We present a construction method for reduced-order models (ROMs) to explore alternatives to numerical simulations. The proposed method can efficiently construct ROMs for non-linear problems with ...contact and impact behaviors by using tensor decomposition for factorizing multidimensional data and Akima-spline interpolation without tuning any parameters. First, we construct learning tensor data of nodal displacements or accelerations using finite element analysis with some representative parameter sets. Second, the data are decomposed into a set of mode matrices and one small core tensor using Tucker decomposition. Third, Akima-spline interpolation is applied to the mode matrices to predict values within the data range. Finally, the time history responses with new parameter sets are generated by multiplying the expanded mode matrices and small core tensor. The performance of the proposed method is studied by constructing ROMs for airbag impact simulations based on limited learning data. The proposed ROMs can accurately predict airbag deployment behavior even for new parameter sets using the Akima-spline interpolation scheme. Furthermore, an extremely high data compression ratio (more than 1000) and efficient predictions of the response surfaces and Pareto frontier (2000 times faster than that of full finite element analyses using all parameter sets) can be realized.
New neurons, continuously added in the adult olfactory bulb (OB) and hippocampus, are involved in information processing in neural circuits. Here, we show that synaptic pruning of adult-born neurons ...by microglia depends on phosphatidylserine (PS), whose exposure on dendritic spines is inversely correlated with their input activity. To study the role of PS in spine pruning by microglia in vivo, we developed an inducible transgenic mouse line, in which the exposed PS is masked by a dominant-negative form of milk fat globule-EGF-factor 8 (MFG-E8), MFG-E8D89E. In this transgenic mouse, the spine pruning of adult-born neurons by microglia is impaired in the OB and hippocampus. Furthermore, the electrophysiological properties of these adult-born neurons are altered in MFG-E8D89E mice. These data suggest that PS is involved in the microglial spine pruning and the functional maturation of adult-born neurons. The MFG-E8D89E-based genetic approach shown in this study has broad applications for understanding the biology of PS-mediated phagocytosis in vivo.
For an understanding of metal transport at the Earth's surface, ferrihydrite (Fe4–5(OH,O)12) transformation experiments were conducted with and without the presence of Zn, and the redistribution of ...Zn between solid and solution during the transformation was examined. Batch experiments were carried out at 0, 20, 200 and 750 μM Zn, initial pH 7.5, and a temperature of 70 °C for 1–3504 h at a constant ferrihydrite concentration (2 mM Fe). Sequential extraction was applied to the resultant samples to measure the concentrations of Zn and Fe at three different extraction stages. Solid phases were examined by X-ray diffraction and X-ray absorption fine structure analysis, and solutions by inductively coupled plasma optical emission spectrometry. Ferrihydrite is transformed to hematite (Fe2O3) and goethite (FeO(OH)) at both 0 and 20 μM Zn while the transformation rate is slightly slower at 20 μM Zn. Almost all initial Zn is likely to be accommodated in the hematite and goethite structures at the completion of the transformation at 20 μM Zn. At 200 μM Zn, most of ferrihydrite is transformed directly to hematite, while at 750 μM Zn, ferrihydrite is transformed to hematite through Zn-bearing maghemite (Fe2O3 or Fe2.67O4), an intermediate, metastable phase. The transformation rate is significantly slower at 200 μM Zn than at 20 μM Zn, and further slower at 750 μM Zn. Zinc-bearing maghemite and hematite can contain Zn with ~0.4 and ~0.07 of Zn/Fe mole ratios, respectively, in their structures. Most of the initial Zn at 750 μM Zn (Zn/Fe of ~0.2 in a system) is likely to be present as dissolved Zn at the completion of the transformation since Zn-bearing maghemite is decomposed with progress in transformation and most of Zn is released into solution with less Zn in the hematite structure. Because of the accommodation capacity of Zn in hematite, only a small amount of the initial Zn is likely to remain in solution at 200 μM Zn at the end of the transformation. The present study clearly indicates that Zn redistribution is significantly affected by the factors: the differences in transformation process and rate, the presence or absence of intermediate phase(s), and metal accommodation capacities of the minerals, which must be taken into account for metal transport in open, natural systems. These factors can be controlled by initial Zn concentration for the present study.
•Redistribution of Zn during transformation of ferrihydrite was examined with different initial Zn concentrations.•Increase in Zn retards the transformation rate drastically.•A Zn/Fe ratio of >~1 in a system forms an intermediate phase (Zn-bearing maghemite) and changes the transformation process.•Redistribution of Zn during transformation is affected by transformation process and rate and intermediate phase.
