51 research outputs found
HORACE: software for the analysis of data from single crystal spectroscopy experiments at time-of-flight neutron instruments
The HORACE suite of programs has been developed to work with large
multiple-measurement data sets collected from time-of-flight neutron
spectrometers equipped with arrays of position-sensitive detectors. The
software allows exploratory studies of the four dimensions of reciprocal space
and excitation energy to be undertaken, enabling multi-dimensional subsets to
be visualized, algebraically manipulated, and models for the scattering to
simulated or fitted to the data. The software is designed to be an extensible
framework, thus allowing user-customized operations to be performed on the
data. Examples of the use of its features are given for measurements exploring
the spin waves of the simple antiferromagnet RbMnF and ferromagnetic
iron, and the phonons in URuSi.Comment: 14 pages, 6 figure
An x-ray resonant diffraction study of multiferroic DyMn2O5
X-ray resonant scattering has been used to measure the magnetic order of the
Dy ions below 40K in multiferroic DyMnO. The magnetic order has a
complex behaviour. There are several different ordering wavevectors, both
incommensurate and commensurate, as the temperature is varied. In addition a
non-magnetic signal at twice the wavevector of one of the commensurate signals
is observed, the maximum intensity of which occurs at the same temperature as a
local maximum in the ferroelectric polarisation. Some of the results, which
bear resemblence to the behaviour of other members of the RMnO
family of multiferroic materials, may be explained by a theory based on
so-called acentric spin-density waves.Comment: 8 pages, 8 figure
High - Temperature Superconductivity in Iron Based Layered Compounds
We present a review of basic experimental facts on the new class of high -
temperature superconductors - iron based layered compounds like REOFeAs
(RE=La,Ce,Nd,Pr,Sm...), AFe_2As_2 (A=Ba,Sr...), AFeAs (A=Li,...) and FeSe(Te).
We discuss electronic structure, including the role of correlations, spectrum
and role of collective excitations (phonons, spin waves), as well as the main
models, describing possible types of magnetic ordering and Cooper pairing in
these compounds.Comment: 43 pages, 30 figures, review talk on 90th anniversary of Physics
Uspekh
Spin-Density-Wave Gap with Dirac Nodes and Two-Magnon Raman Scattering in BaFe2As2
Raman selection rules for electronic and magnetic excitations in BaFe2As2
were theoretically investigated and applied them to the separate detection of
the nodal and anti-nodal gap excitations at the spin density wave (SDW)
transition and the separate detection of the nearest and the next nearest
neighbor exchange interaction energies. The SDW gap has Dirac nodes, because
many orbitals participate in the electronic states near the Fermi energy. Using
a two-orbital band model the electronic excitations near the Dirac node and the
anti-node are found to have different symmetries. Applying the symmetry
difference to Raman scattering the nodal and anti-nodal electronic excitations
are separately obtained. The low-energy spectra from the anti-nodal region have
critical fluctuation just above TSDW and change into the gap structure by the
first order transition at TSDW, while those from the nodal region gradually
change into the SDW state. The selection rule for two-magnon scattering from
the stripe spin structure was obtained. Applying it to the two-magnon Raman
spectra it is found that the magnetic exchange interaction energies are not
presented by the short-range superexchange model, but the second derivative of
the total energy of the stripe spin structure with respect to the moment
directions. The selection rule and the peak energy are expressed by the
two-magnon scattering process in an insulator, but the large spectral weight
above twice the maximum spin wave energy is difficult to explain by the decayed
spin wave. It may be explained by the electronic scattering of itinerant
carriers with the magnetic self-energy in the localized spin picture or the
particle-hole excitation model in the itinerant spin picture. The magnetic
scattering spectra are compared to the insulating and metallic cuprate
superconductors whose spins are believed to be localized.Comment: 38 pages, 11 figure
Pro-inflammatory endothelial cell dysfunction is associated with intersectin-1s down-regulation
<p>Abstract</p> <p>Background</p> <p>The response of lung microvascular endothelial cells (ECs) to lipopolysaccharide (LPS) is central to the pathogenesis of lung injury. It is dual in nature, with one facet that is pro-inflammatory and another that is cyto-protective. In previous work, overexpression of the anti-apoptotic Bcl-X<sub>L</sub> rescued ECs from apoptosis triggered by siRNA knockdown of intersectin-1s (ITSN-1s), a pro-survival protein crucial for ECs function. Here we further characterized the cyto-protective EC response to LPS and pro-inflammatory dysfunction.</p> <p>Methods and Results</p> <p>Electron microscopy (EM) analyses of LPS-exposed ECs revealed an activated/dysfunctional phenotype, while a biotin assay for caveolae internalization followed by biochemical quantification indicated that LPS causes a 40% inhibition in biotin uptake compared to controls. Quantitative PCR and Western blotting were used to evaluate the mRNA and protein expression, respectively, for several regulatory proteins of intrinsic apoptosis, including ITSN-1s. The decrease in ITSN-1s mRNA and protein expression were countered by Bcl-X<sub>L</sub> and survivin upregulation, as well as Bim downregulation, events thought to protect ECs from impending apoptosis. Absence of apoptosis was confirmed by TUNEL and lack of cytochrome c (cyt c) efflux from mitochondria. Moreover, LPS exposure caused induction and activation of inducible nitric oxide synthase (iNOS) and a mitochondrial variant (mtNOS), as well as augmented mitochondrial NO production as measured by an oxidation oxyhemoglobin (oxyHb) assay applied on mitochondrial-enriched fractions prepared from LPS-exposed ECs. Interestingly, expression of myc-ITSN-1s rescued caveolae endocytosis and reversed induction of iNOS expression.</p> <p>Conclusion</p> <p>Our results suggest that ITSN-1s deficiency is relevant for the pro-inflammatory ECs dysfunction induced by LPS.</p
