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A practical synthesis of a D1 potentiator chiral tetrahydroisoquinoline has been accomplished employing diastereoselective Pictet-Spengler methodology to access the required trans-stereochemistry. A dynamic kinetic resolution by crystallization gives high yields of a N-(phenylsulfonyl)alkyloxazolidinone that is converted to an acyl iminium ion when exposed to a variety of Lewis acids resulting in a highly diastereoselective Pictet-Spengler cyclization. An eight-step linear synthesis that starts with commercially available R-2-bromophenylalanine affords the chiral tetrahydroisoquinoline 1 in 54% overall yield.

Advances in drug potency and tailored therapeutics are promoting pharmaceutical manufacturing to transition from a traditional batch paradigm to more flexible continuous processing. Here we report the development of a multistep continuous-flow CGMP (current good manufacturing practices) process that produced 24 kilograms of prexasertib monolactate monohydrate suitable for use in human clinical trials. Eight continuous unit operations were conducted to produce the target at roughly 3 kilograms per day using small continuous reactors, extractors, evaporators, crystallizers, and filters in laboratory fume hoods. Success was enabled by advances in chemistry, engineering, analytical science, process modeling, and equipment design. Substantial technical and business drivers were identified, which merited the continuous process. The continuous process afforded improved performance and safety relative to batch processes and also improved containment of a highly potent compound.

A practical pilot plant convergent synthesis of MR antagonist LY2623091 was established. For synthesis convergence, a vinyl bromide geometric isomer and chiral alaninol derivative were required building blocks. Key to the synthesis route development is a stereoselective synthesis of the E-vinyl bromide via a sequential double Heck reaction, Suzuki–Miyaura cross-coupling of the vinyl bromide, a selective nitro reduction, and a highly sensitive cyanamide hydrolysis to the urea. Improvements in yield and processing were accomplished by two sets of telescoping methods which decreased the manufacturing time and provided purity enhancements.

A single-step method and a two-step method for the synthesis of aminopyrazoles from isoxazoles are presented and compared. Based on in situ NMR monitoring, both processes proceed through a ketonitrile. In the single-step process, hydrazine serves to both open the isoxazole to the unisolated ketonitrile intermediate and form the aminopyrazole. The two-step process involves ring opening of the isoxazole by deprotonation with hydroxide to generate the ketonitrile followed by the addition of acetic acid and hydrazine to form the aminopyrazole.

The synthesis of a MET kinase inhibitor in an overall yield of 22% was achieved over eight steps starting with 3-hydroxybenzaldehyde, an improvement from the initial 12-step process with a 5.4% yield. Highlights of the process chemistry design and development are a Cu-catalyzed cyclization to form an important N1-methylindazole ring, a selective nitro reduction in the presence of an aryl bromide, a late-stage Suzuki cross-coupling, and a base-promoted Boc deprotection to form the desired drug candidate.

A mechanistic approach was undertaken to understand the oxygen sensitivity of a Pd-catalyzed amination reaction used in the synthesis of an active pharmaceutical ingredient. FlowNMR and dissolved oxygen probes were used as process analytical technology alongside kinetic and unit operation models to better characterize the oxidative deactivation pathways of the catalyst. Interplay between ligand excess, oxygen inertion, and additional degassing due to reflux were all found to contribute to reaction rate variability. This mechanistic approach allowed for appreciation and clear communication of the risks, development of protocols to mitigate those risks, and successful scale-up under rapid development timelines.

Deuterium fueling experiments were conducted with the NSTX Liquid Lithium Divertor (LLD). Lithium evaporation recoated the LLD surface to approximate flowing liquid Li to sustain D retention. In the first experiment with the diverted outer strike point on the LLD, the difference between the applied D gas input and the plasma D content reached very high values without disrupting the plasma, as would normally occur in the absence of Li pumping, and there was also little change in plasma D content. In the second experiment, constant fueling was applied, as the LLD temperature was varied to change the surface from solid to liquid. The D retention was relatively constant, and about the same as that for solid Li coatings on graphite, or twice that achieved without Li PFC coatings. Contamination of the LLD surface was also possible due to compound formation and erosion and redeposition from carbon PFCs.

The scrape-off layer plasma at the tokamak region is characterized by open field lines and often contains large variations in plasma properties along these field-lines. Proper characterization of local plasma conditions is critical to assessing plasma–material interaction processes occurring at the target. Langmuir probes are frequently employed in tokamak divertors but are challenging to interpretation. A kinetic interpretation for Langmuir probes in NSTX has yielded non-Maxwellian electron distributions in the divertor characterized by cool bulk populations and energetic tail populations with temperatures of 2–4 times the bulk. Spectroscopic analysis and modeling confirms the bulk plasma temperature and density which can only be obtained with the kinetic interpretation.

