils, plants and caves.

Using Io's Sulfur Isotope Cycle to Understand the History of Tidal Heating

AbstractStable isotope fractionation of sulfur offers a window into Io's tidal heating history, which is difficult to constrain because Io's dynamic atmosphere and high resurfacing rates leave it with a young surface. We constructed a numerical model to describe the fluxes in Io's sulfur cycle using literature constraints on rates and isotopic fractionations of relevant processes. Combining our numerical model with measurements of the 34S/32S ratio in Io's atmosphere, we constrain the rates for the processes that move sulfur between reservoirs and model the evolution of sulfur isotopes over time. Gravitational stratification of SO2 in the upper atmosphere, leading to a decrease in 34S/32S with increasing altitude, is the main cause of sulfur isotopic fractionation associated with loss to space. Efficient recycling of the atmospheric escape residue into the interior is required to explain the 34S/32S enrichment magnitude measured in the modern atmosphere. We hypothesize this recycling occurs by SO2 surface frost burial and SO2 reaction with crustal rocks, which founder into the mantle and/or mix with mantle‐derived magmas as they ascend. Therefore, we predict that magmatic SO2 plumes vented from the mantle to the atmosphere will have lower 34S/32S than the ambient atmosphere, yet are still significantly enriched compared to solar‐system average sulfur. Observations of atmospheric variations in 34S/32S with time and/or location could reveal the average mantle melting rate and hence whether the current tidal heating rate is anomalous compared to Io's long‐term average. Our modeling suggests that tides have heated Io for >1.6 Gyr if Io today is representative of past Io.

Equatorial Plasma Bubbles Characteristics Studies using IRNSS Data around Bangalore

TEC analysis stands as a cornerstone in navigation, enabling the examination of sudden shifts in Total Electron Content (TEC). Equatorial Plasma Bubbles (EPBs) are discerned through TEC analysis, which proves superior to alternative approaches. This method furnishes insights into EPB occurrences, offering valuable data on their daily and seasonal fluctuations within the ionosphere. Analysis of TEC data from January 2015 to 2022, derived from IRNSS observations in Bangalore, reveals patterns in EPB occurrence correlated with the sunspot cycle and solar flux variations. This alignment, observed during a phase of low solar activity, underscores the reliability of TEC analysis in capturing ionospheric dynamics.

Fine particle contents in sediment drive silica transport and deposition to the estuary in the turbid river basin

Changes in riverine sediment transport are an important part of land-sea geochemical cycling and further impact geochemical element fluxes in turbid rivers. However, as a vital nutrient element supporting primary productivity, silica mobilization from drainage in turbid rivers is overlooked. The turbid Yellow River has a strong ability to adsorb reactive silica, thereby exerting a substantial impact on the estuarine deposition of silica. Through an integration of monitoring databases, field sampling and historical hydrological data, we concluded that riverine fine particles control the exchangeable silica in the river and its estuary under soil erosion. Indoor simulation further revealed that the adsorbed content of exchangeable silica (ex-Si) in fine sediment constituted 35 % of total sediment matter. In addition, the transport of phosphorus and ex-Si was jointly regulated by fine sediment in global fluvial sediment transport, thereby exerting additional influence on the trophic structure of estuarine ecosystems. Against the backdrop of sediment budget deficit in the estuary, the heightened content of fine particles is depleting the silica storage from estuarine sediments.

Photochemical processes transform dissolved organic matter differently depending on its initial composition

Dissolved organic matter (DOM) is one of the most important fluxes in the global carbon cycle but its response to light exposure remains unclear at a molecular-level. The chemical response of DOM to light should vary with its molecular composition and environmental conditions while some basic hypotheses are still unclear, such as the balance between photobleaching and photo-humification and the question of oxidative properties. Here we exposed aquatic DOM from diverse freshwaters impacted by different levels of anthropogenic activity and algal exudates to environmentally-realistic light conditions. We found that photobleaching occurred in DOM with relatively high initial humic content producing low H/C molecules, whereas DOM with low initial humic content was humified. DOM pools with relatively high initial saturation and low aromaticity were prone to transform towards more unsaturated molecular formulae and high H/C molecules with a distinct decrease of bioavailability. Photo-transformation was mainly influenced by reactive intermediates, with reactive oxygen species (ROS) playing a dominant role in humification when the initial humus content of DOM was high. In contrast, for algal DOM with high protein content, it was likely that the autoxidation of excited state DOM was more important than indirect oxidation involving ROS. Our results reveal how photo-transformation patterns depend on the initial composition of DOM and provide new insights into the role of photochemical processes in biogeochemical cycling of DOM.

