New 1-ethyl-3-methylimidazolium (EMI) salts [EMI][C(CN)3] and [EMI][Ag(CN)2] were prepared and characterized. The C(CN)3 salt has a melting point at -11 degrees C and shows a low viscosity (18 cP) and a high ionic conductivity (1.8 x 10(-2) S cm(-1)) at room temperature. This conductivity is less than that of [EMI][N(CN)2] salt (2.7 x 10(-2) S cm(-1)), possibly due to the larger molecular weight of the anion. The first EMI salt containing Ag(I) complexes [EMI][Ag(CN)2] has a higher melting point of 73 degrees C. In the crystal, the C-H...pi interionic interactions between cations construct zigzag chains in the cationic two-dimensional layer. Close Ag..Ag interionic contacts of 3.226(1) A were observed in the one-dimensional anionic chain, and the relatively high melting point among the EMI salts with a monoanion appears to be governed essentially by these direct Ag...Ag interactions.
The negative co-stimulatory receptor, programmed cell death 1 (PD-1), is induced on activated T cells and delivers inhibitory signals upon engagement with its ligands PD-L1 and PD-L2, which are expressed on various somatic cells and certain cancers. Accumulating evidence suggests that interfering with the PD-1-PD-L1 interaction may result in the restoration of defective T cell functions in cancer and chronic viral infection. Herein, we established procedures to produce large amounts of renatured recombinant extracellular domain proteins of mouse PD-1 (mPD-1) and PD-L1. While monomeric mPD-1 and mouse PD-L1 (mPD-L1) only marginally interacted with the cells expressing their counterpart proteins, their tetramerization markedly enhanced the affinity with the K(d) of mPD-L1 tetramer being nearly 100-fold lower than that of the corresponding monomer. The affinity of mPD-L1 tetramer was even higher than a high-affinity anti-PD-1 mAb, and it efficiently inhibited the binding of mPD-L1/Fc-chimeric protein to mPD-1(+) cells. Functionally, mPD-L1 tetramer significantly enhanced the proliferative responses as well as the cytotoxic activity of T cells against specific target cells in vitro. The results suggest that oligomeric PD-L1 extracellular domains may provide a potential means to restore T cell functions in cancer and viral infection in humans.
Genome science, including topics such as gene recombination, cloning, genetic tests, and gene therapy, is now an established part of our daily lives; thus we need to learn genome science to better equip ourselves for the present day. Learning from topics directly related to the human has been suggested to be more effective than learning from Mendel's peas not only because many students do not understand that plants are organisms, but also because human biology contains important social and health issues. Therefore, we have developed a teaching program for the introduction to genome science, whose subjects are focused on the human genome. This program comprises mixed multimedia presentations: a large poster with illustrations and text on the human genome (a human genome map for every home), and animations on the basics of genome science. We implemented and assessed this program at four high schools. Our results indicate that students felt that they learned about the human genome from the program and some increases in students' understanding were observed with longer exposure to the mixed multimedia presentations.
Background:Upon activation, effector T‐cells preferably utilize glucose for rapid and extensive proliferation, and cytokine production. Until recently, it has been thought that extracellular fatty acid (FA) uptake and oxidation are severely reduced in alloreactive T‐cells; however, recent studies have suggested that lipid metabolism is rather increased in alloreactive T‐cells, and that metabolic pathways of FA can be a promising therapeutic target for GVHD.Aims:To determine the role of lipid metabolism in human alloreactive T‐cells, we investigated the metabolic changes in human T‐cells in vivo using xenogeneic GVHD models.Methods:NOG mice received 250cGy of total body irradiation (TBI) and were subsequently injected intravenously with human pan T‐cells. Under this condition, all mice developed severe GVHD and died within 2 weeks. Human T‐cells were harvested from GVHD target organs of mice at day 9 after transplantation. For the measurement of glucose and FA uptake by flow cytometry, cells were stained with fluorescent‐labeled deoxyglucose analogue (2‐NBDG) and long‐chain FA analogue (BODIPY 500/510 C12), respectively. PCR array and extracellular flux analysis were performed according to the manufacturer's instructions.Results:Glucose uptake was significantly increased in human T‐cells obtained from GVHD mice as expected. Extracellular FA uptake was also increased in human T‐cells of GVHD mice, and was associated with cell proliferation rate. Effector memory T‐cells followed by central memory T‐cells showed a higher FA uptake than did naive T‐cells. These findings were similarly observed in both CD4+ and CD8+ T‐cells. Extracellular uptake of FA as well as glucose in T‐cells was significantly higher in MHC+/+ GVHD mice compared with MHC−/− GVHD mice, suggesting that the recognition of host MHC molecules is the initial trigger for metabolic shift in alloreactive T‐cells. Quantitative real‐time PCR analysis demonstrated up‐regulation of mRNAs encoding the enzymes involved in FA transport including carnitine palmitoyltransferase (CPT1B), FA binding protein (FABP1–4, FABP6, and FABP7), and FA oxidation (FAO) pathway including acyl‐CoA synthase (ACSBG2) and acyl‐CoA dehydrogenase (ACAD9–11, ACADS, and ACADL) in human T‐cells of GVHD mice. Similarly, the expression of genes encoding the enzymes in triacylglycerol metabolism such as glycerol kinase (GK, GK2) and lipoprotein lipase (LPL) was up‐regulated in GVHD mice. Furthermore, the expression of genes associated with mevalonate pathways such as HMG‐CoA synthase (HMGCS1, HMGCS2), was also upregulated. These observations suggest that alloreactive T‐cells increase lipid hydrolysis, mitochondrial FA transport, and FAO, resulting in greater utilization of intra‐ and extracellular FA. Extracellular flux analysis demonstrated that mitochondrial FA transport blockade by specific CPT1 inhibitor, etomoxir, significantly decreased the maximum respiration and spare respiratory capacity in human T‐cells in MHC+/+ GVHD mice but not in MHC−/− GVHD mice. Even after glucose deprivation or inhibition of mitochondrial pyruvate transport by UK5099, the oxygen consumption rate was precipitously reduced by inhibition of CPT1, suggesting that increasing FAO supported oxidative phosphorylation (OXPHOS) in alloreactive T‐cells of GVHD mice.Summary/Conclusion:Our results clearly indicate that alloreactive T‐cells increase FA uptake, intra‐ and extracellular lipid metabolism, and OXPHOS, and suggest that lipid metabolic processes in T‐cells have potential as a therapeutic target for GVHD.image
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