Human pluripotent stem cells (PSCs) exist in naive and primed states and provide important models to investigate the earliest stages of human development. Naive cells can be obtained through ...primed-to-naive resetting, but there are no reliable methods to prospectively isolate unmodified naive cells during this process. Here we report comprehensive profiling of cell surface proteins by flow cytometry in naive and primed human PSCs. Several naive-specific, but not primed-specific, proteins were also expressed by pluripotent cells in the human preimplantation embryo. The upregulation of naive-specific cell surface proteins during primed-to-naive resetting enabled the isolation and characterization of live naive cells and intermediate cell populations. This analysis revealed distinct transcriptional and X chromosome inactivation changes associated with the early and late stages of naive cell formation. Thus, identification of state-specific proteins provides a robust set of molecular markers to define the human PSC state and allows new insights into the molecular events leading to naive cell resetting.
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•Flow cytometry profiles cell surface proteins in naive and primed human PSCs•The human PSC state can be defined using robust state-specific protein markers•Identified cell surface proteins track the dynamics of naive-primed PSC conversions•Analyses of early-stage naive cells reveal transcription events during conversion
Collier et al. use profiling to identify cell surface proteins that are specific for naive versus primed human pluripotent cells and then use them to isolate and characterize live naive cells arising during primed-to-naive resetting.
We describe the design and performance of the near-infrared (1.51-1.70 m), fiber-fed, multi-object (300 fibers), high resolution (R = λ/Δλ ∼ 22,500) spectrograph built for the Apache Point ...Observatory Galactic Evolution Experiment (APOGEE). APOGEE is a survey of ∼105 red giant stars that systematically sampled all Milky Way populations (bulge, disk, and halo) to study the Galaxy's chemical and kinematical history. It was part of the Sloan Digital Sky Survey III (SDSS-III) from 2011 to 2014 using the 2.5 m Sloan Foundation Telescope at Apache Point Observatory, New Mexico. The APOGEE-2 survey is now using the spectrograph as part of SDSS-IV, as well as a second spectrograph, a close copy of the first, operating at the 2.5 m du Pont Telescope at Las Campanas Observatory in Chile. Although several fiber-fed, multi-object, high resolution spectrographs have been built for visual wavelength spectroscopy, the APOGEE spectrograph is one of the first such instruments built for observations in the near-infrared. The instrument's successful development was enabled by several key innovations, including a "gang connector" to allow simultaneous connections of 300 fibers; hermetically sealed feedthroughs to allow fibers to pass through the cryostat wall continuously; the first cryogenically deployed mosaic volume phase holographic grating; and a large refractive camera that includes mono-crystalline silicon and fused silica elements with diameters as large as ∼400 mm. This paper contains a comprehensive description of all aspects of the instrument including the fiber system, optics and opto-mechanics, detector arrays, mechanics and cryogenics, instrument control, calibration system, optical performance and stability, lessons learned, and design changes for the second instrument.
Abstract Boron (B) powder injection is a potential alternative to glow discharge boronization as a wall conditioning method for tokamaks. This technique is currently being studied in WEST ...experiments, during which B powder is injected by an Impurity Powder Dropper developed by PPPL. In order to interpret and analyse experimental trends, and to help develop future experiments, a modelling workflow using a boundary plasma simulation (SOLEDGE-EIRENE) and powder ablation simulation (Dust Injection Simulator) was developed and tested. The effect of adding a B neutral source to simulated deuterium + oxygen (D + O) plasmas was compared to experimental data from the WEST C5 campaign, where B powder was injected in a dedicated experiment. While the impact of B injection on radiated power P rad measurements at the upper divertor was similar, there were significant differences in measurements of P rad , outer strike point electron temperature T e OSP and O-II line intensity at the lower divertor between experiment and simulation. This discrepancy suggests that those parameters were affected by phenomena not present in the simulations, with the most likely candidates being reduced D recycling and a reduced O sourcing from the divertor.
Acute coronary syndromes (ACSs) are driven by inflammation within coronary plaque. Interleukin-1 (IL-1) has an established role in atherogenesis and the vessel-response to injury. ACS patients have ...raised serum markers of inflammation. We hypothesized that if IL-1 is a driving influence of inflammation in non-ST elevation ACS (NSTE-ACS), IL-1 inhibition would reduce the inflammatory response at the time of ACS.
