Comparing pedestal structure in JET-ILW H-mode plasmas with a model for stiff ETG turbulent heat transport.

A predictive model for the electron temperature profile of the H-mode pedestal is described, and its results are compared with the pedestal structure of JET-ILW plasmas. The model is based on a scaling for the gyro-Bohm normalized, turbulent electron heat flux [Formula: see text] resulting from electron temperature gradient (ETG) turbulence, derived from results of nonlinear gyrokinetic (GK) calculations for the steep gradient region. By using the local temperature gradient scale length [Formula: see text] in the normalization, the dependence of [Formula: see text] on the normalized gradients [Formula: see text] and [Formula: see text] can be represented by a unified scaling with the parameter [Formula: see text], to which the linear stability of ETG turbulence is sensitive when the density gradient is sufficiently steep. For a prescribed density profile, the value of [Formula: see text] determined from this scaling, required to maintain a constant electron heat flux [Formula: see text] across the pedestal, is used to calculate the temperature profile. Reasonable agreement with measurements is found for different cases, the model providing an explanation of the relative widths and shifts of the [Formula: see text] and [Formula: see text] profiles, as well as highlighting the importance of the separatrix boundary conditions. Other cases showing disagreement indicate conditions where other branches of turbulence might dominate. This article is part of a discussion meeting issue 'H-mode transition and pedestal studies in fusion plasmas'.

Pembrolizumab as first-line therapy for patients with PD-L1-positive advanced non-small cell lung cancer: a phase 1 trial.

Background: Pembrolizumab improved survival as first- and second-line therapy compared with chemotherapy in patients with highly programmed death ligand 1 (PD-L1) expressing advanced non-small cell lung cancer (NSCLC). We report the long-term safety and clinical activity of pembrolizumab as first-line therapy for patients with advanced NSCLC and the correlation between PD-L1 expression and efficacy. Patients and methods: In the open-label phase 1b KEYNOTE-001 trial, treatment-naive patients with advanced NSCLC whose tumors expressed PD-L1 (≥1% staining, assessed using a prototype assay) were randomly assigned to intravenous pembrolizumab 2 or 10 mg/kg every 3 (Q3W) or 2 (Q2W) weeks. Response was assessed per central RECIST v1.1 every 9 weeks in all patients who received ≥1 pembrolizumab dose. Using pre-treatment tumor tissue, a clinical assay quantified the percentage of tumor cells expressing PD-L1 as tumor proportion score (TPS). Results: Between 1 March 2013 and 18 September 2015, 101 patients received pembrolizumab 2 mg/kg Q3W (n = 6), 10 mg/kg Q3W (n = 49), or 10 mg/kg Q2W (n = 46). Of these, 27 (26.7%) had TPS ≥50%, 52 (51.5%) had TPS 1%-49%, and 12 (11.9%) had TPS <1%. The objective response rate (ORR) was 27% (27/101, 95% CI 18-37) and median overall survival was 22.1 months (95% CI 17.1-27.2). In patients with PD-L1 TPS ≥50%, ORR, 12-month PFS, and 12-month OS were higher [14/27 (51.9%; 95% CI 32%-71%), 54%, and 85%, respectively] than the overall population [27/101 (26.7%; 95% CI 18.4%-36.5%), 35%, 71%]. Pembrolizumab was well tolerated, with only 12 (11.9%) patients experiencing grade 3/4 treatment-related adverse events and no treatment-related deaths. Conclusions: Pembrolizumab provides promising long-term OS benefit with a manageable safety profile for PD-L1-expressing treatment-naive advanced NSCLC, with greatest efficacy observed in patients with TPS ≥50%. Clinical trial name and number: KEYNOTE-001 (ClinicalTrials.gov, NCT01295827).

Temporary alterations to postpartum milking frequency affect whole-lactation milk production and the energy status of pasture-grazed dairy cows.