Hematopoietic stem cells (HSCs) reside in specialized bone marrow (BM) niches regulated by the sympathetic nervous system (SNS). Here, we have examined whether mononuclear phagocytes modulate the HSC ...niche. We defined three populations of BM mononuclear phagocytes that include Gr-1(hi) monocytes (MOs), Gr-1(lo) MOs, and macrophages (MΦ) based on differential expression of Gr-1, CD115, F4/80, and CD169. Using MO and MΦ conditional depletion models, we found that reductions in BM mononuclear phagocytes led to reduced BM CXCL12 levels, the selective down-regulation of HSC retention genes in Nestin(+) niche cells, and egress of HSCs/progenitors to the bloodstream. Furthermore, specific depletion of CD169(+) MΦ, which spares BM MOs, was sufficient to induce HSC/progenitor egress. MΦ depletion also enhanced mobilization induced by a CXCR4 antagonist or granulocyte colony-stimulating factor. These results highlight two antagonistic, tightly balanced pathways that regulate maintenance of HSCs/progenitors in the niche during homeostasis, in which MΦ cross talk with the Nestin(+) niche cell promotes retention, and in contrast, SNS signals enhance egress. Thus, strategies that target BM MΦ hold the potential to augment stem cell yields in patients that mobilize HSCs/progenitors poorly.
Mycobacteria possess various immunomodulatory molecules on the cell wall. Mannose-capped lipoarabinomannan (Man-LAM), a major lipoglycan of Mycobacterium tuberculosis, has long been known to have ...both inhibitory and stimulatory effects on host immunity. However, the direct Man-LAM receptor that explains its pleiotropic activities has not been clearly identified. Here, we report that a C-type lectin receptor Dectin-2 (gene symbol Clec4n) is a direct receptor for Man-LAM. Man-LAM activated bone-marrow-derived dendritic cells (BMDCs) to produce pro- and anti-inflammatory cytokines, whereas it was completely abrogated in Clec4n–/– BMDCs. Man-LAM promoted antigen-specific T cell responses through Dectin-2 on DCs. Furthermore, Man-LAM induced experimental autoimmune encephalitis (EAE) as an adjuvant in mice, whereas Clec4n–/– mice were resistant. Upon mycobacterial infection, Clec4n–/– mice showed augmented lung pathology. These results demonstrate that Dectin-2 contributes to host immunity against mycobacterial infection through the recognition of Man-LAM.
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•Dectin-2 recognizes mycobacterial Man-LAM•Man-LAM induces both pro- and anti-inflammatory cytokine production through Dectin-2•IL-10 production during mycobacterial infection is abrogated in Clec4n−/− DCs•Man-LAM induces EAE as an adjuvant through Dectin-2-FcRγ signaling axis
Mycobacterial lipoarabinomannan is a well-known immunomodulatory component. Yamasaki and colleagues demonstrate that Dectin-2 is a direct receptor for this lipoglycan.
Cerium (Ce) can be used as a plaeoredox proxy as shown by a recent study of stable isotopic fractionation of Ce during adsorption and precipitation. However, the experiments in that study were ...performed at pH conditions lower than that of natural seawater. In the current study, adsorption and precipitation experiments were performed at pH 6.80, 8.20, and 11.00 with 2.25mM dissolved carbonate to simulate Ce isotopic fractionation in the natural environment and examine the relationship between isotopic fractionation and Ce speciation in the liquid phase. Mean isotopic fractionation factors between liquid and solid phases (αLq-So) of Ce adsorbed on ferrihydrite did not depend on pH conditions or dissolved Ce species. In the Ce/δ-MnO2 system,αLq-So values decreased from 1.000411 (±0.000079) to 1.000194 (±0.000067) with increasing pH or number of carbonate ions, from Ce3+ to Ce(CO3)2−. In the Ce/precipitation system at pH 8.20 and 11.00 where Ce(CO3)2− is present in solution, the αLq-So values were 0.999821 (±0.000071) and 0.999589 (±0.000074), respectively, meaning that lighter isotope enrichment was observed in the liquid phase, which is the contrary to those of the other systems.
Extended X-ray absorption fine structure (EXAFS) analyses were also performed to investigate the coordination structure of the adsorbed or precipitated Ce species that control the isotopic fractionation during adsorption. Even at higher pH, where Ce(CO3)+ or Ce(CO3)2− are the dominant dissolved species, the first coordination sphere of Ce in the solid phase in the Ce/ferrihydrite and Ce/precipitation systems was similar to that observed at pH 5.00 where Ce3+ was the main species in solution. A slight elongation in the CeO bond length in the solid phase at pH 11.00, where negatively charged dissolved species are dominant in the liquid phase, may cause a decrease in isotopic fractionation in the Ce/δ-MnO2 system. The coordination environment of Ce may not change significantly during the adsorption onto ferrihydrite, because Ce binds to the neutral surface OH group on ferrihydrite at pH below 8.5–8.8 (i.e. the pH of the point of zero charge (PZC) for ferrihydrite), similar to other cations when the metal–O distance was similar in hydrated and adsorbed species. At pH above PZC, Ce bonds to the negatively charged surface OH group, while Ce also bonds with CO32− in dissolved species. The reduced partition functions (ln β) for dissolved species (ln βLq) and adsorbed species (ln βSo) with the same trends canceled each other, because ln β of hydrated cation was reduced by the binding anion, resulting in small isotope fractionations. Thus, isotope fractionations for Ce/ferrihydrite may be quite small at the entire pH conditions in this study. The direction of the isotopic fractionation was estimated based on density functional theory (DFT) calculations, which confirmed that lighter Ce is enriched in the liquid phase when Ce forms a complex with carbonate ions. Therefore, this study indicates that the dissolved species can control stable Ce isotopic fractionation during precipitation reactions.
