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Background: Intravenous recombinant tissue plasminogen activator (IV rtPA) is a recommended thrombolytic for the treatment of acute ischemic stroke that has shown to improve outcomes in various trials, but its cost-utility within varying time windows has not been systematically reviewed. Method: A systematic review was conducted using 2 reviewers and 1 adjudicator. Search strategies were implemented in PUBMED/MEDLINE, EMBASE, Web of Science, and Cochrane Review. Forms and data were managed through RedCap. Studies that met specific inclusion criteria, such as authors citing the time window and analytic horizon they investigated, and specifying the type of model they implemented, were further assessed for cost-utility benefit. Results: Of the 385 results from the implemented search strategy, 18 studies met inclusion criteria, with 94% agreement between reviewers. Eleven studies looked at the time window within 3 hours of stroke symptom onset, 3 looked between 3 to 4.5 hours, 3 looked within 4.5 hours of onset, and 1 looked within 6 hours of onset. All but 1 study with an analytic horizon of 1 year looking at a 0-3 hour time window showed that that IV rtPA was either dominant or cost-effective at a willingness to pay of $50,000/QALY. Conclusion: IV rtPA shows to be cost-effective across a variety of assumptions, both at a national and international level. The analytic horizon and time window do significantly impact the cost-effectiveness of IV rtPA, but even at later time windows, the IV rtPA shows to be cost-effective relative to standard treatment and care.

The calculation of neutron reflectivity from raw time-of-flight data including instrumental corrections and an improved resolution calculation is presented. The theoretical calculations are compared with experimental data measured on the vertical sample plane reflectometer D17 and the horizontal sample plane reflectometer FIGARO at the Institut Laue–Langevin (ILL), Grenoble, France. This article comprises the mathematical body of the time-of-flight reflectivity data-reduction software COSMOS which is used on D17 and FIGARO.

International audience; In this study, we report on recent neutron inelastic scattering experiments performed at the Institut Laue-Langevin (ILL) for H2O and D2O. The measured dynamic structure factors S(q, ω) have been reduced, normalised and transformed into the S(α, β) formalism, where α and β stand for the unit-less momentum and energy transfers, respectively. The measurements were complemented with molecular dynamics simulations. After processing with NJOY, new water neutron scattering cross-sections have been generated for use with e.g. the Monte Carlo N-Particle (MCNP) software in view to improve the accuracy of the nuclear facility models. As an example, we present improved accuracy calculations for the safety rod insertion impact on the criticality factor keff for the ILL high flux research reactor. © 2014 © 2014 Atomic Energy Society of Japan. All rights reserved.

The MDANSE software—Molecular Dynamics Analysis of Neutron Scattering Experiments—is presented. It is an interactive application for postprocessing molecular dynamics (MD) simulations. Given the widespread use of MD simulations in material and biomolecular sciences to get a better insight for experimental techniques such as thermal neutron scattering (TNS), the development of MDANSE has focused on providing a user-friendly, interactive, graphical user interface for analyzing many trajectories in the same session and running several analyses simultaneously independently of the interface. This first version of MDANSE already proposes a broad range of analyses, and the application has been designed to facilitate the introduction of new analyses in the framework. All this makes MDANSE a valuable tool for extracting useful information from trajectories resulting from a wide range of MD codes.