This study investigated the immediate and long-term effects of temporary alterations to postpartum milking frequency (MF) on milk production, body condition score (BCS), and indicators of energy status in pasture-grazed cows supplemented with concentrates. Multiparous Holstein-Friesian cows (n = 150) were randomly assigned to 1 of 5 groups at calving: milked twice daily (2 ×) throughout lactation (control), or milked either once daily (1 ×) or 3 times daily (3 ×) for 3 or 6 wk immediately postpartum, and then 2 × for the remainder of lactation. During wk 1 to 3 postpartum, cows milked 1 × produced 15% less milk and 17% less energy-corrected milk (ECM) than cows milked 2 ×. This immediate production loss increased to 20% less milk and 22% less ECM during wk 4 to 6 postpartum for cows that remained on 1 × milking; these animals also produced less than 1 × cows switched to 2 × milking after 3 wk. During wk 8 to 32, when all cows were milked 2 ×, those previously milked 1 × had sustained reductions in milk (-6%) and ECM (-8%) yields, which were not affected by the duration of reduced postpartum MF. In contrast, cows milked 3 × postpartum had 7% greater milk yields during wk 1 to 6 compared with 2 × controls, irrespective of the duration of increased MF. Milk yields also remained numerically greater (+5%) during wk 8 to 32 in cows previously milked 3 ×. Nevertheless, yields of ECM were not increased by 3 × milking, because of lower milk fat and protein contents that persisted for the rest of lactation. In addition, indicators of cow energy status reflected an increasing state of negative energy balance with increasing MF. Cows milked 1 × postpartum had greater plasma glucose and lower plasma nonesterified fatty acid concentrations during the reduced MF, and plasma glucose remained lower for 2 wk after cows had switched to 2 × milking. Moreover, BCS was improved relative to 2 × controls from wk 5 to 6. In contrast, cows milked 3 × had lower plasma glucose concentrations, greater plasma nonesterified fatty acid concentrations, and greater BCS loss during wk 1 to 3; however, greater body fat mobilization was not sustained, indicating that additional energy supplements may be required to achieve better milk production responses. In conclusion, temporary 1 × milking had lactation-long negative effects on milk and milk component yields but improved cow energy status and BCS, whereas temporary 3 × milking immediately increased milk yield but did not improve milk fat and protein yields in pasture-grazed cows.

Kinetic instabilities that limit ß in the edge of a tokamak plasma: a picture of an H-mode pedestal.

Plasma equilibria reconstructed from the Mega-Amp Spherical Tokamak have sufficient resolution to capture plasma evolution during the short period between edge-localized modes (ELMs). Immediately after the ELM, steep gradients in pressure, P, and density, n(e), form pedestals close to the separatrix, and they then expand into the core. Local gyrokinetic analysis over the ELM cycle reveals the dominant microinstabilities at perpendicular wavelengths of the order of the ion Larmor radius. These are kinetic ballooning modes in the pedestal and microtearing modes in the core close to the pedestal top. The evolving growth rate spectra, supported by gyrokinetic analysis using artificial local equilibrium scans, suggest a new physical picture for the formation and arrest of this pedestal.

Zero-turbulence manifold in a toroidal plasma.

Sheared toroidal flows can cause bifurcations to zero-turbulent-transport states in tokamak plasmas. The maximum temperature gradients that can be reached are limited by subcritical turbulence driven by the parallel velocity gradient. Here it is shown that q/ϵ (magnetic field pitch/inverse aspect ratio) is a critical control parameter for sheared tokamak turbulence. By reducing q/ϵ, far higher temperature gradients can be achieved without triggering turbulence, in some instances comparable to those found experimentally in transport barriers. The zero-turbulence manifold is mapped out, in the zero-magnetic-shear limit, over the parameter space (γ(E), q/ϵ, R/L(T)), where γ(E) is the perpendicular flow shear and R/L(T) is the normalized inverse temperature gradient scale. The extent to which it can be constructed from linear theory is discussed.

Turbulent transport in tokamak plasmas with rotational shear.

Nonlinear gyrokinetic simulations are conducted to investigate turbulent transport in tokamak plasmas with rotational shear. At sufficiently large flow shears, linear instabilities are suppressed, but transiently growing modes drive subcritical turbulence whose amplitude increases with flow shear. This leads to a local minimum in the heat flux, indicating an optimal E×B shear value for plasma confinement. Local maxima in the momentum fluxes are observed, implying the possibility of bifurcations in the E×B shear. The critical temperature gradient for the onset of turbulence increases with flow shear at low flow shears; at higher flow shears, the dependence of heat flux on temperature gradient becomes less stiff. The turbulent Prandtl number is found to be largely independent of temperature and flow gradients, with a value close to unity.

