First measurements of an imaging heavy ion beam probe at the ASDEX Upgrade tokamak.

The imaging heavy ion beam probe (i-HIBP) diagnostic has been successfully commissioned at ASDEX Upgrade. The i-HIBP injects a primary neutral beam into the plasma, where it is ionized, leading to a fan of secondary (charged) beams. These are deflected by the magnetic field of the tokamak and collected by a scintillator detector, generating a strike-line light pattern that encodes information on the density, electrostatic potential, and magnetic field of the plasma edge. The first measurements have been made, demonstrating the proof-of-principle of this diagnostic technique. A primary beam of 85/87Rb has been used with energies ranging between 60 and 72 keV and extracted currents up to 1.5 mA. The first signals have been obtained in experiments covering a wide range of parameter spaces, with plasma currents (Ip) between 0.2 and 0.8 MA and on-axis toroidal magnetic field (Bt) between 1.9 and 2.7 T. Low densities appear to be critical for the performance of the diagnostic, as signals are typically observed only when the line integrated density is below 2.0-3.0 × 1019 m-2 in the central interferometer chord, depending on the plasma shape. The strike line moves as expected when Ip is ramped, indicating that current measurements are possible. Additionally, clear dynamics in the intensity of the strike line are often observed, which might be linked to changes in the edge profile structure. However, the signal-to-background ratio of the signals is hampered by stray light, and the image guide degradation is due to neutron irradiation. Finally, simulations have been carried out to investigate the sensitivity of the expected signals to plasma density and temperature. The results are in qualitative agreement with the experimental observations, suggesting that the diagnostic is almost insensitive to fluctuations in the temperature profile, while the signal level is highly determined by the density profile due to the beam attenuation.

Implementation of synthetic fast-ion loss detector and imaging heavy ion beam probe diagnostics in the 3D hybrid kinetic-MHD code MEGA.

A synthetic fast-ion loss (FIL) detector and an imaging Heavy Ion Beam Probe (i-HIBP) have been implemented in the 3D hybrid kinetic-magnetohydrodynamic code MEGA. First synthetic measurements from these two diagnostics have been obtained for neutral beam injection-driven Alfvén Eigenmode (AE) simulated with MEGA. The synthetic FILs show a strong correlation with the AE amplitude. This correlation is observed in the phase-space, represented in coordinates (Pϕ, E), being toroidal canonical momentum and energy, respectively. FILs and the energy exchange diagrams of the confined population are connected with lines of constant E', a linear combination of E and Pϕ. First i-HIBP synthetic signals also have been computed for the simulated AE, showing displacements in the strike line of the order of ∼1 mm, above the expected resolution in the i-HIBP scintillator of ∼100 µm.

In Vitro Cytotoxicity of Zinc Fructoborate, a Novel Zinc-Boron Active Natural Complex.

In recent years, the role of zinc in biological systems has been a subject of intense research. Zinc is required for multiple metabolic processes as a structural, regulatory, or catalytic ion. The objective of this study, was to assess the toxicity profile of a newly synthesized zinc-boron molecule on cultured cells. Zinc fructoborate, at different levels of concentration, was tested for its impact on the Vero kidney cell line (ATCC® CCL-81™) using the MTT assay. The compound exhibited a low cytotoxic effect on the cell line. Thus, our study demonstrates that the zinc fructoborate could become a promising dietary supplement molecule.

Field-Line Localized Destabilization of Ballooning Modes in Three-Dimensional Tokamaks.

Field-line localized ballooning modes have been observed at the edge of high confinement mode plasmas in ASDEX Upgrade with rotating 3D perturbations induced by an externally applied n=2 error field and during a moderate level of edge localized mode mitigation. The observed ballooning modes are localized to the field lines which experience one of the two zero crossings of the radial flux surface displacement during one rotation period. The localization of the ballooning modes agrees very well with the localization of the largest growth rates from infinite-n ideal ballooning stability calculations using a realistic 3D ideal magnetohydrodynamic equilibrium. This analysis predicts a lower stability with respect to the axisymmetric case. The primary mechanism for the local lower stability is the 3D distortion of the local magnetic shear.

A compact lithium pellet injector for tokamak pedestal studies in ASDEX Upgrade.

