330 research outputs found
Physical Chemistry of Chloroquine Permeation through the Cell Membrane with Atomistic Detail
We provide a molecular-level description of the thermodynamics and mechanistic aspects of drug permeation through the cell membrane. As a case study, we considered the antimalaria FDA approved drug chloroquine. Molecular dynamics simulations of the molecule (in its neutral and protonated form) were performed in the presence of different lipid bilayers, with the aim of uncovering key aspects of the permeation process, a fundamental step for the drug’s action. Free energy values obtained by well-tempered metadynamics simulations suggest that the neutral form is the only permeating protomer, consistent with experimental data. H-bond interactions of the drug with water molecules and membrane headgroups play a crucial role for permeation. The presence of the transmembrane potential, investigated here for the first time in a drug permeation study, does not qualitatively affect these conclusions
Common Occupational Trauma: Is There a Relationship with Workers’ Mental Health?
Exposure to major trauma can have significant consequences for workers’ mental health,
but common trauma may also result in poor mental health outcomes. This cross-sectional study
retrospectively investigated the occurrence of common physical or psychological workplace trauma in
901 health, social service, and trading company workers and studied these experiences in relation to
occupational stress, anxiety, and depression. Stress was measured with the effort/reward imbalance
(ERI) model while anxiety and depression were evaluated with the Goldberg Anxiety and Depression
Scale (GADS). Healthcare workers reported a high frequency of trauma and significantly higher levels
of stress, anxiety, and depression than other workers. Even in the entire population of workers of
the various professional categories, verbal violence (harassment and threats), traffic accidents, home
injuries, and family bereavement were significantly associated with high levels of stress, anxiety,
and depression. Major trauma survivors are known to be at increased risk of mental disorders and
require support in the workplace, however, even minor repeated emotional trauma and injuries
can affect mental health. During mandatory health surveillance, the occupational physician should
systematically collect information on minor trauma and mental health outcomes when assessing the
occupational fitness of the workers assigned to him
A Bio-Conjugated Fullerene as a Subcellular-Targeted and Multifaceted Phototheranostic Agent
Fullerenes are candidates for theranostic applications because of their high photodynamic activity and intrinsic multimodal imaging contrast. However, fullerenes suffer from low solubility in aqueous media, poor biocompatibility, cell toxicity, and a tendency to aggregate. C70@lysozyme is introduced herein as a novel bioconjugate that is harmless to a cellular environment, yet is also photoactive and has excellent optical and optoacoustic contrast for tracking cellular uptake and intracellular localization. The formation, water-solubility, photoactivity, and unperturbed structure of C70@lysozyme are confirmed using UV-visible and 2D 1H, 15N NMR spectroscopy. The excellent imaging contrast of C70@lysozyme in optoacoustic and third harmonic generation microscopy is exploited to monitor its uptake in HeLa cells and lysosomal trafficking. Last, the photoactivity of C70@lysozyme and its ability to initiate cell death by means of singlet oxygen (1O2) production upon exposure to low levels of white light irradiation is demonstrated. This study introduces C70@lysozyme and other fullerene-protein conjugates as potential candidates for theranostic applications
The AWAKE Run 2 Programme and beyond
Plasma wakefield acceleration is a promising technology to reduce the size of particle accelerators. The use of high energy protons to drive wakefields in plasma has been demonstrated during Run 1 of the AWAKE programme at CERN. Protons of energy 400 GeV drove wakefields that accelerated electrons to 2 GeV in under 10 m of plasma. The AWAKE collaboration is now embarking on Run 2 with the main aims to demonstrate stable accelerating gradients of 0.5–1 GV/m, preserve emittance of the electron bunches during acceleration and develop plasma sources scalable to 100s of metres and beyond. By the end of Run 2, the AWAKE scheme should be able to provide electron beams for particle physics experiments and several possible experiments have already been evaluated. This article summarises the programme of AWAKE Run 2 and how it will be achieved as well as the possible application of the AWAKE scheme to novel particle physics experiments.info:eu-repo/semantics/publishedVersio
Observation of the TeV gamma-ray source MGRO J1908+06 with ARGO-YBJ
The extended gamma ray source MGRO J1908+06, discovered by the Milagro air
shower detector in 2007, has been observed for about 4 years by the ARGO-YBJ
experiment at TeV energies, with a statistical significance of 6.2 standard
deviations. The peak of the signal is found at a position consistent with the
pulsar PSR J1907+0602. Parametrizing the source shape with a two-dimensional
Gauss function we estimate an extension \sigma = 0.49 \pm 0.22 degrees,
consistent with a previous measurement by the Cherenkov Array H.E.S.S.. The
observed energy spectrum is dN/dE = 6.1 \pm 1.4 \times 10^-13 (E/4 TeV)^{-2.54
\pm 0.36} photons cm^-2 s^-1 TeV^-1, in the energy range 1-20 TeV. The measured
gamma ray flux is consistent with the results of the Milagro detector, but is
2-3 times larger than the flux previously derived by H.E.S.S. at energies of a
few TeV. The continuity of the Milagro and ARGO-YBJ observations and the stable
excess rate observed by ARGO-YBJ along 4 years of data taking support the
identification of MGRO J1908+06 as the steady powerful TeV pulsar wind nebula
of PSR J1907+0602, with an integrated luminosity above 1 TeV about 1.8 times
the Crab Nebula luminosity.Comment: 6 pages, accepted for pubblication by ApJ. Replaced to correct the
author lis
In-cell NMR in E. coli to Monitor Maturation Steps of hSOD1