Samples of the NSTX Liquid Lithium Divertor (LLD) with and without an evaporative Li coating were directly exposed to a neutral beam ex-situ at a power of ~1.5 MW/m2 for 1-3 seconds. Measurements of front face and bulk sample temperature were obtained. Predictions of temperature evolution were derived from a 1D heat flux model. No macroscopic damage occurred when the "bare" sample was exposed to the beam but microscopic changes to the surface were observed. The Li-coated sample developed a lithium hydroxide (LiOH) coating, which did not change even when the front face temperature exceeded the pure Li melting point. These results are consistent with the lack of damage to the LLD surface and imply that heating alone may not expose pure liquid Li if the melting point of surface impurities is not exceeded. This suggests that flow and heat are needed for future PFCs requiring a liquid Li surface. __________________________________________________

Food advertisements often promote choices that are driven by inferences about the hedonic pleasures of eating a particular food. Given the individual and public health consequences of obesity, it is critical to address unanswered questions about the specific neural systems underlying these hedonic inferences. For example, although regions such as the orbitofrontal cortex (OFC) are frequently observed to respond more to pleasant food images than less hedonically pleasing stimuli, one important hedonic brain region in particular has largely remained conspicuously absent among human studies of hedonic response to food images. Based on rodent research demonstrating that activity in the ventral pallidum underlies the hedonic pleasures experienced upon eating food rewards, one might expect that activity in this important 'hedonic hotspot' might also track inferred food pleasantness. To date, however, no human studies have assessed this question. We thus asked human subjects to undergo fMRI and make item-by-item ratings of how pleasant it would be to eat particular visually perceived foods. Activity in the ventral pallidum was strongly modulated with pleasantness inferences. Additionally, activity within a region of the orbitofrontal cortex that tracks the pleasantness of tastes was also modulated with inferred pleasantness. Importantly, the reliability of these findings is demonstrated by their replication when we repeated the experiment at a new site with new subjects. These two experiments demonstrate that the ventral pallidum, in addition to the OFC, plays a central role in the moment-to-moment hedonic inferences that influence food-related decision-making.

NSTX 2010 experiments were conducted using a molybdenum Liquid Lithium Divertor (LLD) surface installed on the outer part of the lower divertor. This tested the effectiveness of maintaining the deuterium retention properties of a static liquid lithium surface when refreshed by lithium evaporation as an approximation to a flowing liquid lithium surface. The LLD molybdenum front face has a 45% porosity to provide sufficient wetting to spread 37 g of lithium, and to retain it in the presence of magnetic forces. Lithium Evaporators were used to deposit lithium on the LLD surface. At the beginning of discharges, the LLD lithium surface ranged from solid to liquefied depending on the amount of applied and plasma heating. Noteworthy improvements in plasma performance were obtained similar to those obtained previously with lithiated graphite, e.g., ELM-free, quiescent edge, H-modes. During these experiments with the plasma outer strike point on the LLD, the rate of deuterium retention in the LLD, as indicated by the fueling needed to achieve and maintain stable plasma conditions, was the about the same as that for solid lithium coatings on the graphite prior to the installation of the LLD, i.e., about two times that of no-lithium conditions. The role of lithium impurities in this result is discussed. Following the 2010 experimental campaign, inspection of the LLD found mechanical damage to the plate supports, and other hardware resulting from forces following plasma current disruptions. The LLD was removed, upgraded, and reinstalled. A row of molybdenum tiles was installed inboard of the LLD for 2011 experiments with both inner and outer strike points on lithiated molybdenum to allow investigation of lithium plasma facing issues encountered in the first testing of the LLD.

Lithium wall coating techniques have been experimentally explored on National Spherical Torus Experiment (NSTX) for the last six years. The lithium experimentation on NSTX started with a few milligrams of lithium injected into the plasma as pellets and it has evolved to a dual lithium evaporation system which can evaporate up to ∼160 g of lithium onto the lower divertor plates between re-loadings. The unique feature of the NSTX lithium research program is that it can investigate the effects of lithium coated plasma-facing components in H-mode divertor plasmas. This lithium evaporation system has produced many intriguing and potentially important results. In 2010, the NSTX lithium program has focused on the effects of liquid lithium divertor (LLD) surfaces including the divertor heat load, deuterium pumping, impurity control, electron thermal confinement, H-mode pedestal physics, and enhanced plasma performance. To fill the LLD with lithium, 1300 g of lithium was evaporated into the NSTX vacuum vessel during the 2010 operations. The routine use of lithium in 2010 has significantly improved the plasma shot availability resulting in a record number of plasma shots in any given year. In this paper, as a follow-on paper from the 1st lithium symposium [1] , we review the recent progress toward developing fundamental understanding of the NSTX lithium experimental observations as well as the opportunities and associated R&D required for use of lithium in future magnetic fusion facilities including ITER.

