Hepatitis e Virus Genotype 3 Genomes from RNA-Positive but Serologically Negative Plasma Donors Have CUG as the Start Codon for ORF3

Hepatitis E virus (HEV) is a pathogen that causes hepatitis worldwide. Molecular studies have identified HEV RNA in blood products although its significance is not understood. This study was undertaken to characterize HEV genomes in asymptomatic plasma donors from Sweden and Germany lacking anti-HEV. Complete open reading frames (ORFs) were obtained from HEV strains in 5 out of 18 plasma donors who tested positive for HEV RNA. All strains had CUG as the start codon of ORF3, while 147 GenBank strains all had AUG as the start codon (p < 0.0001). This substitution was found in both interrelated and unrelated strains belonging to different phylogenetic clades. The HEV strains from the seronegative plasma donors had no other substitution in common, which may be why the CUG substitution seems to explain the seronegativity

Multimodal Chemical Imaging of Amyloid Plaque Polymorphism Reveals A beta Aggregation Dependent Anionic Lipid Accumulations and Metabolism

Amyloid plaque formation constitutes one of the main pathological hallmarks of Alzheimer’s disease (AD) and is suggested to be a critical factor driving disease pathogenesis. Interestingly, in patients that display amyloid pathology but remain cognitively normal, Aβ deposits are predominantly of diffuse morphology suggesting that cored plaque formation is primarily associated with cognitive deterioration and AD pathogenesis. Little is known about the molecular mechanism responsible for conversion of monomeric Aβ into neurotoxic aggregates and the predominantly cored deposits observed in AD. The structural diversity among Aβ plaques, including cored/compact- and diffuse, may be linked to their distinct Aβ profile and other chemical species including neuronal lipids. We developed a novel, chemical imaging paradigm combining matrix assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) and fluorescent amyloid staining. This multimodal imaging approach was used to probe the lipid chemistry associated with structural plaque heterogeneity in transgenic AD mice (tgAPPSwe) and was correlated to Aβ profiles determined by subsequent laser microdissection and immunoprecipitation-mass spectrometry. Multivariate image analysis revealed an inverse localization of ceramides and their matching metabolites to diffuse and cored structures within single plaques, respectively. Moreover, phosphatidylinositols implicated in AD pathogenesis, were found to localize to the diffuse Aβ structures and correlate with Aβ1–42. Further, lysophospholipids implicated in neuroinflammation were increased in all Aβ deposits. The results support previous clinical findings on the importance of lipid disturbances in AD pathophysiology and associated sphingolipid processing. These data highlight the potential of multimodal imaging as a powerful technology to probe neuropathological mechanisms

First-principle based multi-channel integrated modelling in support to the design of the Divertor Tokamak Test facility

An intensive integrated modelling work of main scenarios of the new tokamak DTT (Divertor Tokamak Test facility) with the Single Null divertor configuration has been performed using first-principle quasi-linear transport models, in support to the design of the device and to the definition of its scientific work-programme. First results of this integrated modelling work on DTT (R0= 2.14 m, a= 0.65 m) are presented here along with outcome of the gyrokinetic simulations used to validate the reduced models in the DTT range of parameters. As a result of this work, the heating mix was defined, the size of device was increased to R0= 2.19 m and a= 0.70 m, the use of pellets for fuelling has been advised and reference profiles for diagnostic design, estimates of neutron yields and fast particle losses have become available.</p

