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The problem of localizing small (relative to wavelength) scatterers by diffractions to enhance their use in identifying small-scale details in a seismic image is extremely important in shallow exploration to identify interesting features such as fractures, caves, and faults. The conventional approach based on seismic reflection is limited in resolution by the Rayleigh criterion. In certain acquisition geometries, such as crosswell surveys aimed at obtaining high-resolution signals, the availability of suitable data sets for effective migration depends on the spatial extent of the available source and receiver data intervals. With the aim of overcoming the resolution limits of seismic reflection, we study the detectability, response, and location of meter- and possibly submeter-dimension carbonate concretions (septaria) in the Boom Clay Formation (potential host rocks for radioactive waste disposal) by diffraction analysis of high-frequency signals. We investigate diffraction wavefields by signal separation, focusing, and high-resolution coherency analysis using the multiple signal classification method and semblance. The investigation is performed for two different surveys in Belgium, a shallow and high-resolution reverse vertical seismic profile (RVSP) and a near-offset crosswell application at Kruibeke and ON-MOL-2 sites, respectively. The data analysis is supported by synthetic wavefield modeling. The multioffset RVSP provides the appropriate geometry to observe and investigate the septaria diffractions from depth and the surface. The crosswell approach, calibrated using synthetic data in the analysis of wavefield patterns in 2D, indicates promising imaging results with field data of a selected diffraction zone in the interwell area.

The overexpression of PED/PEA15, the phosphoprotein enriched in diabetes/phosphoprotein enriched in the astrocytes 15 protein (here referred simply to as PED), observed in some forms of type II diabetes, reduces the transport of insulin-stimulated glucose by binding to the phospholipase D1 (PLD1). The inhibition of the PED/PLD1 interaction was shown to restore basal glucose transport, indicating PED as a pharmacological target for the development of drugs capable of improving insulin sensitivity and glucose tolerance. We here report the identification and selection of PED ligands by means of NMR screening of a library of small organic molecules, NMR characterization of the PED/PLD1 interaction in lysates of cells expressing PLD1, and modulation of such interactions using BPH03, the best selected ligand. Overall, we complement the available literature data by providing detailed information on the structural determinants of the PED/PLD1 interaction in a cellular lysate environment and indicate BPH03 as a precious scaffold for the development of novel compounds that are able to modulate such interactions with possible therapeutic applications in type II diabetes.

For four decades, the use of the drill-bit seismic source has been evaluated extensively and investigated for seismic-while-drilling (SWD) purposes. After an initial diffusion phase, however, the routine application on drill-bit reverse vertical seismic profiling (RVSP) has declined because of issues related to variability in the signal-to-noise ratio of drill-bit signals obtained with different drilling conditions. Consequently, additional efforts have been dedicated to improving the recording of reference signals. Recent technology developments enable direct ground-force pilot measurements at downhole positions close to the bit, which enable reliable estimations of the far-field drill-bit-radiated signature. The knowledge of the ground force below the source in the near-field is a key aspect not only for the exploitation of the drill-bit source but also for conventional seismic vibrator sources. The SWD deconvolved results obtained by the ground force are different from those obtained by recording only motion vibration, such as acceleration. The ground force and particle velocity are linked by a complex impedance in the near-field, and together they provide dual measurements. In addition, the ground force provides signals with effective coupling conditions at the bit-rock interface in the presence of the drill-bit displacement action with penetration during rock fracturation. The analysis of the impedance at the bit source includes the drillstring reflections, which are observed in the reference drillstring pilot signal and are simulated by using an appropriate mechanical model. The processing of real seismic signals with different approaches by deconvolution and correlation using ground-force and motion signals produces improvements in the extraction of the source signal, with effective removal of the undesired pilot wavefields, and with cleaner estimations of the drill-bit seismic wavefields in a crosswell survey.

Blocking the interaction between the apoptosis-inducing factor (AIF) and cyclophilin A (CypA) by the AIF fragment AIF(370-394) is protective against glutamate-induced neuronal cell death and brain injury in mice. Starting from AIF(370-394), we report the generation of the disulfide-bridged and shorter variant AIF(381-389) and its structural characterization by nuclear magnetic resonance (NMR) in the free and CypA-bound state. AIF(381-389) in both the free and bound states assumes a β-hairpin conformation similar to that of the fragment in the AIF protein and shows a highly reduced conformational flexibility. This peptide displays a similar in vitro affinity for CypA, an improved antiapoptotic activity in cells and an enhanced proteolytic stability compared to the parent peptide. The NMR-based 3D model of the AIF(381-389)/CypA complex provides a better understanding of the binding hot spots on both the peptide and the protein and can be exploited to design AIF/CypA inhibitors with improved pharmacokinetic and pharmacodynamics features.

The crucial role of integrin in pathological processes such as tumor progression and metastasis formation has inspired intense efforts to design novel pharmaceutical agents modulating integrin functions in order to provide new tools for potential therapies. In the past decade, we have investigated the biological proprieties of the chimeric peptide RGDechi, containing a cyclic RGD motif linked to an echistatin C-terminal fragment, able to specifically recognize αvβ3 without cross reacting with αvβ5 and αIIbβ3 integrin. Additionally, we have demonstrated using two RGDechi-derived peptides, called RGDechi1-14 and ψRGDechi, that chemical modifications introduced in the C-terminal part of the peptide alter or abolish the binding to the αvβ3 integrin. Here, to shed light on the structural and dynamical determinants involved in the integrin recognition mechanism, we investigate the effects of the chemical modifications by exploring the conformational space sampled by RGDechi1-14 and ψRGDechi using an integrated natural-abundance NMR/MD approach. Our data demonstrate that the flexibility of the RGD-containing cycle is driven by the echistatin C-terminal region of the RGDechi peptide through a coupling mechanism between the N- and C-terminal regions.

