Plasmoid Formation and Strong Radiative Cooling in a Driven Magnetic Reconnection Experiment.

We present the first experimental study of plasmoid formation in a magnetic reconnection layer undergoing rapid radiative cooling, a regime relevant to extreme astrophysical plasmas. Two exploding aluminum wire arrays, driven by the Z machine, generate a reconnection layer (S_{L}≈120) in which the cooling rate far exceeds the hydrodynamic transit rate (τ_{hydro}/τ_{cool}>100). The reconnection layer generates a transient burst of >1 keV x-ray emission, consistent with the formation and subsequent rapid cooling of the layer. Time-gated x-ray images show fast-moving (up to 50 km s^{-1}) hotspots in the layer, consistent with the presence of plasmoids in 3D resistive magnetohydrodynamic simulations. X-ray spectroscopy shows that these hotspots generate the majority of Al K-shell emission (around 1.6 keV) prior to the onset of cooling, and exhibit temperatures (170 eV) much greater than that of the plasma inflows and the rest of the reconnection layer, thus providing insight into the generation of high-energy radiation in radiatively cooled reconnection events.

Performance Scaling in Magnetized Liner Inertial Fusion Experiments.

We present experimental results from the first systematic study of performance scaling with drive parameters for a magnetoinertial fusion concept. In magnetized liner inertial fusion experiments, the burn-averaged ion temperature doubles to 3.1 keV and the primary deuterium-deuterium neutron yield increases by more than an order of magnitude to 1.1×10^{13} (2 kJ deuterium-tritium equivalent) through a simultaneous increase in the applied magnetic field (from 10.4 to 15.9 T), laser preheat energy (from 0.46 to 1.2 kJ), and current coupling (from 16 to 20 MA). Individual parametric scans of the initial magnetic field and laser preheat energy show the expected trends, demonstrating the importance of magnetic insulation and the impact of the Nernst effect for this concept. A drive-current scan shows that present experiments operate close to the point where implosion stability is a limiting factor in performance, demonstrating the need to raise fuel pressure as drive current is increased. Simulations that capture these experimental trends indicate that another order of magnitude increase in yield on the Z facility is possible with additional increases of input parameters.

Development of a bolometry diagnostic for SPARC.

To control and optimize the power of the SPARC tokamak, we require information on the total radiated power of the plasma and its 2D and 3D spatial distribution. The SPARC bolometry diagnostic is being designed and built to measure the radiated power for controlling power balance, investigating the dissipation capabilities of various divertor concepts, and measuring the efficacy of the disruption thermal load mitigation. Proven resistive bolometer sensor technology will be used, with 248 lines of sight integrated into pinhole cameras in 20 different locations. This diversity of views will allow the bolometers to view the core, divertor, and particularly X-points of the plasma with high resolution. 14 of these camera locations are dedicated to 2D equilibrium radiated power, while the remaining six locations are designed to measure 3D radiated energy during disruptions. The bolometer sensor holders, pinhole camera boxes, and cabling have been designed to survive the high neutron flux (but low fluence) and up to 400 °C temperatures seen during operation and vacuum bake. The resistive bolometer sensors use Au absorbers with an Al heat conduction layer and C anti-reflective layer. These sensor chips are wire-bonded to an AlN circuit board, both of which are held inside a custom AlN and stainless steel bolometer holder. Design and optimization of the pinhole camera lines of sight are performed using Cherab. This work details the current state of the design of the SPARC bolometry diagnostic and its interfaces, as well as ongoing work to validate the design.

Quantitative study of guide-field effects on Hall reconnection in a laboratory plasma.

The effect of guide field on magnetic reconnection is quantitatively studied by systematically varying an applied guide field in the Magnetic Reconnection Experiment (MRX). The quadrupole field, a signature of two-fluid reconnection at zero guide field, is altered by a finite guide field. It is shown that the reconnection rate is significantly reduced with increasing guide field, and this dependence is explained by a combination of local and global physics: locally, the in-plane Hall currents are reduced, while globally guide field compression produces an increased pressure both within and downstream of the reconnection region.

AC compensation of 3D magnetic diagnostic signals in DIII-D and National Spherical Torus Experiment-Upgrade (NSTX-U) for real-time application.

