Cleavage of the sarcin–ricin loop of 23S rRNA differentially affects EF-G and EF-Tu binding

Ribotoxins are potent inhibitors of protein biosynthesis and inactivate ribosomes from a variety of organisms. The ribotoxin α-sarcin cleaves the large 23S ribosomal RNA (rRNA) at the universally conserved sarcin–ricin loop (SRL) leading to complete inactivation of the ribosome and cellular death. The SRL interacts with translation factors that hydrolyze GTP, and it is important for their binding to the ribosome, but its precise role is not yet understood. We studied the effect of α-sarcin on defined steps of translation by the bacterial ribosome. α-Sarcin-treated ribosomes showed no defects in mRNA and tRNA binding, peptide-bond formation and sparsomycin-dependent translocation. Cleavage of SRL slightly affected binding of elongation factor Tu ternary complex (EF-Tu•GTP•tRNA) to the ribosome. In contrast, the activity of elongation factor G (EF-G) was strongly impaired in α-sarcin-treated ribosomes. Importantly, cleavage of SRL inhibited EF-G binding, and consequently GTP hydrolysis and mRNA–tRNA translocation. These results suggest that the SRL is more critical in EF-G than ternary complex binding to the ribosome implicating different requirements in this region of the ribosome during protein elongation

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

Effect of the relative shift between the electron density and temperature pedestal position on the pedestal stability in JET-ILW and comparison with JET-C

The electron temperature and density pedestals tend to vary in their relative radial positions, as observed in DIII-D (Beurskens et al 2011 Phys. Plasmas 18 056120) and ASDEX Upgrade (Dunne et al 2017 Plasma Phys. Control. Fusion 59 14017). This so-called relative shift has an impact on the pedestal magnetohydrodynamic (MHD) stability and hence on the pedestal height (Osborne et al 2015 Nucl. Fusion 55 063018). The present work studies the effect of the relative shift on pedestal stability of JET ITER-like wall (JET-ILW) baseline low triangularity (\u3b4) unseeded plasmas, and similar JET-C discharges. As shown in this paper, the increase of the pedestal relative shift is correlated with the reduction of the normalized pressure gradient, therefore playing a strong role in pedestal stability. Furthermore, JET-ILW tends to have a larger relative shift compared to JET carbon wall (JET-C), suggesting a possible role of the plasma facing materials in affecting the density profile location. Experimental results are then compared with stability analysis performed in terms of the peeling-ballooning model and with pedestal predictive model EUROPED (Saarelma et al 2017 Plasma Phys. Control. Fusion). Stability analysis is consistent with the experimental findings, showing an improvement of the pedestal stability, when the relative shift is reduced. This has been ascribed mainly to the increase of the edge bootstrap current, and to minor effects related to the increase of the pedestal pressure gradient and narrowing of the pedestal pressure width. Pedestal predictive model EUROPED shows a qualitative agreement with experiment, especially for low values of the relative shift

Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD.

The pathogenic mechanisms underlying the progression of non-alcoholic fatty liver disease (NAFLD) are not fully understood. In this study, we aimed to assess the relationship between endoplasmic reticulum (ER) stress and autophagy in human and mouse hepatocytes during NAFLD. ER stress and autophagy markers were analyzed in livers from patients with biopsy-proven non-alcoholic steatosis (NAS) or non-alcoholic steatohepatitis (NASH) compared with livers from subjects with histologically normal liver, in livers from mice fed with chow diet (CHD) compared with mice fed with high fat diet (HFD) or methionine-choline-deficient (MCD) diet and in primary and Huh7 human hepatocytes loaded with palmitic acid (PA). In NASH patients, significant increases in hepatic messenger RNA levels of markers of ER stress (activating transcription factor 4 (ATF4), glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP)) and autophagy (BCN1) were found compared with NAS patients. Likewise, protein levels of GRP78, CHOP and p62/SQSTM1 (p62) autophagic substrate were significantly elevated in NASH compared with NAS patients. In livers from mice fed with HFD or MCD, ER stress-mediated signaling was parallel to the blockade of the autophagic flux assessed by increases in p62, microtubule-associated protein 2 light chain 3 (LC3-II)/LC3-I ratio and accumulation of autophagosomes compared with CHD fed mice. In Huh7 hepatic cells, treatment with PA for 8 h triggered activation of both unfolding protein response and the autophagic flux. Conversely, prolonged treatment with PA (24 h) induced ER stress and cell death together with a blockade of the autophagic flux. Under these conditions, cotreatment with rapamycin or CHOP silencing ameliorated these effects and decreased apoptosis. Our results demonstrated that the autophagic flux is impaired in the liver from both NAFLD patients and murine models of NAFLD, as well as in lipid-overloaded human hepatocytes, and it could be due to elevated ER stress leading to apoptosis. Consequently, therapies aimed to restore the autophagic flux might attenuate or prevent the progression of NAFLD