The noncondensable gases in most geothermal resources include CO2 and smaller amounts of other gases. Currently, the worldwide geothermal power is a small sector within the energy industry, and CO2 emissions related to the utilisation of geothermal resources are consequently small. In some countries, however, such as Turkey and Iceland, geothermal energy production contributes significantly to their energy budget, and their CO2 emissions are relatively significant. SUCCEED is a targeted innovation and research project, which aims to investigate the reinjection of CO2 produced at geothermal power production sites and develop, test, and demonstrate at field scale innovative measurement, monitoring and verification (MMV) technologies that can be used in most CO2 geological storage projects. The project is carried out at two operating geothermal energy production sites, the Kızıldere geothermal field in Turkey and the CarbFix project site at the Hellisheiði geothermal field in Iceland. Together with a brief description of the project, this paper presents the details of the two field sites and the progress made in seismic velocity characterisation and modelling relevant to the Kızıldere geothermal field in Turkey.

Graphical abstract, Structural investigations of receptor-ligand interactions on living cells surface by high-resolution Nuclear Magnetic Resonance (NMR) are problematic due to their short lifetime, which often prevents the acquisition of experiments longer than few hours. To overcome these limitations, we developed an on-cell NMR-based approach for exploring the molecular determinants driving the receptor-ligand recognition mechanism under native conditions. Our method relies on the combination of high-resolution structural and dynamics NMR data with Molecular Dynamics simulations and Molecular Docking studies. The key point of our strategy is the use of Non Uniform Sampling (NUS) and T1ρ-NMR techniques to collect atomic-resolution structural and dynamics information on the receptor-ligand interactions with living cells, that can be used as conformational constraints in computational studies. In fact, the application of these two NMR methodologies allows to record spectra with high S/N ratio and resolution within the lifetime of cells. In particular, 2D NUS [1H–1H] trNOESY spectra are used to explore the ligand conformational changes induced by receptor binding; whereas T1ρ-based experiments are applied to characterize the ligand binding epitope by defining two parameters: T1ρ Attenuation factor and T1ρ Binding Effect. This approach has been tested to characterize the molecular determinants regulating the recognition mechanism of αvβ5-integrin by a selective cyclic binder peptide named RGDechi15D. Our data demonstrate that the developed strategy represents an alternative in-cell NMR tool for studying, at atomic resolution, receptor-ligand recognition mechanism on living cells surface. Additionally, our application may be extremely useful for screening of the interaction profiling of drugs with their therapeutic targets in their native cellular environment.

This paper deals with the design, acquisition and processing of vertical seismic profiling data collected in 2016 at the directional Thonex‐01 geothermal well, drilled in 1993 in the Geneva Canton (Switzerland). The aim of the study was to obtain additional information from existing‐abandoned well for downhole geophysical characterization of potential geothermal reservoirs in the Geneva area. The main results obtained by this study allowed an improved subsurface image by multi‐offset acquisitions near and around the deviated well. Specifically we were able to (1) improve the velocity model of the Geneva Basin, which, at present, is only constrained by one unique deep exploration well, located at the south‐west of the basin, far away from the study area; (2) image the transition between the Tertiary Molasse siliciclastic sediments and the Mesozoic carbonates; (3) define an acquisition strategy for future vertical seismic profiling surveys in support of the geothermal exploration campaigns in the area. This study has demonstrated the value of vertical seismic profiling method for the refinement of the subsurface geology at local scale, and its usefulness to assist the planning of second well associated with geothermal doublets.

The complex formation between the proteins apoptosis-inducing factor (AIF) and cyclophilin A (CypA) following oxidative stress in neuronal cells has been suggested as a main target for reverting ischemia-stroke damage. Recently, a peptide encompassing AIF residues 370–394 has been developed to target the AIF-binding site on CypA, to prevent the association between the two proteins and suppress glutamate-induced cell death in neuronal cells. Using a combined approach based on NMR spectroscopy, synthesis and in vitro testing of all Ala-scan mutants of the peptide and molecular docking/molecular dynamics, we have generated a detailed model of the AIF (370–394)/CypA complex. The model suggests us that the central region of the peptide spanning residues V374–K384 mostly interacts with the protein and that for efficient complex inhibition and preservation of CypA activity, it is bent around amino acids F46–G75 of the protein. The model is consistent with experimental data also from previous works and supports the concept that the peptide does not interfere with other CypA activities unrelated to AIF activation; therefore, it may serve as an ideal template for generating future non-peptidic antagonists.

Seismic propagation in the upper part of the crust, where geothermal reservoirs are located, shows generally strong velocity dispersion and attenuation due to varying permeability and saturation conditions and is affected by the brittleness and/or ductility of the rocks, including zones of partial melting. From the elastic-plastic aspect, the seismic properties (seismic velocity, quality factor and density) depend on effective pressure and temperature. We describe the related effects with a Burgers mechanical element for the shear modulus of the dry-rock frame. The Arrhenius equation combined to the octahedral stress criterion define the Burgers viscosity responsible of the brittle-ductile behaviour. The effects of permeability, partial saturation, varying porosity and mineral composition on the seismic properties is described by a generalization of the White mesoscopic-loss model to the case of a distribution of heterogeneities of those properties. White model involves the wave-induced fluid flow attenuation mechanism, by which seismic waves propagating through small-scale heterogeneities, induce pressure gradients between regions of dissimilar properties, where part of the energy of the fast P-wave is converted to slow P (Biot)-wave. We consider a range of variations of the radius and size of the patches and thin layers whose probability density function is defined by different distributions. The White models used here are that of spherical patches (for partial saturation) and thin layers (for permeability heterogeneities). The complex bulk modulus of the composite medium is obtained with the Voigt-Reuss-Hill average. Effective pressure effects are taken into account by using exponential functions. We then solve the 3D equation of motion in the space-time domain, by approximating the White complex bulk modulus with that of a set of Zener elements connected in series. The Burgers and generalized Zener models allows us to solve the equations with a direct grid method by the introduction of memory variables. The algorithm uses the Fourier pseudospectral method to compute the spatial derivatives. It is tested against an analytical solution obtained with the correspondence principle. We consider two main cases, namely the same rock frame (uniform porosity and permeability) saturated with water and a distribution of steam patches, and water-saturated background medium with thin layers of dissimilar permeability. Our model indicates how seismic properties change with the geothermal reservoir temperature and pressure, showing that both seismic velocity and attenuation can be used as a diagnostic tool to estimate the in situ conditions.