Experiments have been performed at ASDEX Upgrade, aiming to investigate the impact of lithium in an all-metal-wall tokamak and attempting to enhance the pedestal operational space. For this purpose, a lithium pellet injector has been developed, capable of injecting pellets carrying a particle content ranging from 1.82 × 10(19) atoms (0.21 mg) to 1.64 × 10(20) atoms (1.89 mg). The maximum repetition rate is about 2 Hz. Free flight launch from the torus outboard side without a guiding tube was realized. In such a configuration, angular dispersion and speed scatter are low, and a transfer efficiency exceeding 90% was achieved in the test bed. Pellets are accelerated in a gas gun; hence special care was taken to avoid deleterious effects by the propellant gas pulse. Therefore, the main plasma gas species was applied as propellant gas, leading to speeds ranging from 420 m/s to 700 m/s. In order to minimize the residual amount of gas to be introduced into the plasma vessel, a large expansion volume equipped with a cryopump was added into the flight path. In view of the experiments, an optimal propellant gas pressure of 50 bars was chosen for operation, since at this pressure maximum efficiency and low propellant gas flux coincide. This led to pellet speeds of 585 m/s ± 32 m/s. Lithium injection has been achieved at ASDEX Upgrade, showing deep pellet penetration into the plasma, though pedestal broadening has not been observed yet.

Experimental Validation of a Filament Transport Model in Turbulent Magnetized Plasmas.

In a wide variety of natural and laboratory magnetized plasmas, filaments appear as a result of interchange instability. These convective structures substantially enhance transport in the direction perpendicular to the magnetic field. According to filament models, their propagation may follow different regimes depending on the parallel closure of charge conservation. This is of paramount importance in magnetic fusion plasmas, as high collisionality in the scrape-off layer may trigger a regime transition leading to strongly enhanced perpendicular particle fluxes. This work reports for the first time on an experimental verification of this process, linking enhanced transport with a regime transition as predicted by models. Based on these results, a novel scaling for global perpendicular particle transport in reactor relevant tokamaks such as ASDEX-Upgrade and JET is found, leading to important implications for next generation fusion devices.

Method for estimating the propagation direction of a coherent plasma structure using a one-dimensional diagnostic array.

This article proposes a new method to evaluate basic characteristics of the dynamics of a coherent plasma structure (blob). With this method, one can evaluate the propagation angle of a blob in a two-dimensional plasma cross section as well as the blob velocity, size, and amplitude from one-dimensional data. The method is applied to blob measurements from the Lithium beam emission spectroscopy system in ASDEX-Upgrade. Statistical features of the observed blob velocities, angles of propagation, blob sizes, and amplitudes are discussed. The validity of the method is examined by comparing two values of the propagation angle that are evaluated in an independent manner.

Experimental evidence of turbulent transport regulation by zonal flows.

The regulation of turbulent transport by zonal flows is studied experimentally on a flux surface of the stellarator experiment TJ-K. Data of 128 Langmuir probes at different toroidal and poloidal positions on a single flux surface enable us to measure simultaneously the zonal flow activity and the turbulent transport in great detail. A reduction of turbulent transport by 30% during the zonal flow phase is found. It is shown that the reduction process is initiated by a modification in the cross phase between density and electric field followed by a reduction in the fluctuation levels, which sustain low transport levels on larger time scales than the zonal flow lifetime.

Experimental investigation of the magnetic configuration dependence of turbulent transport.

The dependence of turbulent transport on magnetic field properties is measured in detail on a plasma in a stellarator configuration. Pronounced poloidal asymmetries of fluctuation amplitudes and turbulent transport are observed. The transport maximum is located in regions where normal curvature of the magnetic field is negative and simultaneously the geodesic curvature has positive values. A major role of the local magnetic shear cannot be confirmed. The results can have important implications for the optimization of stellarators and the power influx into the scrape-off layer.

Observation of anomalous ion heating by broadband drift-wave turbulence.

Using laser induced fluorescence and passive spectroscopy on a magnetically confined low-temperature plasma, anomalous ion heating is observed which exceeds collisional heating from the electrons by a factor of up to five. Direct wave heating due to the 2.45 GHz microwave as well as stochastic heating by large-amplitude fluctuations could be ruled out as explanations. Good quantitative agreement is found when comparing the missing power in the ion species with heating power due to the dissipation of drift-wave turbulence. This turbulent energy transfer into the ion channel could have important consequences for the interpretation of transport in fusion plasmas.

Plasma levels of transforming growth factor-1beta and alpha2-macroglobulin before and after radical prostatectomy: association to clinicopathological parameters.