Whole-brain dynamic CT angiography and perfusion imaging.

The availability of whole brain computed tomography (CT) perfusion has expanded the opportunities for analysing the haemodynamic parameters associated with varied neurological conditions. Examples demonstrating the clinical utility of whole-brain CT perfusion imaging in selected acute and chronic ischaemic arterial neurovascular conditions are presented. Whole-brain CT perfusion enables the detection and focused haemodynamic analyses of acute and chronic arterial conditions in the central nervous system without the limitation of partial anatomical coverage of the brain.

Transport bifurcation in a rotating tokamak plasma.

The effect of flow shear on turbulent transport in tokamaks is studied numerically in the experimentally relevant limit of zero magnetic shear. It is found that the plasma is linearly stable for all nonzero flow shear values, but that subcritical turbulence can be sustained nonlinearly at a wide range of temperature gradients. Flow shear increases the nonlinear temperature gradient threshold for turbulence but also increases the sensitivity of the heat flux to changes in the temperature gradient, except over a small range near the threshold where the sensitivity is decreased. A bifurcation in the equilibrium gradients is found: for a given input of heat, it is possible, by varying the applied torque, to trigger a transition to significantly higher temperature and flow gradients.

An unexpected extended conformation for the third TPR motif of the peroxin PEX5 from Trypanosoma brucei.

A number of helix-rich protein motifs are involved in a variety of critical protein-protein interactions in living cells. One of these is the tetratrico peptide repeat (TPR) motif that is involved, amongst others, in cell cycle regulation, chaperone function and post-translation modifications. So far, these helix-rich TPR motifs have always been observed to be a compact unit of two helices interacting with each other in antiparallel fashion. Here, we describe the structure of the first three TPR-motifs of the peroxin PEX5 from Trypanosoma brucei, the causative agent of sleeping sickness. Peroxins are proteins involved in peroxisome, glycosome and glyoxysome biogenesis. PEX5 is the receptor of the proteins targeted to these organelles by the "peroxisomal targeting signal-1", a C-terminal tripeptide called PTS-1. The first two of the three TPR-motifs of T. brucei PEX5 appear to adopt the canonical antiparallel helix hairpin structure. In contrast, the third TPR motif of PEX5 has a dramatically different conformation in our crystals: the two helices that were supposed to form a hairpin are folded into one single 44 A long continuous helix. Such a conformation has never been observed before for a TPR motif. This raises interesting questions including the potential functional importance of a "jack-knife" conformational change in TPR motifs.

Lovastatin biosynthesis in Aspergillus terreus: characterization of blocked mutants, enzyme activities and a multifunctional polyketide synthase gene.

BACKGROUND: Lovastatin, an HMG-CoA reductase inhibitor produced by the fungus Aspergillus terreus, is composed of two polyketide chains. One is a nonaketide that undergoes cyclization to a hexahydronaphthalene ring system and the other is a simple diketide, 2-methylbutyrate. Fungal polyketide synthase (PKS) systems are of great interest and their genetic manipulation should lead to novel compounds. RESULTS: An A. terreus mutant (BX102) was isolated that could not synthesize the nonaketide portion of lovastatin and was missing a approximately 250 kDa polypeptide normally present under conditions of lovastatin production. Other mutants produced lovastatin intermediates without the methylbutyryl sidechain and were missing a polypeptide of approximately 220 kDa. The PKS inhibitor cerulenin reacted covalently with both polypeptides. Antiserum raised against the approximately 250 kDa polypeptide was used to isolate the corresponding gene, which complemented the BX102 mutation. The gene encodes a polypeptide of 269 kDa containing catalytic domains typical of vertebrate fatty acid and fungal PKSs, plus two additional domains not previously seen in PKSs: a centrally located methyltransferase domain and a peptide synthetase elongation domain at the carboxyl terminus. CONCLUSIONS: The results show that the nonaketide and diketide portions of lovastatin are synthesized by separate large multifunctional PKSs. Elucidation of the primary structure of the PKS that forms the lovastatin nonaketide, as well as characterization of blocked mutants, provides new details of lovastatin biosynthesis.

Crystal structure of heat-labile enterotoxin from Escherichia coli with increased thermostability introduced by an engineered disulfide bond in the A subunit.

