Turbulence Transition in Magnetically Confined Hydrogen and Deuterium Plasmas.

In this study, we discovered a turbulence transition in a large helical device. The turbulence level and turbulence-driven energy transport decrease to a specific transition density and increase above it. The ruling turbulences below and above the transition density were ion-temperature gradient (ITG) and resistive-interchange (RI) turbulences, consistent with the predictions of gyrokinetic theory and two-fluid MHD model, respectively. Isotope experiments on hydrogen (H) and deuterium (D) clarified the role of transitions. In the ITG regime, turbulence levels and energy transport were comparable in the H and D plasmas. In contrast, in the RI regime, they were clearly suppressed in the D plasma. The results provide crucial knowledge for understanding isotope effects and future optimization of stellarator and heliotron devices.

Impact of Magnetic Field Configuration on Heat Transport in Stellarators and Heliotrons.

We assess the magnetic field configuration in modern fusion devices by comparing experiments with the same heating power, between a stellarator and a heliotron. The key role of turbulence is evident in the optimized stellarator, while neoclassical processes largely determine the transport in the heliotron device. Gyrokinetic simulations elucidate the underlying mechanisms promoting stronger ion scale turbulence in the stellarator. Similar plasma performances in these experiments suggests that neoclassical and turbulent transport should both be optimized in next step reactor designs.

Effect of body posture on chewing behaviours in healthy volunteers.

Mastication is essential to the eating process and forms an important part of feeding behaviour. Many factors related to the food bolus, such as bolus texture and size, are known to influence mastication. The aim of this study was to determine the effects of body posture on (i) chewing duration prior to the first swallow and (ii) patterns of mastication-related EMG activity. We asked 10 healthy adults to chew 8 g of steamed rice with barium sulphate while we recorded masseter, suprahyoid and infrahyoid muscle activity and simultaneously collected videofluorographic images. Participants chewed in either an upright or reclining position. Chewing duration, which was defined as the time from the start of mastication to the first swallow, was not different between the positions. However, the variability of chewing duration was larger in the upright versus reclining position, and the chewing duration in the reclining position was distributed around 15 s. Masseter activity gradually decreased in a time-dependent manner and was significantly larger at the early versus late stage of mastication. Suprahyoid activity was significantly larger at the early versus middle stage of mastication in the upright position only. Finally, masseter activity per second was negatively correlated with changes in chewing duration, that is, the larger the increase in chewing duration in the reclining position, the more the decrease in masseter activity per second. These results suggest that position-dependent changes in chewing behaviours, as described by chewing duration and EMG activity, may vary among participants.

Receiver circuit improvement of dual frequency-comb ka-band Doppler backscattering system in the large helical device (LHD).

Doppler-backscattering (DBS) has been used in several fusion plasma devices because it can measure the perpendicular velocity of electron density perturbation v⊥, the radial electric field Er, and the perpendicular wavenumber spectrum S(k⊥) with high wavenumber and spatial resolution. In particular, recently constructed frequency comb DBS systems enable observation of turbulent phenomena at multiple observation points in the radial direction. A dual-comb microwave DBS system has been developed for the large helical device plasma measurement. Since it is desirable to control the gain of each frequency-comb separately, a frequency-comb DBS system was developed with a function to adjust the gain of the scattered signal intensity of each channel separately. A correction processing method was also developed to correct the amplitude ratio and the phase difference between the in-phase and quadrature-phase signals of the scattered signals. As a result, the error in Doppler-shift estimation required to observe vertical velocity and the radial electric field was reduced, which enables more precise measurements.

Hydrogen isotope effect on self-organized electron internal transport barrier criticality and role of radial electric field in toroidal plasmas.

Self-organized structure formation in magnetically confined plasmas is one of the most attractive subjects in modern experimental physics. Nonequilibrium media are known to often exhibit phenomena that cannot be predicted by superposition of linear theories. One representative example of such phenomena is the hydrogen isotope effect in fusion plasmas, where the larger the mass of the hydrogen isotope fuel is the better the plasma confinement becomes, contrary to what simple scaling models anticipate. In this article, threshold condition of a plasma structure formation is shown to have a strong hydrogen isotope effect. To investigate the underlying mechanism of this isotope effect, the electrostatic potential is directly measured by a heavy ion beam probe. It is elucidated that the core electrostatic potential transition occurs with less input power normalized by plasma density in plasmas with larger isotope mass across the structure formation. This observation is suggestive of the isotope effect in the radial electric field structure formation.