BACKGROUND: To study the levels of transforming growth factor-1beta (TGF-beta1) and of alpha2-macroglobulin (alpha2-M), a high affinity binding protein of TGF-beta1, in comparison to prostate-specific antigen (PSA) in prostate cancer (PCa) patients before and up to 12 months after prostatectomy, and to correlate the results with clinicopathological parameters. METHODS: Eighty-one patients who underwent radical prostatectomy for PCa were included in this study. Pre- and postoperatively, plasma levels of TGF-beta1, alpha2-M and PSA were measured in the same samples by ELISA, and were correlated with pathological parameters and clinical outcomes. RESULTS: The preoperative TGF-beta1 levels were significantly elevated as compared to the controls; they showed a positive correlation with the Gleason score. Patients with initial androgen-deprivation therapy had lower TGF-beta1 levels than untreated patients. Elevated concentrations of TGF-beta1 levelled off 12 months after prostatectomy approaching values of healthy individuals. Decreased plasma levels of total and transformed alpha2-M (proteinase-complexed form) were observed in PCa. Preoperative levels of TGF-beta1 but not of alpha2-M seem to be influenced by the body mass index (BMI). CONCLUSIONS: Elevated TGF-beta1 and decreased alpha2-M were consistently found in patients with PCa, and may be considered as risk factors for tumor development and progression. In comparison to PSA, the TGF-beta1 levels displayed a slow decline after radical prostatectomy; this indicates that TGF-beta1 is mainly produced outside the prostatic tissue. Since TGF-beta1 levels are influenced by the BMI, this indicates that PCa might be sensitive to diet.

Human alpha2-macroglobulin: genotype-phenotype relation.

A pentanucleotide deletion polymorphism in the gene of alpha2-macrolgobulin (alpha2-M) is suggested to be associated with late-onset Alzheimer's disease (AD), though controversial results have been reported. The underlying assumption is that the intronic pentanucleotide deletion may affect the biological function and quantity of the inhibitor and thus contribute to the AD pathology. In the present study we have analyzed the distribution of the deletion polymorphism within a group of 227 healthy Caucasians. In parallel studies, we determined the plasma concentrations of total and transformed alpha2-M. A strong correlation of the total concentration of alpha2-M with age was ascertained (r(s) = -0.54, P < 0.001). However, no significant correlation between age and the genotypes (P = 0.68) was detected, and no statistically significant effect of the genotype on the concentrations of total and transformed alpha2-M was found (P = 0.49 and 0.96, respectively). A significant correlation was observed between total and transformed alpha2-M in the genotype groups Ins/Ins (r(s) = 0.56, P < 0.001) and Ins/Del (r(s) = 0.35, P < 0.004). Furthermore, in the entire data set, a significantly elevated concentration of total alpha2-M was found in females as compared to males (P = 0.003). There was a slight but nonsignificant difference in the genotype distributions between males and females (P = 0.14). To test the proposed existence of genotype-specific alterations of functional properties of alpha2-M, we isolated alpha2-M from the plasma of carriers with different genetic background and analyzed the alpha2-M subunit structure as well as the binding of the inhibitor to growth factors/cytokines, to amyloid-beta and to the receptor. The experiments failed to reveal any genotype-specific functional alterations of the alpha2-M. The absence of abnormalities in alpha2-M mRNA and protein suggests that the alpha2-M deletion polymorphism is probably not associated with functional deficiencies important in AD pathology. However, it can be speculated that the observed general age-related alpha2-M deficiency may lead to accelerated accumulation of amyloid-beta, which might be relevant to AD pathology.

Localization of alpha(2)-macroglobulin receptor/low-density lipoprotein receptor in third-trimester human placentas: a preliminary immunohistochemical study.

The alpha(2)-macroglobulin receptor/low-density lipoprotein receptor-related protein (alpha(2)-M-R/LRP) is involved in a variety of transcellular transportations, e.g. of apolipoprotein E, and represents an inhibitor of proteinases. After creation of monoclonal antibodies of the alpha- and beta-subunits of the alpha(2)-M-R/LRP and its receptor-associated protein, we have tested their distribution in five 3rd-trimester placentas, using cryosections, immunohistochemically and by immunofluorescence. All three monoclonal antibodies showed positive staining in villous and extravillous cytotrophoblasts and intravillous vessels, but not in syncytiotrophoblasts. Thus, alpha(2)-M-R/LRP plays a possible role in the transplacental nutritional transportation process. It is necessary to search the distribution of alpha(2)-M-R/LRP under pathological conditions, like fetal growth retardation and preeclampsia.