ERK1/2 signalling protects against apoptosis following endoplasmic reticulum stress but cannot provide long-term protection against BAX/BAK-independent cell death
Disruption of protein folding in the endoplasmic reticulum (ER) causes ER stress. Activation of the unfolded protein response (UPR) acts to restore protein homeostasis or, if ER stress is severe or persistent, drive apoptosis, which is thought to proceed through the cell intrinsic, mitochondrial pathway. Indeed, cells that lack the key executioner proteins BAX and BAK are protected from ER stress-induced apoptosis. Here we show that chronic ER stress causes the progressive inhibition of the extracellular signal-regulated kinase (ERK1/2) signalling pathway. This is causally related to ER stress since reactivation of ERK1/2 can protect cells from ER stress-induced apoptosis whilst ERK1/2 pathway inhibition sensitises cells to ER stress. Furthermore, cancer cell lines harbouring constitutively active BRAFV600E are addicted to ERK1/2 signalling for protection against ER stress-induced cell death. ERK1/2 signalling normally represses the pro-death proteins BIM, BMF and PUMA and it has been proposed that ER stress induces BIM-dependent cell death. We found no evidence that ER stress increased the expression of these proteins; furthermore, BIM was not required for ER stress-induced death. Rather, ER stress caused the PERK-dependent inhibition of cap-dependent mRNA translation and the progressive loss of pro-survival proteins including BCL2, BCLXL and MCL1. Despite these observations, neither ERK1/2 activation nor loss of BAX/BAK could confer long-term clonogenic survival to cells exposed to ER stress. Thus, ER stress induces cell death by at least two biochemically and genetically distinct pathways: a classical BAX/BAK-dependent apoptotic response that can be inhibited by ERK1/2 signalling and an alternative ERK1/2- and BAX/BAK-independent cell death pathway
Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial
Background
The antiviral drug molnupiravir was licensed for treating at-risk patients with COVID-19 on the basis of data from unvaccinated adults. We aimed to evaluate the safety and virological efficacy of molnupiravir in vaccinated and unvaccinated individuals with COVID-19.
Methods
This randomised, placebo-controlled, double-blind, phase 2 trial (AGILE CST-2) was done at five National Institute for Health and Care Research sites in the UK. Eligible participants were adult (aged ≥18 years) outpatients with PCR-confirmed, mild-to-moderate SARS-CoV-2 infection who were within 5 days of symptom onset. Using permuted blocks (block size 2 or 4) and stratifying by site, participants were randomly assigned (1:1) to receive either molnupiravir (orally; 800 mg twice daily for 5 days) plus standard of care or matching placebo plus standard of care. The primary outcome was the time from randomisation to SARS-CoV-2 PCR negativity on nasopharyngeal swabs and was analysed by use of a Bayesian Cox proportional hazards model for estimating the probability of a superior virological response (hazard ratio [HR]>1) for molnupiravir versus placebo. Our primary model used a two-point prior based on equal prior probabilities (50%) that the HR was 1·0 or 1·5. We defined a priori that if the probability of a HR of more than 1 was more than 80% molnupiravir would be recommended for further testing. The primary outcome was analysed in the intention-to-treat population and safety was analysed in the safety population, comprising participants who had received at least one dose of allocated treatment. This trial is registered in ClinicalTrials.gov, NCT04746183, and the ISRCTN registry, ISRCTN27106947, and is ongoing.
Findings
Between Nov 18, 2020, and March 16, 2022, 1723 patients were assessed for eligibility, of whom 180 were randomly assigned to receive either molnupiravir (n=90) or placebo (n=90) and were included in the intention-to-treat analysis. 103 (57%) of 180 participants were female and 77 (43%) were male and 90 (50%) participants had received at least one dose of a COVID-19 vaccine. SARS-CoV-2 infections with the delta (B.1.617.2; 72 [40%] of 180), alpha (B.1.1.7; 37 [21%]), omicron (B.1.1.529; 38 [21%]), and EU1 (B.1.177; 28 [16%]) variants were represented. All 180 participants received at least one dose of treatment and four participants discontinued the study (one in the molnupiravir group and three in the placebo group). Participants in the molnupiravir group had a faster median time from randomisation to negative PCR (8 days [95% CI 8–9]) than participants in the placebo group (11 days [10–11]; HR 1·30, 95% credible interval 0·92–1·71; log-rank p=0·074). The probability of molnupiravir being superior to placebo (HR>1) was 75·4%, which was less than our threshold of 80%. 73 (81%) of 90 participants in the molnupiravir group and 68 (76%) of 90 participants in the placebo group had at least one adverse event by day 29. One participant in the molnupiravir group and three participants in the placebo group had an adverse event of a Common Terminology Criteria for Adverse Events grade 3 or higher severity. No participants died (due to any cause) during the trial.
Interpretation
We found molnupiravir to be well tolerated and, although our predefined threshold was not reached, we observed some evidence that molnupiravir has antiviral activity in vaccinated and unvaccinated individuals infected with a broad range of SARS-CoV-2 variants, although this evidence is not conclusive
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