Seismic attenuation and velocity dispersion in heterogeneous partially saturated porous rocks

Using a numerical approach, we explore wave-induced fluid flow effects in partially saturated porous rocks in which the gas-water saturation patterns are governed by mesoscopic heterogeneities associated with the dry frame properties. The link between the dry frame properties and the gas saturation is defined by the assumption of capillary pressure equilibrium, which in the presence of heterogeneity implies that neighbouring regions can exhibit different levels of saturation. To determine the equivalent attenuation and phase velocity of the synthetic rock samples considered in this study, we apply a numerical upscaling procedure, which permits to take into account mesoscopic heterogeneities associated with the dry frame properties as well as spatially continuous variations of the pore fluid properties. The multiscale nature of the fluid saturation is taken into account by locally computing the physical properties of an effective fluid, which are then used for the larger-scale simulations. We consider two sets of numerical experiments to analyse such effects in heterogeneous partially saturated porous media, where the saturation field is determined by variations in porosity and clay content, respectively. In both cases we also evaluate the seismic responses of corresponding binary, patchy-type saturation patterns. Our results indicate that significant attenuation and modest velocity dispersion effects take place in this kind of media for both binary patchy-type and spatially continuous gas saturation patterns and in particular in the presence of relatively small amounts of gas. The numerical experiments also show that the nature of the gas distribution patterns is a critical parameter controlling the seismic responses of these environments, since attenuation and velocity dispersion effects are much more significant and occur over a broader saturation range for binary patchy-type gas-water distributions. This analysis therefore suggests that the physical mechanisms governing partial saturation should be accounted for when analysing seismic data in a poroelastic framework. In this context, heterogeneities associated with the dry frame properties, which do not play important roles in wave-induced fluid flow processes per se, should be taken into account since they may determine the kind of gas distribution pattern taking place in the porous rock.

Bgee: integrating and comparing heterogeneous transcriptome data among species

Gene expression patterns are a key feature in understanding gene function, notably in development. Comparing gene expression patterns between animals is a major step in the study of gene function as well as of animal evolution. It also provides a link between genes and phenotypes. Thus we have developed Bgee, a database designed to compare expression patterns between animals, by implementing ontologies describing anatomies and developmental stages of species, and then designing homology relationships between anatomies and comparison criteria between developmental stages. To define homology relationships between anatomical features we have developed the software Homolonto, which uses a modified ontology alignment approach to propose homology relationships between ontologies. Bgee then uses these aligned ontologies, onto which heterogeneous expression data types are mapped. These already include microarrays and ESTs.

Quantification of typical antipsychotics in human plasma by ultra-high performance liquid chromatography tandem mass spectrometry for therapeutic drug monitoring.

A selective and sensitive method was developed for the simultaneous quantification of seven typical antipsychotic drugs (cis-chlorprothixene, flupentixol, haloperidol, levomepromazine, pipamperone, promazine and zuclopenthixol) in human plasma. Ultra-high performance liquid chromatography (UHPLC) was used for complete separation of the compounds in less than 4.5min on an Acquity UPLC BEH C18 column (2.1mm×50mm; 1.7μm), with a gradient elution of ammonium formate buffer pH 4.0 and acetonitrile at a flow rate of 400μl/min. Detection was performed on a tandem quadrupole mass spectrometer (MS/MS) equipped with an electrospray ionization interface. A simple protein precipitation procedure with acetonitrile was used for sample preparation. Thanks to the use of stable isotope-labeled internal standards for all analytes, internal standard-normalized matrix effects were in the range of 92-108%. The method was fully validated to cover large concentration ranges of 0.2-90ng/ml for haloperidol, 0.5-90ng/ml for flupentixol, 1-450ng/ml for levomepromazine, promazine and zuclopenthixol and 2-900ng/ml for cis-chlorprothixene and pipamperone. Trueness (89.1-114.8%), repeatability (1.8-9.9%), intermediate precision (1.9-16.3%) and accuracy profiles (<30%) were in accordance with the latest international recommendations. The method was successfully used in our laboratory for routine quantification of more than 500 patient plasma samples for therapeutic drug monitoring. To the best of our knowledge, this is the first UHPLC-MS/MS method for the quantification of the studied drugs with a sample preparation based on protein precipitation.

