Plasmodium genetic loci linked to host cytokine and chemokine responses.

Both host and parasite factors contribute to disease severity of malaria infection; however, the molecular mechanisms responsible for the disease and the host-parasite interactions involved remain largely unresolved. To investigate the effects of parasite factors on host immune responses and pathogenesis, we measured levels of plasma cytokines/chemokines (CCs) and growth rates in mice infected with two Plasmodium yoelii strains having different virulence phenotypes and in progeny from a genetic cross of the two parasites. Quantitative trait loci (QTL) analysis linked levels of many CCs, particularly IL-1ß, IP-10, IFN-γ, MCP-1 and MIG, and early parasite growth rate to loci on multiple parasite chromosomes, including chromosomes 7, 9, 10, 12 and 13. Comparison of the genome sequences spanning the mapped loci revealed various candidate genes. The loci on chromosomes 7 and 13 had significant (P<0.005) additive effects on IL-1ß, IL-5 and IP-10 responses, and the chromosome 9 and 12 loci had significant (P=0.017) interaction. Infection of knockout mice showed critical roles of MCP-1 and IL-10 in parasitemia control and host mortality. These results provide important information for a better understanding of malaria pathogenesis and can be used to examine the role of these factors in human malaria infection.

Observation of reversed-shear Alfvén eigenmodes excited by energetic ions in a helical plasma.

Reversed-shear Alfvén eigenmodes were observed for the first time in a helical plasma having negative q0'' (the curvature of the safety factor q at the zero shear layer). The frequency is swept downward and upward sequentially via the time variation in the maximum of q. The eigenmodes calculated by ideal MHD theory are consistent with the experimental data. The frequency sweeping is mainly determined by the effects of energetic ions and the bulk pressure gradient. Coupling of reversed-shear Alfvén eigenmodes with energetic ion driven geodesic acoustic modes generates a multitude of frequency-sweeping modes.

Optical measurement of Cs distribution in the large negative ion source.

To investigate a Cs behavior, optical diagnostic tools have been installed in the large negative ion source, an arc discharge used at large helical device neutral beam injector. A large Cs sputtering is observed during beam extraction due to the backstreaming H(+) ions. Distribution of Cs(+) light is uniform in the case of a balanced arc discharge, but large increase of Cs(+) light during beam extraction is observed in a nonuniform arc discharge. Controlling of the discharge uniformity is effective to reduce the local heat loading from the backstreaming H(+) ions at the backplate of ion source.

Neutral beam injection with an improved accelerator for LHD.

The beam profiles, port-through, rates and injection powers obtained with an improved accelerator with the multislot grounded grid are described. The accelerator has a combination of a steering grid with racetrack shaped aperture and multislot grounded grid to improve the beam optics. The optimal beam optics is obtained at the voltage ratio of 16.5-16.8, and the profiles are well fit by superposing multibeamlets with the divergent angles of 5.0 and 7.2 mrad along the direction parallel to the long and short axes of the slots of grounded grid. By adopting the racetrack shaped steering grid, the port-through rate increases from 34% to 38%, and the maximum injection power reaches 6 MW/187 keV.

Development of a strongly focusing high-intensity He(+) ion source for a confined alpha particle measurement at ITER.

A strongly focusing high-intensity He(+) ion source has been designed and constructed as a beam source for a high-energy He(0) beam probe system for diagnosis of fusion produced alpha particles in the thermonuclear fusion plasmas. The He(+) beam was extracted from the ion source at an acceleration voltage of 18-35 kV. Temperature distributions of the beam target were observed with an IR camera. The 1/e-holding beam profile half-width was about 15 mm at optimum perveance (Perv) of 0.03 (I(beam)=2.4 A). A beam current about 3 A was achieved at an acceleration voltage of 26.7 kV with an arc power of 10 kW (Perv=0.023).

Spectroscopic observations of beam and source plasma light and testing Cs-deposition monitor in the large area negative ion source for LHD-NBI.

In the large area negative ion source for the LHD negative-ion-(H(-))-based neutral beam system, (I) we used the spectrometer to measure caesium lines in the source plasma during beam shots. (II) With Doppler-shifted measurements, the H(alpha) line at three different locations along the beam as well as the spectrum profile for cases of different plasma grid areas. (III) Caesium deposition monitor with a high speed shutter was tested to measure the weight of the deposited Cs layer. In the observation, cleaner spectra of Doppler-shifted H(alpha) line with only a small level of background light were obtained at a new observation port which viewed the blueshifted light in the drift region after the accelerator of a LHD ion source. Both the amounts of Cs I (852 nm, neutral Cs(0)) and Cs II (522 nm, Cs(+)) in the source plasma light rose sharply when beam acceleration began, and continued rising during a 10 s pulse. It was thought that this was because the cesium was evaporated/sputtered from the source back plate by the back-streaming positive ions. Cs deposition rate to the crystal sensor measured by adjusting the shutter open time was evaluated to be 2.9 nanograms/s cm(2) for preliminary testing. More neutral Cs tended to be evolved in the source after arc discharge. Much Cs could be consumed in a high rate-pulsed operation (such as LHD source).