Part of the crust shows generally brittle behaviour while areas of high temperature and/or high pore pressure, including the mantle, may present ductile behaviour. For instance, the potential heat source of geothermal fields, overpressured formations and molten rocks. Seismic waves can be used to detect these conditions on the basis of reflection and transmission events. Basically, from the elastic-plastic point of view the seismic properties (seismic velocity, quality factor and density) depend on effective pressure and temperature. Confining and pore pressures have opposite effects on these properties, and high temperatures may induce a similar behaviour by partial melting. In order to model these effects, we consider a poro-viscoelastic model based on the Burgers mechanical element and the squirt-flow model to represent the properties of the rock frame to describe ductility in which deformation takes place by shear plastic flow, and to model local and global fluid flow effects. The Burgers element allows us to model the effects of the steady-state creep flow on the dry-rock frame. The stiffness components of the brittle and ductile media depend on stress and temperature through the shear viscosity, which is obtained by the Arrhenius equation and the octahedral stress criterion. Effective pressure effects are taken into account in the dry-rock moduli by using exponential functions whose parameters are obtained by fitting experimental data as a function of confining pressure. Since fluid effects are important, the density and bulk modulus of the saturating fluids (water at sub- and supercritical conditions) are modeled by using the equations provided by the NIST website. The squirt-flow model has a single free parameter represented by the aspect ratio of the grain contacts. The theory generalizes a preceding theory based on Gassmann (low-frequency) moduli to the more general case of the presence of local (squirt) flow and global (Biot) flow, which contribute with additional attenuation mechanisms to the wave propagation.

The upper part of the crust shows generally brittle behaviour while deeper zones, including the mantle, may present ductile behaviour, depending on the pressure–temperature conditions; moreover, some parts are melted. Seismic waves can be used to detect these conditions on the basis of reflection and transmission events. Basically, from the elastic–plastic point of view the seismic properties (seismic velocity and density) depend on effective pressure and temperature. Confining and pore pressures have opposite effects on these properties, such that very small effective pressures (the presence of overpressured fluids) may substantially decrease the P- and S-wave velocities, mainly the latter, by opening of cracks and weakening of grain contacts. Similarly, high temperatures induce the same effect by partial melting. To model these effects, we consider a poro-viscoelastic model based on Gassmann equations and Burgers mechanical model to represent the properties of the rock frame and describe ductility in which deformation takes place by shear plastic flow. The Burgers elements allow us to model the effects of seismic attenuation, velocity dispersion and steady-state creep flow, respectively. The stiffness components of the brittle and ductile media depend on stress and temperature through the shear viscosity, which is obtained by the Arrhenius equation and the octahedral stress criterion. Effective pressure effects are taken into account in the dry-rock moduli using exponential functions whose parameters are obtained by fitting experimental data as a function of confining pressure. Since fluid effects are important, the density and bulk modulus of the saturating fluids (water and steam) are modeled using the equations provided by the NIST website, including supercritical behaviour. The theory allows us to obtain the phase velocity and quality factor as a function of depth and geological pressure and temperature as well as time frequency. We then obtain the PS and SH equations of motion recast in the velocity–stress formulation, including memory variables to avoid the computation of time convolutions. The equations correspond to isotropic anelastic and inhomogeneous media and are solved by a direct grid method based on the Runge–Kutta time stepping technique and the Fourier pseudospectral method. The algorithm is tested with success against known analytical solutions for different shear viscosities. An example shows how anomalous conditions of pressure and temperature can in principle be detected with seismic waves.

Distributed acoustic sensing (DAS) using fiber optic cables is an emerging seismic acquisition technology for the oil and gas industry, geothermal resource exploration, and underground fluid-storage monitoring. This technology offers the advantage of improving seismic acquisition by enabling massive arrays for monitoring of seismic wavefields at reduced cost with respect to conventional methods. In general, it is accepted that this method provides acoustic signals comparable with conventional seismic data, however, without the multicomponent directional information typical of geophones. We have developed a modified data extraction method and found that, as a result of the dense spatial distribution of recording points along the optic cable, DAS can provide two linked wavefield components in the axial direction, even when using a single 1D cable line. These signal pairs consist of dual components that are related to native strain rate (or strain) and particle acceleration (or velocity) fields at a given recording location. These dual signals are easily usable for wavefield separation purposes simply performing a trace-by-trace combination by appropriate scaling coefficient. The analysis performed with borehole data from linear and helically wound cables demonstrates the effectiveness of polarity recovery and dual-wavefield separation. We show real examples in which the data can be combined to provide separation of up- and downgoing wavefields. The ratio of the dual components provides information on local slowness properties in the formation.