Tandem use of solid-phase extraction and dispersive liquid-liquid microextraction for the determination of mononitrotoluenes in aquatic environment.

Solid-phase extraction (SPE) in tandem with dispersive liquid-liquid microextraction (DLLME) has been developed for the determination of mononitrotoluenes (MNTs) in several aquatic samples using gas chromatography-flame ionization (GC-FID) detection system. In the hyphenated SPE-DLLME, initially MNTs were extracted from a large volume of aqueous samples (100 mL) into a 500-mg octadecyl silane (C(18) ) sorbent. After the elution of analytes from the sorbent with acetonitrile, the obtained solution was put under the DLLME procedure, so that the extra preconcentration factors could be achieved. The parameters influencing the extraction efficiency such as breakthrough volume, type and volume of the elution solvent (disperser solvent) and extracting solvent, as well as the salt addition, were studied and optimized. The calibration curves were linear in the range of 0.5-500 μg/L and the limit of detection for all analytes was found to be 0.2 μg/L. The relative standard deviations (for 0.75 μg/L of MNTs) without internal standard varied from 2.0 to 6.4% (n=5). The relative recoveries of the well, river and sea water samples, spiked at the concentration level of 0.75 μg/L of the analytes, were in the range of 85-118%.

Presence of an oligodendroglioma-like component in newly diagnosed glioblastoma identifies a pathogenetically heterogeneous subgroup and lacks prognostic value: central pathology review of the EORTC_26981/NCIC_CE.3 trial.

Glioblastoma (GBM) is a morphologically heterogeneous tumor type with a median survival of only 15 months in clinical trial populations. However, survival varies greatly among patients. As part of a central pathology review, we addressed the question if patients with GBM displaying distinct morphologic features respond differently to combined chemo-radiotherapy with temozolomide. Morphologic features were systematically recorded for 360 cases with particular focus on the presence of an oligodendroglioma-like component and respective correlations with outcome and relevant molecular markers. GBM with an oligodendroglioma-like component (GBM-O) represented 15% of all confirmed GBM (52/339) and was not associated with a more favorable outcome. GBM-O encompassed a pathogenetically heterogeneous group, significantly enriched for IDH1 mutations (19 vs. 3%, p = 0.003) and EGFR amplifications (71 vs. 48%, p = 0.04) compared with other GBM, while co-deletion of 1p/19q was found in only one case and the MGMT methylation frequency was alike (47 vs. 46%). Expression profiles classified most of the GBM-O into two subtypes, 36% (5/14 evaluable) as proneural and 43% as classical GBM. The detection of pseudo-palisading necrosis (PPN) was associated with benefit from chemotherapy (p = 0.0002), while no such effect was present in the absence of PPN (p = 0.86). In the adjusted interaction model including clinical prognostic factors and MGMT status, PPN was borderline nonsignificant (p = 0.063). Taken together, recognition of an oligodendroglioma-like component in an otherwise classic GBM identifies a pathogenetically mixed group without prognostic significance. However, the presence of PPN may indicate biological features of clinical relevance for further improvement of therapy.

Scalable inference of heterogeneous reaction kinetics from pooled single-cell recordings.

Mathematical methods combined with measurements of single-cell dynamics provide a means to reconstruct intracellular processes that are only partly or indirectly accessible experimentally. To obtain reliable reconstructions, the pooling of measurements from several cells of a clonal population is mandatory. However, cell-to-cell variability originating from diverse sources poses computational challenges for such process reconstruction. We introduce a scalable Bayesian inference framework that properly accounts for population heterogeneity. The method allows inference of inaccessible molecular states and kinetic parameters; computation of Bayes factors for model selection; and dissection of intrinsic, extrinsic and technical noise. We show how additional single-cell readouts such as morphological features can be included in the analysis. We use the method to reconstruct the expression dynamics of a gene under an inducible promoter in yeast from time-lapse microscopy data.