Neutron scattering techniques have been employed to investigate 1,2-dimyristoyl-sn -glycero-3-phosphocholine (DMPC) membranes in the form of multilamellar vesicles (MLVs) and deposited, stacked multilamellar-bilayers (MLBs), covering transitions from the gel to the liquid phase. Neutron diffraction was used to characterise the samples in terms of transition temperatures, whereas elastic incoherent neutron scattering (EINS) demonstrates that the dynamics on the sub-macromolecular length-scale and pico- to nano-second time-scale are correlated with the structural transitions through a discontinuity in the observed elastic intensities and the derived mean square displacements. Molecular dynamics simulations have been performed in parallel focussing on the length-, time- and temperature-scales of the neutron experiments. They correctly reproduce the structural features of the main gel-liquid phase transition. Particular emphasis is placed on the dynamical amplitudes derived from experiment and simulations. Two methods are used to analyse the experimental data and mean square displacements. They agree within a factor of 2 irrespective of the probed time-scale, i.e. the instrument utilized. Mean square displacements computed from simulations show a comparable level of agreement with the experimental values, albeit, the best match with the two methods varies for the two instruments. Consequently, experiments and simulations together give a consistent picture of the structural and dynamical aspects of the main lipid transition and provide a basis for future, theoretical modelling of dynamics and phase behaviour in membranes. The need for more detailed analytical models is pointed out by the remaining variation of the dynamical amplitudes derived in two different ways from experiments on the one hand and simulations on the other.

Protein low-frequency vibrational modes are an important portion of a proteins' dynamical repertoire. Yet, it is notoriously difficult to isolate specific vibrational features in the spectra of proteins. Given an appropriately chosen model peptide, and using different experimental conditions, we can simplify the system and gain useful insights into the protein vibrational properties. Combining neutron scattering, depolarized light scattering, and molecular dynamics simulations, we analyse the low frequency vibrations of biological molecules, comparing the results from a small globular protein, lysozyme, and an amphiphilic peptide, NALMA, both in solution and in powder states. Lysozyme and NALMA present similar spectral features in the frequency range between 1 and 10 THz. With the aid of MD simulations, we assign the spectral features to methyl groups' librations (1-5 THz) and hindered torsions (5-10 THz) in NALMA. Our data also show that, while proteins display boson peak vibrations in both powder and solution forms, NALMA exhibits boson peak vibrations in powder form only. This provides insight into the nature of this feature, suggesting a connection of BP collective motions to a characteristic length scale of heterogeneities present in the system. These results provide context for the use of model peptide systems to study protein dynamics; demonstrating both their utility, and the great care that has to be used in extrapolating results observed in powder to solutions.

Generalized-born surface-area (GBSA) models have proved to be effective tools for estimating rapidly and with reasonable accuracy the solvation energies of molecular and macromolecular systems, and they have been employed in conjunction with both molecular mechanical (MM) and quantum mechanical (QM) potentials. In this article, we present our work to develop a GBSA model for calculations on macromolecules using hybrid potentials in which part of the system is treated with a semiempirical QM potential and the remaining atoms with a MM potential. Our efforts have centered principally on finding an approach for the calculation of the Born radii which is appropriate for MM and QM potentials and for small and large molecules, but inevitably, the competing requirements of these goals have meant a compromise in the design and parametrization of the model. We have, however, produced a scheme that we feel is suitable for macromolecular hybrid potential studies of processes, such as protein−ligand binding.

International audience; Neutron spectroscopy provides experimental data on time-dependent trajectories, which can be directly compared to molecular dynamics simulations. Its importance in helping us to understand biological macromolecules at a molecular level is demonstrated by the results of a literature survey over the last two to three decades. Around 300 articles in refereed journals relate to neutron scattering studies of biological macromolecular dynamics, and the results of the survey are presented here. The scope of the publications ranges from the general physics of protein and solvent dynamics, to the biologically relevant dynamics-function relationships in live cells. As a result of the survey we are currently setting up a neutron Dynamics Data Bank (nDDB) with the aim to make the neutron data on biological systems widely available. This will benefit, in particular, the MD simulation community to validate and improve their force fields. The aim of the database is to expose and give easy access to a body of experimental data to the scientific community. The database will be populated with as much of the existing data as possible. In the future it will give value, as part of a bigger whole, to high throughput data, as well as more detailed studies. A range and volume of experimental data will be of interest in determining how quantitatively MD simulations can reproduce trends across a range of systems and to what extent such trends may depend on sample preparation and data reduction and analysis methods. In this context, we strongly encourage researchers in the field to deposit their data in the nDDB.