The "White Gray Sign" Identifies the Central Sulcus on 3T High-Resolution T1-Weighted Images.

BACKGROUND AND PURPOSE: The central sulcus is an important anatomic landmark, but most methods of identifying it rely on variable gyral and sulcal patterns. We describe and assess the accuracy of reduced gray-white contrast along the central sulcus, an observation we term the "white gray sign." MATERIALS AND METHODS: We conducted a retrospective review of 51 fMRIs with a T1-weighted 3D inversion recovery fast-spoiled gradient-echo and concomitant hand-motor fMRI, which served as confirmation for the location of the central sulcus. To measure gray-white contrast across the central and adjacent sulci, we performed a quantitative analysis of 25 normal hemispheres along the anterior and posterior cortices and intervening white matter of the pre- and postcentral gyri. 3D inversion recovery fast-spoiled gradient-echo axial images from 51 fMRIs were then evaluated by 2 raters for the presence of the white gray sign as well as additional established signs of the central sulcus: the bracket, cortical thickness, omega, and T signs. RESULTS: The mean gray-white contrast along the central sulcus was 0.218 anteriorly and 0.237 posteriorly, compared with 0.320 and 0.295 along the posterior precentral and anterior postcentral sulci, respectively (P < .001). Both raters correctly identified the central sulcus in all 35 normal and 16 abnormal hemispheres. The white gray sign had the highest agreement of all signs between raters and was rated as present the most often among all the signs. CONCLUSIONS: Reduced gray-white contrast around the central sulcus is a reliable sign for identification of the central sulcus on 3D inversion recovery fast-spoiled gradient-echo images.

Upgraded millimeter-wave interferometer for measuring the electron density during the beam extraction in the negative ion source.

The upgraded millimeter-wave interferometer with the frequency of 70 GHz is installed on a large-scaled negative ion source. Measurable line-averaged electron density is from 2 × 1015 to 3 × 1018 m-3 in front of the plasma grid. Several improvements such as the change to shorter wavelength probing with low noise, the installation of special ordered horn antenna, the signal modulation for a high accuracy digital phase detection, the insertion of insulator, and so on, are carried out for the measurement during the beam extraction by applying high voltage. The line-averaged electron density is successfully measured and it is found that it increases linearly with the arc power and drops suddenly at the beam extraction.

Charged particle flows in the beam extraction region of a negative ion source for NBI.

Experiments by a four-pin probe and photodetachment technique were carried out to investigate the charged particle flows in the beam extraction region of a negative hydrogen ion source for neutral beam injector. Electron and positive ion flows were obtained from the polar distribution of the probe saturation current. Negative hydrogen ion flow velocity and temperature were obtained by comparing the recovery times of the photodetachment signals at opposite probe tips. Electron and positive ions flows are dominated by crossed field drift and ambipolar diffusion. Negative hydrogen ion temperature is evaluated to be 0.12 eV.

Installation of spectrally selective imaging system in RF negative ion source.

A spectrally selective imaging system has been installed in the RF negative ion source in the International Thermonuclear Experimental Reactor-relevant negative ion beam test facility ELISE (Extraction from a Large Ion Source Experiment) to investigate distribution of hydrogen Balmer-α emission (Hα) close to the production surface of hydrogen negative ion. We selected a GigE vision camera coupled with an optical band-path filter, which can be controlled remotely using high speed network connection. A distribution of Hα emission near the bias plate has been clearly observed. The same time trend on Hα intensities measured by the imaging diagnostic and the optical emission spectroscopy is confirmed.

Improvement of accelerator of negative ion source on the Large Helical Device.

To improve the performance of negative-ion based neutral beam injection on the Large Helical Device, the accelerator was modified on the basis of numerical investigations. A field limiting ring was installed on the upper side of a grounded grid (GG) support and a multi-slot GG was adopted instead of a multi-aperture GG. As a result, the voltage holding capability is improved and the heat load on the GG decreases by 40%. In addition, the arc efficiency is improved significantly only by replacing the GG.

Negative ion production and beam extraction processes in a large ion source (invited).