Seven families of double-stranded DNA viruses have been identified, among which the Fuselloviridae and Rudiviridae are the most well-studied specimens and therefore represent model systems for detailed studies of archaeal virus biology. Two distinct genetic elements, SSV2 and pSSVx, belong to Fuselloviridae and coexist in the same Sulfolobus islandicus REY15/4 host, thus representing one of the few known two-virus systems in Archaea (1). pSSVx is a satellite virus that generates virus particles with the help of SSV2-associated packaging mechanisms. The transcriptional pattern of pSSVx undergoes a temporal variation of gene expression during its own life cycle, thus providing a good model for studying regulation of gene expression in Archaea (2). This genetic element encodes four TFs possibly implicated in the regulation of gene expression, i.e. ORF-c68, ORF51, ORF91 and ORF76. Among these, ORF76, here named Stf76 (Sulfolobus transcription factor 76 aminoacid protein), has homologs in almost all conjugative and cryptic plasmids from Sulfolobus (3), thus suggesting a relevant role for this protein in replication and/or maintenance of the plasmid. In this study, we have performed a detailed structural and functional characterization of Stf76. The corresponding gene has been cloned, expressed in Escherichia coli and the recombinant protein purified to homogeneity. To elucidate its interaction with the identified DNA operator sequence, analyses regarding its DNA binding capabilities by means of EMSA, circular dichroism, spectrofluorimetric and isothermal titration calorimetry experiments have been performed. Moreover, a structural study has been undertaken by Nuclear Magnetic Resonance spectroscopy leading to:(i) the solution structure of Stf76 based on CS-Rosetta approach, (ii) the characterization of the Stf76-DNA interaction by chemical shift perturbation analysis, (iii) a structural model describing the interaction of a single Stf76 monomer with its DNA operator. Altogether these results contribute to elucidate the regulatory mechanism underpinning the role of this protein (4). REFERENCES: 1. ARNOLD, H.P., ET AL.(1999) THE GENETIC ELEMENT PSSVX OF THE EXTREMELY THERMOPHILIC CRENARCHAEON SULFOLOBUS IS A HYBRID BETWEEN A PLASMID AND A VIRUS. MOL MICROBIOL, 34, 217-226. 2. CONTURSI, P., ET.AL. (2010) TRANSCRIPTION TERMINATION IN THE PLASMID/VIRUS HYBRID PSSVX FROM SULFOLOBUS ISLANDICUS. EXTREMOPHILES, 14, 453-463. 3. LIPPS, G. (2006) PLASMIDS AND VIRUSES OF THE THERMOACIDOPHILIC CRENARCHAEOTE SULFOLOBUS. EXTREMOPHILES, 10, 17-28. 4. CONTURSI P., FARINA B., PIRONE L. ET AL. NUCLEIC ACIDS RES. ACCEPTED 28 FEB. 2014.

We compare viscoelastic models to obtain the seismic properties of a partially molten rock as a function of temperature, pressure and tectonic stress. Invoking the correspondence principle, the material of the inclusions is represented by a Maxwell mechanical model, where the Arrhenius equation and the octahedral stress criterion define the Maxwell viscosity. One of the most advanced models is the self-consistent or coherent-potential approximation (CPA), which considers oblate spheroidal inclusions of arbitrary aspect ratio and high concentration. The physical mechanism behind the Arrhenius equation is grain-boundary relaxation, and melt occurs beyond a critical temperature. The seismic properties (stiffness, wave velocity and dissipation factor) are obtained with the CPA, Hill, Hashin-Shtrikman, Walsh and Krief-Gassmann equations. The latter model and the Hashin-Shtrikman average make no assumption on the shape of the inclusions. All the models show similar trends, predicting relaxation peaks at seismic frequencies and at the brittle-ductile transition.

Integrins are heterodimeric cell-surface proteins that play important roles during developmental and pathological processes. Diverse human pathologies involve integrin adhesion including thrombotic diseases, inflammation, tumour progression, fibrosis, and infectious diseases. Although in the past decade, novel integrin-inhibitor drugs have been developed for integrin-based medical applications, the structural determinants modulating integrin-ligands recognition mechanisms are still poorly understood, reducing the number of integrin subtype exclusive antagonists. In this scenario, we have very recently showed, by means of chemical and biological assays, that a chimeric peptide (named RGDechi), containing a cyclic RGD motif linked to an echistatin C-terminal fragment, is able to interact with the components of integrin family with variable affinities, the highest for αv β3. Here, in order to understand the mechanistic details driving the molecular recognition mechanism of αv β3 by RGDechi, we have performed a detailed structural and dynamics characterization of the free peptide by natural abundance nuclear magnetic resonance (NMR) spectroscopy. Our data indicate that RGDechi presents in solution an heterogeneous conformational ensemble characterized by a more constrained and rigid pentacyclic ring and a largely unstructured acyclic region. Moreover, we propose that the molecular recognition of αv β3 integrin by RGDechi occurs by a combination of conformational selection and induced fit mechanisms. Finally, our study indicates that a detailed NMR characterization, by means of natural abundance 15 N and 13 C, of a mostly unstructured bioactive peptide may provide the molecular basis to get essential structural insights into the binding mechanism to the biological partner.

Background The peptide VLL-28, identified in the sequence of an archaeal protein, the transcription factor Stf76 from Sulfolobus islandicus, was previously identified and characterized as an antimicrobial peptide, possessing a broad-spectrum antibacterial activity. Methods Through a combined approach of NMR and Circular Dichroism spectroscopy, Dynamic Light Scattering, confocal microscopy and cell viability assays, the interaction of VLL-28 with the membranes of both parental and malignant cell lines has been characterized and peptide mechanism of action has been studied. Results It is here demonstrated that VLL-28 selectively exerts cytotoxic activity against murine and human tumor cells. By means of structural methodologies, VLL-28 interaction with the membranes has been proven and the binding residues have been identified. Confocal microscopy data show that VLL-28 is internalized only into tumor cells. Finally, it is shown that cell death is mainly caused by a time-dependent activation of apoptotic pathways. Conclusions VLL-28, deriving from the archaeal kingdom, is here found to be endowed with selective cytotoxic activity towards both murine and human cancer cells and consequently can be classified as an ACP. General significance VLL-28 represents the first ACP identified in an archaeal microorganism, exerting a trans-kingdom activity.