Stoneley wave modeling in heterogeneous porous media with viscous pore fluids

We implemented Biot-type porous wave equations in a pseudo-spectral numerical modeling algorithm for the simulation of Stoneley waves in porous media. Fourier and Chebyshev methods are used to compute the spatial derivatives along the horizontal and vertical directions, respectively. To prevent from overly short time steps due to the small grid spacing at the top and bottom of the model as a consequence of the Chebyshev operator, the mesh is stretched in the vertical direction. As a large benefit, the Chebyshev operator allows for an explicit treatment of interfaces. Boundary conditions can be implemented with a characteristics approach. The characteristic variables are evaluated at zero viscosity. We use this approach to model seismic wave propagation at the interface between a fluid and a porous medium. Each medium is represented by a different mesh and the two meshes are connected through the above described characteristics domain-decomposition method. We show an experiment for sealed pore boundary conditions, where we first compare the numerical solution to an analytical solution. We then show the influence of heterogeneity and viscosity of the pore fluid on the propagation of the Stoneley wave and surface waves in general.

Seismic attenuation in heterogeneous partially saturated rocks

We study wave-induced fluid flow effects in porous rocks partially saturated with gas and water, where the saturation patterns are governed by mesoscopic heterogeneities associated with the dry frame properties. The link between the dry frame properties and the gas saturation is defined by the assumption of capillary pressure equilibrium, which in the presence of heterogeneity implies that neighboring regions can exhibit different levels of saturation. In order to determine the equivalent attenuation and phase velocity of the synthetic rock samples considered in this study, we apply a numerical upscaling procedure, which permits to take into account mesoscopic heterogeneities associated with the dry frame properties as well as spatially continuous variations of the pore fluid properties. We consider numerical experiments to analyze such effects in heterogeneous partially saturated porous media, where the saturation field is determined by realistic variations in porosity. Our results indicate that the spatially continuous nature of gas saturation inherent to this study is a critical parameter controlling the seismic response of these environments, which in turn suggests that the physical mechanisms governing partial saturation should be accounted for when analyzing seismic data in a poro-elastic context.

Heterogeneous 40Ar* distributions in naturally deformed muscovite: in situ UV-laser ablation evidence for micro structurally controlled intragrain diffusion

Micas are commonly used in Ar-40/Ar-39 thermochronological studies of variably deformed rocks yet the physical basis by which deformation may affect radiogenic argon retention in mica is poorly constrained. This study examines the relationship between deformation and deformation-induced microstructures on radiogenic argon retention in muscovite, A combination of furnace step-heating and high-spatial resolution in situ UV-laser ablation Ar-40/Ar-39 analyses are reported for deformed muscovites sampled from a granitic pegmatite vein within the Siviez-Mischabel Nappe, western Swiss Alps (Penninic domain, Brianconnais unit). The pegmatite forms part of the Variscan (similar to 350 Ma) Alpine basement and exhibits a prominent Alpine S-C fabric including numerous mica `fish' that developed under greenschist facies metamorphic conditions, during the dominant Tertiary Alpine tectonic phase of nappe emplacement. Furnace step-heating of milligram quantities of separated muscovite grains yields an Ar-40/Ar-39 age spectrum with two distinct staircase segments but without any statistical plateau, consistent with a previous study from the same area. A single (3 X 5 mm) muscovite porphyroclast (fish) was investigated by in situ UV-laser ablation. A histogram plot of 170 individual Ar-40/Ar-39 UV-laser ablation ages exhibit a range from 115 to 387 Ma with modes at approximately 340 and 260 Ma. A variogram statistical treatment of the (40)Ad/Ar-39 results reveals ages correlated with two directions; a highly correlated direction at 310 degrees and a lesser correlation at 0 degrees relative to the sense of shearing. Using the highly correlated direction a statistically generated (Kriging method) age contour map of the Ar-40/Ar-39 data reveals a series of elongated contours subparallel to the C-surfaces which where formed during Tertiary nappe emplacement. Similar data distributions and slightly younger apparent ages are recognized in a smaller mica fish. The observed intragrain age variations are interpreted to reflect the partial loss of radiogenic argon during Alpine (similar to 35 Ma) greenschist facies metamorphism. One-dirnensional diffusion modelling results are consistent with the idea that the zones of youngest apparent age represent incipient shear band development within the mica porphyroclasts, thus providing a network of fast diffusion pathways. During Alpine greenschist facies metamorphism the incipient shear bands enhanced the intragrain loss of radiogenic argon. The structurally controlled intragrain age variations observed in this investigation imply that deformation has a direct control on the effective length scale for argon diffusion, which is consistent with the heterogeneous nature of deformation. (C) 2001 Elsevier Science B.V. All rights reserved.