W-band millimeter-wave back-scattering system for high wavenumber turbulence measurements in LHD.

A 90 GHz W-band millimeter-wave back-scattering system is designed and installed for measuring electron scale turbulence (k⊥ρs ∼ 40). A metal lens relay antenna is used for in-vessel beam focusing, and a beam diameter of less than 40 mm is achieved in the plasma core region. This antenna can be steered at an angle of 159° ± 6°, which almost covers the plasma radius. The estimated size of the scattering volume is ∼105 mm at the edge and 135 mm at the core, respectively. A 60 m corrugated waveguide is used to achieve a low transmission loss of ∼8 dB. A heterodyne detection system for millimeter-wave circuits with probing power modulation can distinguish the scattered signal from background noise.

IkappaB kinase alpha is essential for mature B cell development and function.

IkappaB kinase (IKK) alpha and beta phosphorylate IkappaB proteins and activate the transcription factor, nuclear factor (NF)-kappaB. Although both are highly homologous kinases, gene targeting experiments revealed their differential roles in vivo. IKKalpha is involved in skin and limb morphogenesis, whereas IKKbeta is essential for cytokine signaling. To elucidate in vivo roles of IKKalpha in hematopoietic cells, we have generated bone marrow chimeras by transferring control and IKKalpha-deficient fetal liver cells. The mature B cell population was decreased in IKKalpha(-/-) chimeras. IKKalpha(-/-) chimeras also exhibited a decrease of serum immunoglobulin basal level and impaired antigen-specific immune responses. Histologically, they also manifested marked disruption of germinal center formation and splenic microarchitectures that depend on mature B cells. IKKalpha(-/-) B cells not only showed impairment of survival and mitogenic responses in vitro, accompanied by decreased, although inducible, NF-kappaB activity, but also increased turnover rate in vivo. In addition, transgene expression of bcl-2 could only partially rescue impaired B cell development in IKKalpha(-/-) chimeras. Taken together, these results demonstrate that IKKalpha is critically involved in the prevention of cell death and functional development of mature B cells.

Impairment of natural killer cytotoxic activity and interferon gamma production in CCAAT/enhancer binding protein gamma-deficient mice.

We have investigated in vivo roles of CCAAT/enhancer binding protein gamma (C/EBPgamma) by gene targeting. C/EBPgamma-deficient (C/EBPgamma(2/-)) mice showed a high mortality rate within 48 h after birth. To analyze the roles of C/EBPgamma in lymphoid lineage cells, bone marrow chimeras were established. C/EBPgamma(2/-) chimeras showed normal T and B cell development. However, cytolytic functions of their splenic natural killer (NK) cells after stimulation with cytokines such as interleukin (IL)-12, IL-18, and IL-2 were significantly reduced as compared with those of control chimera NK cells. In addition, the ability of C/EBPgamma(-/-) chimera splenocytes to produce interferon (IFN)-gamma in response to IL-12 and/or IL-18 was markedly impaired. NK cells could be generated in vitro with normal surface marker expression in the presence of IL-15 from C/EBPgamma(2/-) newborn spleen cells. However, they also showed lower cytotoxic activity and IFN-gamma production when stimulated with IL-12 plus IL-18 than control NK cells, as observed in C/EBPgamma(2/-) chimera splenocytes. In conclusion, our study reveals that C/EBPgamma is a critical transcription factor involved in the functional maturation of NK cells.

The absence of interleukin 1 receptor-related T1/ST2 does not affect T helper cell type 2 development and its effector function.