A time domain algorithm has been developed to remove the vacuum pickup generated by both coil current (DC) and induced vessel current (AC) in real time from three dimensional (3D) magnetic diagnostic signals in the National Spherical Torus Experiment-Upgrade (NSTX-U) and DIII-D tokamaks. The possibility of detecting 3D plasma perturbations in real time is essential in modern and future tokamaks to avoid and control MHD instabilities. The presence of vacuum field pickup, due to toroidally asymmetric (3D) coils or to misalignment between sensors and axisymmetric (2D) coils, pollutes the measured plasma 3D field, making the detection of the magnetic field produced by the plasma challenging. Although the DC coupling between coils and sensors can be easily calculated and removed, the AC part is more difficult. An algorithm based on a layered low-pass filter approach for the AC compensation and its application for DIII-D and NSTX-U data is presented, showing that this method reduces the vacuum pickup to the noise level. Comparison of plasma response measurements with and without vacuum compensation shows that accurate mode locking detection and plasma response identification require precise AC and DC compensations.

Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response.

The antitumor antibiotic, adriamycin, induces severe cardiac toxicity associated with peroxidation of cardiac lipids in mice. Both this lipid peroxidation and cardiac toxicity of adriamycin are reduced by prior treatment of the animals with the free radical scavenger tocopherol. Such treatment with tocopherol does not, however, alter the magnitude or duration of the adriamycin-induced suppression of DNA synthesis in P388 ascites tumor, nor does it diminish the antitumor responsiveness of P388 ascites tumor. These results suggest that adriamycin has at least two mechanisms of tissue damage: one, which involves lipid peroxidation, is blocked by tocopherol and results in cardiac toxicity; the other, which involves binding to DNA, is not antagonized by tocopherol and is responsible for tumor response.

Acquired equivalence changes stimulus representations.

Acquired equivalence is a paradigm in which generalization is increased between two superficially dissimilar stimuli (or antecedents) that have previously been associated with similar outcomes (or consequents). Several possible mechanisms have been proposed, including changes in stimulus representations, either in the form of added associations or a change of feature salience. A different way of conceptualizing acquired equivalence is in terms of strategic inference: Confronted with a choice on which it has no evidence, the organism may infer from its history of reinforcement what the best option is, and that inference is observed as acquired equivalence. To test this account, we combined an incremental learning task with an episodic memory test. Drawings of faces were made equivalent through acquired equivalence training, and then paired with words in a list learning paradigm. When participants were asked to recognize specific face-word pairings, they confused faces more often when they had been made equivalent. This suggests that prior acquired equivalence training does influence how memories are coded. We also tested whether this change in coding reflected acquisition of new associations, as suggested by the associative mediation account, or whether stimuli become more similar through a reweighting of stimulus features, as assumed by some categorization theories. Results supported the associative mediation view. We discuss similarities between this view and exemplar theories of categorization performance.

A computer-based avatar task can differentiate avoidant and non-avoidant coping styles.

Background/Objective: Coping styles play a role in how individuals respond to stress and therapy. One aspect of coping which has been linked to adverse outcomes including anxiety disorders and PTSD is avoidance. However, a tendency to avoid may affect the accuracy of paper and pencil inventories used to identify avoidant temperaments. Previously, we showed that a computer-based task in which an on-screen "avatar" is guided through a series of onscreen events could predict avoidance including behavioral inhibition, harm avoidance, and self-reported PTSD symptoms. Since some coping styles involve avoidance, we extended this work to determine whether scores on the avatar task would also differentiate avoidant and non-avoidant coping styles as measured by the Brief COPE. Methods: One hundred and fifty undergraduates voluntarily completed the avatar task and the Brief COPE. Results: Scores on the avatar task had a significant positive relationship with an aggregate score for the five avoidant coping styles and a significant negative relationship with an aggregate score for the nine non-avoidant coping styles. Conclusions: The effectiveness of the avatar task to differentiate coping styles based on avoidance further validates this task and also shows selectivity to avoidant coping styles as opposed to other non-avoidant coping styles.

Basal ganglia and dopamine contributions to probabilistic category learning.

