Noble gases and nitrogen in samples of asteroid Ryugu record its volatile sources and recent surface evolution.

The near-Earth carbonaceous asteroid (162173) Ryugu is expected to contain volatile chemical species that could provide information on the origin of Earth's volatiles. Samples of Ryugu were retrieved by the Hayabusa2 spacecraft. We measured noble gas and nitrogen isotopes in Ryugu samples and found that they are dominated by presolar and primordial components, incorporated during Solar System formation. Noble gas concentrations are higher than those in Ivuna-type carbonaceous (CI) chondrite meteorites. Several host phases of isotopically distinct nitrogen have different abundances among the samples. Our measurements support a close relationship between Ryugu and CI chondrites. Noble gases produced by galactic cosmic rays, indicating a ~5 million year exposure, and from implanted solar wind record the recent irradiation history of Ryugu after it migrated to its current orbit.

First asteroid gas sample delivered by the Hayabusa2 mission: A treasure box from Ryugu.

The Hayabusa2 spacecraft returned to Earth from the asteroid 162173 Ryugu on 6 December 2020. One day after the recovery, the gas species retained in the sample container were extracted and measured on-site and stored in gas collection bottles. The container gas consists of helium and neon with an extraterrestrial 3He/4He and 20Ne/22Ne ratios, along with some contaminant terrestrial atmospheric gases. A mixture of solar and Earth's atmospheric gas is the best explanation for the container gas composition. Fragmentation of Ryugu grains within the sample container is discussed on the basis of the estimated amount of indigenous He and the size distribution of the recovered Ryugu grains. This is the first successful return of gas species from a near-Earth asteroid.

Spectrally blue hydrated parent body of asteroid (162173) Ryugu.

Ryugu is a carbonaceous rubble-pile asteroid visited by the Hayabusa2 spacecraft. Small rubble pile asteroids record the thermal evolution of their much larger parent bodies. However, recent space weathering and/or solar heating create ambiguities between the uppermost layer observable by remote-sensing and the pristine material from the parent body. Hayabusa2 remote-sensing observations find that on the asteroid (162173) Ryugu both north and south pole regions preserve the material least processed by space weathering, which is spectrally blue carbonaceous chondritic material with a 0-3% deep 0.7-µm band absorption, indicative of Fe-bearing phyllosilicates. Here we report that spectrally blue Ryugu's parent body experienced intensive aqueous alteration and subsequent thermal metamorphism at 570-670 K (300-400 °C), suggesting that Ryugu's parent body was heated by radioactive decay of short-lived radionuclides possibly because of its early formation 2-2.5 Ma. The samples being brought to Earth by Hayabusa2 will give us our first insights into this epoch in solar system history.

Immunoregulatory Monocyte Subset Promotes Metastasis Associated With Therapeutic Intervention for Primary Tumor.

Systemic and local inflammation associated with therapeutic intervention of primary tumor occasionally promotes metastatic recurrence in mouse and human. However, it remains unclear what types of immune cells are involved in this process. Here, we found that the tissue-repair-promoting Ym1+Ly6Chi monocyte subset expanded as a result of systemic and local inflammation induced by intravenous injection of lipopolysaccharide or resection of primary tumor and promoted lung metastasis originating from circulating tumor cells (CTCs). Deletion of this subset suppressed metastasis induced by the inflammation. Furthermore, transfer of Ym1+Ly6Chi monocytes into naïve mice promoted lung metastasis in the mice. Ym1+Ly6Chi monocytes highly expressed matrix metalloproteinase-9 (MMP-9) and CXCR4. MMP-9 inhibitor and CXCR4 antagonist decreased Ym1+Ly6Chi-monocyte-promoted lung metastasis. These findings indicate that Ym1+Ly6Chi monocytes are therapeutic target cells for metastasis originating from CTCs associated with systemic and local inflammation. In addition, these findings provide a novel predictive cellular biomarker for metastatic recurrence after intervention for primary tumor.

Modification of platelet proteins by 4-hydroxynonenal: Potential Mechanisms for inhibition of aggregation and metabolism.