T1/ST2, an orphan receptor with homology with the interleukin (IL)-1 receptor family, is expressed constitutively and stably on the surface of T helper type 2 (Th2) cells, but not on Th1 cells. T1/ST2 is also expressed on mast cells, which are critical for Th2-mediated effector responses. To evaluate whether T1/ST2 is required for Th2 responses and mast cell function, we have generated T1/ST2-deficient (T1/ST2(-/-)) mice and examined the roles of T1/ST2. Naive CD4(+) T cells isolated from T1/ST2(-/-) mice developed to Th2 cells in response to IL-4 in vitro. T1/ST2(-/-) mice showed normal Th2 responses after infection with the helminthic parasite Nippostrongylus brasiliensis as well as in the mouse model of allergen-induced airway inflammation. In addition, differentiation and function of bone marrow-derived cultured mast cells were unaffected. These findings demonstrate that T1/ST2 does not play an essential role in development and function of Th2 cells and mast cells.

Limb and skin abnormalities in mice lacking IKKalpha.

The gene encoding inhibitor of kappa B (IkappaB) kinase alpha (IKKalpha; also called IKK1) was disrupted by gene targeting. IKKalpha-deficient mice died perinatally. In IKKalpha-deficient fetuses, limb outgrowth was severely impaired despite unaffected skeletal development. The epidermal cells in IKKalpha-deficient fetuses were highly proliferative with dysregulated epidermal differentiation. In the basal layer, degradation of IkappaB and nuclear localization of nuclear factor kappa B (NF-kappaB) were not observed. Thus, IKKalpha is essential for NF-kappaB activation in the limb and skin during embryogenesis. In contrast, there was no impairment of NF-kappaB activation induced by either interleukin-1 or tumor necrosis factor-alpha in IKKalpha-deficient embryonic fibroblasts and thymocytes, indicating that IKKalpha is not essential for cytokine-induced activation of NF-kappaB.

Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy.

The zinc finger protein glioma-associated oncogene homologue 1 (Gli-1) is a critical component of the Hedgehog (Hh) signalling pathway, which is essential for morphogenesis and stem-cell renewal, and is dysregulated in many cancer types. As data were not available on the role of Gli-1 expression in oesophageal cancer progression, we analysed whether it could be used to predict disease progression and prognosis in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy (CRT). Among 69 patients with histologically confirmed oesophageal squamous cell carcinomas (ESCCs), 25 showed a pathological complete response after preoperative CRT. Overall survival (OS) was significantly associated with lymph-node metastasis, distant metastasis, and CRT, and was further correlated with the absence of both Gli-1 nuclear expression and residual tumour. All patients with Gli-1 nuclear expression (10.1%) had distant or lymph-node metastasis, and six out of seven died within 13 months. Furthermore, patients with Gli-1 nuclear-positive cancers showed significantly poorer prognoses than those without (disease-free survival: mean DFS time 250 vs 1738 months, 2-year DFS 0 vs 54.9%, P=0.009; OS: mean OS time 386 vs 1742 months, 2-year OS 16.7 vs 54.9%, P=0.001). Our study provides the first evidence that Gli-1 nuclear expression is a strong and independent predictor of early relapse and poor prognosis in ESCC after CRT. These findings suggest that Hh signal activation might promote cancer regrowth and progression after CRT.

Cold thermal oral stimulation produces immediate excitability in human pharyngeal motor cortex.

BACKGROUND: Current strategies of swallowing therapy include facilitation of swallowing initiation by sensory modulation. Although thermal tactile oral stimulation is a common method to treat dysphagic patients to improve swallowing movement, little is known about the possible mechanisms. This study is aimed to investigate whether thermal oral (tongue) stimulation can modulate the cortico-pharyngeal neural motor pathway in humans. METHODS: Eighteen healthy volunteers participated and were intubated with an intraluminal catheter for recording pharyngeal electromyography. Each participant underwent baseline transcranial magnetic stimulation (TMS) cortico-pharyngeal motor evoked potential (MEP) measurements bilaterally. MEPs were then measured during thermal stimulation over the dorsal tongue, applied using the Peltier device at three different temperatures; 45°C, 37°C, and 15°C, in a pre-ordered manner. Each of the three temperatures was given twice with a 5-min resting time between each trial. Averaged MEP amplitude changes were analyzed using ANOVA and post-hoc t-tests. KEY RESULTS: Two-way repeated measures ANOVA with factors of Temperature × Trial in amplitude of MEP demonstrated a significant effect of Temperature both in the stronger (F2,34  = 5.775, P = .007) and weaker (F2,34  = 4.771, P = .017) pharyngeal hemispheres. Subsequent post-hoc tests showed the significant increase in pharyngeal MEPs at 15° compared to 37° in both hemispheres (P < .05). CONCLUSIONS & INFERENCES: Cold oral stimulation was able to induce significant changes in pharyngeal cortical excitability, demonstrating evidence for a sensorimotor interaction between oral and pharyngeal cortical areas.