A phase II, double-blinded, randomized, placebo-controlled, study recruited 182 patients with NSTE-ACS, presenting <48 h from onset of chest pain. Treatment was 1:1 allocation to daily, subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. Baseline characteristics were well matched. Treatment compliance was 85% at 7 days. The primary endpoint (area-under-the-curve for C-reactive protein over the first 7 days) was: IL-1ra group, 21.98 mg day/L (95%CI 16.31-29.64); placebo group, 43.5 mg day/L (31.15-60.75) (geometric mean ratio = 0.51 mg/L; 95%CI 0.32-0.79; P = 0.0028). In the IL-1ra group, 14-day achieved high-sensitive C-reactive protein (P < 0.0001) and IL-6 levels (P = 0.02) were lower than Day 1. Sixteen days after discontinuation of treatment (Day 30) high-sensitive C-reactive protein levels had risen again in the IL-1ra group IL-1ra; 3.50 mg/L (2.65-4.62): placebo; 2.21 mg/L (1.67-2.92), P = 0.022. MACE at Day 30 and 3 months was similar but at 1 year there was a significant excess of events in the IL-1ra group.
IL-1 drives C-reactive protein elevation at the time of NSTE-ACS. Following 14 days IL-1ra treatment inflammatory markers were reduced. These results show the importance of IL-1 as a target in ACS, but also indicate the need for additional studies with anti-IL-1 therapy in ACS to assess duration and safety.
2006-001767-31-GB: www.clinicaltrialsregister.eu/ctr-search/trial/2006-001767-31/GB.
The present paper deals with the surface heat flux estimation with thermocouples (TC) and fiber Bragg grating (FBG) embedded in the plasma facing components (PFC) of the WEST tokamak. A 2D heat ...transfer model combined with the conjugate gradient method and the adjoint state is used to estimate the plasma heat flux deposited on the PFC. The plasma heat flux is characterized by the time evolution of its amplitude and spatial shape on the target (heat flux decay length λqt, power spreading in the private flux region St and the strike point location x0). As a first step, five ohmic pulses have been investigated with different magnetic configuration and divertor X-point height varying from 44 to 68 mm from the surface. Despite an outboard shift, the relative displacements of the outer strike point as well as the heat flux decay length derived from the TC/FBG systems are consistent with the magnetic equilibrium reconstruction.
A novel method to measure net secondary electron emission yield due to primary electron irradiation from a tokamak scrape-off layer plasma is described. High emission coefficients close to unity are ...obtained independent of the electron temperature. Enhanced elastic backscattering of low-energy primary electrons, already identified as an important phenomenon in many other fields of research, is likely to explain the high yields.
Opioid neurotransmission has a key role in mediating reward-related behaviours. Opioid receptor (OR) antagonists, such as naltrexone (NTX), can attenuate the behaviour-reinforcing effects of primary ...(food) and secondary rewards. GSK1521498 is a novel OR ligand, which behaves as an inverse agonist at the μ-OR sub-type. In a sample of healthy volunteers, we used (11)C-carfentanil positron emission tomography to measure the OR occupancy and functional magnetic resonance imaging (fMRI) to measure activation of brain reward centres by palatable food stimuli before and after single oral doses of GSK1521498 (range, 0.4-100 mg) or NTX (range, 2-50 mg). GSK1521498 had high affinity for human brain ORs (GSK1521498 effective concentration 50 = 7.10 ng ml(-1)) and there was a direct relationship between receptor occupancy (RO) and plasma concentrations of GSK1521498. However, for both NTX and its principal active metabolite in humans, 6-β-NTX, this relationship was indirect. GSK1521498, but not NTX, significantly attenuated the fMRI activation of the amygdala by a palatable food stimulus. We thus have shown how the pharmacological properties of OR antagonists can be characterised directly in humans by a novel integration of molecular and functional neuroimaging techniques. GSK1521498 was differentiated from NTX in terms of its pharmacokinetics, target affinity, plasma concentration-RO relationships and pharmacodynamic effects on food reward processing in the brain. Pharmacological differentiation of these molecules suggests that they may have different therapeutic profiles for treatment of overeating and other disorders of compulsive consumption.