Modulation of growth factor binding properties of alpha2-macroglobulin by enzyme therapy.

PURPOSE: To investigate the binding of transforming growth factor-beta (TGF-beta) to human alpha2-macroglobulin upon oral treatment of patients with proteases. METHODS: Volunteers were given a cocktail of active proteinases (Phlogenzym) composed of trypsin, bromelain and the additive rutoside orally over a period of 7 days at low dose followed by a bolus application. Before and after medication plasma was immediately withdrawn and binding of 125I-TGF-beta to the proteinase inhibitor alpha2-macroglobulin was determined by electrophoresis and gamma-counting. Cell culture experiments were performed to study the effect of transformed alpha2-macroglobulin on TGF-beta-stimulated proliferation of skin fibroblasts. RESULTS: Ingestion of proteinases was found to trigger the formation of intermediate forms of alpha2-macroglobulin displaying high affinity to TGF-beta. Maximum binding of TGF-beta was observed 1-2 h after bolus ingestion, and steadily levelled off with time. In vitro experiments demonstrated that complex formation of diverse proteinases (trypsin, alpha-chymotrypsin, bromelain and plasmin) with alpha2-macroglobulin conferred binding of 125I-TGF-beta, alpha2-Macroglobulin transformed by methylamine or proteinases was found to abolish the TGF-beta effect on fibroblasts in cell culture. CONCLUSIONS: Intestinal absorption of proteinases triggers the formation of TGF-beta binding species of alpha2-macroglobulin in blood. Mediated by this process high concentrations of TGF-beta might be reduced via enhanced clearance of alpha2-macroglobulin-TGF-beta complexes. Thus, proteinase therapy may have beneficial effects in treatment of fibrosis and certain cancers accompanied by excessively high TGF-beta concentrations.

Alpha 2-macroglobulin-mediated degradation of amyloid beta 1--42: a mechanism to enhance amyloid beta catabolism.

Peptides derived from proteolytic degradation of the amyloid precursor protein, e.g., amyloid beta (A beta), are considered to be central to the pathology of Alzheimer's disease (AD). Soluble A beta is present in measurable concentrations in cerebrospinal fluid and blood. There are indications that soluble A beta present in circulation can cross the blood-brain barrier via transcytosis mediated by brain capillary endothelial cells. It implies that A beta originating from circulation may contribute to vascular and parenchymal A beta deposition in AD. Enhancing of A beta catabolism mediated by proteolytic degradation or receptor-mediated endocytosis could be a key mechanism to maintain low concentrations of soluble A beta. To launch A beta clearance we have exploited the A beta-degrading activity of diverse alpha 2-macroglobulin (alpha 2-M)-proteinase complexes. Complexes with trypsin, alpha-chymotrypsin, and bromelain strongly degrade (125)I-A beta 1--42 whereas complexes with endogenous proteinases, e.g., plasmin and prostate-specific antigen, were not effective. A beta degradation by the complexes was not inhibited by alpha 1-antichymotrypsin and soybean trypsin inhibitor which normally would inactivate the free serine proteinases. A prerequisite for A beta degradation is its binding to specific binding sites in alpha 2-M that may direct A beta to the active site of the caged proteinase. Ex vivo, enhanced degradation of (125)I-A beta 1--42 in blood could be achieved upon oral administration of high doses of proteinases to volunteers. These results suggest that up-regulation of A beta catabolism could probably reduce the risk of developing AD by preventing A beta accumulation in brain and vasculature.

Protease administration decreases enhanced transforming growth factor-beta 1 content in isolated glomeruli of diabetic rats.