Microwave frequency comb Doppler reflectometer applying fast digital data acquisition system in LHD.

We succeeded in increasing the radial observation points of the microwave frequency comb Doppler reflectometer system from 8 to 20 (or especially up to 45) using the high sampling rate of 40 GS/s digital signal processing. For a new acquisition system, the estimation scheme of the Doppler shifted frequency is constructed and compared with the conventional technique. Also, the fine radial profile of perpendicular velocity is obtained, and it is found that the perpendicular velocity profile is consistent with the E × B drift velocity one.

Identification of mutations in the coding sequence of the proto-oncogene c-kit in a human mast cell leukemia cell line causing ligand-independent activation of c-kit product.

The c-kit proto-oncogene encodes a receptor tyrosine kinase. Binding of c-kit ligand, stem cell factor (SCF) to c-kit receptor (c-kitR) is known to activate c-kitR tyrosine kinase, thereby leading to autophosphorylation of c-kitR on tyrosine and to association of c-kitR with substrates such as phosphatidylinositol 3-kinase (PI3K). In a human mast cell leukemia cell line HMC-1, c-kitR was found to be constitutively phosphorylated on tyrosine, activated, and associated with PI3K without the addition of SCF. The expression of SCF mRNA transcript in HMC-1 cells was not detectable by means of PCR after reverse transcription (RT-PCR) analysis, suggesting that the constitutive activation of c-kitR was ligand independent. Sequencing of whole coding region of c-kit cDNA revealed that c-kit genes of HMC-1 cells were composed of a normal, wild-type allele and a mutant allele with two point mutations resulting in intracellular amino acid substitutions of Gly-560 for Val and Val-816 for Asp. Amino acid sequences in the regions of the two mutations are completely conserved in all of mouse, rat, and human c-kit. In order to determine the causal role of these mutations in the constitutive activation, murine c-kit mutants encoding Gly-559 and/or Val-814, corresponding to human Gly-560 and/or Val-816, were constructed by site-directed mutagenesis and expressed in a human embryonic kidney cell line, 293T cells. In the transfected cells, both c-kitR (Gly-559, Val-814) and c-kitR (Val-814) were abundantly phosphorylated on tyrosine and activated in immune complex kinase reaction in the absence of SCF, whereas tyrosine phosphorylation and activation of c-kitR (Gly-559) or wild-type c-kitR was modest or little, respectively. These results suggest that conversion of Asp-816 to Val in human c-kitR may be an activating mutation and responsible for the constitutive activation of c-kitR in HMC-1 cells.

Novel analysis technique for measuring edge density fluctuation profiles with reflectometry in the Large Helical Device.

A new method for measuring density fluctuation profiles near the edge of plasmas in the Large Helical Device (LHD) has been developed utilizing reflectometry combined with pellet-induced fast density scans. Reflectometer cutoff location was calculated by proportionally scaling the cutoff location calculated with fast far infrared laser interferometer (FIR) density profiles to match the slower time resolution results of the ray-tracing code LHD-GAUSS. Plasma velocity profile peaks generated with this reflectometer mapping were checked against velocity measurements made with charge exchange spectroscopy (CXS) and were found to agree within experimental uncertainty once diagnostic differences were accounted for. Measured density fluctuation profiles were found to peak strongly near the edge of the plasma, as is the case in most tokamaks. These measurements can be used in the future to inform inversion methods of phase contrast imaging (PCI) measurements. This result was confirmed with both a fixed frequency reflectometer and calibrated data from a multi-frequency comb reflectometer, and this method was applied successfully to a series of discharges. The full width at half maximum of the turbulence layer near the edge of the plasma was found to be only 1.5-3 cm on a series of LHD discharges, less than 5% of the normalized minor radius.