The ternary water cycle of ‘nature–society–trade’ in the inland arid areas

AbstractWater cycle is important for maintaining the dynamic balance of regional water resources. Here, based on the input–output water circulation flux accounting model, we take Xinjiang as a case area to empirically explore the mechanism of the ‘nature‐society‐trade’ ternary water cycle. The results show that the water transferred out was much larger than the transferred in in Xinjiang. The scale of water resources development and utilization and the social water cycle fluxes have been constantly expanding, but there was a mismatch between the hydrological system and the socio‐economic system in terms of water resource utilization. From 2007 to 2017, agriculture had always been the department with the largest amount of direct water consumption and virtual water transfer in Xinjiang, which mainly transferred virtual water to the light industry and service sector where the production of final products requires large amounts of agricultural products as raw materials or intermediate products. In Xinjiang, the virtual water transferred outside through trade in products and services was much larger than the virtual water transferred in from other regions, and it was thus always in a state of net virtual water outflow as a whole. In inter‐provincial trade of China, Xinjiang mainly transferred virtual water to areas with abundant water resources, developed economies and dense populations in eastern China. Lastly, we put forward targeted suggestions on the optimal allocation of water resources to promote the sustainable development of Xinjiang and we hope that our study will be instructive for water resources management in other arid inland river basins.

Disruption of hepatic mitochondrial pyruvate and amino acid metabolism impairs gluconeogenesis and endurance exercise capacity in mice.

Exercise robustly increases the glucose demands of skeletal muscle. This demand is met by not only muscle glycogenolysis but also accelerated liver glucose production from hepatic glycogenolysis and gluconeogenesis to fuel mechanical work and prevent hypoglycemia during exercise. Hepatic gluconeogenesis during exercise is dependent on highly coordinated responses within and between muscle and liver. Specifically, exercise increases the rate at which gluconeogenic precursors such as pyruvate/lactate or amino acids are delivered from muscle to the liver, extracted by the liver, and channeled into glucose. Herein, we examined the effects of interrupting hepatic gluconeogenic efficiency and capacity on exercise performance by deleting mitochondrial pyruvate carrier 2 (MPC2) and/or alanine transaminase 2 (ALT2) in the liver of mice. We found that deletion of MPC2 or ALT2 alone did not significantly affect time to exhaustion or postexercise glucose concentrations in treadmill exercise tests, but mice lacking both MPC2 and ALT2 in hepatocytes (double knockout, DKO) reached exhaustion faster and exhibited lower circulating glucose during and after exercise. Use of 2H/1³C metabolic flux analyses demonstrated that DKO mice exhibited lower endogenous glucose production owing to decreased glycogenolysis and gluconeogenesis at rest and during exercise. Decreased gluconeogenesis was accompanied by lower anaplerotic, cataplerotic, and TCA cycle fluxes. Collectively, these findings demonstrate that the transition of the liver to the gluconeogenic mode is critical for preventing hypoglycemia and sustaining performance during exercise. The results also illustrate the need for interorgan cross talk during exercise as described by the Cahill and Cori cycles.NEW & NOTEWORTHY Martino and colleagues examined the effects of inhibiting hepatic gluconeogenesis on exercise performance and systemic metabolism during treadmill exercise in mice. Combined inhibition of gluconeogenesis from lactate/pyruvate and alanine impaired exercise endurance and led to hypoglycemia during and after exercise. In contrast, suppressing either pyruvate-mediated or alanine-mediated gluconeogenesis alone had no effect on these parameters. These findings provide new insight into the molecular nodes that coordinate the metabolic responses of muscle and liver during exercise.

