Experimental Validation of a Kinetic Ballooning Mode in High-Performance High-Bootstrap Current Fraction Fusion Plasmas.

We report the observation of a set of coherent high frequency electromagnetic fluctuations that leads to a turbulence induced self-regulating phenomenon in the DIII-D high bootstrap current fraction plasma. The fluctuations have frequency of 130-220 kHz, the poloidal wavelength and phase velocity are 16-30 m^{-1} and ∼30 km/s, respectively, in the outboard midplane with the estimated toroidal mode number n∼5-9. The fluctuations are located in the internal transport barrier (ITB) region at large radius and are experimentally validated to be kinetic ballooning modes (KBM). Quasilinear estimation predicts the KBM to be able to drive experimental particle flux and non-negligible thermal flux, suggesting its significant role in regulating the ITB saturation.

Promising High-Confinement Regime for Steady-State Fusion.

A reproducible stationary high-confinement regime with small "edge-localized modes" (ELMs) has been achieved recently in the Experimental Advanced Superconducting Tokamak, which has a metal wall and low plasma rotation as projected for a fusion reactor. We have uncovered that this small ELM regime is enabled by a wide edge transport barrier (pedestal) with a low density gradient and a high density ratio between the pedestal foot and top. Nonlinear simulations reveal, for the first time, that the underlying mechanism for the observed small ELM crashes is the upper movement of the peeling boundary induced by an initial radially localized collapse in the pedestal, which stops the growth of instabilities and further collapse of the pedestal, thus providing a physics basis for mitigating ELMs in future steady-state fusion reactors.

Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo.

The serine/threonine kinase protein kinase B (PKB)/Akt mediates cell survival in a variety of systems. We have generated transgenic mice expressing a constitutively active form of PKB (gag-PKB) to examine the effects of PKB activity on T lymphocyte survival. Thymocytes and mature T cells overexpressing gag-PKB displayed increased active PKB, enhanced viability in culture, and resistance to a variety of apoptotic stimuli. PKB activity prolonged the survival of CD4(+)CD8(+) double positive (DP) thymocytes in fetal thymic organ culture, but was unable to prevent antigen-induced clonal deletion of thymocytes expressing the major histocompatibility complex class I-restricted P14 T cell receptor (TCR). In mature T lymphocytes, PKB can be activated in response to TCR stimulation, and peptide-antigen-specific proliferation is enhanced in T cells expressing the gag-PKB transgene. Both thymocytes and T cells overexpressing gag-PKB displayed elevated levels of the antiapoptotic molecule Bcl-X(L). In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-kappaB activation via accelerated degradation of the NF-kappaB inhibitory protein IkappaBalpha. Our data highlight a physiological role for PKB in promoting survival of DP thymocytes and mature T cells, and provide evidence for the direct association of three major survival molecules (PKB, Bcl-X(L), and NF-kappaB) in vivo in T lymphocytes.

Sequence and Observer Variability in Gadoxectic Acid-Enhanced MRI Lesion Measurements in Hepatocellular Carcinoma.

RATIONALE AND OBJECTIVES: The purpose of the study was to investigate interobserver and intersequence variability in measuring hepatocellular carcinoma on magnetic resonance imaging (MRI). METHODS AND MATERIALS: Twenty treatment-naïve lesions on Gadoxetic Acid enhanced MRI scans from 20 patients were retrospectively measured by six reviewers with different levels of experience, twice, six weeks apart, on eight different MRI sequences, in randomized order. The sequences include arterial, hepatobiliary, transitional, portal venous, T2, and diffusion weighted images. The single longest diameter (SLD) and longest diameter perpendicular to the longest overall diameter were measured on axial images and products of diameters calculated in accordance to response evaluation criteria in solid tumors v1.1 and World Health Organization response criteria respectively. Lesion-wise intraclass correlation coefficients were used to estimate measurement agreement. RESULTS: All intraclass correlation coefficients were greater than 0.95. No substantive differences between SLD and products of diameters metrics. Means (∼2.8 mm, SLD) and standard deviations (∼2 mm, SLD) were similar across sequences and observers. Similarly, pairwise comparison between observers grouped by experience showed statistically significant differences, but the effect size was minor (∼2 mm). Arterial and HPB-weighted images had similar mean dimensions (2.76 cm) while the smallest mean was in the transitional phase (2.62 cm). A lesion was not measured on 140 occasions (7%), mostly in ADC. CONCLUSION: There is high interobserver and intersequence reliability despite small differences between observers based on experience level. Our results suggest that accurate measurements can be made on arterial phase despite the possibility of indistinct margins. Lesions, however, are more likely to be missed on diffusion-related sequences.

