A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment

Within tumors, some areas are less oxygenated than others. Since their home ground is under chronic hypoxia, tumor cells adapt to this condition by activating aerobic glycolysis; however, this hypoxic environment is very harsh for incoming immune cells. Deprivation of oxygen limits availability of energy sources and induces accumulation of extracellular adenosine in tumors. Extracellular adenosine, upon binding with adenosine receptors on the surface of various immune cells, suppresses pro-inflammatory activities. In addition, signaling through adenosine receptors upregulates a number of anti-inflammatory molecules and immunoregulatory cells, leading to the establishment of a long-lasting immunosuppressive environment. Thus, due to hypoxia and adenosine, tumors can discourage anti-tumor immune responses no matter how the response was induced, whether it was spontaneous or artificially introduced with a therapeutic intention. Preclinical studies have shown the significance of adenosine in tumor survival strategy by demonstrating tumor regression after inactivation of adenosine receptors, inhibition of adenosine-producing enzymes or reversal of tissue hypoxia. These promising results indicate a potential use of the inhibitors of the hypoxia-adenosine pathway for cancer immunotherapy

Photoemission characterization of interface dipoles and electronic defect states for gate dielectrics

In the development of Metal-Insulator-Semiconductor (MIS) devices, gate dielectric technology is of great importance and includes major scientific and technological issues to be solved for required device performance and reliability [1]. In particular, characterization of electronic defects in dielectrics and at their interfaces with semiconductor substrates as well as energy band profiles has been imperative to gain a better understanding of physics of dielectric/semiconductor heterostructures [2, 3]. In this work, our recent achievements on the characterization of gate dielectrics and their stacked interfaces by means of photoemission techniques have been reviewed. First, we have shown how valuable the cut-off energy of photoelectrons is to measure directly the potential change due to electrical dipoles at the interface in stacked dielectrics [4]. And then, we have demonstrated how powerful total photoelectron electron yield spectroscopy (PYS) [5, 6] is to quantify the energy distribution of electronic defect states in gate dielectrics and at dielectric/semiconductor interfaces. The inner potential changes in dielectric stacks reflect in changes in the cut-off energy of secondary photoelectrons (SEs) measured in high-resolution x-ray photoelectron spectroscopy (XPS) [4]. After calibration of the kinetic energy of core-line signals from the underlying layer, an abrupt potential change due to electrical dipoles at the interface between dielectrics, resultant abrupt potential change can be measured as a change in the cut-off energy of SEs. The observation of cut-off energy provides us an advantage in simple and precise evaluation of the potential change due to electrical dipoles as compared to a discussion on dipole formation based on the energy shift of core-line signals which reflects not only the potential change due to dipoles but also the chemical shift, that is, change in the chemical bonding features. From SE spectra near the lowest limit in kinetic energy for the samples before and after the formation of various high-k dielectrics on thermally-grown thick SiO2, we found that, with the formation of either ultrathin Al2O3 or HfO2 or TiO2 on SiO2, the cut-off energy of SEs was shifted toward the higher kinetic energy side. On the other hand, in the cases of Y- and Sr-oxides with silicate formation at the interfaces, a slight opposite energy shift was detected. The analyses of the core line signals confirm that there is a linear correlation between the observed potential changes and the ratios in the oxygen anion density at the interfaces between SiO2 and high-k dialectics as suggested in Ref. [8]. In the photoelectron yield measurements, the total number of photoelectrons emitting from the sample is counted considering the incident photon flux, the yield spectrum is related to an integral over the occupied density of states existing near the sample surface [5, 6]. From photoelectron yield spectra of 2nm-thick SiO2 formed 500ºC by remote plasma enhanced CVD on n-type GaN(0001) before and after N2 anneal at 800ºC, we found that, with the N2 anneal at 800ºC, the yield from the defects was reduced markedly. The 1st derivative of the measured yield spectrum with respect to incident photon energy leads us to the energy distribution of occupied defect state densities in consideration of density of states of the GaN valence band, measured photoelectron yield from the GaN VB and photoelectron escape depth. As a result, occupied states are reduced down to ~1x1011cm-2eV-1 at the energy corresponding to the midgap of GaN near the SiO2/GaN interface with the N2 anneal at 800ºC. The defect state density near the conduction band edge, which was crudely estimated in consideration of electron occupation probability based on the Fermi-Dirac distribution, is in good agreements with the result obtained from the capacitance-voltage (C-V) analysis using the Terman method [7] Acknowledgements The authors wish to thank Assoc. Prof. K. Makihara and Dr. M. Ikeda for their supports about the experiments and Drs. N. Fujimura and N. X. Truyen for their contributions to sample fabrication and characterizations. References [1] For example, ECS Trans. 80(1) (2017). [2] Z. Yatabe et al., J. Phys. D: Appl. Phys. 49 (2016) 393001. [3] J. Robertson and R. M. Wallace, Materials Science and Engineering: R: Reports, 88 (2014) 1. [4] N. Fujimura et al., Jpn. J. Appl. Phys., 57 (2018) 04FB07. [5] A.Ohta et al., Microelectro. Eng., 178 (2017) 85. [6] A.Ohta et al., Jpn. J. Appl. Phys., 57 (2018) 06KA08. [7] N. X. Truhen, Jpn. J. Appl. Phys, 57 (2018) 01AD02. [8] K. Kita and A. Toriumi, Appl. Phys. Lett. 94 (2009) 132902