Overproduction of transforming growth factor (TGF)-beta 1 messenger RNA is of fundamental importance in the pathogenesis of diabetic nephropathy. In vitro studies have recently shown that the serine protease trypsin diminishes the enhanced TGF-beta 1-expression induced by advanced glycation end products. Moreover, proteolytic enzymes may accelerate the removal of TGF-beta 1 from renal tissue via a protease-induced activation of alpha 2-macroglobulin (alpha 2M). This activation results in the binding of numerous cytokines, including TGF-beta 1 and is followed by enhanced plasma clearance of the protease alpha 2M-cytokine complex. In the present study in streptozotocin-diabetic rats we investigated whether the administration of Phlogenzym, a fixed combination of the proteases trypsin and bromelain combined with the antioxidant rutosid, modulates renal hypertrophy and the formation of TGF-beta 1 in isolated glomeruli. Three weeks after induction of diabetes, renal hypertrophy developed with an enhanced kidney/body weight ratio. When compared with normal rats, an elevated content of intraglomerular TGF-beta 1 (44.25 +/- 21.9 vs. 71.1 +/- 23.4 ng/microgram DNA, p < 0.05) as well as fibronectin (2.62 +/- 0.49 vs. 3.42 +/- 0.62 ng/microgram DNA, p < 0.05) was observed. In the diabetic rats, treatment with intraperitoneal proteases prevented the rise of intraglomerular TGF-beta 1 content (34.9 +/- 22.2 ng/microgram DNA, p < 0.01) and attenuated the rise of fibronectin (3.03 +/- 1.12 ng/microgram DNA NS). Furthermore, a decrease in the kidney/body weight ratio (p < 0.01) was achieved. Protease administration did not affect blood glucose concentration and was without visible adverse effects.

Clearance mechanism of prostate specific antigen and its complexes with alpha2-macroglobulin and alpha1-antichymotrypsin.

PURPOSE: To investigate the rate of elimination of prostate specific antigen (PSA) and its complexes with human alpha2-macroglobulin (alpha2-M) and alpha1-antichymotrypsin (ACT) and to elucidate the role of the alpha2-macroglobulin-receptor/low density lipoprotein receptor-related protein (alpha2-M-R/LRP) in the clearance mechanism. MATERIALS AND METHODS: PSA and complexes of PSA with alpha2-M and ACT were prepared and radiolabeled with [125I]Na (Amersham, Braunschweig, Germany). Radiolabeled proteins were injected into rats and the elimination of radioactivity from circulation was measured by gamma-counting of 20 microL aliquots over time. After 30 minutes different organs were removed and the total radioactivity was counted. The elimination rate and distribution of PSA and PSA-complexes was studied in the absence and presence of an excess of transformed alpha2-M. RESULTS: Radiolabeled PSA is rapidly eliminated from circulation with an initial half-life of 6.4+/-2.1 minutes mainly due to extraction by the liver and kidney. The clearance is slightly inhibited by transformed alpha2-M. PSA-alpha2-M is solely eliminated by the liver with a half-life of 6.7+/-1 minutes. Uptake by the liver is competitively inhibited by transformed alpha2-M. PSA-ACT is eliminated by the liver and kidney with an initial half-life of 3.51+/-1.1 minutes. Transformed alpha2-M failed to inhibit the clearance of PSA-ACT. CONCLUSIONS: Free PSA and PSA-inhibitor complexes are removed from the circulation by different clearance mechanisms. The sites of metabolism of the different forms of PSA are different but include liver and kidney as main organs for uptake. There are indications that alpha2-M-R/LRP is involved in PSA elimination. Thus, factors which modulate the receptor function and expression as well as the concentration of its natural ligands may interfere with the steady state concentrations of different PSA forms in blood.

Epitope mapping of a monoclonal antibody directed against the alpha-subunit of phosphofructokinase-1 from Saccharomyces cerevisiae by screening phage display libraries.

Phosphofructokinase-1 from Saccharomyces cerevisiae is composed of two types of subunits, alpha and beta. Subunit-specific monoclonal antibodies were raised to elucidate structural and functional properties of both subunits. One monoclonal antibody, alpha-F3, binds to an epitope either at the C-terminal or at the N-terminal part of the alpha-polypeptide chain. By screening a heptapeptide library with this monoclonal antibody, a set of heptapeptides was selected, which contained the consensus sequences D-A-F and D-S-F. Two heptapeptides with these motifs were synthesized in order assess their capacity to inhibit the binding of antibody alpha-F3 to native phosphofructokinase-1. The peptide G-I-K-D-A-F-L inhibited the binding more strongly (IC50 = 1.5 microM) than the peptide A-P-W-H-D-S-F (IC50 = 33.3 microM). Sequence matching revealed the presence of the D-A-F motif in the polypeptide chain of phosphofructokinase-1 at amino acid position 172-174. As a control, the nonapeptide A-P-T-S-K-D-A-F-L which corresponds to the sequence of the putative epitope was tested in the inhibition assay. In view of the high inhibitory capacity (IC50 = 0.3 microM) it was concluded that this nonapeptide represents the continuous epitope of phosphofructokinase-1 that is recognized by antibody alpha-F3.