We report a detailed study of the dynamics of oxide ionic conduction in brownmillerite-type Sr2Fe2O5, including lat-tice anisotropy, based on neutron scattering studies of a large (partially twinned) single crystal in combination with ab initio molecular dynamics simulations. Single-crystal diffraction reveals supercell peaks due to long-range order-ing among chains of corner-sharing FeO4 tetrahedra, which disappears on heating above 540 °C due to confined local rotations of tetrahedra. Our simulations show that these rotations are essentially isotropic, but are a precondition for the anisotropic motion that moves oxide ions into the tet-rahedral layers from the octahedral layers, which we observe experimentally as a Lorentzian broadening of the quasielas-tic neutron scattering spectrum. This continual but incoher-ent movement of oxide ions in turn creates conduction pathways and activates long-range diffusion at the interface between layers, which appears to be largely isotropic in two dimensions, in contrast with previously proposed mecha-nisms that suggest diffusion occurs preferentially along the c axis.

Molecular dynamics simulations and elastic neutron scattering experiments have been used to highlight how the structural organization of hydration water is able in some cases to locally constrain atomic movements at biologic interfaces. Using fully hydrated small peptides as models of protein interfaces, we show that the length of the side chains and the hydrophilic backbone have specific signatures. The dynamics of the side chain, which is part of biomolecules, have not only a crucial role in the whole flexibility as compared to the backbone, but also modify the values of transition temperatures. The analysis of the activation energies of methyl group dynamics suggests that the interaction between hydrophobic side chain and surrounding water plays an important role in the whole flexibility as well. We suggest that the progressive water cluster organization, around hydrophobic interfaces increases the activation energy and that a plateau regime is reached only when an extended hydrogen-bond network is established. The cluster size corresponds to a single layer of water molecules.

International audience; We present a new version of the program package nMoldyn, which has been originally developed for a neutron-scattering oriented analysis of molecular dynamics simulations of macromolecular systems (Kneller et al., Comput. Phys. Commun. 1995, 91, 191) and was later rewritten to include in-depth time series analyses and a graphical user interface (Rog et al., J. Comput. Chem. 2003, 24, 657). The main improvement in this new version and the focus of this article are the parallelization of all the analysis algorithms for use on multicore desktop computers as well as distributed-memory computing clusters. The parallelization is based on a task farming approach which maintains a simple program structure permitting easy modification and extension of the code to integrate new analysis methods. © 2012 Wiley Periodicals, Inc.

The availability of user-friendly software and affordable multi-processor computers opens the door to the world of simulations to experimentalists, for “advanced data analysis”. Neutron scattering (NS), which explores length and time scales and probes the relative positions and motions of atoms as in simulations, constitutes the ideal partner for atomistic simulations. On the experimental side, the ever-increasing complexity of samples and therefore data requires more elaborate and realistic models. This chapter therefore describes, in practical terms, the simulation methods that can be used to interpret quasielastic and inelastic NS data, namely molecular dynamics and lattice dynamics. Both of these methods are based on the knowledge of inter-atomic interactions and total energy for which density functional theory and classical, force field-based methods are presented as the most viable.

Inelastic neutron scattering experiments and molecular dynamics simulations have been used to investigate the low frequency modes, in the region between 0 and 100 meV, of hydration water in selected hydrophilic and hydrophobic biomolecules. The results show changes in the plasticity of the hydrogen-bond network of hydration water molecules depending on the biomolecular site. At 200 K, the measured low frequency density of states of hydration water molecules of hydrophilic peptides is remarkably similar to that of high density amorphous ice, whereas, for hydrophobic biomolecules, it is comparable to that of low density amorphous ice behavior. In both hydrophilic and hydrophobic biomolecules, the high frequency modes show a blue shift of the libration mode as compared to the room temperature data. These results can be related to the density of water molecules around the biological interface, suggesting that the apparent local density of water is larger in a hydrophilic environment