Closing the Sex-Based Differences in Stroke Care: Insights from a Large Telestroke Network on Treatment and Postacute Management

Background: The evolution of ischemic stroke is different accordin'g to sex and is one of the main causes of death in women. Previous studies have shown that women are less likely to receive acute treatment, and stroke center type is an important predictor of door-to-needle times. We investigated whether women are attended in a similar way to men in the telestroke network with specialized stroke physicians. Methods: A prospective registry of ischemic strokes recorded in the centralized Andalusian telestroke network was analyzed, focusing on sex differences. Demographic data, clinical characteristics, neuroimaging data, treatment intervals, follow-up visits, and clinical outcomes were collected. Results: A total of 3009 suspected stroke patients were attended to in the telestroke network from 2019 to 2023, of which 42.74% were women. Women were older (p < 0.001) and less independent upon arrival (p = 0.006) than men. There was no difference in the treatment received or in the treatment time intervals between the groups. Importantly, there was no difference in modified Rankin scale scores at 3 months between sexes. At 3 months post-stroke follow-up, women had fewer imaging tests (p = 0.018) and fewer outpatient visits (p < 0.001) than men. Conclusions: No significant difference between men and women has been found in the acute treatment of stroke in a large telestroke network. However, the same is not true for the follow-up and management of patients after the acute phase. This fact supports that strict adherence to protocols and specialization of care lead to equal care that avoids sex differences in stroke treatment and functional outcomes

Overview of the JET ITER-like wall divertor

The work presented draws on new analysis of components removed following the second JET ITER-like wall campaign 2013–14 concentrating on the upper inner divertor, inner and outer divertor corners, lifetime issues relating to tungsten coatings on JET carbon fibre composite divertor tiles and dust/particulate generation. The results show that the upper inner divertor remains the region of highest deposition in the JET-ILW. Variations in plasma configurations between the first and second campaign have altered material migration to the corners of the inner and outer divertor. Net deposition is shown to be beneficial in the sense that it reduces W coating erosion, covers small areas of exposed carbon surfaces and even encapsulates particles

Neutron emission spectroscopy of DT plasmas at enhanced energy resolution with diamond detectors

This work presents measurements done at the Peking University Van de Graaff neutron source of the response of single crystal synthetic diamond (SD) detectors to quasi-monoenergetic neutrons of 14-20 MeV. The results show an energy resolution of 1% for incoming 20 MeV neutrons, which, together with 1% detection efficiency, opens up to new prospects for fast ion physics studies in high performance nuclear fusion devices such as SD neutron spectrometry of deuterium-tritium plasmas heated by neutral beam injection

Determining the prediction limits of models and classifiers with applications for disruption prediction in JET

Understanding the many aspects of tokamak physics requires the development of quite sophisticated models. Moreover, in the operation of the devices, prediction of the future evolution of discharges can be of crucial importance, particularly in the case of the prediction of disruptions, which can cause serious damage to various parts of the machine. The determination of the limits of predictability is therefore an important issue for modelling, classifying and forecasting. In all these cases, once a certain level of performance has been reached, the question typically arises as to whether all the information available in the data has been exploited, or whether there are still margins for improvement of the tools being developed. In this paper, a theoretical information approach is proposed to address this issue. The excellent properties of the developed indicator, called the prediction factor (PF), have been proved with the help of a series of numerical tests. Its application to some typical behaviour relating to macroscopic instabilities in tokamaks has shown very positive results. The prediction factor has also been used to assess the performance of disruption predictors running in real time in the JET system, including the one systematically deployed in the feedback loop for mitigation purposes. The main conclusion is that the most advanced predictors basically exploit all the information contained in the locked mode signal on which they are based. Therefore, qualitative improvements in disruption prediction performance in JET would need the processing of additional signals, probably profiles

The upgraded JET toroidal Alfvén eigenmode diagnostic system

The main characteristics of toroidal Alfven eigenmodes (TAEs) have been successfully investigated in JET (Joint European Torus) using the scheme of sweeping-frequency external excitation with tracking of the synchronously-detected resonances. However, due to technical limitations, only modes with low values of the toroidal mode number n ≤7 could be effectively excited and unambiguously identified by the Alfven Eigenmode Active Diagnostic (AEAD) system. This represents a serious restriction because theoretical models indicate that medium-n Alfven eigenmodes (AEs) are the most prone to be destabilized by energetic particles in ignited plasmas and, therefore, reliable measurement of their damping rates remains a relevant issue to properly access their effect in ignited plasmas. For this reason, a major upgrade of the AEAD system has been carried out aiming at providing a state-of-the-art excitation and real-time detection system for the planned DT campaign in JET. This required the development of a new type of radio frequency amplifier and filter, not commercially available, and also a control system. In this paper, details of the concepts that are relevant to understand the operation of the new system in the next experimental campaigns are presented, as are the results of numerical simulations to model its performance