An ultra performance liquid chromatography-tandem MS assay for tamoxifen metabolites profiling in plasma: first evidence of 4'-hydroxylated metabolites in breast cancer patients.

There is increasing evidence that the clinical efficacy of tamoxifen, the first and most widely used targeted therapy for estrogen-sensitive breast cancer, depends on the formation of the active metabolites 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen (endoxifen). Large inter-individual variability in endoxifen plasma concentrations has been observed and related both to genetic and environmental (i.e. drug-induced) factors altering CYP450s metabolizing enzymes activity. In this context, we have developed an ultra performance liquid chromatography-tandem mass spectrometry method (UPLC-MS/MS) requiring 100 μL of plasma for the quantification of tamoxifen and three of its major metabolites in breast cancer patients. Plasma is purified by a combination of protein precipitation, evaporation at room temperature under nitrogen, and reconstitution in methanol/20 mM ammonium formate 1:1 (v/v), adjusted to pH 2.9 with formic acid. Reverse-phase chromatographic separation of tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and 4-hydroxy-N-desmethyl-tamoxifen is performed within 13 min using elution with a gradient of 10 mM ammonium formate and acetonitrile, both containing 0.1% formic acid. Analytes quantification, using matrix-matched calibration samples spiked with their respective deuterated internal standards, is performed by electrospray ionization-triple quadrupole mass spectrometry using selected reaction monitoring detection in the positive mode. The method was validated according to FDA recommendations, including assessment of relative matrix effects variability, as well as tamoxifen and metabolites short-term stability in plasma and whole blood. The method is precise (inter-day CV%: 2.5-7.8%), accurate (-1.4 to +5.8%) and sensitive (lower limits of quantification comprised between 0.4 and 2.0 ng/mL). Application of this method to patients' samples has made possible the identification of two further metabolites, 4'-hydroxy-tamoxifen and 4'-hydroxy-N-desmethyl-tamoxifen, described for the first time in breast cancer patients. This UPLC-MS/MS assay is currently applied for monitoring plasma levels of tamoxifen and its metabolites in breast cancer patients within the frame of a clinical trial aiming to assess the impact of dose increase on tamoxifen and endoxifen exposure.

Determination of oseltamivir and oseltamivir carboxylate in human plasma by liquid chromatography-tandem mass spectrometry