Abstract GRADE suggests that examination of 95% confidence intervals (CIs) provides the optimal primary approach to decisions regarding imprecision. For practice guidelines, rating down the quality ...of evidence (i.e., confidence in estimates of effect) is required if clinical action would differ if the upper versus the lower boundary of the CI represented the truth. An exception to this rule occurs when an effect is large, and consideration of CIs alone suggests a robust effect, but the total sample size is not large and the number of events is small. Under these circumstances, one should consider rating down for imprecision. To inform this decision, one can calculate the number of patients required for an adequately powered individual trial (termed the “optimal information size” OIS). For continuous variables, we suggest a similar process, initially considering the upper and lower limits of the CI, and subsequently calculating an OIS. Systematic reviews require a somewhat different approach. If the 95% CI excludes a relative risk (RR) of 1.0, and the total number of events or patients exceeds the OIS criterion, precision is adequate. If the 95% CI includes appreciable benefit or harm (we suggest an RR of under 0.75 or over 1.25 as a rough guide) rating down for imprecision may be appropriate even if OIS criteria are met.
AbstractObjectivesTo collect, appraise, select, and report the best available national estimates of cigarette consumption since 1970.DesignSystematic collection of comparable data.Setting and ...population71 of 214 countries for which searches for national cigarette consumption data were conducted, representing over 95% of global cigarette consumption and 85% of the world’s population.Main outcome measuresValidated cigarette consumption data covering 1970-2015 were identified for 71 countries. Data quality appraisal was conducted by two research team members in duplicate, with greatest weight given to official government sources. All data were standardised into units of cigarettes consumed per year in each country, a detailed accounting of data quality and sourcing was prepared, and all collected data and metadata were made freely available in an open access dataset.ResultsCigarette consumption fell in most countries over the past three decades but trends in country specific consumption were highly variable. For example, China consumed 2.5 million metric tonnes (MMT) of cigarettes in 2013, more than Russia (0.36 MMT), the United States (0.28 MMT), Indonesia (0.28 MMT), Japan (0.20 MMT), and the next 35 highest consuming countries combined. The US and Japan achieved reductions of more than 0.1 MMT from a decade earlier, whereas Russian consumption plateaued, and Chinese and Indonesian consumption increased by 0.75 MMT and 0.1 MMT, respectively. These data generally concord with modelled country level data from the Institute for Health Metrics and Evaluation and have the additional advantage of not smoothing year-over-year discontinuities that are necessary for robust quasi-experimental impact evaluations.ConclusionsBefore this study, publicly available data on cigarette consumption have been limited; they have been inappropriate for quasi-experimental impact evaluations (modelled data), held privately by companies (proprietary data), or widely dispersed across many national statistical agencies and research organisations (disaggregated data). This new dataset confirms that cigarette consumption has decreased in most countries over the past three decades, but that secular country specific consumption trends are highly variable. The findings underscore the need for more robust processes in data reporting, ideally built into international legal instruments or other mandated processes. To monitor the impact of the WHO Framework Convention on Tobacco Control and other tobacco control interventions, data on national tobacco production, trade, and sales should be routinely collected and openly reported.
•New design of flush-mounted Langmuir probes in the WEST divertor made of tantalum.•Great flushness of the probes within specifications and confirmed during experiments.•Probes successfully measuring ...since the WEST operation start with consistent results.•Probes still in operation after 22000s of plasma and 1.5 GJ of additional RF power.
The design of the Langmuir probes for the lower divertor of the WEST tokamak is presented, in which uncooled, tungsten-coated graphite targets were installed for the first phase of operation in anticipation of full-tungsten, actively cooled, ITER-like divertor components. Due to the long plasma discharges and high heat loads, the probe tips are flush with the divertor tiles in which they are embedded, as it is foreseen and indeed required in ITER. Tantalum metal was chosen for the probe tips because of its high melting point, and ductility at room temperature which allows simple crimping to electrically connect them to cables, as well as being compatible with the full metal environment of WEST. High heat flux tests of Ta Langmuir probe prototypes confirmed the robustness of the design for energy flux densities up to 8 MW/m2 for 5.5 s, and at lower 3.5 MW/m² energy flux density for 40 s long discharges. The probes were operational from the first discharge in WEST and the good alignment of all probes with the surrounding surface was confirmed by a good match of each adjacent probe's data when the strike points were swept across the target.
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