Platelet aggregation is an essential response to tissue injury and is associated with activation of pro-oxidant enzymes, such as cyclooxygenase, and is also a highly energetic process. The two central energetic pathways in the cell, glycolysis and mitochondrial oxidative phosphorylation, are susceptible to damage by reactive lipid species. Interestingly, how platelet metabolism is affected by the oxidative stress associated with aggregation is largely unexplored. To address this issue, we examined the response of human platelets to 4-hydroxynonenal (4-HNE), a reactive lipid species which is generated during thrombus formation and during oxidative stress. Elevated plasma 4-HNE has been associated with renal failure, septic shock and cardiopulmonary bypass surgery. In this study, we found that 4-HNE decreased thrombin stimulated platelet aggregation by approximately 60%. The metabolomics analysis demonstrated that underlying our previous observation of a stimulation of platelet energetics by thrombin glycolysis and TCA (Tricarboxylic acid) metabolites were increased. Next, we assessed the effect of both 4-HNE and alkyne HNE (A-HNE) on bioenergetics and targeted metabolomics, and found a stimulatory effect on glycolysis, associated with inhibition of bioenergetic parameters. In the presence of HNE and thrombin glycolysis was further stimulated but the levels of the TCA metabolites were markedly suppressed. Identification of proteins modified by A-HNE followed by click chemistry and mass spectrometry revealed essential targets in platelet activation including proteins involved in metabolism, adhesion, cytoskeletal reorganization, aggregation, vesicular transport, protein folding, antioxidant proteins, and small GTPases. In summary, the biological effects of 4-HNE can be more effectively explained in platelets by the integrated effects of the modification of an electrophile responsive proteome rather than the isolated effects of candidate proteins.

Defining the effects of storage on platelet bioenergetics: The role of increased proton leak.

The quality of platelets decreases over storage time, shortening their shelf life and potentially worsening transfusion outcomes. The changes in mitochondrial function associated with platelet storage are poorly defined and to address this we measured platelet bioenergetics in freshly isolated and stored platelets. We demonstrate that the hypotonic stress test stimulates both glycolysis and oxidative phosphorylation and the stored platelets showed a decreased recovery to this stress. We found no change in aggregability between the freshly isolated and stored platelets. Bioenergetic parameters were changed including increased proton leak and decreased basal respiration and this was reflected in a lower bioenergetic health index (BHI). Mitochondrial electron transport, measured in permeabilized platelets, showed only minor changes which are unlikely to have a significant impact on platelet function. There were no changes in basal glycolysis between the fresh and stored platelets, however, glycolytic rate was increased in stored platelets when mitochondrial ATP production was inhibited. The increase in proton leak was attenuated by the addition of albumin, suggesting that free fatty acids could play a role in increasing proton leak and decreasing mitochondrial function. In summary, platelet storage causes a modest decrease in oxidative phosphorylation driven by an increase in mitochondrial proton leak, which contributes to the decreased recovery to hypotonic stress.

Metabolic plasticity in resting and thrombin activated platelets.

Platelet thrombus formation includes several integrated processes involving aggregation, secretion of granules, release of arachidonic acid and clot retraction, but it is not clear which metabolic fuels are required to support these events. We hypothesized that there is flexibility in the fuels that can be utilized to serve the energetic and metabolic needs for resting and thrombin-dependent platelet aggregation. Using platelets from healthy human donors, we found that there was a rapid thrombin-dependent increase in oxidative phosphorylation which required both glutamine and fatty acids but not glucose. Inhibition of fatty acid oxidation or glutamine utilization could be compensated for by increased glycolytic flux. No evidence for significant mitochondrial dysfunction was found, and ATP/ADP ratios were maintained following the addition of thrombin, indicating the presence of functional and active mitochondrial oxidative phosphorylation during the early stages of aggregation. Interestingly, inhibition of fatty acid oxidation and glutaminolysis alone or in combination is not sufficient to prevent platelet aggregation, due to compensation from glycolysis, whereas inhibitors of glycolysis inhibited aggregation approximately 50%. The combined effects of inhibitors of glycolysis and oxidative phosphorylation were synergistic in the inhibition of platelet aggregation. In summary, both glycolysis and oxidative phosphorylation contribute to platelet metabolism in the resting and activated state, with fatty acid oxidation and to a smaller extent glutaminolysis contributing to the increased energy demand.