The similar, but not identical chemical properties of W compared with Mo suggest that the stable isotope system of W could be a novel proxy to explore the modern and ancient ocean as is the case in ...the well-established utility of Mo isotopes. We experimentally investigated the isotopic fractionation of W during adsorption on Fe and Mn (oxyhydr)oxides (ferrihydrite and δ-MnO2), a key process in the global ocean budget of this element. Our adsorption experiments confirmed that W isotopes fractionate substantially on both ferrihydrite and δ-MnO2: lighter W isotopes are preferentially adsorbed on both oxides as a result of equilibrium isotopic exchange between dissolved and adsorbed species, and the obtained values of Δ186/183Wliquid–solid (=δ186Wdissolved−δ186Wadsorbed) are 0.76±0.09‰ for ferrihydrite and 0.88±0.21‰ for δ-MnO2 (2σ, n=6). Compared with the case of Mo isotopes, fractionation of W isotopes is (i) of comparable magnitude between ferrihydrite and δ-MnO2, and (ii) much smaller than that of Mo on δ-MnO2. Our previous XAFS observations and newly-performed DFT calculations both indicate that the observed W isotopic fractionations are caused by the symmetry change from Td (tetrahedral) WO42− to distorted Oh (octahedral) monomeric W species via formation of inner-sphere complexes on both ferrihydrite and δ-MnO2. The similar isotopic fractionations between the two oxides relate to the strong tendency for W to form inner-sphere complexes, which causes the symmetry change, in contrast to the outer-sphere complex of Mo on ferrihydrite. The smaller isotopic fractionation of W compared with Mo on δ-MnO2 despite their similar molecular symmetry seems to be due to their different degrees of distortion of Oh species. Our findings imply that the isotopic composition of W in modern oxic seawater is likely to become heavier relative to the input by removal of lighter W isotopes via adsorption on ferromanganese oxides in analogy with the Mo isotope budget. In contrast, the isotopic composition of W in ancient seawater should have evolved in response to the extent of deposition of both Fe and Mn oxides; this is likely to be different compared with that of the Mo isotopes, which is strongly associated with the occurrence of Mn oxides relative to Fe oxides.
More than 50 years ago, cells were observed to die during insect development via a process that was named 'programmed cell death'. Later, a similar cell death process was found to occur in humans, ...and the process was renamed 'apoptosis'. In the 1990s, a number of apoptosis-regulating molecules were identified, and apoptosis was found to have essential roles in the immune system. In this Timeline article, we highlight the key events that have demonstrated the importance of programmed cell death processes, including apoptosis and programmed necrosis, in the immune system.
The generation of tumor-directed cytotoxic T lymphocytes is considered crucial for the induction of antitumor immunity. To activate these CD8+ T cells, antigen-presenting cells (APCs) must initially ...acquire tumor cell-associated antigens. The major source of tumor antigens is dead tumor cells, but little is known about how APCs in draining lymph nodes acquire and crosspresent these antigens. Here we show that CD169+ macrophages phagocytose dead tumor cells transported via lymphatic flow and subsequently crosspresent tumor antigens to CD8+ T cells. Subcutaneous immunization with irradiated tumor cells protects mice from syngenic tumor. However, tumor antigen-specific CD8+ T cell activation and subsequent antitumor immunity are severely impaired in mice depleted with CD169+ macrophages. Neither migratory dendritic cells (DCs) nor lymph node-resident conventional DCs are essential for the crosspresentation of tumor antigens. Thus, we have identified CD169+ macrophages as lymph node-resident APCs dominating early activation of tumor antigen-specific CD8+ T cells.
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► Dead tumor cells in periphery accumulate in the draining lymph node sinus ► CD169+ macrophages phagocytose and crosspresent dead cell-associated antigens ► CD169+ macrophage-depleted mice fail to crossprime tumor-specific CD8 T cells ► CD169+ macrophages link tumor cell death and induction of antitumor immunity
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