Molecular dynamics simulations have been used to investigate the dynamics of hydrogen bonds (HBs) formed by hydration water in selected hydrophilic and hydrophobic biomolecules. Labelling all of atoms in the molecule allows analysing the HB relaxation time at specific donor and acceptor binding sites. The results show that the water–water HBs present a longer relaxation time around the completely hydrophilic peptide, and that the water–biomolecule HBs exhibit a distinct behaviour depending on the binding sites at the hydrophilic or hydrophobic bio-interface. The presence of a large hydrophobic surface enhances, in particular at low temperature, the dynamical heterogeneity in the neighbouring hydrogen bond network.

Myocardial angiogenesis following reperfusion of an infarcted area may impact on patient prognosis and pro-angiogenic treatments are currently evaluated. The non-invasive imaging of angiogenesis would therefore be of potential clinical relevance in these settings. (99m)Tc-RAFT-RGD is a novel (99m)Tc-labeled tracer that targets the alpha(v)beta(3) integrin. Our objective was to determine whether this tracer was suitable for myocardial angiogenesis imaging.A rat model of reperfused myocardial infarction was employed. Fourteen days following reperfusion, the animals were injected with (99m)Tc-RAFT-RGD or with its negative control (99m)Tc-RAFT-RAD. Fourteen animals were dedicated to autoradiographic imaging, infarct staining, and gamma-well counting of myocardial activity. In vivo dual-isotope pinhole SPECT imaging of (201)Tl and (99m)Tc-RAFT-RGD or (99m)Tc-RAFT-RAD was also performed in 11 additional animals. Neovessels were observed by immunostaining in the infarcted and peri-infarct areas. (99m)Tc-RAFT-RGD infarct-to-normal ratios by gamma-well counting and ex vivo imaging (2.5 +/- 0.6 and 4.9 +/- 0.9, respectively) were significantly higher than those of (99m)Tc-RAFT-RAD (1.7 +/- 0.2 and 2.2 +/- 0.4, respectively, P.05). The infarcted area was readily visible in vivo by SPECT with (99m)Tc-RAFT-RGD but not with (99m)Tc-RAFT-RAD (infarct-to-normal zone activity ratio, 2.5 +/- 0.6 and 1.7 +/- 0.4, respectively, P.05).(99m)Tc-RAFT-RGD allowed the experimental in vivo molecular imaging of myocardial angiogenesis.

Introduction - Myocardial angiogenesis following reperfusion of an infarcted area affects postinfarct remodelling and may therefore impact on patient prognosis. The non-invasive molecular imaging of angiogenesis is thus of potential clinical relevance in this setting. Angiogenic vessels overexpress the α v β 3 integrin. Tc-RAFT-RGD is a novel 99m Tc-labelled tracer composed of four α v β 3 integrin-specific cyclo(RGDfK) sequences tethered on a cyclodecapeptide platform. Hypothesis - We hypothesized that Tc-RAFT-RGD binding to the α v β 3 integrin would allow the molecular imaging of myocardial angiogenesis in vivo. Methods - Myocardial infarction was induced by left anterior descending coronary artery occlusion for 45 min prior to reperfusion in 24 anesthetized male Wistar rats. Fourteen days later, the animals were injected intravenously with Tc-RAFT-RGD (n = 16) or Tc-RAFT-RAD (negative control, n = 8). Tracer uptake was assessed 60 min following injection in 12 and 4 animals injected with Tc-RAFT-RGD and Tc-RAFT-RAD, respectively. In those animals, the hearts were quickly excised for autoradiographic imaging, nitroblue tetrazolium (NBT) infarct staining, CD31 immunostaining of neovessels, and for gamma-well counting of myocardial tracer activity in the infarcted and normal areas. The remaining animals were dedicated to in vivo dual-isotope pinhole SPECT imaging following the simultaneous injection of Tl-201 and Tc-RAFT-RGD (n = 4) or Tc-RAFT-RAD (n = 4). Results - Neovessels were observed in the infarcted area using CD31 immunostaining. The Tc-RAFT-RGD infarcted-to-normal zone activity ratios by gamma-well counting and ex vivo imaging (2.6 ± 0.6 and 3.9 ± 1.0, respectively) were significantly higher than those of Tc-RAFT-RAD (1.7 ± 0.5 and 2.1 ± 0.4, respectively, P< 0.05). Quantification of short-axis images from SPECT acquisitions indicated similar Tl-201 defect magnitudes in animals injected with Tc-RAFT-RGD and Tc-RAFT-RAD (0.3 ± 0.1 and 0.4 ± 0.1, P =NS). The infarcted area was readily visible in vivo with Tc-RAFT-RGD but not with Tc-RAFT-RAD (infarct-to-normal zone activity ratio, 2.8 ± 0.6 and 1.6 ± 0.4, respectively, P< 0.05). Conclusions - Tc-RAFT-RGD allowed the experimental in vivo molecular imaging of myocardial angiogenesis.