Transient events such as Edge Localized Modes (ELMs) or disruptions can lead to large particle and power loads on the divertor plates of tokamak experiments. These events can cause significant erosion and are detrimental to the lifetime of the plasma facing components. Understanding the impact of ELMs remains a complex problem and a major challenge. In this study, an effort is made to characterize these ELMs and other transients based on their characteristics using a particle flux probe and surface temperature measurements from a dual-band IR camera. Typically, the temporal evolution of an ELM from the particle flux probe is characterized by a steep rise and a gradual decrease of current signal. This burst like structure is seen by the Langmuir probes as a rise in the ion saturation current with a width of a few milliseconds. This study entails gathering statistics of typical ELM-like events for various shots in order to assess the typical loading of ELMs on the Liquid Lithium Divertor (LLD) that was installed in the FY10 run campaign. Later, the power deposition profiles during ELMs are also characterized from IR camera measurements for certain discharges to find that only 15% of the energy flux arrives at the divertor target before the surface temperature reached its maximum value. Finally, a correlation was found between the particle flux from the probes during the ELMs and the neutral particle flux from Dα signal indicating the utility of the particle flux probe as a means to characterize ELMs.

The National Spherical Torus Experiment (NSTX) has recently studied the use of a liquid lithium divertor (LLD). Divertor Langmuir probes have also been installed for making measurements of the local plasma conditions. A non-local probe interpretation method is used to supplement the classical probe interpretation and obtain measurements of the electron energy distribution function (EEDF) which show the occurrence of a hot-electron component. Analysis is made of two discharges within a sequence that exhibited changes in plasma fueling efficiency. It is found that the local electron temperature increases and that this increase is most strongly correlated with the energy contained within the hot-electron population. Preliminary interpretative modeling indicates that kinetic effects are likely in the NSTX.

NSTX experiments have explored lithium evaporated on a graphite divertor and other plasma-facing components in both L- and H- mode confinement regimes heated by high-power neutral beams. Improvements in plasma performance have followed these lithium depositions, including a reduction and eventual elimination of the HeGDC time between discharges, reduced edge neutral density, reduced plasma density, particularly in the edge and the SOL, increased pedestal electron and ion temperature, improved energy confinement and the suppression of ELMs in the H-mode. However, with improvements in confinement and suppression of ELMs, there was a significant secular increase in the effective ion charge Zeff and the radiated power in H-mode plasmas as a result of increases in the carbon and medium-Z metallic impurities. Lithium itself remained at a very low level in the plasma core

Liquid metal plasma facing components (PFCs) have been identified as an alternative material for fusion plasma experiments. The use of a liquid conductor where significant magnetic fields are present is considered risky, with the possibility of macroscopic fluid motion and possible ejection into the plasma core. Analysis is carried out on thermoelectric magnetohydrodynamic (TEMHD) forces caused by temperature-gradients in the liquid-container system itself in addition to scrape-off-layer currents interacting with the PFC from a diverted plasma. Capillary effects at the liquid-container interface will be examined which govern droplet ejection criteria. Stability of the interface is determined using linear stability methods. In addition to application to liquid metal PFCs, thin film liquid metal effects have application to current and future devices where off-normal events may liquefy portions of the first wall and other plasma facing components.