FLVCR1a Controls Cellular Cholesterol Levels through the Regulation of Heme Biosynthesis and Tricarboxylic Acid Cycle Flux in Endothelial Cells.

Feline leukemia virus C receptor 1a (FLVCR1a), initially identified as a retroviral receptor and localized on the plasma membrane, has emerged as a crucial regulator of heme homeostasis. Functioning as a positive regulator of δ-aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in the heme biosynthetic pathway, FLVCR1a influences TCA cycle cataplerosis, thus impacting TCA flux and interconnected metabolic pathways. This study reveals an unexplored link between FLVCR1a, heme synthesis, and cholesterol production in endothelial cells. Using cellular models with manipulated FLVCR1a expression and inducible endothelial-specific Flvcr1a-null mice, we demonstrate that FLVCR1a-mediated control of heme synthesis regulates citrate availability for cholesterol synthesis, thereby influencing cellular cholesterol levels. Moreover, alterations in FLVCR1a expression affect membrane cholesterol content and fluidity, supporting a role for FLVCR1a in the intricate regulation of processes crucial for vascular development and endothelial function. Our results underscore FLVCR1a as a positive regulator of heme synthesis, emphasizing its integration with metabolic pathways involved in cellular energy metabolism. Furthermore, this study suggests that the dysregulation of heme metabolism may have implications for modulating lipid metabolism. We discuss these findings in the context of FLVCR1a's potential heme-independent function as a choline importer, introducing additional complexity to the interplay between heme and lipid metabolism.

Simulation of gross primary productivity and impact of drought in Liulin watershed of Taihang mountains over 2000–2020

As the largest flux in the global terrestrial carbon cycle, Gross Primary Productivity (GPP) is a key factor for the terrestrial carbon budget. Based on the eddy flux tower data, remote sensing data and the meteorological precipitation data, we calibrated three parameters of maximum light use efficiency, optimum temperature, and maximum temperature in the Vegetation Photosynthesis Model (VPM) to reproduce the GPP spatiotemporal characteristic in Liulin watershed of Taihang Mountains. We further analyzed the time lag effect and cumulative effect of the standard precipitation index (SPI) on GPP by the Pearson correlation coefficients. Results show that VPM captures the GPP characteristics of eddy flux tower observation in Liulin watershed. During the calibration period (R2 = 0.94, RMSE = 0.47 g C m-2·d-1) and validation period (R2 = 0.91, RMSE = 0.60 g C m-2 d-1), the adjusted VPM model successfully reproduced the temporal dynamics of site-observed GPP. From 2000 to 2020, VPM model can effectively reproduce the long-term variations in GPP (R2 = 0.69 vs. NIRv_GPP), with the GPP ranging from 446.4 to 828.1 g C m-2 y-1 and an average value of 545.6 g C m-2 y-1 in Liulin watershed. The GPP exhibited an increasing trend from 2000 to 2020. A mutation in the GPP occurred in 2010, with an average annual increase of 13.9 g C m-2 y-1 from 2000 to 2010 (p < 0.05), followed by an average annual increase of 10.22 g C m-2 y-1 from 2011 to 2020 (p > 0.05). The SPI effectively monitored drought events in the Liulin watershed. With a cumulative effect of 9 months and a lag effect of 6–7 months, the time lag and cumulative effects of drought had a long-term effect on GPP. It is imperative to have long-term eddy flux tower data and meteorological data to better evaluate the spatiotemporal dynamics of GPP and the impact of drought.