Positive regulation of T cell activation and integrin adhesion by the adapter Fyb/Slap.

The molecular adapter Fyb/Slap regulates signaling downstream of the T cell receptor (TCR), but whether it plays a positive or negative role is controversial. We demonstrate that Fyb/Slap-deficient T cells exhibit defective proliferation and cytokine production in response to TCR stimulation. Fyb/Slap is also required in vivo for T cell-dependent immune responses. Functionally, Fyb/Slap has no apparent role in the activation of known TCR signaling pathways, F-actin polymerization, or TCR clustering. Rather, Fyb/Slap regulates TCR-induced integrin clustering and adhesion. Thus, Fyb/Slap is the first molecular adapter to be identified that couples TCR stimulation to the avidity modulation of integrins governing T cell adhesion.

Role of polymorphisms of the inflammatory response genes and DC-SIGNR in genetic susceptibility to SARS and other infections.

1. A genetic risk-association study involving more than 1200 subjects showed individuals homozygous for L-SIGN tandem repeats are less susceptible to SARS infection. 2. This was supported by in vitro binding studies that demonstrated homozygous L-SIGN, compared to heterozygous, had higher binding capacity for SARS coronavirus (SARS-CoV), with higher proteasome-dependent viral degradation. In contrast, homozygous L-SIGN demonstrated lower binding capacity for HIV1-gp120.3. Genetic-association studies for single nucleotide polymorphisms of the inflammatory response genes, namely TNF-alpha, INF-alpha, INF-beta, INF-gamma, IL1-alpha, IL1-beta, IL-4, IL-6 and iNOS, failed to show a significant association with SARS clinical outcomes or susceptibility.

Progestins inhibit the growth of MDA-MB-231 cells transfected with progesterone receptor complementary DNA.

Because progesterone exerts its effects mainly via estrogen-dependent progesterone receptor (PgR), the expression of progesterone's effects may be overshadowed by the priming effect of estrogen. PgR expression vectors were transfected into estrogen receptor (ER)-alpha and PgR-negative breast cancer cells MDA-MB-231; thus the functions of progesterone could be studied independent of estrogens and ERs. Eight stable transfectant clones expressing both PgR isoform A and B were studied for their growth response to progesterone and its analogues. Although progesterone had no effect on growth in the control transfectant, the hormone markedly inhibited DNA synthesis and cell growth in all of the PgR-transfectants dose-dependently from 10(-12)-10(-6) M. This growth inhibition was associated with an arrest of cells in the G0/G1 phase of the cell cycle. Progestins medroxyprogesterone acetate, Org2058, and R5020 also strongly inhibited DNA synthesis, and their doses required for maximal inhibition of 60-70% were 10(-17) M, 10(-13) M, and 10(-7) M, respectively. Antiprogestin ZK98299 alone had no effect, but the compound was capable of counteracting the inhibitory effect of progesterone. In contrast, RU486 inhibited DNA synthesis, and it showed no further effects when it was used concurrently with progesterone. These results indicate that progestins are per se antiproliferative via a PgR-mediated mechanism in breast cancer cells. More importantly, we have shown that progestins may exert effective inhibitory control over the cell growth if the PgR expression is reactivated in ER- and PgR-negative breast cancer cells.