In the present work we performed a combined experimental and computational study on the interaction of the natural antimalarial endoperoxide plakortin and its synthetic analogue 4a with heme. Obtained results indicate that the studied compounds produce reactive carbon radical species after being reductively activated by heme. In particular, similarly to artemisinin, the formation of radicals prone to inter-molecular reactions should represent the key event responsible for Plasmodium death. To our knowledge this is the first experimental investigation on the reductive activation of simple antimalarial endoperoxides (1,2-dioxanes) by heme and results were compared to the ones previously obtained from the reaction with FeCl2. The obtained experimental data and the calculated molecular interaction models represent crucial tools for the rational optimization of our promising class of low-cost synthetic antimalarial endoperoxides.

This work studies the wave motion in a fluid-filled borehole in the presence of drill string and geological formation. The synthetic waveforms are obtained by a three-dimensional axis-symmetric full-wave numerical simulation in a two-dimensional multi-domain where the medium is uniform with respect to the azimuth. The discretization is performed in cylindrical coordinates. In order to simulate the waves at the origin (axis of the polar radius), a very small radius is used to avoid the singularity. The free-surface and rigid boundary conditions are tested and it is shown that the rigid one constitutes the best approximation. The simulations provide the amplitude distribution and motion diagrams in the borehole vertical cross-sections and at the outer boundary, away from the borehole. Propagation in the presence of hard and soft formations is analysed. The dispersion, the amplitude, and the orbital polarization of the modes excited by a point source acting in the fluid inside a drillstring are considered and examples of comparison with literature results obtained using multi-modal analysis are shown. The proposed approach is more general than the multi-modal analysis, since it allows for arbitrary variations of the properties in the plane of symmetry.

We present a modified interferometry method based on local tangent-phase analysis, which corrects the cross-correlated data before summation. The approach makes it possible to synthesize virtual signals usually vanishing in the conventional seismic interferometry summation. For a given pair of receivers and a set of different source positions, a plurality of virtual traces is obtained at new stationary projected points located along the signal wavefronts passing through the real reference receiver. The position of the projected points is estimated by minimizing travel times using wavefront constraint and correlation-signal tangent information. The method uses mixed processing, which is partially based on velocity-model knowledge and on data-based blind interferometry. The approach can be used for selected events, including reflections with different stationary conditions and projected points with respect to those of the direct arrivals, to extend the interferometry representation in seismic exploration data where conventional illumination coverage is not sufficient to obtain the stationary-phase condition. We discuss possible applications in crosswell geometry with a velocity anomaly and a time lapse.

The earth's crust presents two dissimilar rheological behaviors depending on the in situ stress-temperature conditions. The upper, cooler part is brittle, while deeper zones are ductile. Seismic waves may reveal the presence of the transition but a proper characterization is required. We first obtain a stress–strain relation, including the effects of shear seismic attenuation and ductility due to shear deformations and plastic flow. The anelastic behavior is based on the Burgers mechanical model to describe the effects of seismic attenuation and steady-state creep flow. The shear Lamé constant of the brittle and ductile media depends on the in situ stress and temperature through the shear viscosity, which is obtained by the Arrhenius equation and the octahedral stress criterion. The P and S wave velocities decrease as depth and temperature increase due to the geothermal gradient, an effect which is more pronounced for shear waves. We then obtain the P−S and SH equations of motion recast in the velocity-stress formulation, including memory variables to avoid the computation of time convolutions. The equations correspond to isotropic anelastic and inhomogeneous media and are solved by a direct grid method based on the Runge–Kutta time stepping technique and the Fourier pseudospectral method. The algorithm is tested with success against known analytical solutions for different shear viscosities. A realistic example illustrates the computation of surface and reverse-VSP synthetic seismograms in the presence of an abrupt brittle–ductile transition.

The specific arrangement of secondary elements in a local motif often totally relies on the formation of coordination bonds between metal ions and protein ligands. This is typified by the -30 amino acid eukaryotic zinc finger motif in which a beta-sheet and an or-helix are clustered around a zinc ion by various combinations of four ligands. The prokaryotic zinc finger domain (found in the Ros protein from Agrobacterium tumefaciens) is different from the eukaryotic counterpart as it consists of 58 amino acids arranged in a beta beta beta alpha alpha topology stabilized by a 15-residue hydrophobic core. Also, this domain tetrahedrally coordinates zinc and unfolds in the absence of the metal ion.The characterization of proteins belonging to the Ros homologs family has however shown that the prokaryotic zinc finger domain can overcome the metal requirement to achieve the same fold and DNA-binding activity. In the present work, two zinc-lacking Ros homologs (MI4 and MI5 proteins) have been thoroughly characterized using bioinformatics, biochemical and NMR techniques.We show how in these proteins a network of hydrogen bonds and hydrophobic interactions surrogate the zinc coordination role in the achievement of the same functional fold.(c) 2013 Published by Elsevier B.V.

In this work, a sensitive and convenient protease-based fluorimetric high-throughput screening (HTS) assay for determining peptidyl-prolyl cis-trans isomerase activity was developed. The assay was based on a new intramolecularly quenched substrate, whose fluorescence and structural properties were examined together with kinetic constants and the effects of solvents on its isomerization process. Pilot screens performed using the Library of Pharmacologically Active Compounds (LOPAC) and cyclophilin A (CypA), as isomerase model enzyme, indicated that the assay was robust for HTS, and that comparable results were obtained with a CypA inhibitor tested both manually and automatically. Moreover, a new compound that inhibits CypA activity with an IC50 in the low micromolar range was identified. Molecular docking studies revealed that the molecule shows a notable shape complementarity with the catalytic pocket confirming the experimental observations. Due to its simplicity and precision in the determination of extent of inhibition and reaction rates required for kinetic analysis, this assay offers many advantages over other commonly used assays.