Photoemission study of gate dielectrics on gallium nitride

In the development of gallium nitride (GaN) power devices, gate dielectric technology on GaN is of great importance and includes major scientific and technological issues to be solved for required device performance and reliability[1]. In particular, characterization of electronic defects in dielectrics and at their interfaces with GaN as well as energy band profiles has been imperative to gain a better understanding of physics of dielectrics/GaN heterostructures. In this work, we have demonstrated how useful the analysis of energy loss signals of photoelectrons [2] is to characterize dielectric functions of dielectrics on GaN and how powerful photoelectron electron yield spectroscopy [3] is to quantify the energy distribution of electronic defect states in dielectric/GaN heterostructures. After wet-chemical cleaning of a GaN epitaxial layer with an Si concentration of 1.5x1016cm-3 on sapphire (0001) and subsequent dipping in a 4.5% HF solution, as a representative dielectric, SiO2 layers in the thickness range of 5-50nm were deposited at 500 ºC by remote plasma CVD, in which the decomposition of SiH4 was induced by remote plasma of Ar/O2 gas mixture to suppress ion dimages. AFM images confirm uniform depositon of SiO2 on GaN. In XPS measurements using monochromitzed AlKa radiation, Ga3d and N1s spectra from ~5nm-thick SiO2/GaN show no detectable interfacial oxidation and no change in stoikiometry near the SiO2/GaN interface. Also, in Si2p, O1s and valence band spectra from deposited SiO2, no difference from thermally-grown SiO2 was detectable. From the analysis of valence band spectrum taken for the ~5nm-thick SiO2/GaN, the valence band offset was determined to be 2.2 eV, from which the conduction band offsetwas derived to be 3.35eV in consideration of energy bandgap values of GaN and SiO2. The energy bandgap of deposited SiO2 was directly measured to be 8.95eV within an accracy of 50meV, being identical to the value measured for thermally-grown SiO2, from the onset energy of energy loss signals of O1s photoelectrons. For further information about electronic structures, taking into acount the relationship among energy loss spectrum, dielectric function and optical constants (n and k values) and using Kramers-Kronig relations for the real and imaginary parts of complex functions such as dielectric function and refractive index, elaborately measured energy loss signals of O1s and Si2p3/2 photoeelectrons were convered into the dielectric finction below ~30eV, in which the contribution of surface plasmon into the measured energy loss signals was first eliminated by difference signals between the cases taken at photoelectron take-off angles of 15 and 30º. As a result, peaks in k values corresponding to characteristic transitions including excitonic transition reported in SiO2 glass were discerned. For quantification of electronic defects in SiO2/GaN heterostructures without additional process steps, photoelectron yield spectra in the incident photon energy region of 3 -10eV, in which Xe arc and high brightness D2 lamps were used as light sources, were measured at each step of SiO2 thinning in a dilute HF solution. Occupied states located in energy region deeper than the conduction band edge of GaN were clearly detected although photoemissions from the GaN valence band became significant in the photon energy region over ~7eV with progressive SiO2 thinning. When measured photoelectron yield spectra were normalized with the yield from mainly from the GaN valence band for photons over ~9eV, almost no change in the yield due to defects was detectable until the SiO2 thickness was reduced down to ~1.5nm. With further SiO2 thinning, a marked decrease in the yield for defects was observed. The results indicates occupied defect states are located within ~1.5nm from the SiO2/GaN interface. Since the energy derivatives of the measured yield spectra lead us to energy distribution of occupied defect state density in consideration of density of states of the GaN valence band, measured photoelectron yield from the GaN valence band and photoelectron escape depth. As a result, occupied states as many as ~3x1011 cm-2eV-1 were detected even at the energy corresponding to the midgap of GaN near the SiO2/GaN interface. Acknowledgements This work was supported in part by NEDO through a co-operative research with AIST. Authors wish to thank Assoc. Prof. K. Makihara and Dr. M. Ikeda for their supports about sample characterization and Prof. Amano’s Laboratory, Nagoya Univ. for the preparation of epitaxial GaN on sapphire substrate. References [1] Z. Yatabe et al., J. Phys. D: Appl. Phys. 49 (2016) 393001. [2] T. Yamamoto et al., ECS Trans. vol.75, No.8 (2016) 777. [3] S. Miyazaki et al., Microelectro. Eng., 48 (1999) 63