Studies of the medial temporal lobe and basal ganglia memory systems have recently been extended towards understanding the neural systems contributing to category learning. The basal ganglia, in particular, have been linked to probabilistic category learning in humans. A separate parallel literature in systems neuroscience has emerged, indicating a role for the basal ganglia and related dopamine inputs in reward prediction and feedback processing. Here, we review behavioral, neuropsychological, functional neuroimaging, and computational studies of basal ganglia and dopamine contributions to learning in humans. Collectively, these studies implicate the basal ganglia in incremental, feedback-based learning that involves integrating information across multiple experiences. The medial temporal lobes, by contrast, contribute to rapid encoding of relations between stimuli and support flexible generalization of learning to novel contexts and stimuli. By breaking down our understanding of the cognitive and neural mechanisms contributing to different aspects of learning, recent studies are providing insight into how, and when, these different processes support learning, how they may interact with each other, and the consequence of different forms of learning for the representation of knowledge.

Probabilistic categorization: how do normal participants and amnesic patients do it?

In probabilistic categorization tasks, various cues are probabilistically (but not perfectly) predictive of class membership. This means that a given combination of cues sometimes belongs to one class and sometimes to another. It is not yet clear how categorizers approach such tasks. Here, we review evidence in favor of two alternative conceptualizations of learning in probabilistic categorization: as rule-based learning, or as incremental learning. Each conceptualization forms the basis of a way of analyzing performance: strategy analysis assumes rule-based learning, while rolling regression analysis assumes incremental learning. Here, we contrasted the ability of each to predict performance of normal categorizers. Both turned out to predict responses about equally well. We then reviewed performance of patients with damage to regions deemed important for either rule-based or incremental learning. Evidence was again about equally compatible with either alternative conceptualization of learning, although neither predicted an involvement of the medial temporal lobe. We suggest that a new way of conceptualizing probabilistic categorization might be fruitful, in which the medial temporal lobe help set up representations that are then used by other regions to assign patterns to categories.

US alone trials presented during acquisition do not disrupt classical eyeblink conditioning: Empirical and computational findings.

Studies of partial reinforcement in eyeblink conditioning have typically shown slower learning of a CS-US association when paired CS-US trials are interleaved with CS-alone trials. However, recent work has shown that CS-US learning is not slowed by interleaved US-alone trials. This discrepancy is surprising since both partial reinforcement protocols reduce the total number of paired CS-US trials. Previously, Kimble et al. (1955) reported that inserting a block of US-alone trials during CS-US training did not disrupt eyeblink acquisition. Here, we sought to replicate and extend these findings by comparing interleaved vs. blocked US-alone trials during CS-US paired training. Ninety-seven undergraduates volunteered for this experiment for research credit. Participants received 60 acquisition trials, consisting of either 100% CS-US paired trials, 50% US-alone trials intermixed with CS-US paired trials, or a block of 20 US-alone trials inserted between blocks of 20 CS-US trials. We also utilized a previously published computational model of hippocampal and cerebellar learning to test the effects of these US-alone protocols. Both empirical and computational results supported the finding that US-alone trials, either intermixed or inserted as a block of trials, do not disrupt acquisition of conditioned eyeblinks. Possible neural substrates of these US-alone effects are discussed.

Selective growth arrest and phenotypic reversion of prostate cancer cells in vitro by nontoxic pharmacological concentrations of phenylacetate.

Differentiation therapy may provide an alternative for treatment of cancers that do not respond to cytotoxic chemotherapy or hormonal manipulations. This hypothesis led us to evaluate the effect of a nontoxic differentiation inducer, sodium phenylacetate (NaPA), on hormone-refractory prostate cancer, the second most common cause of cancer deaths in men. NaPA treatment of androgen-independent PC3 and DU145 prostate cell lines, like that of hormone-responsive LNCaP cultures, resulted in dose-dependent inhibition of cell proliferation. Similar treatments were not significantly inhibitory to replicating normal endothelial cells and skin fibroblasts. In addition to the selective cytostatic effect, NaPA induced reversion of the prostatic cells to a nonmalignant phenotype, evidenced by their reduced invasiveness and loss of tumorigenicity in athymic mice. Phenotypic reversion was accompanied by alterations in gene expression, including selective reduction in tumor growth factor-beta 2 mRNA levels and increased amounts of class I major histocompatibility complex HLA transcripts. Furthermore, there was a decrease in tumor-associated proteolysis mediated by urokinase plasminogen activator, a molecular marker of disease progression in humans. When tumor cells were treated with NaPA together with suramin, a drug with demonstrable activity in patients, there was complete abrogation of cell growth under conditions in which each treatment alone produced only a partial effect. The in vitro antineoplastic activity was observed with drug concentrations that have been achieved in humans with no significant toxicities, suggesting that PA, used alone or in combination with other antitumor agents, warrants evaluation in the treatment of advanced prostatic cancer.