It has been estimated that nearly one-third of functional proteins contain a metal ion. These constitute a wide variety of possible drug targets including metalloproteinases, dehydrogenases, oxidoreductases, hydrolases, deacetylases, or many others in which the metal ion is either of catalytic or of structural nature. Despite the predominant role of a metal ion in so many classes of drug targets, current high-throughput screening techniques do not usually produce viable hits against these proteins, likely due to the lack of proper metal-binding pharmacophores in the current screening libraries. Herein, we describe a novel fragment-based drug discovery approach using a metal-targeting fragment library that is based on a variety of distinct classes of metal-binding groups designed to reliably anchor the fragments at the target’s metal ions. We show that the approach can effectively identify novel, potent and selective agents that can be readily developed into metalloprotein-targeted therapeutics.

Seismic interferometry based on cross-correlation of traces recorded at different positions makes it possible to recover new Green's functions and to obtain signals as if sources were placed at the receiver positions. This case history describes results obtained using sea-bottom hydrophone signals recorded in shallow water below the ice plate in an Alaska seismic survey. The aim was to simulate new shots at the sea-bottom receiver positions and to redatum the surface-generated seismic signals below the ice layer. The application was performed and the method investigated to attenuate the strong noise due to dispersive wave modes (mainly flexural waves) which propagate in the ice layer.

We present the results of a seismic interferometry experiment in a shallow cased borehole. The experiment is an initial study for subsequent borehole seismic surveys in an instrumented well site, where we plan to test other surface/borehole seismic techniques. The purpose of this application is to improve the knowledge of the reflectivity sequence and to verify the potential of the seismic interferometry approach to retrieve high-frequency signals in the single well geometry, overcoming the loss and attenuation effects introduced by the overburden. We used a walkaway vertical seismic profile (VSP) geometry with a seismic vibrator to generate polarized vertical and horizontal components along a surface seismic line and an array of 3C geophones cemented outside the casing. The recorded traces are processed to obtain virtual sources in the borehole and to simulate single-well gathers with a variable sourcereceiver offset in the vertical array. We compare the results obtained by processing the field data with synthetic signals calculated by numerical simulation and analyse the signal bandwidth and amplitude versus offset to evaluate near-field effects in the virtual signals. The application provides direct and reflected signals with improved bandwidth after vibrator signal deconvolution. Clear reflections are detected in the virtual seismic sections in agreement with the geology and other surface and borehole seismic data recorded with conventional seismic exploration techniques.

PED/PEA-15 (phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes) is a ubiquitously expressed protein and a key regulator of cell growth and glucose metabolism. PED/PEA-15 mediates both homotypic and heterotypic interactions and is constituted by an N-terminal canonical death effector domain and a C-terminal tail. In the present study, the backbone dynamics of PED/PEA-15 via (15)N R(1) and R(2) and steady-state [(1)H]-(15)N NOE measurements is reported. The dynamic parameters were analyzed using both Lipari-Szabo model-free formalism and a reduced spectral density mapping approach. The results obtained define a polar and charged surface of the death effector domain characterized by internal motions in the micro- to millisecond timescale, which is crucial for the multiple heterotypic functional protein-protein interactions in which PED/PEA-15 is involved. The present study contributes to a better understanding of the molecular basis of the PED/PEA-15 functional interactions and provides a more detailed surface for the design and development of PED/PEA-15 binders.

The virtual-reflector (VR) method creates new seismic signals by processing seismic traces that have been produced by impulsive or transient sources. Under proper recording-coverage conditions, this technique allows a seismogram to be obtained as if there were an ideal reflector at the position of the receivers (or sources). Only the reflected signals from this reflector are synthesized. The algorithm is independent of the medium-velocity model and is based on convolution of the recorded traces and on subsequent integration of the crossconvolved signals in the receiver (or source) space. We use the VR method in combination with seismic interferometry (SI) by crosscorrelation to compose corresponding virtual-reflection events in seismic exploration. For that purpose, we use weighted-summation and data-crossfiltering approaches. In applying these combination methods, we assume common travel paths in the virtual signals, taking into account that VR and SI by crosscorrelation imply different stationary-phase conditions. We present applications in which we combine the SI-by-crosscorrelation and VR signals to (1) suppress unwanted effects, such as marine water-layer reflections in synthetic ocean-bottom-cable data, and (2) obtain virtual two-way traveltime seismograms with real borehole data from walkaway vertical seismic profiling (VSP). Analysis shows that time gating and selection of reflection events are critical steps in processing water-layer multiples.

We describe a method to process the seismic data generated by a plurality of sources and registered by an appropriate distribution of receivers, which provides new seismic signals as if in the position of the receivers (or sources) there was an ideal reflector, even if this reflector is not present there. The data provided by this method represent the signals of a virtual reflector. The proposed algorithm performs the convolution and the subsequent sum of the real traces without needing subsurface model information. The approach can be used in combination with seismic interferometry to separate wavefields and process the reflection events. The application is described with synthetic examples, including stationary phase analysis and with real data in which the virtual reflector signal can be appreciated.

Integrins are a large family of heterodimeric receptors critically engaged in pathological processes such as tumor progression and metastasis. Although they are validated therapeutic targets, the molecular determinants governing integrin-ligand interactions are not yet fully understood, leading to a scarcity of integrin sub-type exclusive antagonists. In the past decade, we have investigated the biological behavior of the RGDechi, a chimeric peptide able to specifically bind avb3 integrin without cross reacting with avb5 and aIIbb3 integrins. Here we have investigated the capability of the peptide to bind a5b1 integrin and characterized the molecular determinants governing this interaction through a combined experimental and computational approach. The detailed comparison of RGDechi-a5b1 structural model with that previously determined of RGDechi in complex with avb3 shows how the bifunctional nature of the peptide renders the molecule an important tool to recognize integrins with different recognition modalities, providing novel insight on the structural requirements needed to their specific recognition.