Comparative induction of unscheduled DNA synthesis in cultured rat hepatocytes by allylbenzenes and their 1'-hydroxy metabolites.

The allylbenzenes estragole, methyleugenol and safrole are hepatocarcinogens in rodents at very high doses, but allylbenzene itself is neither hepatotoxic nor hepatocarcinogenic. To elucidate further the significance of metabolic 1'-hydroxylation in the carcinogenicity of the allylbenzenes and to give further insights into the structure-metabolism-genotoxicity relationships of these compounds, comparative data were established on the ability of estragole, methyleugenol, safrole, allylbenzene and their 1'-hydroxy metabolites to induce unscheduled DNA synthesis (UDS) in hepatocytes derived from male Fischer 344 rats. Cytotoxicity was assessed by lactate dehydrogenase leakage. The first three compounds increased UDS in a dose-related fashion but allylbenzene was non-genotoxic. 1'-Hydroxyestragole, -methyleugenol and -safrole were more potent genotoxins than their parent compounds. This difference in genotoxicity indicates the importance of the attachment of the electron-withdrawing methoxy or methylenedioxy substituents to the benzene ring. The non-linear dose-response curves for genotoxicity obtained with the allylbenzenes and their 1'-hydroxy metabolites indicate that it is important to consider dose-dependence in metabolism when interpreting the significance to humans of animal data obtained with very high doses of the compounds studied. It is likely that the use of these high doses markedly overestimates the potential hazard to humans of low doses of allylbenzenes, which generate only very small quantities of genotoxic metabolites.

Structure-specificity of the genotoxicity of some naturally occurring alkenylbenzenes determined by the unscheduled DNA synthesis assay in rat hepatocytes.

A number of alkenylbenzenes related to safrole and estragole are known to be hepatocarcinogenic in rats and/or mice, apparently by a genotoxic mechanism. However, they are not bacterial mutagens in the Ames test. We have studied the ability of a series of carcinogenic and non-carcinogenic congeners to induce unscheduled DNA synthesis (UDS) in freshly isolated rat hepatocytes in primary culture. The cytotoxicity of these compounds was assessed by lactate dehydrogenase leakage. There was an excellent correlation between UDS induction and known rodent hepatocarcinogenicity, with safrole, estragole and methyleugenol all inducing UDS. Anethole, isosafrole, eugenol and allylbenzene, for which evidence of carcinogenicity is equivocal or negative, did not induce UDS. All compounds were markedly cytotoxic at concentrations between 10(-3) and 10(-2) M, irrespective of their structural features. The data are discussed with reference to the known structure dependence of the disposition of the alkenylbenzenes, notably their metabolic activation, with which there are excellent correlations. The demonstration of the genotoxicity of rodent hepatocarcinogenic alkenylbenzenes in cells cultured from the in vivo target organ will allow the direct investigation of factors influencing these processes and facilitate the safety evaluation of these important natural flavours.

Large-aspect-ratio limit of neoclassical transport theory.

This paper presents a comprehensive description of neoclassical transport theory in the banana regime for large-aspect-ratio flux surfaces of arbitrary shapes. The method of matched-asymptotic expansions is used to obtain analytical solutions for plasma distribution functions and to compute transport coefficients. The method provides justification for retaining only the part of the Fokker-Planck operator that involves the second derivative with respect to the cosine of the pitch angle for the trapped and barely circulating particles. It leads to a simple equation for the freely circulating particles with boundary conditions that embody a discontinuity separating particles moving in opposite directions. Corrections to the transport coefficients are obtained by generalizing an existing boundary layer analysis. The system of moment and field equations is consistently taken in the cylinder limit, which facilitates the discussion of the treatment of dynamical constraints. It is shown that the nonlocal nature of Ohm's law in neoclassical theory renders the mathematical problem of plasma transport with changing flux surfaces nonstandard.

Quantitative analysis on the localization of chondroitin sulfate proteoglycan in renal tissues of patients with calcium nephrolithiasis.