Biochemical determinants of 5-fluorouracil response in vivo. The role of deoxyuridylate pool expansion.

5-Fluorodeoxyuridine monophosphate (FdUMP), the active metabolite of 5-fluorouracil (5-FU), is a tight-binding inhibitor of thymidylate synthetase, the enzyme which converts dUMP to TMP. Newly developed assays for FdUMP and dUMP were utilized to assess the competitive roles played by these nucleotides in determining the inhibition of TMP synthesis in mice bearing the P1534 ascites tumor. After 5-FU administration, levels of FdUMP reached a dose-dependent peak within 6 h in the ascites tumor and in bone marrow, and declined thereafter in a biphasic manner with an initial t 1/2 of 6 h and a final t 1/2 of 7-9 days. In duodenal mucosa, FdUMP levels were 1.8-2-fold higher than in the other tissues, but elimination was much more rapid. Simultaneous with the fall in FdUMP a progressive accumulation of the competitive substrate dUMP was observed in each tissue after 5-FU; and peak dUMP levels coincided with recovery of thymidylate synthesis, as determined by the incorporation of [3H]deoxyuridine into DNA. In vitro experiments with partially purifed thymidylate synthetase revealed and initial competitive interaction of dUMP and FdUMP, which, at high concentrations of dUMP was capable of markedly slowing the rate of irreversible inactivation of enzyme by FdUMP. These studies were found to be quantitatively consistent with a two-phase model of enzyme inactivation involving an initial competition between dUMP and FdUMP, with subsequent irreversible inactivation of enzyme by covalent linkage to the inhibitor. Recovery of thymidylate synthesis after 5-FU appears to result from both a fall in intracellular levels of inhibitor and a progressive accumulation of the competitive substrate dUMP.

Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin.

The endogenous defenses of the mouse heart against reactive oxygen metabolites were investigated. The activities of three enzymes capable of detoxifying activated oxygen were determined in both the heart and liver; cardiac muscle contains 150 times less catalase and nearly four times less superoxide dismutase than liver. Glutathione peroxidase activities were, however, similar to the two tissues. Assay of glutathione peroxidase in the heart after 6 wk of selenium depletion with both hydrogen peroxide and cumene hydroperoxide as substrates revealed a >80% drop in enzyme activity and gave no indication that murine cardiac tissue contains nonselenium-dependent glutathione peroxidase. The selenium-deficient state, which was characterized by markedly decreased cardiac glutathione peroxidase levels, led to significantly enhanced doxorubicin toxicity at a dose of 15 mg/kg i.p. Doxorubicin administration in selenium-sufficient animals resulted in a dose-dependent decrease in cardiac glutathione peroxidase activity; the decrease in enzyme activity lasted 72 h after 15 mg/kg i.p. In contrast, cardiac superoxide dismutase and hepatic superoxide dismutase and glutathione peroxidase were unaffected by this dose of doxorubicin. These results suggest that the major pathway in cardiac tissue for detoxification of reactive oxygen metabolites is via the concerted action of superoxide dismutase and selenium-dependent glutathione peroxidase. The latter enzyme may be depleted by a selenium-deficient diet or doxorubicin treatment, leaving the heart with limited mechanisms for disposing of hydrogen peroxide or lipid peroxides.

Suramin rapidly alters cellular tyrosine phosphorylation in prostate cancer cell lines.