Major developments on the Mega Amp Spherical Tokamak (MAST) have enabled important advances in support of ITER and the physics basis of a spherical tokamak (ST) based component test facility (CTF), as well as providing new insight into underlying tokamak physics. For example, L–H transition studies benefit from high spatial and temporal resolution measurements of pedestal profile evolution (temperature, density and radial electric field) and in support of pedestal stability studies the edge current density profile has been inferred from motional Stark effect measurements. The influence of the q-profile and E × B flow shear on transport has been studied in MAST and equilibrium flow shear has been included in gyro-kinetic codes, improving comparisons with the experimental data. H-modes exhibit a weaker q and stronger collisionality dependence of heat diffusivity than implied by IPB98(y,2) scaling, which may have important implications for the design of an ST-based CTF. ELM mitigation, an important issue for ITER, has been demonstrated by applying resonant magnetic perturbations (RMPs) using both internal and external coils, but full stabilization of type-I ELMs has not been observed. Modelling shows the importance of including the plasma response to the RMP fields. MAST plasmas with q > 1 and weak central magnetic shear regularly exhibit a long-lived saturated ideal internal mode. Measured plasma braking in the presence of this mode compares well with neo-classical toroidal viscosity theory. In support of basic physics understanding, high resolution Thomson scattering measurements are providing new insight into sawtooth crash dynamics and neo-classical tearing mode critical island widths. Retarding field analyser measurements show elevated ion temperatures in the scrape-off layer of L-mode plasmas and, in the presence of type-I ELMs, ions with energy greater than 500 eV are detected 20 cm outside the separatrix. Disruption mitigation by massive gas injection has reduced divertor heat loads by up to 70%.

Recent experiments on the National Spherical Torus eXperiment (NSTX) have shown the benefits of solid lithium coatings on carbon PFC's to diverted plasma performance, in both L- and H-mode confinement regimes. Better particle control, with decreased inductive flux consumption, and increased electron temperature, ion temperature, energy confinement time, and DD neutron rate were observed. Successive increases in lithium coverage resulted in the complete suppression of ELM activity in H-mode discharges. A liquid lithium divertor (LLD), which will employ the porous molybdenum surface developed for the LTX shell, is being installed on NSTX for the 2010 run period, and will provide comparisons between liquid walls in the Lithium Tokamak eXperiment (LTX) and liquid divertor targets in NSTX. LTX, which recently began operations at the Princeton Plasma Physics Laboratory, is the world's first confinement experiment with full liquid metal plasma-facing components (PFCs). All materials and construction techniques in LTX are compatible with liquid lithium. LTX employs an inner, heated, stainless steel-faced liner or shell, which will be lithium-coated. In order to ensure that lithium adheres to the shell, it is designed to operate at up to 500–600 °C to promote wetting of the stainless by the lithium, providing the first hot wall in a tokamak to operate at reactor-relevant temperatures. The engineering of LTX will be discussed.

NSTX high power divertor plasma experiments have used in succession lithium pellet injection (LPI), evaporated lithium, and injected lithium powder to apply lithium coatings to graphite plasma facing components. In 2005, following the wall conditioning and LPI, discharges exhibited edge density reduction and performance improvements. Since 2006, first one, and now two lithium evaporators have been used routinely to evaporate lithium onto the lower divertor region at total rates of 10-70 mg/min for periods 5-10 min between discharges. Prior to each discharge, the evaporators are withdrawn behind shutters. Significant improvements in the performance of NBI heated divertor discharges resulting from these lithium depositions were observed. These evaporators are now used for more than 80% of NSTX discharges. Initial work with injecting fine lithium powder into the edge of NBI heated deuterium discharges yielded comparable changes in performance. Several operational issues encountered with lithium wall conditions, and the special procedures needed for vessel entry are discussed. The next step in this work is installation of a liquid lithium divertor surface on the outer part of the lower divertor.

Two lithium evaporators were used to evaporate more than 100 g of lithium on to the NSTX lower divertor region. Prior to each discharge, the evaporators were withdrawn behind shutters, where they also remained during the subsequent HeGDC applied for periods up to 9.5 min. After the HeGDC, the shutters were opened and the LITERs were reinserted to deposit lithium on the lower divertor target for 10 min, at rates of 10–70 mg/min, prior to the next discharge. The major improvements in plasma performance from these lithium depositions include: (1) plasma density reduction as a result of lithium deposition; (2) suppression of ELMs; (3) improvement of energy confinement in a low-triangularity shape; (4) improvement in plasma performance for standard, high-triangularity discharges; (5) reduction of the required HeGDC time between discharges; (6) increased pedestal electron and ion temperature; (7) reduced SOL plasma density; and (8) reduced edge neutral density.

Recent National Spherical Tokamak Experiment (NSTX) high-power divertor experiments have shown significant and recurring benefits of solid lithium coatings on plasma facing components (PFCs) to the performance of divertor plasmas in both L- and H-mode confinement regimes heated by high-power neutral beams. The next step in this work is installation of a liquid lithium divertor (LLD) to achieve density control for inductionless current drive capability (e.g., about a 15–25% n e decrease from present highest non-inductionless fraction discharges which often evolve toward the density limit, n e / n GW ∼ 1), to enable n e scan capability (×2) in the H-mode, to test the ability to operate at significantly lower density (e.g., n e / n GW = 0.25), for future reactor designs based on the Spherical Tokamak, and eventually to investigate high heat-flux power handling (10 MW/m 2 ) with long pulse discharges (>1.5 s). The first step (LLD-1) physics design encompasses the desired plasma requirements, the experimental capabilities and conditions, power handling, radial location, pumping capability, operating temperature, lithium filling, MHD forces, and diagnostics for control and characterization.