Introduction: Oseltamivir phosphate (OP), the prodrug of oseltamivir carboxylate (OC; active metabolite), is marketed since 10 years for the treatment of seasonal influenza flu. It has recently received renewed attention because of the threat of avian flu H5N1 in 2006-7 and the 2009-10 A/H1N1 pandemic. However, relatively few studies have been published on OP and OC clinical pharmacokinetics. The disposition of OC and the dosage adaptation of OP in specific populations, such as young children or patients undergoing extrarenal epuration, have also received poor attention. An analytical method was thus developed to assess OP and OC plasma concentrations in patients receiving OP and presenting with comorbidities or requiring intensive care. Methods: A high performance liquid chromatography coupled to tandem mass spectrometry method (HPLC-MS/MS) requiring 100-µL aliquot of plasma for quantification within 6 min of OP and OC was developed. A combination of protein precipitation with acetonitrile, followed by dilution of supernant in suitable buffered solvent was used as an extraction procedure. After reverse phase chromatographic separation, quantification was performed by electro-spray ionization-triple quadrupole mass spectrometry. Deuterated isotopic compounds of OP and OC were used as internal standards. Results: The method is sensitive (lower limit of quantification: 5 ng/mL for OP and OC), accurate (intra-/inter-assay bias for OP and OC: 8.5%/5.5% and 3.7/0.7%, respectively) and precise (intra-/inter-assay CV%: 5.2%/6.5% and 6.3%/9.2%, respectively) over the clinically relevant concentration range (upper limits of quantification 5000 ng/mL). Of importance, OP, as in other previous reports, was found not to be stable ex vivo in plasma on standard anticoagulants (i.e. EDTA, heparin or citrate). This poor stability of OP has been prevented by collecting blood samples on commercial fluoride/oxalate tubes. Conclusions: This new simple, rapid and robust HPLC-MS/MS assay for quantification of OP and OC plasma concentrations offers an efficient tool for concentration monitoring of OC. Its exposure can probably be controlled with sufficient accuracy by thorough dosage adjustment according to patient characteristics (e.g. renal clearance). The usefulness of systematic therapeutic drug monitoring in patients appears therefore questionable. However, pharmacokinetic studies are still needed to extend knowledge to particular subgroups of patients or dosage regimens.

Bilateral dorsal and ventral fiber pathways for the processing of affective prosody identified by probabilistic fiber tracking.

Dorsal and ventral pathways for syntacto-semantic speech processing in the left hemisphere are represented in the dual-stream model of auditory processing. Here we report new findings for the right dorsal and ventral temporo-frontal pathway during processing of affectively intonated speech (i.e. affective prosody) in humans, together with several left hemispheric structural connections, partly resembling those for syntacto-semantic speech processing. We investigated white matter fiber connectivity between regions responding to affective prosody in several subregions of the bilateral superior temporal cortex (secondary and higher-level auditory cortex) and of the inferior frontal cortex (anterior and posterior inferior frontal gyrus). The fiber connectivity was investigated by using probabilistic diffusion tensor based tractography. The results underscore several so far underestimated auditory pathway connections, especially for the processing of affective prosody, such as a right ventral auditory pathway. The results also suggest the existence of a dual-stream processing in the right hemisphere, and a general predominance of the dorsal pathways in both hemispheres underlying the neural processing of affective prosody in an extended temporo-frontal network.

Evolution in heterogeneous populations: from migration models to fixation probabilities.

Although dispersal is recognized as a key issue in several fields of population biology (such as behavioral ecology, population genetics, metapopulation dynamics or evolutionary modeling), these disciplines focus on different aspects of the concept and often make different implicit assumptions regarding migration models. Using simulations, we investigate how such assumptions translate into effective gene flow and fixation probability of selected alleles. Assumptions regarding migration type (e.g. source-sink, resident pre-emption, or balanced dispersal) and patterns (e.g. stepping-stone versus island dispersal) have large impacts when demes differ in sizes or selective pressures. The effects of fragmentation, as well as the spatial localization of newly arising mutations, also strongly depend on migration type and patterns. Migration rate also matters: depending on the migration type, fixation probabilities at an intermediate migration rate may lie outside the range defined by the low- and high-migration limits when demes differ in sizes. Given the extreme sensitivity of fixation probability to characteristics of dispersal, we underline the importance of making explicit (and documenting empirically) the crucial ecological/ behavioral assumptions underlying migration models.