Intraperitoneal injection of oxygenated perfluorochemical improves the outcome of intraportal islet transplantation in a rat model.

A 50% to 75% early graft loss upon engraftment has been suggested to in intraportal islet transplantation (IPIT). Hypoxia in the portal vein contributes to graft loss in immediately posttransplantation. Herein we examined the effect on the outcome of IPIT of intraperitoneal oxygenated perfluorochemical (PFC) as an oxygen carrier. Isolated Lewis rat islets were transplanted into the portal vein of a chemically induced diabetic syngeneic rat. First, 1500 IEQ was determined to be the optimal dose in this study. When oxygenated PFC (group 1) was intraperitoneally injected following IPIT of 1500 IEQ, the success rate of transplantation was 5/6, in contrast to 1/6 when PFC with no oxygen was injected (group 2) and 1/6 in IPIT without PFC, respectively. The area under the glucose profile curve on intraperitoneal glucose tolerance tests on posttransplant day 28 in group 1 was significantly smaller than that for group 2. In conclusion, intraperitoneal oxygenated PFC improved the outcome of IPIT.

A role of interferon-gamma (IFN-gamma) in tumor immunity: T cells with the capacity to reject tumor cells are generated but fail to migrate to tumor sites in IFN-gamma-deficient mice.

IFN-gamma-deficient (IFN-gamma-/-) mice induce potent in vitro immune responses such as anti-allo mixed lymphocyte reaction and CTL responses, whereas they often fail to exhibit in vivo immunity. Here, we investigated whether there exists a defect in tumor rejection responses and if so, which process of responses is impaired. IFN-gamma-/- and wild-type (WT) BALB/c mice were immunized with attenuated syngeneic CSA1M tumor cells. The capacity of T cells to mediate tumor protection was examined in Winn assays to assess the growth of tumor cells admixed with tumor-sensitized T cells. Splenic T cells from both groups of mice exhibited comparable levels of tumor-neutralizing activity. When portions of immunized mice were directly challenged with viable tumor cells, tumor rejection was induced only in WT mice. CD4(+) and CD8(+) T-cell infiltration were observed at the site of tumor challenge in WT mice, whereas such a T-cell infiltration did not occur in IFN-gamma-/- mice. Similarly, splenic T cells from interleukin 12-treated CSA1M-bearing IFN-gamma-/- and WT mice neutralized tumor cells at comparable efficacies in Winn assays. However, the migration of these T cells to tumor masses and the resultant interleukin 12-induced tumor regression took place in WT mice, but neither intratumoral T-cell infiltration nor tumor regression occurred in IFN-gamma-/- mice. These results indicate a critical requirement for IFN-gamma in the process of inducing T-cell migration to tumor sites rather than of generating antitumor protective T cells.

bcl-2 deficiency in mice leads to pleiotropic abnormalities: accelerated lymphoid cell death in thymus and spleen, polycystic kidney, hair hypopigmentation, and distorted small intestine.

Transgenic mice homozygously lacking in the bcl-2 gene were generated using homologous recombination in embryonal stem cells. The complete absence of Bcl-2 alpha and -beta proteins did not interfere with normal embryonic development. Abnormalities became evident after birth, although the severity varied among homozygous null mice, bcl-2-/- mice displayed pleiotropic abnormalities similar to those in the previously described bcl-2-/- mice, including growth retardation, smaller ears, short lives, polycystic kidney, atrophic thymus and spleen with accelerated apoptotic cell death of lymphocytes, and hair hypopigmentation in the second hair follicle cycle. Our bcl-2-/- mice also revealed novel defects in the small intestine, characterized by retarded development, accelerated exfoliation of epithelial cells, and very few mitotic progenitor cells.

A critical role for a peritumoral stromal reaction in the induction of T-cell migration responsible for interleukin-12-induced tumor regression.