Lithium evaporated onto plasma facing components in the NSTX lower divertor has made dramatic improvements in discharge performance. As lithium accumulated, plasmas previously exhibiting robust Type 1 ELMs gradually transformed into discharges with intermittent ELMs and finally into continuously evolving ELM-free discharges. During this sequence, other discharge parameters changed in a complicated manner. As the ELMs disappeared, energy confinement improved and remarkable changes in edge and scrape-off layer plasma properties were observed. These results demonstrate that active modification of plasma surface interactions can preempt large ELMs.

An efficient, scalable synthesis of the multipotent eicosanoid pathway modulator 2-[3-[3[[5-ethyl-4′-fluoro-2-hydroxyl[1,1′-biphenyl]-4-yl]oxy]-propoxy]2-propoxylphenoxy]benzoic acid (1) is described. The process consists of nine chemical steps with the longest linear sequence having six isolations. Palladium metal-mediated cross-coupling assembles the biaryl fragment, and selective SNAr chemistry is used to construct the resorcinol fragment. The synthesis converges at a phenolic coupling with an alkyl chloride to give the core structure of the active pharmaceutical ingredient (API). Further elaborations of the core and salt formation provides the final API. This process produced the drug candidate in 41% overall yield at multikilogram scale.

The synthesis of 5-bromo-thiophene-2-sulfonic acid 2,4-dichlorobenzoylamide sodium salt on multikilogram scale is described. The initial clinical supplies were made using carbonyl diimidazole to converge the two fragments. A more efficient acid chloride process has been developed, which also provides better control of impurities and color throughout the synthesis.

The present study examined auditory backward masking in a task requiring subjects to label a target sound as having a long or short duration. Perception of target duration was influenced by the interaction of the effects of (1) the similarity of the target/mask duration, (2) the acoustic similarity of the target and mask (tone vs. white noise), and (3) the interstimulus interval (ISI) between the target and mask. Specifically, relative to the long duration (100 ms) mask, the short duration (40 ms) mask helped performance for the target having a similar short duration (55 ms) but hurt performance for the target having a dissimilar long duration (85 ms). This effect of the similarity of target/mask duration was greater for acoustically similar targets and masks than for acoustically dissimilar targets and masks, and particularly so at the intermediate (45, 105, 165, 205 ms) ISIs. These results can be explained within the framework of Massaro and Idson's (1976) two-stage model by assuming that masking of perceived auditory duration is the result of two processes: (a) the mask's interruption of target processing in a peripheral auditory processing stage, and (b) a confusion of which item is the target vs. the mask, due to temporal uncertainty in the transfer of the target and mask into a central auditory processing stage.

The results of a preliminary study on the effects of reduced speech intelligibility on dual-task performance are reported. The speech task was a sentence-verification task, and speech degradation was accomplished using a narrowband digital voice-transmission system operating with and without random bit errors. The second task was a visual picture-sorting task. There was a dualtask decrement on the sorting task and, in addition, there was a further decrease in sorts per minute as the speech was increasingly degraded. Reaction time for the speech task increased with the concurrent sorting task, but the dual-task condition did not affect speech-task error rates.

Prevailing theories hold that the insula is functionally organized along its caudal-to-rostral axis, with posterior regions coding lower-level sensory information, and anterior regions coding higher-level stimulus significance relative to the body’s homeostatic needs. Contrary to predictions of this model, the response of the taste-sensitive region of the caudal, but not rostral, insula to food images was directly related to the body’s homeostatic state as indexed by levels of peripheral glucose.