CLA, a natural, highly hydrophobic cyclic nonapeptide with sequence c(Pro(1)-Pro(2)-Phe(3)-Phe(4)-Leu(5)-Ile(6)-Ile(7)-Leu(8)-Val(9)-), isolated from linseed oil, was found to possess a strong immunosuppressive activity comparable, in low doses, with that of CsA, with a mechanism that depends on the inhibition of the interleukin-1 and interleukin-2 action. Structural analysis of CLA and its related compounds has underlined that the presence of the tetrapeptide Pro-Pro-Phe-Phe sequence, the Pro-Pro cis amide bond, and the 'edge-to-face' interaction are possible important features for the immunosuppressive activity of CLA. To evaluate the role and significance of 'edge-to-face' interaction in the process of molecular recognition by receptors, we have synthesised three linear precursors and three cyclic analogues of CLA, in which one or both Phe residues have been replaced by beta(3)Phe residues. A conformational analysis by NMR in CD(3)CN/H(2)O mixture has been carried out on the CLA analogue, in which Phe(3) has been replaced by a betaPhe, to study the influence of the mutation on the three-dimensional structure. All linear and cyclic CLA analogues containing betaPhe have been tested in the humoral and cellular immune response in vivo assays in mice. The peptide activities have been compared with CsA, as a reference drug.

A numerical algorithm for simulation of 2-D (axis-symmetric) wave propagation using a multidomain approach is proposed. The method uses a cylindrical coordinate system, Chebyshev and Fourier differential operators to calculate the spatial derivatives along the radial and vertical direction, respectively, and a Runge–Kutta time-integration scheme. The numerical technique is based on the solution of the equations of momentum conservation combined with the stress–strain relations of the fluid (drilling mud) and isotropic elastic media (drill string and formation). Wave modes and radiated waves are simulated in the borehole-formation system. The algorithm satisfies the reciprocity condition and the results agree with an analytical solution and low-frequency simulation of wave-propagation modes reported in the literature. Examples illustrating the propagation of waves are presented for hard and soft formations. Moreover, the presence of casing, cement, and formation heterogeneity have been considered. Since the algorithm is based on a direct (grid) method, the geometry and the properties defining the media at each grid point, can be general, i.e., there are no limitations such as planar interfaces or uniform (homogeneous) properties for each medium.

The critical role of integrins in tumor progression and metastasis has stimulated intense efforts to identify pharmacological agents that can modulate integrin function. In recent years, alpha(v)beta(3) and alpha(v)beta(5) integrin antagonists were demonstrated to be effective in blocking tumor progression. RGDechi-hCit, a chimeric peptide containing a cyclic RGD motif linked to an echistatin C-terminal fragment, is able to recognize selectively alpha(v)beta(3) integrin both in vitro and in vivo. High-resolution molecular details of the selective alpha(v)beta(3) recognition of the peptide are certainly required, nonetheless RGDechi-hCit internalization limited the use of classical in cell NMR experiments. To overcome such limitations, we used WM266 isolated cellular membranes to accomplish a detailed NMR interaction study that, combined with a computational analysis, provides significant structural insights into alpha(v)beta(3) molecular recognition by RGDechi-hCit. Remarkably, on the basis of the identified molecular determinants, we design a RGDechi-hCit mutant that is selective for alpha(v)beta(5) integrin.

In this work, a sensitive and convenient protease-based fluorimetric high-throughput screening (HTS) assay for determining peptidyl-prolyl cis-trans isomerase activity was developed. The assay was based on a new intramolecularly quenched substrate, whose fluorescence and structural properties were examined together with kinetic constants and the effects of solvents on its isomerization process. Pilot screens performed using the Library of Pharmacologically Active Compounds (LOPAC) and cyclophilin A (CypA), as isomerase model enzyme, indicated that the assay was robust for HTS, and that comparable results were obtained with a CypA inhibitor tested both manually and automatically. Moreover, a new compound that inhibits CypA activity with an IC50 in the low micromolar range was identified. Molecular docking studies revealed that the molecule shows a notable shape complementarity with the catalytic pocket confirming the experimental observations. Due to its simplicity and precision in the determination of extent of inhibition and reaction rates required for kinetic analysis, this assay offers many advantages over other commonly used assays.

Summary Distributed acoustic sensors (DAS) using fiber opticcables is an emergingacquisitiontechnologyforO&G industry.It offers the advantage of improvingseismic acquisition by massive monitoring of seismic waves at reduced cost .In this paperwe show that,as a result of the dense spatial distribution o f recording points along the optic cable ,DAS can providetwo fieldcomponents in theaxial direction , even when usinga single one-dimensional line .These signalpairsconsist ofdualcomponents,whicharerelated to strainand particle velocity fields at a given recording location.We show withreal exampleswhere the datacan becombined to provideseparation ofup-and down-going wavefields. T he ratioof the dualcomponents provides informationon localslowness properties inthe formation.