Two classification models were developed based on a data set of 220 phenols with four associated Modes of Toxic Action (MOA). Counter-propagation neural networks (CPG NN) and multinomial logistic regression (multinom) were used as classification methods. The combination of topological autocorrelation of empirical pi-charge and sigma-electronegativity and of surface autocorrelation of hydrogen-bonding potential resulted in a 21-dimensional model that successfully discriminated between the four MOAs. Its overall predictive power was estimated to 92% using 5-fold cross-validation. Subsequently, a simple score for the distance to the training data was used to determine the prediction space of the model and used in an exploratory study on the phenols contained in the open NCI database. The use of a prediction space metric proved indispensable for the screening of such a diverse database. The prediction space covered by the proposed model is still of rather local nature which is either caused by the limited diversity and size of the training set or by the high dimensionality of the descriptors.

In this article we present an implementation of a de novo drug-design algorithm. The algorithm starts with a molecule placed in the binding site of a protein and then modifies it using a sequential growth approach. This involves successive cycles of suppression of randomly picked groups in the molecule and their replacement by other groups chosen from databanks of linear or cyclic fragments. The algorithm has been coupled with the DYNAMO library which allows the simulation of macromolecules using molecular mechanical and quantum chemical methods. The main body of the article describes the methodologies we use to create, characterize and evaluate putative ligands. We also consider briefly an application of the algorithm to a protein of pharmacological interest, the neuraminidase of the influenza virus, and discuss the strengths and weaknesses of our approach.

The instanton or stationary-phase formula has received much attention recently as a way of determining transition paths in reacting systems. In this paper, we analyze the instanton approach for some one-dimensional problems and compare the results it gives with data from a numerical simulation. We show that a proper comparison of the analytic and numerical results must take into account the boundary conditions used in the numerical simulations and also suggest values for the integration constant in the instanton formula that gives the best agreement with the simulated results.

The removal of the heme group from myoglobin (Mb) results in a destabilization of the protein structure. The dynamic basis of the destabilization was followed by comparative measurements on holo- (holo-Mb) and apomyoglobin (apo-Mb). Mean-squared displacements (MSD) and protein resilience on the picosecond-to-nanosecond timescale were measured by elastic incoherent neutron scattering. Differences in thermodynamic parameters, MSD, and resilience were observed for both proteins. The resilience of holo-Mb was significantly lower than that of apo-Mb, indicating entropic stabilization by a higher degree of conformational sampling in the heme-bound folded protein. Molecular dynamics simulations provided site-specific information. Averaged over the whole structure, the molecular dynamics simulations yielded similar MSD and resilience values for the two proteins. The mobility of residues around the heme group in holo-Mb showed a smaller MSD and higher resilience compared to the same residue group in apo-Mb. It is of interest that in holo-Mb, higher MSD values are observed for the residues outside the heme pocket, indicating an entropic contribution to protein stabilization by heme binding, which is in agreement with experimental results.