LY426965 [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl- 2-phenyl-1-butanone monohydrochloride] is a novel compound with high affinity for the cloned human 5-hydroxytryptamine (HT)(1A) receptor (K(i) = 4.66 nM) and 20-fold or greater selectivity over other serotonin and nonserotonin receptor subtypes. Both in vitro and in vivo studies indicate that LY426965 is a full antagonist and has no partial agonist properties. LY426965 did not stimulate [(35)S]guanosine-5'-O-(3-thio) triphosphate (GTPgammaS) binding to homogenates of cells expressing the cloned human 5-HT(1A) receptor in vitro but did inhibit 300 nM 5-HT-stimulated [(35)S]GTPgammaS binding with a K(i) value of 3.07 nM. After both p.o. and s.c. administration, LY426965 blocked the lower lip retraction, flat body posture, hypothermia, and increase in rat serum corticosterone induced by the 5-HT(1A) agonist 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin). In pigeons, LY426965 dose-dependently blocked the stimulus cue induced by 8-OH-DPAT but had no 8-OH-DPAT-like discriminative properties. LY426965 completely reversed the effects of nicotine withdrawal on the auditory startle reflex in rats. In microdialysis experiments, LY426965 administered together with fluoxetine significantly increased extracellular levels of serotonin above those achievable with fluoxetine alone. In electrophysiological studies, the administration of LY426965 produced a slight elevation of the firing rate of 5-HT neurons in the dorsal raphe nucleus of anesthetized rats and both blocked and reversed the effects of fluoxetine on 5-HT neuronal activity. These preclinical results indicate that LY426965 is a selective, full 5-HT(1A) antagonist that may have clinical use as pharmacotherapy for smoking cessation and depression and related disorders.

LY354740 is a conformationally constrained analog of glutamate which is a potent agonist for group II cAMP coupled metabotropic glutamate receptors (mGluRs). The discovery of this novel pharmacological agent has allowed the exploration of the functional consequences of activating group II mGluRs in vivo. In an effort to evaluate the clinical utility of LY354740 as an anxiolytic, we examined its effects in the fear potentiated startle and elevated plus maze models of anxiety and compared the results with the clinically prescribed anxiolytic diazepam. In the fear potentiated startle and elevated plus maze models, both LY354740 and diazepam produced significant anxiolytic activity (ED50 values of 0.3 and 0.4 mg/kg p. o. for fear potentiated startle and 0.2 and 0.5 mg/kg for the elevated plus maze, respectively). The duration of pharmacological effect for LY354740 in the efficacy models was 4 to 8 hr. In contrast to diazepam, acute administration of LY354740 did not produce sedation, cause deficits in neuromuscular coordination, interact with central nervous system depressants, produce memory impairment or change convulsive thresholds at doses 100- to 1000-fold the efficacious doses in animal models of anxiety. Thus, LY354740 has anxiolytic activity in animal models that are sensitive to benzodiazepines such as diazepam. However, at anxiolytic doses in these models, LY354740 produced none of the unwanted secondary pharmacology associated with diazepam. These data indicate a functional role for group II mGluRs in fear/anxiety responses in animals and suggest that compounds in this class may be beneficial in the treatment of anxiety-related disorders in humans without the side effects seen with currently prescribed medications.

Withdrawal from the chronic administration of nicotine has previously been shown to lead to an enhanced auditory startle response in rats. In order to explore the neuropharmacology and neurophysiology underlying this phenomenon, we examined the effects of various 5-hydroxytryptamine (5-HT)-1A antagonists and agonists on the nicotine-withdrawal-enhanced auditory startle response in male rats. Animals were treated with nicotine (6 mg/kg/day nicotine base, via subcutaneously implanted osmotic minipumps) for 12 days. After 12 days the pumps were removed and the animals allowed to undergo spontaneous withdrawal for several days. In agreement with previous results, nicotine withdrawal led to a significant elevation of the auditory startle response. Pretreatment with the 5-HT-1A agonists (+)8-OH-DPAT (0.001-0.1 mg/kg) and LY274600 (0.3-3.0 mg/kg) either had no affect or exacerbated the nicotine-withdrawal-enhanced startle response. Pretreatment with the 5-HT-1A antagonists NAN-190 (1-3 mg/kg), LY206130 (1-10 mg/kg), or WAY-100635 (0.1-1.0 mg/kg) blocked the increase in the startle response caused by nicotine withdrawal at doses that had no effect on baseline startle responses. These data indicate that 5-HT-1A receptors play a role in the neurophysiology of nicotine withdrawal. In addition, 5-HT-1A antagonists may be able to relieve some nicotine withdrawal symptoms in man and may represent a novel pharmacotherapy for smoking cessation.

