The regions within the N-terminus critical for human glucagon like peptide-1 receptor (hGLP-1R) cell Surface expression

The hGLP-1R is a target for the treatment of type 2 diabetes and belongs to the class B family of GPCRs. Like other class B GPCRs, the GLP-1R contains an N-terminal signal peptide (SP) and undergoes N-linked glycosylation, which are important for its trafficking and maturation. This study analysed the role of the SP, the hydrophobic region after the SP (HRASP), glycosylation and the conserved residues within the N-terminus in GLP-1R trafficking. HGLP-1R targeted to the cell surface showed no SP, and the SP deleted mutant, but not the mutants defective in SP cleavage, showed cell surface expression, demonstrating the importance of SP cleavage for hGLP-1R cell surface expression. The N-terminal deletions of hGLP-1R revealed that the HRASP, not the SP, is essential for cell surface expression of GLP-1R. Further, inhibition of hGLP-1R glycosylation prevented cell surface expression of the receptor. Mutation of Trp39, Tyr69 and Tyr88, which are required for agonist binding, in the GLP-1R abolished cell surface expression of the receptor independent of the SP cleavage or N-linked glycosylation. In conclusion, the N-terminus of hGLP-1R regulates receptor trafficking and maturation. Therefore this study provides insight into the role of hGLP-1R N-terminus on the receptor cell surface expression

Fusion power predictions for β N≈ 1.8 baseline scenario with 50-50 D-T fuel mix and NBI injection in preparation to D-T operations at JET

The fusion performance of ELMy H-mode 50-50 deuterium-tritium (DT) plasmas with 50-50 DT NBI injection and q 95 ≈ 3 and β N ≈ 1.8 (also referred to as medium-β N baseline scenario in the rest of this paper) are predicted with the JINTRAC suite of codes and the QuaLiKiZ transport model. The predictions are based on the analysis of plasmas from the first DT campaign on JET in 1997 (DTE1) and pure deuterium plasmas developed at JET in preparation for the DT experimental campaign in 2021 (DTE2), after the installation of a Be/W ITER-like wall in 2011. The sensitivity of the predictions to plasma parameters such as current, toroidal field, pedestal confinement and impurity content are analysed together with the sensitivity to the amount of auxiliary heating power available. The simulations indicate that a fusion power of 10 MW should be achievable under a fairly wide range of assumptions, provided that the auxiliary heating power is around or above 38 MW. Higher fusion power approaching 15 MW could be achievable for this value of β N only for particularly pure plasmas and with 40 MW of additional heating power

Integrated core–SOL–divertor modelling for ITER including impurity: effect of tungsten on fusion performance in H-mode and hybrid scenario

The compatibility of two operational constraints—operation above the L–H power threshold and at low power to divertor—is examined for ITER long pulse H-mode and hybrid scenarios in integrated core–scrape off layer (SOL)–divertor modelling including impurities (intrinsic Be, He, W and seeded Ne). The core thermal, particle and momentum transport is simulated with the GLF23 transport model tested in the self-consistent simulations of temperatures, density and toroidal rotation velocity in JET hybrid discharges and extrapolated to ITER. The beneficial effect of toroidal rotation velocity on fusion gain is shown. The sensitivity studies with respect to operational (separatrix and pedestal density, Ne gas puff) and unknown physics (W convective velocity and perpendicular diffusion in SOL as well as W prompt re-deposition) parameters are performed to determine their influence on the operational window and fusion gain.</p

Genetic Variation in the EGFR Gene and the Risk of Glioma in a Chinese Han Population

Previous studies have shown that regulation of the epidermal growth factor gene (EGFR) pathway plays a role in glioma progression. Certain genotypes of the EGFR gene may be related to increased glioblastoma risk, indicating that germ line EGFR polymorphisms may have implications in carcinogenesis. To examine whether and how variants in the EGFR gene contribute to glioma susceptibility, we evaluated nine tagging single-nucleotide polymorphisms (tSNPs) of the EGFR gene in a case–control study from Xi'an city of China (301 cases, 302 controls). EGFR SNP associations analyses were performed using SPSS 16.0 statistical packages, PLINK software, Haploview software package (version 4.2) and SHEsis software platform. We identified two susceptibility tSNPs in the EGFR gene that were potentially associated with an increased risk of glioma (rs730437, p = 0.016; OR: 1.32; 95%CI: 1.05–1.66 and rs1468727, p = 0.008; OR: 1.31; 95%CI: 1.04–1.65). However, after a strict Bonferroni correction analysis was applied, the significance level of the association between EGFR tSNPs and risk of glioma was attenuated. We observed a protective effect of haplotype “AATT” of the EGFR gene, which was associated with a 29% reduction in the risk of developing glioma, while haplotype “CGTC” increased the risk of developing glioma by 36%. Our results, combined with previous studies, suggested an association between the EGFR gene and glioma development

Abnormal accumulation of autophagic vesicles correlates with axonal and synaptic pathology in young Alzheimer’s mice hippocampus

Dystrophic neurites associated with amyloid plaques precede neuronal death and manifest early in Alzheimer’s disease (AD). In this work we have characterized the plaque-associated neuritic pathology in the hippocampus of young (4- to 6-month-old) PS1M146L/APP751SL mice model, as the initial degenerative process underlying functional disturbance prior to neuronal loss. Neuritic plaques accounted for almost all fibrillar deposits and an axonal origin of the dystrophies was demonstrated. The early induction of autophagy pathology was evidenced by increased protein levels of the autophagosome marker LC3 that was localized in the axonal dystrophies, and by electron microscopic identification of numerous autophagic vesicles filling and causing the axonal swellings. Early neuritic cytoskeletal defects determined by the presence of phosphorylated tau (AT8-positive) and actin–cofilin rods along with decreased levels of kinesin-1 and dynein motor proteins could be responsible for this extensive vesicle accumulation within dystrophic neurites. Although microsomal Aβ oligomers were identified, the presence of A11-immunopositive Aβ plaques also suggested a direct role of plaque-associated Aβ oligomers in defective axonal transport and disease progression. Most importantly, presynaptic terminals morphologically disrupted by abnormal autophagic vesicle buildup were identified ultrastructurally and further supported by synaptosome isolation. Finally, these early abnormalities in axonal and presynaptic structures might represent the morphological substrate of hippocampal dysfunction preceding synaptic and neuronal loss and could significantly contribute to AD pathology in the preclinical stages

Interpretative and predictive modelling of Joint European Torus collisionality scans

Transport modelling of Joint European Torus (JET) dimensionless collisionality scaling experiments in various operational scenarios is presented. Interpretative simulations at a fixed radial position are combined with predictive JETTO simulations of temperatures and densities, using the TGLF transport model. The model includes electromagnetic effects and collisions as well as □(→┬E ) X □(→┬B ) shear in Miller geometry. Focus is on particle transport and the role of the neutral beam injection (NBI) particle source for the density peaking. The experimental 3-point collisionality scans include L-mode, and H-mode (D and H and higher beta D plasma) plasmas in a total of 12 discharges. Experimental results presented in (Tala et al 2017 44th EPS Conf.) indicate that for the H-mode scans, the NBI particle source plays an important role for the density peaking, whereas for the L-mode scan, the influence of the particle source is small. In general, both the interpretative and predictive transport simulations support the experimental conclusions on the role of the NBI particle source for the 12 JET discharges