In vivo T Cell Activation in Lymphoid Tissues is Inhibited in the Oxygen-Poor Microenvironment

Activation of immune cells is under control of immunological and physiological regulatory mechanisms to ensure adequate destruction of pathogens with the minimum collateral damage to “innocent” bystander cells. The concept of physiological negative regulation of immune response has been advocated based on the finding of the critical immunoregulatory role of extracellular adenosine. Local tissue oxygen tension was proposed to function as one of such physiological regulatory mechanisms of immune responses. In the current study, we utilized in vivo marker of local tissue hypoxia pimonidazole hydrochloride (Hypoxyprobe-1) in the flowcytometric analysis of oxygen levels to which lymphocytes are exposed in vivo. The level of exposure to hypoxia in vivo was low in B cells and the levels increased in the following order: T cells < NKT cells < NK cells. The thymus was more hypoxic than the spleen and lymph nodes, suggesting the variation in the degree of oxygenation among lymphoid organs and cell types in normal mice. Based on in vitro studies, tissue hypoxia has been assumed to be suppressive to T cell activation in vivo, but there was no direct evidence demonstrating that T cells exposed to hypoxic environment in vivo are less activated. We tested whether the state of activation of T cells in vivo changes due to their exposure to hypoxic tissue microenvironments. The parallel analysis of more hypoxic and less hypoxic T cells in the same mouse revealed that the degree of T cell activation was significantly stronger in better-oxygenated T cells. These observations suggest that the extent of T cell activation in vivo is dependent on their localization and is decreased in environment with low oxygen tension

Percentage body fat and results of a periodic health examination

肥満や栄養過剰は多くの慢性疾患、とりわけ成人病と関連が強いことが従来から指摘されている。肥満の判定には体脂肪率を測定することが重要であるが、その方法の一つとして、集団検診に使用しやすい生体電気インピーダンス法（bioelectrical impedance analysis）がある。今回、1ビール製造工場の定期健康診断において、対象者男235人および女137人の体脂肪率をこの方法により測定した。まずこの体脂肪率とBMIおよび肥満度との相関関係を求め、男性より女性において相関が高いことを認めた。ついで肥満群と正常群に分けて、血圧および血液検査の異常率の出現頻度を統計的に比較したところ、肥満群では男女共に総コレステロールで、また男性では尿酸、γGTP、SGPTの各値で、異常者が高率であることを認めた。またSGPTは30才台から、γGTP及びTchは40才台からその傾向が見られた。しかし、肥満指数とこれらの検査値との相関係数は高くはなかった。Data from periodic health examinations such as ALP, UA, RBC, Hb, SGOT, SGPT, Tch(total choresterol), TG(triglyceride), blood pressure, body length, body weight and also percentage body fat(% Fat) as measured by bioelectrical impedance mehtod were obtained from 235 male and 137 female workers at a brewery factory in Okayama Prefecture and results were analyzed. The correlation coefficients for % Fat and Body Mass Index values(BMI) are found to be 0.678 for males and 0.803 for females. Examinees were then devided into normal and obesity groups respectively, and the frequency of values over normal ranges (classified by obesity indicators such as % Fat, BMI and obesity rate calculated from standard weight) were statistically compared. Results showed that % Fat and BMI were more sensitive than obesity rate and that the obesity group had statistically high frequencies of abnormality in some of the data as in the case of SGPT, γGTP and TG compared to the control group. Furthermore this tendency was found to be more significant among male workers than female ones

Convenient Estimation for Counterion Dissociation of Cationic Micelles Using Chloride-Sensitive Fluorescence Probe