The present study examined the effects of bilateral 6-hydroxydopamine lesions in the ventrolateral striatum on the operant behavior of rats. Use of the specially modified operant chambers allowed the measurement of forelimb response force and duration as well as the time intervals between selected behavior in the press-consume-press sequence. More specifically, four time intervals between separate behavioral events were measured: 1) the time from the end of forelimb response to entry of muzzle into the reinforcement well, 2) the time from muzzle entry to the first tongue lick of the water reinforcer; 3) the time from the last lick to muzzle withdrawal from the reinforcement well, and 4) the time from muzzle withdrawal to the beginning of the next forelimb operant response. As determined by neurochemical (HPLC) analysis, the lesioned group exhibited dopamine levels that were 35% of the control group. The operant behavioral deficits were most profoundly appeared in the first week of postoperative test. Behaviorally, the lesioned group exhibited longer forelimb response durations (bradykinesia), and decrements were seen in both the number of muzzle entries and the number of recorded licks during reward consumption. Furthermore, the lesion significantly increased the average latency to switch from the forelimb response to the entry of the muzzle into the reward well. The latency from well entry to the first tongue extension to the reward was also increased by the lesion. These data support the view that the rodent neostriatum is important in the control of behavioral sequences for psychomotor function and at the same time demonstrate the utility of new quantitative behavioral methods for investigating such functions.

The selective neurokinin (NK)-1 antagonist LY303870 has high affinity and specificity for human and guinea pig brain NK-1 receptors labeled with 125I-substance P. It has approximately 15- to 30-fold lower affinity for rat and mouse brain NK-1 receptors, consistent with previously reported species differences in the affinities of nonpeptide antagonists for NK-1 receptors. In vivo, LY303870 blocked the characteristic, caudally directed, biting and scratching response elicited by intrathecal administration of the selective NK-1 agonist Ac-[Arg6,Sar9,Met(O2)11]substance P6-11 in conscious mice. The potentiation of the tail-flick response elicited by intrathecal administration of the NK-1 agonist [Sar9,Met(O2)11]substance P in rats was also selectively blocked by LY303870. When tested in a model of persistent nociceptive activation induced by tissue injury (the formalin test), LY303870 blocked licking behavior in the late phase of the formalin test, in a dose-dependent manner. After oral administration of 10 mg/kg, the blockade of the late-phase licking behavior was evident for at least 24 hr. Ex vivo binding studies in guinea pigs showed that orally administered LY303870 potently inhibited binding to central and peripheral NK-1 receptors labeled with 125I-substance P. This inhibition was long-lasting, consistent with other in vivo activities. LY306155, the opposite enantiomer of LY303870, was less active in all of the functional assays. In rodents, LY303870 did not exhibit any neurological, motor, cardiovascular, gastrointestinal or autonomic side effects at doses ofor = 50 mg/kg p.o. Thus, LY303870 is a potent, centrally active, NK-1 antagonist in vivo, with long-lasting oral activity.

Developing a reactor-compatible divertor has been identified as a particularly challenging technology problem for magnetic confinement fusion. Application of lithium (Li) in NSTX resulted in improved H-mode confinement, H-mode power threshold reduction, and other plasma performance benefits. During the 2010 NSTX campaign, application of a relatively modest amount of Li (300 mg prior to the discharge) resulted in a ∼50% reduction in heat load on the liquid lithium divertor (LLD) attributable to enhanced divertor bolometric radiation. These promising Li results in NSTX and related modelling calculations motivated the radiative LLD concept proposed here. Li is evaporated from the liquid lithium (LL) coated divertor strike-point surface due to the intense heat flux. The evaporated Li is readily ionized by the plasma due to its low ionization energy, and the poor Li particle confinement near the divertor plate enables ionized Li ions to radiate strongly, resulting in a significant reduction in the divertor heat flux. This radiative process has the desired effect of spreading the localized divertor heat load to the rest of the divertor chamber wall surfaces, facilitating the divertor heat removal. The LL coating of divertor surfaces can also provide a ‘sacrificial’ protective layer to protect the substrate solid material from transient high heat flux such as the ones caused by the edge localized modes. By operating at lower temperature than the first wall, the LL covered large divertor chamber wall surfaces can serve as an effective particle pump for the entire reactor chamber, as impurities generally migrate towards lower temperature LL divertor surfaces. To maintain the LL purity, a closed LL loop system with a modest circulating capacity (e.g., ∼1 l s−1 for ∼1% level ‘impurities’) is envisioned for a steady-state 1 GW-electric class fusion power plant.

Large-scale WDM systems contain wavelength-selective filters, switches and multiplexers which must be tolerant of moderate wavelength channel misalignment and can be cascaded without severe accumulated shrinkage of the effective passband width. These requirements demand that wavelength-selective components possess nearly rectangular spectral profiles. In this paper, we describe the flattest acousto-optic wavelength-routing switch yet reported. A multi-cycle SAW directional-coupler-weighted AOTF was fabricated on XY lithium niobate which posessed a 3-dB width of 2.52 nm and a -20-dB width of 0.89 run. For comparison, an ideal apodized AOTF with the same 3-dB width would have a -20 dB width of only 0.33 nm. In this paper we describe WDM switch ; requirements for transmission band flatness, present our filter design and device evaluation and compare our results with the work of previous authors.