Suramin, a synthetic polysulfonated anionic compound, is known to abrogate the activity of a variety of growth factors that serve as ligands for receptor-class protein-tyrosine kinases. Based on this information, we initially hypothesized that suramin treatment would be associated with decreased tyrosine phosphorylation. Upon testing this hypothesis in prostate cancer cell lines, we found that the most conspicuous effect of suramin was to increase the tyrosine phosphorylation of several distinct proteins. Further analyses indicate that suramin-induced increases in tyrosine phosphorylation represent a generalized, but not universal, phenomenon found in cell lines derived from a variety of human tissues. These rapid and specific suramin-induced alterations represent a novel finding for a non-polypeptide pharmaceutical agent and question the hypothesis that suramin exerts its antitumor action simply by abrogation of growth factor action.

Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine.

This study was undertaken to investigate the effect of exogenous sulfhydryl compound administration on the toxicity of doxorubicin in mice. Pretreatment of CDF1 mice with a pharmacologic dose (2,000 mg/kg) of n-acetyl-l-cysteine 1 h before doxorubicin (20 mg/kg, i.p.) decreased lethality from 100% (n = 44) to 37.7% (n = 53), P less than 0.001. Variation in the timing and dose of n-acetylcysteine significantly diminished its protective activity. Pretreatment with n-acetylcysteine also significantly reduced long-term mortality in animals receiving multiple doses of doxorubicin; 10 wk after the third of three doxorubicin doses (5 mg/kg, i.p.) administered at 2-wk intervals, survival in the n-acetylcysteine pretreated group was 51.4% (n = 35) compared with 16.7% (n = 30) for animals receiving saline before doxorubicin, P less than 0.01. In this experiment, n-acetylcysteine pretreatment also diminished doxorubicin-related losses in total body weight and heart wet weight by 55.2% (P less than 0.05), and 60.9% (P less than 0.02), respectively, compared with animals pretreated with saline. N-acetylcysteine pretreatment also ablated electron microscopic evidence of doxorubicin cardiomyopathy without alleviating morphological features of its toxic effects on the liver or small intestinal mucosa. The cardioprotective action of n-acetylcysteine may be partially explained by the 429 +/- 60% increase in cardiac nonprotein sulfhydryl content (P less than 0.01) that was measured one hour after n-acetylcysteine administration; nonprotein sulfhydryl concentration in the liver at the same time was insignificantly different from control levels. Treatment with n-acetylcysteine also increased the nonprotein sulfhydryl content of P388 leukemia cells nearly threefold; however, it did not after the chemotherapeutic activity of doxorubicin against this murine tumor. Whereas n-acetylcysteine blocked doxorubicin cardiac toxicity, it did not affect the uptake or metabolism of doxorubicin in the heart or liver. These results suggest that the concentration of free sulfhydryl groups in the heart may play a role in the development of doxorubicin cardiac toxicity and that augmenting cardiac nonprotein sulfhydryl group content with n-acetylcysteine may provide a means to enhance the chemotherapeutic index of doxorubicin.

P2-purinergic receptor agonists inhibit the growth of androgen-independent prostate carcinoma cells.

To develop a new approach to the treatment of advanced, hormone-refractory prostate cancer, the signal transductions regulating the growth of human androgen-independent prostate carcinoma cell lines were studied. Agonist-stimulated Ca2+ mobilization, a critical regulatory event in other secretory cell types, was studied as a means of identifying previously undescribed plasma membrane receptors that may transduce a growth inhibitory signal. In all of the cell lines tested, P2-purinergic receptor agonists, including ATP and certain hydrolysis-resistant adenine nucleotides, induced a rapid, transient increase in cytoplasmic free Ca2+ that was detectable at 50 to 100 nM ATP, was maximal at 100 microM ATP, and was inhibited approximately 50% by chelation of extracellular Ca2+. Within 8 s after addition, ATP stimulated accumulation of the polyphosphatidylinositol products inositol (1, 4, 5) trisphosphate, inositol (1, 3, 4) trisphosphate, and inositol tetrakisphosphate. In addition to stimulating phosphatidylinositol turnover and Ca2+ mobilization, ATP and hydrolysis-resistant ATP analogues induced greater than 90% inhibition of the growth of all lines tested. These data demonstrate that human androgen-independent prostate carcinoma cells express functional P2-purinergic receptors linked to phospholipase C, and that agonists of this receptor are markedly growth inhibitory, suggesting a novel therapeutic approach to this common adult neoplasm.