Interleukin (IL) 12 has been shown to elicit tumor regression when this cytokine induces the migration of T cells to tumor sites. The present study investigates the role of a peritumoral stromal reaction in IL-12-induced T-cell migration. In the CSA1M and OV-HM tumor models, IL-12 treatment induced tumor regression that is associated with T-cell migration. Neither T-cell migration nor tumor regression was observed in the Meth A and MCH-1-A1 models. Stromal tissue containing neovascular blood vessels developed at the peritumoral area of the former two IL-12-responsive tumors but not at the peritumoral area of the latter two IL-12-unresponsive tumors. The significance of stroma development was investigated using a pair of tumor models (CSA1M and a subline derived from CSA1M designated the CSA1M variant), both of which exhibit the same tumor immunogenicity. In contrast to the parental CSA1M cell line, the variant cell line was not responsive to IL-12, and neither stroma development nor T-cell migration was observed, even after IL-12 treatment. Histological analyses revealed that the parental cell line had peritumoral stroma with intrastromal vessels but only a few vessels in tumor parenchyma, whereas the variant cell line showed no stroma but had abundant vasculature in the tumor parenchyma. Most importantly, only stromal vessels in the parental tumors expressed detectable and enhanced levels of vascular cell adhesion molecule 1 (VCAM-1)/ intercellular adhesion molecule 1 (ICAM-1) before and after IL-12 treatment, respectively. In contrast, parenchymal vasculature in the variant cell line failed to express VCAM-1/ICAM-1 even after IL-12 treatment. When transferred into recipient tumor-bearing mice, IL-12-stimulated T cells from the parental CSA1M-bearing or the variant CSA1M-bearing mice migrated into the parental but not into the variant tumor mass. Together with our previous finding that T-cell migration depends on the VCAM-1/ICAM-1 adhesive interactions, the present results indicate a critical role for peritumoral stroma/stromal vasculature in the acceptance of tumor-infiltrating T cells that is a prerequisite for IL-12-induced tumor regression.

Multiple roles of interferon-gamma in the mediation of interleukin 12-induced tumor regression.

Administration of recombinant interleukin 12 (IL-12) induces tumor regression that is associated with T-cell infiltration in the OV-HM ovarian carcinoma and CSA1M fibrosarcoma models. After confirming the blocking of regression by injection of anti-IFN-gamma monoclonal antibody (mAb), we investigated the mechanisms underlying the requirement of IFN-gamma in T-cell migration and tumor regression. T-cell migration was inhibited by injection of anti-IFN-gamma mAb to OV-HM tumor-bearing mice prior to IL-12 treatment. We examined, using the lymphoid cell migration assay, whether IFN-gamma is required for enhancing the migratory capacity of T cells or the T cell-accepting potential of tumor masses during IL-12 treatment. Spleen cells from IL-12-treated or untreated OV-HM-bearing mice were stained in vitro with a fluorescein chemical and transferred i.v. into OV-HM-bearing mice that were not treated with IL-12. Migration of donor cells was quantitated by counting the number of fluorescent cells on cryostat sections of tumor masses from recipient mice. Compared to spleen cells from OV-HM-bearing mice that were not treated with IL-12, enhanced migration was observed for cells from IL-12-treated OV-HM-bearing mice. Anti-IFN-gamma pretreatment of donor mice before IL-12 treatment did not reduce the migratory capacity of T cells, whereas migration was markedly inhibited in recipient mice injected with anti-IFN-gamma. Anti-IFN-gamma pretreatment decreased vascular cell adhesion molecule-1 (VCAM-1)-/intercellular adhesion molecule-1 (ICAM-1)-positive blood vessels at tumor sites. Consistent with this, migration was also inhibited by treatment of recipient mice with either anti-VCAM-1 or anti-ICAM-1 mAb. In contrast to the OV-HM model, T-cell migration was not affected in the CSA1M model following preinjection of anti-IFN-gamma mAb. In this model, VCAM-1-/ICAM-1-positive blood vessels existed even after anti-IFN-gamma treatment, although tumor regression was completely inhibited. These results indicate that IFN-gamma plays two distinct roles in expressing the antitumor efficacy of IL-12: one is to support the T-cell acceptability of tumor masses, and the other is to mediate the antitumor effects of migrated T cells.