Low-lying level structure of 56^{56}Cu and its implications on the rp process

The low-lying energy levels of proton-rich $^{56}$Cu have been extracted using in-beam $\gamma$-ray spectroscopy with the state-of-the-art $\gamma$-ray tracking array GRETINA in conjunction with the S800 spectrograph at the National Superconducting Cyclotron Laboratory at Michigan State University. Excited states in $^{56}$Cu serve as resonances in the $^{55}$Ni(p,$\gamma$)$^{56}$Cu reaction, which is a part of the rp-process in type I x-ray bursts. To resolve existing ambiguities in the reaction Q-value, a more localized IMME mass fit is used resulting in $Q=639\pm82$~keV. We derive the first experimentally-constrained thermonuclear reaction rate for $^{55}$Ni(p,$\gamma$)$^{56}$Cu. We find that, with this new rate, the rp-process may bypass the $^{56}$Ni waiting point via the $^{55}$Ni(p,$\gamma$) reaction for typical x-ray burst conditions with a branching of up to $\sim$40$\%$. We also identify additional nuclear physics uncertainties that need to be addressed before drawing final conclusions about the rp-process reaction flow in the $^{56}$Ni region.Comment: 8 pages, accepted for Phys. Rev.

Thermodynamic theory of epitaxial ferroelectric thin films with dense domain structures

A Landau-Ginsburg-Devonshire-type nonlinear phenomenological theory is presented, which enables the thermodynamic description of dense laminar polydomain states in epitaxial ferroelectric thin films. The theory explicitly takes into account the mechanical substrate effect on the polarizations and lattice strains in dissimilar elastic domains (twins). Numerical calculations are performed for PbTiO3 and BaTiO3 films grown on (001)-oriented cubic substrates. The "misfit strain-temperature" phase diagrams are developed for these films, showing stability ranges of various possible polydomain and single-domain states. Three types of polarization instabilities are revealed for polydomain epitaxial ferroelectric films, which may lead to the formation of new polydomain states forbidden in bulk crystals. The total dielectric and piezoelectric small-signal responses of polydomain films are calculated, resulting from both the volume and domain-wall contributions. For BaTiO3 films, strong dielectric anomalies are predicted at room temperature near special values of the misfit strain.Comment: 19 pages, 8 figure

Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases

The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy

A stochastic automaton shows how enzyme assemblies may contribute to metabolic efficiency

<p>Abstract</p> <p>Background</p> <p>The advantages of grouping enzymes into metabolons and into higher order structures have long been debated. To quantify these advantages, we have developed a stochastic automaton that allows experiments to be performed in a virtual bacterium with both a membrane and a cytoplasm. We have investigated the general case of transport and metabolism as inspired by the phosphoenolpyruvate:sugar phosphotransferase system (PTS) for glucose importation and by glycolysis.</p> <p>Results</p> <p>We show that PTS and glycolytic metabolons can increase production of pyruvate eightfold at low concentrations of phosphoenolpyruvate. A fourfold increase in the numbers of enzyme EI led to a 40% increase in pyruvate production, similar to that observed <it>in vivo </it>in the presence of glucose. Although little improvement resulted from the assembly of metabolons into a hyperstructure, such assembly can generate gradients of metabolites and signaling molecules.</p> <p>Conclusion</p> <p><it>in silico </it>experiments may be performed successfully using stochastic automata such as HSIM (Hyperstructure Simulator) to help answer fundamental questions in metabolism about the properties of molecular assemblies and to devise strategies to modify such assemblies for biotechnological ends.</p

Absolute Flux Density Calibration of the Greenland Telescope Data for Event Horizon Telescope Observations

Starting from the observing campaign in April 2018, the Greenland Telescope (GLT) has been added as a new station of the Event Horizon Telescope (EHT) array. Visibilities on baselines to the GLT, particularly in the North-South direction, potentially provide valuable new constraints for the modeling and imaging of sources such as M87*. The GLT's location at high Northern latitudes adds unique challenges to its calibration strategies. Additionally, the performance of the GLT was not optimal during the 2018 observations due to it being only partially commissioned at the time. This document describes the steps taken to estimate the various parameters (and their uncertainties) required for the absolute flux calibration of the GLT data as part of the EHT. In particular, we consider the non-optimized status of the GLT in 2018, as well as its improved performance during the 2021 EHT campaign.Comment: 17 pages, 4 figures, EHT Memo Series 2023-L1-0