Root-derived resources fuel earthworms predominantly via bacterial and plant energy channels – Insights from bulk and compound-specific isotope analyses

Soil food webs rely on both brown and green energy, i.e., litter material and root-derived resources such as exudates. Earthworms have traditionally been viewed as macro-detritivores fuelled by brown energy and playing a central role in nutrient cycling and belowground energy flux. However, the role of root-derived resources for earthworm nutrition remains controversial. We studied the dietary contribution of root-derived resources from different plant functional groups to earthworms using bulk and compound-specific stable isotope analyses in a microcosm experiment with five earthworm species, grasses and legumes in monoculture and mixture, and an unplanted control by preventing leaf litter from entering the microcosms. The presence of plants consistently depleted bulk 13C values of the five earthworm species studied suggesting that root-derived carbon contributed to earthworm nutrition in each of the species. The response of bulk 15N values was less consistent, which is in line with the assumption that root-derived resources fuel soil food webs mainly via carbon-based root exudates. These observations were corroborated by 13C values of essential amino acids suggesting that most of the tissue carbon of earthworms was incorporated via bacterial- (∼60%) and plant-derived resources (∼30%), with the presence of legumes enhancing the incorporation via plant-derived resources. The high proportion of bacterial resources in the earthworms was consistent with the relative dominance of bacteria in the experimental soil and suggests that bacteria serve as important link in the acquisition of food resources. However, it remains an open question whether earthworms feed directly on soil bacteria, bacterial residues in soil or rely on nutritional supplementation by gut microorganisms. Overall, our results show that when root-derived resources are available, earthworms, as macro-detritivores, also incorporate green energy, with these resources being assimilated mainly via the bacterial energy channel, pointing to the importance of bacterial energy channelling in ecosystems with high earthworm biomass.

Ex Vivo 13C-Metabolic Flux Analysis of Porcine Circulating Immune Cells Reveals Cell Type-Specific Metabolic Patterns and Sex Differences in the Pentose Phosphate Pathway.

In general, females present with stronger immune responses than males, but scarce data are available on sex-specific differences in immunometabolism. In this study, we characterized porcine peripheral blood mononuclear cell (PBMC) and granulocyte energy metabolism using a Bayesian 13C-metabolic flux analysis, which allowed precise determination of the glycolytic, pentose phosphate pathway (PPP), and tricarboxylic acid cycle (TCA) fluxes, together with an assessment of the superoxide anion radical (O2•-) production and mitochondrial O2 consumption. A principal component analysis allowed for identifying the cell type-specific patterns of metabolic plasticity. PBMCs displayed higher TCA cycle activity, especially glutamine-derived aspartate biosynthesis, which was directly related to mitochondrial respiratory activity and inversely related to O2•- production. In contrast, the granulocytes mainly utilized glucose via glycolysis, which was coupled to oxidative PPP utilization and O2•- production rates. The granulocytes of the males had higher oxidative PPP fluxes compared to the females, while the PBMCs of the females displayed higher non-oxidative PPP fluxes compared to the males associated with the T helper cell (CD3+CD4+) subpopulation of PBMCs. The observed sex-specific differences were not directly attributable to sex steroid plasma levels, but we detected an inverse correlation between testosterone and aldosterone plasma levels and showed that aldosterone levels were related with non-oxidative PPP fluxes of both cell types.

Dynamic flux balance analysis of high cell density fed-batch culture of Escherichia coli BL21 (DE3) with mass spectrometry-based spent media analysis.

Dynamic flux balance analysis (FBA) allows estimation of intracellular reaction rates using organism-specific genome-scale metabolic models (GSMM) and by assuming instantaneous pseudo-steady states for processes that are inherently dynamic. This technique is well-suited for industrial bioprocesses employing complex media characterized by a hierarchy of substrate uptake and product secretion. However, knowledge of exchange rates of many components of the media would be required to obtain meaningful results. Here, we performed spent media analysis using mass spectrometry coupled with liquid and gas chromatography for a fed-batch, high-cell density cultivation of Escherichia coli BL21(DE3) expressing a recombinant protein. Time course measurements thus obtained for 246 metabolites were converted to instantaneous exchange rates. These were then used as constraints for dynamic FBA using a previously reported GSMM, thus providing insights into how the flux map evolves through the process. Changes in tri-carboxylic acid cycle fluxes correlated with the increased demand for energy during recombinant protein production. The results show how amino acids act as hubs for the synthesis of other cellular metabolites. Our results provide a deeper understanding of an industrial bioprocess and will have implications in further optimizing the process.