[Lys(B28),Pro(B29)]-human insulin (insulin lispro, CAS 133107-64-9, LY275585, Humalog) is a quick acting insulin analog which is currently undergoing clinical evaluation for the treatment of diabetes. The potential secondary pharmacological activity of insulin lispro was profiled in studies for the evaluation of effects on the central and autonomic nervous system, the cardiovascular system, urine and electrolyte excretion, and gastrointestinal function. In vivo doses ranged from 0.03 to 10 U/kg, administered by the subcutaneous route, while pharmacologic activity in vitro was examined in smooth and cardiac muscle at concentrations of 1 x 10(-9) to 1 x 10(-5) mol/l. Insulin lispro exhibited secondary pharmacological activity in central nervous system tests only at higher doses with the most prominent observations being sedation and decreased responsiveness. Insulin lispro was essentially inactive in tests of autonomic (smooth and cardiac muscle), cardiovascular (mean arterial pressure, heart rate, systolic pressure, diastolic pressure, and pulse pressure), renal (urine and electrolyte excretion) and gastrointestinal (motility) function. In summary, insulin lispro had minimal effect in these pharmacodynamic studies indicating that insulin lispro has minimal potential to produce adverse pharmacological side effects at clinically relevant doses.

The effects of trimethyltin (TMT) on behavioral and histological parameters were investigated in rats maintained on low, mid, and high levels of ascorbic acid (AA). Male osteogenic disorder Shionogi (ODS) rats were used. Like man, ODS rats are unable to synthesize AA. AA was administered in the drinking water. Radial arm maze (RAM) performance and locomotor activity were measured before (i.e., baseline) and after (i.e., retest) TMT administration. During baseline, all rats learned the RAM task. Also during baseline, locomotor activity of rats maintained on high levels of AA was found to be lower than the other groups. After administration of 7.5 mg/kg TMT chloride (p.o.), RAM performance of all the groups declined, but RAM performance of rats maintained on low levels of AA appeared least affected by TMT. Also, rats in the high AA group had a significant increase in locomotor activity compared to baseline. These results suggest that in the ODS rat, TMT toxicity may be influenced by levels of AA intake.

A dense array of 99 Langmuir probes has been installed in the lower divertor region of the National Spherical Torus Experiment (NSTX). This array is instrumented with a system of electronics that allows flexibility in the choice of probes to bias as well as the type of measurement (including standard swept, single probe, triple probe, and operation as passive floating potential and scrape-off-layer SOL current monitors). The use of flush-mounted probes requires careful interpretation. The time dependent nature of the SOL makes swept-probe traces difficult to interpret. To overcome these challenges, the single- and triple-Langmuir probe signals are used in complementary fashion to determine the temperature and density at the probe location. A comparison to midplane measurements is made.

The low-aspect ratio, low magnetic field and wide range of plasma beta of NSTX plasmas provide new insight into the origins and effects of magnetic field errors. An extensive array of magnetic sensors has been used to analyse error fields, to measure error-field amplification and to detect resistive wall modes (RWMs) in real time. The measured normalized error-field threshold for the onset of locked modes shows a linear scaling with plasma density, a weak to inverse dependence on toroidal field and a positive scaling with magnetic shear. These results extrapolate to a favourable error-field threshold for ITER. For these low-beta locked-mode plasmas, perturbed equilibrium calculations find that the plasma response must be included to explain the empirically determined optimal correction of NSTX error fields. In high-beta NSTX plasmas exceeding the n = 1 no-wall stability limit where the RWM is stabilized by plasma rotation, active suppression of n = 1 amplified error fields and the correction of recently discovered intrinsic n = 3 error fields have led to sustained high rotation and record durations free of low-frequency core MHD activity. For sustained rotational stabilization of the n = 1 RWM, both the rotation threshold and the magnitude of the amplification are important. At fixed normalized dissipation, kinetic damping models predict rotation thresholds for RWM stabilization to scale nearly linearly with particle orbit frequency. Studies for NSTX find that orbit frequencies computed in general geometry can deviate significantly from those computed in the high-aspect ratio and circular plasma cross-section limit, and these differences can strongly influence the predicted RWM stability. The measured and predicted RWM stability is found to be very sensitive to the E × B rotation profile near the plasma edge, and the measured critical rotation for the RWM is approximately a factor of two higher than predicted by the MARS-F code using the semi-kinetic damping model.