Cholera toxin (CT) produced by Vibrio cholerae and heat-labile enterotoxin (LT-I), produced by enterotoxigenic Escherichia coli, are AB5 heterohexamers with an ADP-ribosylating A subunit and a GM1 receptor binding B pentamer. These toxins are among the most potent mucosal adjuvants known and, hence, are of interest both for the development of anti-diarrheal vaccines against cholera or enterotoxigenic Escherichia coli diarrhea and also for vaccines in general. However, the A subunits of CT and LT-I are known to be relatively temperature sensitive. To improve the thermostability of LT-I an additional disulfide bond was introduced in the A1 subunit by means of the double mutation N40C and G166C. The crystal structure of this double mutant of LT-I has been determined to 2.0 A resolution. The protein structure of the N40C/G166C double mutant is very similar to the native structure except for a few local shifts near the new disulfide bond. The introduction of this additional disulfide bond increases the thermal stability of the A subunit of LT-I by 6 degrees C. The enhancement in thermostability could make this disulfide bond variant of LT-I of considerable interest for the design of enterotoxin-based vaccines.

Diazepam loading: simplified treatment of alcohol withdrawal.

Alcohol withdrawal therapy can be simplified with a loading dose of diazepam, taking advantage of the kinetic tapering afforded by the drug's long t 1/2s and its metabolites, and of the effectiveness of nonpharmacologic maneuvers. In a double-blind trial, 50 inpatients in moderate to severe alcohol withdrawal received 20 mg oral diazepam and supportive care (n = 25) or placebo and supportive care (n = 25) every 2 hr until they were asymptomatic. Fifty-six percent of patients responded to placebo within 5 +/- 2.9 hr (mean +/- SD), whereas 72% responded to initial diazepam within 6.3 +/- 3.9 hr. Patients treated with diazepam had more rapid and greater improvement than those treated with placebo. Patients who did not respond to six doses of diazepam received further (unblinded) diazepam, 20 mg, every 1 to 2 hr. All patients who did not initially respond (n = 18) improved after more diazepam. Thus all patients who received diazepam (n = 36), during the experimental phase or subsequently, were effectively treated. There were no adverse effects. The median number of 20-mg diazepam doses to treat alcohol withdrawal were three, given over a period of 7.6 hr (range = 1 to 12 and 0.33 to 45 hr). Complications occurred only in those who received placebo during the experimental phase, indicating that delay in therapy may be responsible for the appearance of complications in alcohol withdrawal.

Nonpharmacologic intervention in acute alcohol withdrawal.

The importance of nonpharmacologic and pharmacologic interventions in the treatment of alcohol withdrawal is not known. A randomized, double-blind, placebo-controlled trial was conducted with 41 patients in alcohol withdrawal in an emergency department. The patients received either supportive care (10 min of standardized assessments, reassurance, reality orientation, and nursing care an hour) with three doses of sublingual lorazepam 2 mg every 2 hr (21 patients, drug group) or supportive care with three doses of sublingual placebo every 2 hr (20 patients, no-drug group). Immediately before each drug dose, the clinical course of alcohol withdrawal was assessed hourly by the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-A). Interraters reliability in using CIWA-A was high. After each assessment, supportive care was given for 10 min before each dose. After completion of a 7-hr initial phase, patients were discharged and reassessed daily for 5 days. Thirty-seven patients (90.2%) improved in the initial phase. Treatment failures (CIWA-A greater than 10) were more common in the patients treated without drug (3/20, 15%) than in those treated with drug (1/21, 4.8%). Overall variations in intergroup CIWA-A scores during the initial phase were not significant. The rate of improvement of CIWA-A scores over the first 2 hr after drug was slightly faster in patients receiving lorazepam than in the control group. CIWA-A scores were the same during follow-up. These results indicate that most outpatients in mild to moderate alcohol withdrawal without medical complications improve without drug therapy in the emergency department setting.

Zimelidine-induced variations in alcohol intake by nondepressed heavy drinkers.