Preparation of [1'-13 C]citric acid as a probe in a breath test to evaluate tricarboxylic acid cycle flux.

[1'-13 C]Citric acid (1) was efficiently prepared from dimethyl 1,3-acetonedicarboxylate in two steps as a probe for a breath test. The synthetic method was selected because of the yield and reproducibility. Compound 1 was orally administrated to rats, and the time course of the increase of 13 CO2 /12 CO2 ratios (Δ13 CO2 ) in their breath was successfully followed, indicating the metabolism of 1. Thus, the 13 C-breath test using 1 is a promising method to evaluate tricarboxylic acid (TCA) cycle flux.

Cycling Rates of Particulate Organic Carbon Along the GEOTRACES Pacific Meridional Transect GP15

AbstractUnderstanding particle cycling processes in the ocean is critical for predicting the response of the biological carbon pump to external perturbations. Here, measurements of particulate organic carbon (POC) concentration in two size fractions (1–51 and &gt;51 μm) from GEOTRACES Pacific meridional transect GP15 are combined with a POC cycling model to estimate rates of POC production, (dis)aggregation, sinking, remineralization, and vertical transport mediated by migrating zooplankton, in the euphotic zone (EZ) and upper mesopelagic zone (UMZ) of distinct environments. We find coherent variations in POC cycling parameters and fluxes throughout the transect. Thus, the settling speed of POC in the &gt;51 μm fraction increased with depth in the UMZ, presumably due to higher particle densities at depth. The settling flux of total POC (&gt;1 μm) out of the EZ was positively correlated with primary production integrated over the EZ; the highest export occurred in the subarctic gyre while the lowest occurred in the subtropical gyres. The ratio of POC settling flux to integrated primary production was low (&lt;5%) along GP15, which suggests an efficient recycling of POC in the EZ in all trophic regimes. Specific rates of POC remineralization did not show clear variations with temperature or dissolved oxygen concentration, that is, POC recycling was apparently controlled by other factors such as microbial colonization and substrate lability. Particle cohesiveness, as approximated by the second‐order rate constant for particle aggregation, was negatively correlated with trophic regime: particles appeared more cohesive in low‐productivity regions than in high‐productivity regions.

Integration of proteomics and metabolomics reveals energy and metabolic alterations induced by glucokinase (GCK) partial inactivation in hepatocytes

AimsGlucokinase (GCK) acts as the glucose sensor in maintaining glucose homeostasis. The inactivating mutation of the GCK gene leads to glucokinase-maturity onset diabetes of the young (GCK-MODY). This study aims to gain further insights into the molecular alterations triggered by GCK partial inactivation in hepatocytes, potentially underlying the favorable prognosis of GCK-MODY. Main methodsA GCK knockdown HepG2 cell model was established, and the integration of proteomics and metabolomics was used to gain a comprehensive understanding of the molecular pathway changes caused by GCK inactivation in the liver. Key findingsProteomic analysis identified 257 differential proteins. KEGG pathway enrichment analysis showed that protein expression changes in the GCK knockdown group were significantly enriched in central carbon metabolism, the TCA cycle, amino acid metabolism and the oxidative phosphorylation pathway. Among them, enzymes in the TCA cycle (PC, IDH2, SDH) were significantly downregulated in GCK-knockdown group. Targeted metabolomics revealed that in the GCK knockdown hepatocytes, TCA cycle intermediates were significantly decreased, including pyruvate, oxaloacetate, citrate and succinic acid, and three metabolites increased including glycine, betaine and homocysteine. These metabolic alterations in turn reduced the accumulation of reactive oxygen species in GCK knockdown hepatocytes. Correlation analysis indicated that TCA cycle metabolites were positively correlated with proteins involved in the TCA cycle, carbon metabolism, glycolysis, Ras signaling, fibrosis and inflammation. SignificanceIn conclusion, GCK knockdown reduced TCA cycle flux and oxidative stress in hepatocytes by influencing the levels of key transcription factors and enzymes, providing a comprehensive understanding of the effects of GCK partial inactivation on liver metabolism and molecular mechanisms.