Recent research results on negative-ion-rich plasmas in a large negative ion source have been reviewed. Spatial density and flow distributions of negative hydrogen ions (H(-)) and positive hydrogen ions together with those of electrons are investigated with a 4-pin probe and a photodetachment (PD) signal of a Langmuir probe. The PD signal is converted to local H(-) density from signal calibration to a scanning cavity ring down PD measurement. Introduction of Cs changes the slope of plasma potential local distribution depending upon the plasma grid bias. A higher electron density H2 plasma locally shields the bias potential and behaves like a metallic free electron gas. On the other hand, the bias and extraction electric fields penetrate in a Cs-seeded electronegative plasma even when the electron density is similar. Electrons are transported by the penetrated electric fields from the driver region along and across the filter and electron deflection magnetic fields. Plasma ions exhibited a completely different response against the penetration of electric fields.

Selection and genetic drift of polymorphisms within the merozoite surface protein-1 gene of Plasmodium falciparum.

Intragenic recombination in the merozoite surface protein-1 gene (Msp-1) of Plasmodium falciparum is a major mechanism for allelic variation among natural parasite populations. The frequency of recombination depends on the intensity of transmission in the vector mosquito. In the present study, linkage disequilibrium between polymorphic 'loci' in the 5'- and 3'-regions of Msp-1 was examined in parasite populations from Brazilian Amazon and southern Vietnam and compared with that in a Thai population previously reported. The R2 test identified clusters of linkage disequilibria between the 5'- and 3'-regions, which are different among the three populations. However, the overall strength of linkage disequilibria was stronger in Brazil, a hypoendemic area, than in Vietnam and Thailand, mesoendemic areas, suggesting that linkage disequilibrium in Msp-1 inversely correlates with the intensity of transmission. To investigate possible mechanisms for linkage disequilibrium in Msp-1, we applied the Fst index, which measures the inter-population variance in allele frequency, to 'loci' in Msp-1 among the three populations. The Fst test identified two distinct regions with respect to inter-population allele frequency in Msp-1: one for highly divergent 'loci' in the 5'-region and the other for non-divergent 'loci' in the 3'-region. These results suggest that genetic drift is not the sole mechanism for linkage disequilibrium, but selection operates on 'loci' in the 3'-region in hypo- and mesoendemic areas of malaria.

Disruption of the C-terminal region of EBA-175 in the Dd2/Nm clone of Plasmodium falciparum does not affect erythrocyte invasion.

EBA-175 is a Plasmodium falciparum micronemal protein that binds to sialic acid in the context of the peptide backbone of glycophorin A and has been implicated in sialic acid-dependent invasion of erythrocytes. The existence of an alternative invasion pathway has been suggested by the finding that the P. falciparum clone Dd2/Nm can invade sialic acid-depleted erythrocytes. To study the role of EBA-175 in this alternative pathway, we have generated Dd2/Nm clones expressing a truncated form of EBA-175 that lacks region 6 and the cytoplasmic domain. The protein still appears to be localized to the apical end in the vicinity of the micronemes, suggesting that region 6 and the cytoplasmic domain are not involved in EBA-175 trafficking to the micronemes. In these genetically modified clones, the level of truncated EBA-175 protein expression was greatly reduced. EBA-175-disrupted clones displayed normal rates of invasion of untreated and enzyme-treated human and animal erythrocytes, suggesting a lack of involvement of EBA-175 in this alternative invasion pathway.

The high molecular mass rhoptry protein, RhopH1, is encoded by members of the clag multigene family in Plasmodium falciparum and Plasmodium yoelii.

Malarial merozoite rhoptries contain a high molecular mass protein complex called RhopH. RhopH is composed of three polypeptides, RhopH1, RhopH2, and RhopH3, encoded by distinct genes. Using monoclonal antibody-purified protein complex from both Plasmodium falciparum and Plasmodium yoelii, peptides were obtained by digestion of RhopH1 and their sequence determined either by mass spectrometry or Edman degradation. In both species the genes encoding RhopH1 were identified as members of the cytoadherence linked asexual gene (clag) family. In P. falciparum the family members on chromosome 3 were identified as encoding RhopH1. In P. yoelii two related genes were identified and sequenced. One of the genes, pyrhoph1a, was positively identified as encoding RhopH1 by the peptide analysis and the other gene, pyrhoph1a-p, was at least transcribed. Genes in the clag family present in both parasite species have a number of conserved features. The size and location of the P. yoelii protein complex in the rhoptries was confirmed. The first clag gene identified on chromosome 9 was implicated in cytoadherence, the binding of infected erythrocytes to host endothelial cells; this study shows that other members of the family encode merozoite rhoptry proteins, proteins that may be involved in merozoite-erythrocyte interactions. We propose that the family should be renamed as rhoph1/clag.