The effect of zimelidine, a specific serotonin-reuptake inhibitor, on alcohol intake was tested in 13 healthy male, nondepressed heavy drinkers who were randomly allocated to receive zimelidine or placebo in a double-blind, crossover experiment. There were five 2-wk experimental periods (baseline, placebo 1 and 2, and zimelidine 1 and 2). Treatment was discontinued in three subjects due to a suspected adverse reaction and three other subjects dropped out. Thus, 13 subjects participated in at least two experimental drug periods and only 10 participated in all the periods. In the 13 subjects zimelidine increased the days of abstinence and decreased the daily number of drinks consumed, whereas in the 10 subjects only the number of days of abstinence increased. Subjects did not report aversive alcohol-sensitizing reactions. Spielberger state-anxiety test scores and depression scores (Montgomery/Asberg and Hamilton) were low at the beginning and throughout the study. Our data suggest that zimelidine modifies alcohol intake by a different mechanism than previously tested drugs, possibly by modulating the central neural mechanism that controls drinking of alcohol.

Pavlovian control of cross-tolerance between pentobarbital and ethanol.

Tolerance to several effects of a number of drugs has been shown to depend on Pavlovian conditioning processes. Experiment I extended the compensatory conditioning model (Siegel 1975) to tolerance to the hypothermic effect of pentobarbital (30 mg/kg). In Experiment I, rats that acquired hypothermic tolerance in one environment did not display tolerance when tested in an environment not previously associated with drug administration. In Experiment II, rats were made tolerant to the hypothermic effect of pentobarbital (30 mg/kg) and tested for cross-tolerance to ethanol (2.5 g/kg). Cross-tolerance was observed, but it was significantly reduced if the test was in an environment different from the one in which tolerance to pentobarbital was originally acquired. Thus, the compensatory conditioning model accounts for at least part of the tolerance and cross-tolerance to the thermic effects of alcohol and pentobarbital. The physiological processes in the CNS underlying tolerance and cross-tolerance for these drugs, therefore, are controlled by associative processes.

Mutants of Streptomyces cattleya defective in the synthesis of a factor required for thienamycin production.

Thienamycin non-producing mutants of Streptomydes cattleya were identified that displayed a cross-feeding relationship. A diffusible product from one of these mutants (RK-11) resulted in restoration of thienamycin production when fed to cultures of another mutant (RK-4). In vivo radiolabeling experiments were conducted to test whether the RK-11 mutant produced a late biosynthetic intermediate which contained a carbapenem ring and a cysteaminyl and/or a hydroxyethyl side chain. Both [35S]cystine and [methyl-3H]methionine were used to label the RK-11 product which was then fed to RK-4 cultures. None of the thienamycin subsequently produced by RK-4 converter cells was labeled, implying the lack of either side chain of the thienamycin molecule in the RK-11 product. Further stability studies suggested that the RK-11 product does not contain a carbapenem ring. Additional feeding experiments with RK-4 cells also ruled out the possibility that the RK-11 product is a co-factor necessary for thienamycin production. It is concluded that the RK-11 product may regulate expression of the thienamycin gene cluster.

Serological survey of ruminant livestock in some countries of the Caribbean region and South America for antibody to bluetongue virus.

A serological survey of 6250 sera from cattle, sheep and goats in seven Caribbean and two South American countries showed that antibody to bluetongue virus was widely distributed in each species throughout the survey area. Overall prevalences of antibody were 70 per cent in cattle, 67 per cent in sheep and 76 per cent in goats as assessed by an immunodiffusion test. Within countries the percentage prevalences were Jamaica 77, St Kitts/Nevis 70, Antigua 76, St Lucia 82, Barbados 61, Grenada 88, Trinidad and Tobago 79, Guyana 52 and Surinam 84. No clinical cases of bluetongue have been confirmed in the area surveyed and there are no virus isolates available to indicate which serotype(s) of virus is/are causing the infection(s).

Serological survey of ruminants in some Caribbean and South American countries for type-specific antibody to bluetongue and epizootic haemorrhagic disease viruses.

The results of a serological survey of ruminant livestock in some countries of the Caribbean and South America for type-specific antibody to bluetongue virus are reported. Using the microneutralisation test with the international serotypes 1 to 22 of bluetongue virus, antibodies to several types were detected. Analysis of the data indicated that in 1981-82 bluetongue virus types 6, 14 and 17, or viruses closely related to them, were infecting ruminants in this region of the world. Antibody to the related virus of epizootic haemorrhagic disease (serotype 1) was also detected in cattle. The difficulty in interpreting the epidemiological significance of data generated by a serological survey of this kind is discussed.