In-cell NMR allows characterizing the folding state of a protein as well as posttranslational events at molecular level, in the cellular context. Here, the initial maturation steps of human copper, zinc superoxide dismutase 1 are characterized in the E. coli cytoplasm by in-cell NMR: from the apo protein, which is partially unfolded, to the zinc binding which causes its final quaternary structure. The protein selectively binds only one zinc ion, whereas in vitro also the copper site binds a non-physiological zinc ion. However, no intramolecular disulfide bridge formation occurs, nor copper uptake, suggesting the need of a specific chaperone for those purposes
SOD1 and Amyotrophic Lateral Sclerosis: Mutations and Oligomerization
There are about 100 single point mutations of copper, zinc superoxide dismutase 1 (SOD1) which are reported (http://alsod.iop.kcl.ac.uk/Als/index.aspx) to be related to the familial form (fALS) of amyotrophic lateral sclerosis (ALS). These mutations are spread all over the protein. It is well documented that fALS produces protein aggregates in the motor neurons of fALS patients, which have been found to be associated to mitochondria. We selected eleven SOD1 mutants, most of them reported as pathological, and characterized them investigating their propensity to aggregation using different techniques, from circular dichroism spectra to ThT-binding fluorescence, size-exclusion chromatography and light scattering spectroscopy. We show here that these eleven SOD1 mutants, only when they are in the metal-free form, undergo the same general mechanism of oligomerization as found for the WT metal-free protein. The rates of oligomerization are different but eventually they give rise to the same type of soluble oligomeric species. These oligomers are formed through oxidation of the two free cysteines of SOD1 (6 and 111) and stabilized by hydrogen bonds, between beta strands, thus forming amyloid-like structures. SOD1 enters the mitochondria as demetallated and mitochondria are loci where oxidative stress may easily occur. The soluble oligomeric species, formed by the apo form of both WT SOD1 and its mutants through an oxidative process, might represent the precursor toxic species, whose existence would also suggest a common mechanism for ALS and fALS. The mechanism here proposed for SOD1 mutant oligomerization is absolutely general and it provides a common unique picture for the behaviors of the many SOD1 mutants, of different nature and distributed all over the protein
Performance Assessment in Fingerprinting and Multi Component Quantitative NMR Analyses
An interlaboratory comparison (ILC) was organized with the aim to set up quality control indicators suitable for multicomponent quantitative analysis by nuclear magnetic resonance (NMR) spectroscopy. A total of 36 NMR data sets (corresponding to 1260 NMR spectra) were produced by 30 participants using 34 NMR spectrometers. The calibration line method was chosen for the quantification of a five-component model mixture. Results show that quantitative NMR is a robust quantification tool and that 26 out of 36 data sets resulted in statistically equivalent calibration lines for all considered NMR signals. The performance of each laboratory was assessed by means of a new performance index (named Qp-score) which is related to the difference between the experimental and the consensus values of the slope of the calibration lines. Laboratories endowed with a Qp-score falling within the suitable acceptability range are qualified to produce NMR spectra that can be considered statistically equivalent in terms of relative intensities of the signals. In addition, the specific response of nuclei to the experimental excitation/relaxation conditions was addressed by means of the parameter named NR. NR is related to the difference between the theoretical and the consensus slopes of the calibration lines and is specific for each signal produced by a well-defined set of acquisition parameters
Accommodating a Non-Conservative Internal Mutation by WaterMediated Hydrogen-Bonding Between β-Sheet Strands: A Comparison of Human and Rat Type B (Mitochondrial) Cytochrome b5
Mammalian type B (mitochondrial) cytochromes b5 exhibit greater amino acid sequence diversity than their type A (microsomal) counterparts, as exemplified by the type B proteins from human (hCYB5B) and rat (rCYB5B). The comparison of X-ray crystal structures of hCYB5B and rCYB5B reported herein reveals a striking difference in packing involving the five-stranded β-sheet, attributable to fully buried residue 21 in strand β4. The greater bulk of Leu21 in hCYB5B in comparison to Thr21 in rCYB5B results in a substantial displacement of the first two residues in β5, and consequent loss of two of the three hydrogen bonds between β5 and β4. Hydrogen-bonding between the residues is instead mediated by two well-ordered, fully buried water molecules. In a 10 ns molecular dynamics simulation, one of the buried water molecules in the hCYB5B structure exchanged readily with solvent via intermediates having three water molecules sandwiched between β4 and β5. When the buried water molecules were removed prior to a second 10 ns simulation, β4 and β5 formed persistent hydrogen bonds identical to those in rCYB5B, but the Leu21 side chain was forced to adopt a rarely observed conformation. Despite the apparently greater ease of water access to the interior of hCYB5B than of rCYB5B suggested by these observations, the two proteins exhibit virtually identical stability, dynamic and redox properties. The results provide new insight into the factors stabilizing the cytochrome b5 fold
Status of the compactlight design study*
CompactLight (XLS) is an International Collaboration of 24 partners and 5 third parties, funded by the European Union through the Horizon 2020 Research and Innovation Programme. The main goal of the project, which started in January 2018 with a duration of 36 months, is the design of an hard X-ray FEL facility beyond today’s state of the art, using the latest concepts for bright electron photo-injectors, high-gradient accelerating structures, and innovative short-period undulators. The specifications of the facility and the parameters of the future FEL are driven by the demands of potential users and the associated science cases. In this paper we will give an overview on the ongoing activities and the major results achieved until now
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