Bioenergetic programming of macrophages by the apolipoprotein A-I mimetic peptide 4F.

The apoA-I (apolipoprotein A-I) mimetic peptide 4F favours the differentiation of human monocytes to an alternatively activated M2 phenotype. The goal of the present study was to test whether the 4F-mediated differentiation of MDMs (monocyte-derived macrophages) requires the induction of an oxidative metabolic programme. 4F treatment induced several genes in MDMs that play an important role in lipid metabolism, including PPARγ (peroxisome-proliferator-activated receptor γ) and CD36. Addition of 4F was associated with a significant increase in FA (fatty acid) uptake and oxidation compared with vehicle treatment. Mitochondrial respiration was assessed by measurement of the OCR (oxygen-consumption rate). 4F increased basal and ATP-linked OCR as well as maximal uncoupled mitochondrial respiration. These changes were associated with a significant increase in ΔΨm (mitochondrial membrane potential). The increase in metabolic activity in 4F-treated MDMs was attenuated by etomoxir, an inhibitor of mitochondrial FA uptake. Finally, addition of the PPARγ antagonist T0070907 to 4F-treated MDMs reduced the expression of CD163 and CD36, cell-surface markers for M2 macrophages, and reduced basal and ATP-linked OCR. These results support our hypothesis that the 4F-mediated differentiation of MDMs to an anti-inflammatory phenotype is due, in part, to an increase in FA uptake and mitochondrial oxidative metabolism.

Enhanced CD36 expression changes the role of Nrf2 activation from anti-atherogenic to pro-atherogenic in apoE-deficient mice.

Oxidative stress has been implicated as a causative factor of atherosclerosis. Defense systems against oxidative stress are maintained by radical scavenging antioxidants and/or by regulating the expression of antioxidant genes by activating oxidative stress-sensitive transcription factor: nuclear factor (erythroid-derived 2)-like 2 (Nrf2). We investigated the anti-atherogenic effects of three synthesized compounds (shogaol A: radical scavenging antioxidant activity; shogaol N: Nrf2-activating activity; shogaol N + A: both activities) and curcumin (both activities) in apolipoprotein E (apoE)-deficient mice. We expected compounds with both activities to have additive or synergistic anti-atherogenic effects; however, atherosclerosis was exacerbated significantly by curcumin and slightly by shogaol N + A. Shogaol A, shogaol N, and shogaol N + A showed no significant effect on atherosclerosis development. Immunohistochemical analysis of the aorta revealed that expression of CD36, an Nrf2-regulated gene, was strongly induced by treatment with curcumin. The total antioxidant capacity of plasma collected from mice administered the three compounds was evaluated using a hydrophilic probe, pyranine. Shogaol N or shogaol N + A significantly enhanced the antioxidant capacity of plasma, whereas shogaol A and curcumin did not show this activity. The concentrations of the three shogaol derivatives in plasma were similar (approximately 100 nM), while that of curcumin was much lower. These results suggest that plasma antioxidant capacity is maintained at high levels via Nrf2 activation and that CD36 expression enhances atherosclerosis development.

The effect of the source of nitrogen supplementation on nitrogen balance, rates of plasma leucine turnover, protein synthesis and degradation in sheep.

Combined experiments of the isotope dilution method of [1-(13)C]leucine, open-circuit calorimetry and nitrogen (N) balance test were used to determine the effect of the source of N supplementation on N balance, whole body protein synthesis (WBPS) and degradation (WBPD) in sheep. The experiment was performed in a replicated 3 × 3 Latin square design. The control diet consisted of timothy hay, ground maize and soybean meal. The urea diet was the control diet supplemented with 1.5% urea. The SBM diet contained the same N and metabolisable energy as the urea diet, which was reached by changing ground maize and soybean meal weights of the control diet. Nitrogen retention was greater (p < 0.05) for the urea diet than the control and SBM diets. Plasma urea concentrations were highest for the SBM diet, followed by the urea diet, and the control diet was lowest. The WBPS and WBPD did not differ between diets, but were numerically lower for the urea and SBM diets. These results suggest that in sheep, urea supplementation influenced N retention without clear changes in WBPS and WBPD.