Conditional discrimination and reversal in amnesia subsequent to hypoxic brain injury or anterior communicating artery aneurysm rupture.

Human anterograde amnesia can develop following bilateral damage to the hippocampus and medial temporal lobes, as in hypoxic brain injury, or following damage to the basal forebrain, as following anterior communicating artery (ACoA) aneurysm rupture. In both cases, the mnestic deficit may be similar when assessed by standard neuropsychological measures. However, animal and computational models suggest that there are qualitative differences in the pattern of impaired and spared memory abilities following damage to hippocampus versus basal forebrain. Here, we show such a dissociation in human amnesia using a single two-stage task, involving conditional discrimination and reversal. Consistent with a prior study, 10 individuals with anterograde amnesia subsequent to hypoxic brain injury were spared on acquisition but impaired at reversal. However, 10 individuals with amnesia subsequent to ACoA aneurysm showed the opposite pattern of impaired acquisition but spared reversal. The differences between groups cannot be easily ascribed to severity of mnestic or cognitive deficit, since the two amnesic groups performed similarly on neuropsychological tests of memory, intelligence and attention. The results illustrate qualitative differences in memory impairments in hypoxic and ACoA amnesics and highlight the importance of considering etiology in evaluating mnemonic deficits in amnesic populations.

Synergistic activity of suramin with tumor necrosis factor alpha and doxorubicin on human prostate cancer cell lines.

We evaluated the action of suramin, doxorubicin, and tumor necrosis factor alpha (TNF-alpha) on the testosterone-responsive human prostate cell line LNCaP and on the testosterone-independent human prostate cell line PC-3. The synergistic action of these agents in combination was tested by the Chou and Talalay method (quantitative analysis of dose-effect relationships) to determine whether in vitro doses were active at levels safely achieved in vivo. The action of suramin was potentiated threefold by doxorubicin for the PC-3 line and seven-fold by doxorubicin for the LNCaP line. Both the suramin-TNF-alpha and the doxorubicin-TNF-alpha combinations showed synergistic action against the LNCaP line. Synergistic activity was noted at drug concentrations routinely achieved clinically. This study demonstrates that suramin, doxorubicin, and TNF-alpha are active agents against prostate cancer cell lines and that their activity can be enhanced when they are used in combination.

Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer.

BACKGROUND: The best treatment for patients with "hormone-refractory" metastatic prostate cancer is unclear, particularly in patients for whom suramin and hydrocortisone have failed. PURPOSE: We investigated a combination of flutamide withdrawal and aminoglutethimide in suramin- and hydrocortisone-pretreated patients with "hormone-refractory" prostate cancer. METHODS: Twenty-nine patients with metastatic prostate cancer were treated with simultaneous flutamide withdrawal and aminoglutethimide (250 mg given orally four times daily). All patients were taking flutamide at the time of entry, and previous treatments with medical or surgical castration, flutamide, suramin, and hydrocortisone had failed in all of these patients. Because of suramin-induced adrenal insufficiency, all patients had previously received, and continued to receive, physiological doses of hydrocortisone. Treatment of all non-surgically castrated patients had previously failed; however, these patients continued to receive depot leuprolide. RESULTS: In 14 (48%) of 29 patients, the prostate-specific antigen (PSA) decreased by more than 80% for 4 or more weeks. Improvements in anemia, thrombocytopenia, soft-tissue masses, bone scans, and symptoms were also noted. Factors associated with response included prolonged flutamide pretreatment, a markedly elevated pretreatment PSA, and the absence of soft-tissue disease. CONCLUSIONS: Flutamide withdrawal, when combined with the simultaneous administration of aminoglutethimide, is a therapeutically active approach in patients with "hormone-refractory" prostate cancer. IMPLICATIONS: On the basis of these and additional data, we hypothesize that prolonged exposure to flutamide results in the selective proliferation of cancer cells containing a mutant androgen receptor that aberrantly recognizes flutamide metabolites and nonandrogenic steroids as androgenic stimuli.