Previous studies have shown a significant decrease of heparin sulfate proteoglycan (HSPG) in the basement membrane of the glomerulus and the mucosa of the ureter/renal pelvis in patients with calcium nephrolithiasis. In this study, we looked at the localization of another influential proteoglycan, chondroitin sulfate (CSPG), using similar study groups by indirect immunofluorescence staining. Microscopic images were digitized and image analysis was used to quantitate the staining intensity of CSPG present in the basement membrane of the nephron. Our data showed significant loss of CSPG in the Bowman's capsule and the basement membrane of the mucosa of the ureter/renal pelvis using Mann-Whitney U-Wilcoxon Rank Sum W test with P-values of 0.0043 and 0.0041, respectively. However, absence of staining was noted in the basement membrane of the glomerulus and no significant change in the basement membrane of the tubular epithelium was observed. In conclusion, our results showed changes in the localization of CSPG in the basement membrane of the nephron, accompanied with HSPG, which may contribute to the pathological condition of calcium nephrolithiasis.

T cell tolerance and autoimmunity.

A functional immune system requires a T cell repertoire that is extremely diverse so as to allow for the elimination of all possible pathogens. However, the production of an immense T cell repertoire also increases the likelihood of generating autoreactive T cells. The immune system must therefore also incorporate a means of silencing or eliminating autoreactive T cells, while minimally sacrificing T cell diversity. The induction and maintenance of T cell unresponsiveness to self antigens is thus defined as T cell tolerance. This review provides an overview of the T cell tolerance mechanisms invoked in the thymus and in the periphery to prevent the induction of autoimmunity. Factors that can influence the induction of tolerance and autoimmunity are also discussed.

Subtle effects on myelin basic protein-specific T cell responses can lead to a major reduction in disease susceptibility in experimental allergic encephalomyelitis.

The presence of potentially autoreactive T cells is a necessary, but not sufficient, condition for the development of autoimmune disease. However, the relationship between T cell response and susceptibility to disease is not straightforward. In this report, we use experimental allergic encephalomyelitis as a model to demonstrate that subtle alterations of the T cell response to an encephalitogenic epitope are sufficient to cause a dramatic decrease in disease susceptibility. Transgenic expression of a fusion protein of hen egg lysozyme and an encephalitogenic peptide of myelin basic protein (MBP) residues 84-105, coexpressed with MHC class II, causes profound tolerance to hen egg lysozyme, while maintaining a near normal response to MBP. Detailed analysis of the T cell repertoire of transgenic animals using a panel of T cell hybridomas revealed a highly selective loss of one minor component of the response to the MBP84-104 region. Despite this, transgenic animals were highly resistant to experimental allergic encephalomyelitis induction with the MBP peptide, indicating that minor changes to the T cell repertoire may result in major alterations in disease susceptibility. Possible reasons for this are discussed.

Determination of heparan sulphate in kidney tissues of patients with calcium nephrolithiasis.

While the pathogenic mechanisms responsible for calcium nephrolithiasis remain unknown, the influence of heparan sulphate proteoglycan (HSPG) on disease progression of other diseases, such as polycystic kidneys and diabetic glomerulosclerosis, makes it an important candidate for the study of stone formation. Using the indirect immunofluorescence assay and image analysis, we were able to quantify and visualize the loss of HSPG localized in the basement membrane of the glomerulus and the mucosa of ureter or renal pelvis in patients with recurrent calcium nephrolithiasis as compared to normal subjects. However, no significant change in HSPG was observed in the basement membrane of the tubular epithelium. The decreased HSPG in the glomerulus may reflect the potentially disrupted anion/neutral barrier for glomerular filtration, which would encourage the accumulation of stone solutes. The drop in HSPG staining intensity in the basement membrane of the mucosa of ureter/renal pelvis may suggest the tendency of adhesion of crystal to urothelial surfaces. Based on these immunological data, it appears that HSPG plays a modulatory role in the pathogenesis of this disease.