Energy confinement time and heat transport in initial neutral beam heated plasmas on the large helical device

The confinement characteristics of large net-current-free plasmas heated by neutral-beam injection have been investigated in the Large Helical Device (LHD). A systematic enhancement in energy-confinement times from the scaling derived from the medium-sized heliotron/torsatron experiments have been observed, which is attributed to the edge pedestal. The core confinement is scaled with the Bohm term divided by the square root of the gyro radii. The comparative analysis using a dimensionally similar discharge in the Compact Helical System indicates gyro-Bohm dependence in the core and transport improvement in the edge region of LHD plasmas.

Edge thermal transport barrier In LHD discharges

In LHD discharges a significant enhancement of the global energy confinement has been achieved for the first time in a helical device with an edge thermal barrier, which exhibits a sharp gradient at the edge of the temperature profile. Key features associated with the barrier are quite different from those seen in tokamaks: (i) almost no change in particle (including impurity) transport, (ii) a gradual formation of the barrier, (iii) a very high ratio of the edge temperature to the average temperature, and (iv) no edge relaxation phenomenon. These features are very attractive in applying the thermal barrier to future reactor grade devices.

Allelic diversity at the merozoite surface protein-1 locus of Plasmodium falciparum in clinical isolates from the southwestern Brazilian Amazon.

Nucleotide sequences of each variable block in the Plasmodium falciparum merozoite surface protein-1 gene (PfMSP-1) may be grouped into one of two or three possible allelic types, named after the reference isolates MAD20, K1, and RO33. Allelic diversity at this locus basically results from different combinations of allelic types in variable blocks. We used a polymerase chain reaction (PCR)-based strategy to type the variable blocks 2, 4a, 4b, and 10 of the PfMSP-1 gene of P. falciparum isolates from 54 symptomatic malaria patients living in Rondonia, a hypoendemic area in the southwestern Brazilian Amazon. Ten different PfMSP-1 gene types, defined as unique combinations of allelic types in variable blocks, were identified among the 54 isolates. Twenty-one isolates (39%) harbored more than one gene type and two had at least three genetically distinct clones. Hybrid sequences, with a MAD20-type sequence in the 5' segment (4a) and a K1-type sequence in the 3' segment (4b), were quite common in block 4. Direct sequencing of block 4 PCR products revealed a new putative recombination site in four isolates. In contrast with previous studies, the observed distribution of gene types does not deviate significantly from that expected under the null hypothesis of random association between allelic types detected in each variable block. These contradictory data are discussed with reference to the immunoepidemiologic features prevailing in distinct malaria-endemic areas.

Do obesity and non-insulin dependent diabetes mellitus aggravate exercise-induced microproteinuria?

We evaluated the role of obesity in proteinuria by treadmill exercising of simple obese subjects and non-obese subjects with non-insulin dependent diabetes mellitus in whom the albumin excretion rate at rest was within normal range. Non-obese healthy volunteers were studied as the controls. The fractional renal clearances of four endogenous proteins, albumin, IgG, IgG4, and beta2-microglobulin were measured before, during, and after treadmill exercise in 17 simple obese and 15 non-obese diabetic subjects, and in 21 normal subjects. Exercise increased the fractional albumin clearance in all groups. In diabetic subjects, the fractional IgG4 clearance also increased: fractional beta2-microglobulin clearance increased in normal controls and in diabetics. In obese subjects, the fractional clearances of albumin, IgG, and IgG4 were similar to those in normal controls, but fractional beta2-microglobulin clearance was significantly lower. These results suggest that enhanced microalbuminuria in obese subjects is probably of glomerular origin. In normal subjects and diabetics, exercise-induced microproteinuria is probably of both glomerular and tubular origin. Defect in the charge-selective barrier of the glomerular capillary wall has been implicated in diabetics. Thus some additional factors relevant to obesity must be taken into account in the consideration of the mechanism of microalbuminuria in diabetics with obesity.

[Administration of cephradine to dermatoses by injection (author's transl)].

Ten cases of various kinds of dermatoses underwent cephradine by injection. Two cases injected cephradine intramuscularly resulted in severe pain. Three of 4 cases with pyogenic skin infection revealed excellent results. Three cases were prevented from secondary infection. Adverse effects such as vertigo were avoided by lowering the speed of intravenous injection. No abnormal findings of serum GOT and GPT levels after the completion of the treatment was noted in 7 of 8 cases, but one case which was administrated large dosis of corticosteroid concomitantly revealed elevated level in this finding.