The zinc coordination sphere in prokaryotic zinc finger domain is extremely versatile and influences the stability and the folding property of the domain. Of a particular interest is the fourth zinc coordinating position, which is frequently occupied by two successive histidines, both able to coordinate the metal ion. To clarify their structural and functional role we report the NMR solution structure and the dynamics behavior of Ros87 H42A, which is a functional mutant of Ros87, the DNA binding domain of the Ros protein containing a prokaryotic Cys(2)His(2) zinc finger domain. The structural analysis indicates that reducing the spacer among the two coordinating histidines from 4 (among His37 and His42) amino acids to 3 (among His37 and His41) increases the helicity of the first a-helix. At the same time, the second helix appears more mobile in the mu s-ms timescale and the hydrophobic core is reduced. These data explain the high frequency of three-residue His spacers in the eukaryotic zinc finger domain and their absence in the prokaryotic counterpart. Furthermore, the structural comparison shows that the second coordination position is more sensitive to H42A mutation with respect to the first and the third position, providing the rationale of the high variability of the second and the fourth zinc coordinating position in Ros homologs, which adopt different metal coordination but preserve similar tertiary structures and DNA binding activities. Finally, H/D exchange measurements and NMR thermal unfolding analysis indicate that this mutant likely unfolds via a different mechanism with respect to the wild-type. (C) 2013 Published by Elsevier Inc.

Tangent-phase interferometry approach makes it possible to reconstruct seismic signals when the conventional stationarity conditions are not satisfied because of insufficient illumination by real sources around receivers. The virtual method is based on tangent-phase correction for the wavefield crosscorrelations in a modified representation integral, and provides results for selected events. In this work we investigate the representation for diffraction signals and for direct events, with applications in the crosswell geometry. The results show that it is possible to reconstruct local diffraction patterns from buried objects, thus obtaining improved information about their dimensions and imaging, also in the case of insufficient illumination coverage for the signal representation by conventional seismic interferometry.

In this work we investigate the use of seismic interferometry based on a generalized-phase concept using natural and model-based information. We present a generalized-phase interferometry method based on tangent analysis, which corrects the correlation data before summation. The approach makes it possible to synthesize virtual signals usually vanishing in the conventional seismic interferometry summation. New traces are obtained at new stationary projected points for different source positions along the signal wavefronts passing through the real reference receiver. The position of the projected points is estimated by minimization of traveltimes using wavefront constraint and tangent information. The method, using a mixed processing, partially based on velocity-model knowledge and partially on interferometry, can be used for selected events, including reflections with different stationary conditions and projection points, to extend the interferometry to seismic exploration data where conventional illumination coverage is not sufficient to obtain stationary-phase condition.

We present the results of a seismic-while-drilling (SWD) survey performed using the working drill-bit as a seismic source to support drilling from a geophysical point of view in a well drilled for geothermal purposes. In this application we perform revers

In this work we present the results of a seismic while drilling (SWD) application using the drill-bit as a seismic source in geothermal wells. The survey was performed in a well drilled in the Nevada desert with the aim of providing geophysical information while drilling and images of the geological structures around the well. We present a summary description of the drill-bit seismic technology adapted for geothermal purposes, and the SWD results obtained along 2D profiles passing through the well. The good-quality seismic-while-drilling results have been subsequently used to obtain images of the well area in the direction normal to the main fault system, with SWD reverse vertical seismic profiling (RVSP) data migration, using seismic interferometry to extend laterally the coverage of the SWD RVSP images. The migrated seismic interferometry results confirm the main trends of the 2D geological model in the geothermal area.

The RNA binding motif protein 5 (RBM5), also known as Luca15 or H37, is a component of prespliceosomal complexes that regulates the alternative splicing of several mRNAs, such as Fas and caspase-2. The RBM5 gene is located at the 2p21.3 chromosomal region, which is strongly associated with lung cancer and many other cancers. Both increased and decreased levels of RBM5 can play a role in tumor progression. In particular, downregulation of rbm5 is involved in lung cancer and other cancers upon Ras activation, and, also, represents a molecular signature associated with metastasis in various solid tumors. On the other hand, upregulation of RBM5 occurs in breast and ovarian cancer. Moreover, RBM5 was also found to be involved in the early stage of the HIV-1 viral cycle, representing a potential target for the treatment of the HIV-1 infection. While the molecular basis for RNA recognition and ubiquitin interaction has been structurally characterized, small molecules binding this zinc finger (ZF) domain that might contribute to characterizing their activity and to the development of potential therapeutic agents have not yet been reported. Using an NMR screening of a fragment library we identified several binders and the complex of the most promising one, compound 1, with the RBM5 ZF1 was structurally characterized in solution. Interestingly, the binding mechanism reveals that 1 occupies the RNA binding pocket and is therefore able to compete with the RNA to bind RBM5 RanBP2-type ZF domain, as indicated by NMR studies. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Virtual seismic signals are synthesized by composing traces recorded by a plurality of sources and receivers. Seismic interferometry typically uses cross-correlation to compose the recorded traces, and to get virtual sources at the position of receivers.

CLA, a natural, highly hydrophobic cyclic nonapeptide with sequence c(Pro(1)-Pro(2)-Phe(3)-Phe(4)-Leu(5)-Ile(6)-Ile(7)-Leu(8)-Val(9)-), isolated from linseed oil, was found to possess a strong immunosuppressive activity comparable, in low doses, with that of CsA, with a mechanism that depends on the inhibition of the interleukin-1 and interleukin-2 action. Structural analysis of CLA and its related compounds has underlined that the presence of the tetrapeptide Pro-Pro-Phe-Phe sequence, the Pro-Pro cis amide bond, and the 'edge-to-face' interaction are possible important features for the immunosuppressive activity of CLA. To evaluate the role and significance of 'edge-to-face' interaction in the process of molecular recognition by receptors, we have synthesised three linear precursors and three cyclic analogues of CLA, in which one or both Phe residues have been replaced by beta(3)Phe residues. A conformational analysis by NMR in CD(3)CN/H(2)O mixture has been carried out on the CLA analogue, in which Phe(3) has been replaced by a betaPhe, to study the influence of the mutation on the three-dimensional structure. All linear and cyclic CLA analogues containing betaPhe have been tested in the humoral and cellular immune response in vivo assays in mice. The peptide activities have been compared with CsA, as a reference drug.