Chloride-sensitive fluorescence probe provides a new approach to studying the degree of micellar counterion dissociation (α). The fluorescence of N-ethoxycarbonylmethyl-6-methoxyquinolinium bromide (MQAE) is quenched by chloride ion with linear Stern–Volmer plots. Thus the fluorescence intensity can be used to monitor the concentration of free chloride ion in micellar solutions. The Stern–Volmer plot gave a distinct break at critical micelle concentration (CMC) due to the counterion binding to micelles. The estimated α and CMCs of cationic surfactants including fluorocarbon ones were in fair agreement with the reported experimental values. The MQAE has greater sensitivity to bromide ion of CTAB than chloride ion of CTAC. The α of 0.16 for CTAB micelles was almost constant up to 0.2 M CTAB at 35°C. The α values of CTAB micelles decreased with increasing the concentrations of CTAB and NaBr along with micellar growth

JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase (DGAT) 1 inhibitor, improves glucose metabolism in diet-induced obesity and genetic T2DM mice

AbstractType 2 diabetes mellitus (T2DM) arises primarily due to lifestyle factors and genetics. A number of lifestyle factors are known to be important in the development of T2DM, including obesity. JTT-553, a novel Acyl CoA:diacylglycerol acyltransferase 1 inhibitor, reduced body weight depending on dietary fat in diet-induced obesity (DIO) rats in our previous study. Here, the effect of JTT-553 on glucose metabolism was evaluated using body weight reduction in T2DM mice.JTT-553 was repeatedly administered to DIO and KK-Ay mice. JTT-553 reduced body weight gain and fat weight in both mouse models. In DIO mice, JTT-553 decreased insulin, non-esterified fatty acid (NEFA), total cholesterol (TC), and liver triglyceride (TG) plasma concentrations in non-fasting conditions. JTT-553 also improved insulin-dependent glucose uptake in adipose tissues and glucose intolerance in DIO mice. In KK-Ay mice, JTT-553 decreased glucose, NEFA, TC and liver TG plasma concentrations in non-fasting conditions. JTT-553 also decreased glucose, insulin, and TC plasma concentrations in fasting conditions. In addition, JTT-553 decreased TNF-α mRNA levels and increased GLUT4 mRNA levels in adipose tissues in KK-Ay mice.These results suggest that JTT-553 improves insulin resistance in adipose tissues and systemic glucose metabolism through reductions in body weight

Krafft temperature and enthalpy of solution of N-acyl amino acid surfactants and their racemic modifications: Effect of the amino acid residue

金沢大学工学部The Krafft temperatures and the enthalpies of solution of six kinds of N-hexadecanoyl amino acid surfactant (Gly, Ala, Val, Leu, Ile, and Phe) were obtained from both solubility measurements and differential scanning calorimetry. It was shown that the Krafft temperature of N-hexadecanoyl amino acid surfactant increased with decreasing size of the amino acid residue except for the case of phenylalanine. On the other hand, the enthalpy of solution was endothermic and increased with decreasing size of the amino acid residue except for the cases of glycine and phenylalanine. It was found from these results that the D-L interaction was superior to the L-L interaction in solid state of N-hexadecanoyl amino acid surfactant salt for both the alanine and phenylalanine systems. It was suggested by ab initio calculations that the difference of the magnitude of the peptide-peptide hydrogen bonding was the dominant factor for the chiral effect

Effect of the side chain of N-acyl amino acid surfactants on micelle formation: An isothermal titration calorimetry study

金沢大学大学院自然科学研究科物質情報解析The enthalpy of micelle formation, critical micelle concentration (CMC), and aggregation number of micelles for seven amino acid type surfactants, sodium N-dodecanoyl-glycinate (C12Gly), -l-alaninate (C12Ala), -l-valinate (C12Val), -l-leucinate (C12Leu), -l-phenylalaninate (C12Phe), -l-glutaminate (C12Gln), and -l-threoninate (C12Thr), were obtained at three temperatures ranging from 288.15 to 308.15 K by isothermal titration calorimetry. The enthalpies of micelle formation for these surfactants were positive at 288.15 K and decreased with increasing temperature to ultimately become negative above 308.15 K. The CMC of the amino acid surfactants decreased monotonously with increasing hydrophobicity of the amino acid residue without exception, while with the exception of the C12Phe system, the enthalpy of micelle formation increased. The micellization behavior of C12Phe also deviated from that of other amino acid systems in terms of the heat capacity and the aggregation number. These results suggest the presence of a strong intra-micelle interaction between the side chains of phenylalanine. © 2007 Elsevier B.V. All rights reserved