Contributions to uncertainty related to hydrostratigraphic modeling using multiple-point statistics

Forecasting the flow of groundwater requires a hydrostratigraphic model, which describes the architecture of the subsurface. State-of-the-art multiple-point statistical (MPS) tools are readily available for creating models depicting subsurface geology. We present a study of the impact of key parameters related to stochastic MPS simulation of a real-world hydrogeophysical dataset from Kasted, Denmark, using the snesim algorithm. The goal is to study how changes to the underlying datasets propagate into the hydrostratigraphic realizations when using MPS for stochastic modeling. This study focuses on the sensitivity of the MPS realizations to the geophysical soft data, borehole lithology logs, and the training image (TI). The modeling approach used in this paper utilizes a cognitive geological model as a TI to simulate ensemble hydrostratigraphic models. The target model contains three overall hydrostratigraphic categories, and the MPS realizations are compared visually as well as quantitatively using mathematical measures of similarity. The quantitative similarity analysis is carried out exhaustively, and realizations are compared with each other as well as with the cognitive geological model.The results underline the importance of geophysical data for constraining MPS simulations. Relying only on borehole data and the conceptual geology, or TI, results in a significant increase in realization uncertainty. The airborne transient electromagnetic SkyTEM data used in this study cover a large portion of the Kasted model area and are essential to the hydrostratigraphic architecture. On the other hand, the borehole lithology logs are sparser, and 410 boreholes were present in this study. The borehole lithology logs infer local changes in the immediate vicinity of the boreholes, thus, in areas with a high degree of geological heterogeneity, boreholes only provide limited large-scale structural information. Lithological information is, however, important for the interpretation of the geophysical responses. The importance of the TI was also studied. An example was presented where an alternative geological model from a neighboring area was used to simulate hydrostratigraphic models. It was shown that as long as the geological settings are similar in nature, the realizations, although different, still reflect the hydrostratigraphic architecture. If a TI containing a biased geological conceptualization is used, the resulting realizations will resemble the TI and contain less structure in particular areas, where the soft data show almost even probability to two or all three of the hydrostratigraphic units.</p

Timing and consequences of Bering Strait opening: new insights from 40Ar/39 1 Ar dating 2 of the Barmur Group (Tjörnes beds), northern Iceland

The Barmur Group (informally Tjörnes beds) sedimentary succession of northern Iceland is key to reconstructing the opening of the Bering Strait oceanic gateway because these rocks record migration of bivalve molluscs from the Pacific to the Atlantic via the Arctic. However, the timing of the migration event is poorly constrained owing to a lack of reliable absolute ages. To address this problem, we present the first Ar-Ar radiometric dates from four basaltic lavas that underlie, are intercalated with, and overlie the Barmur Group, and integrate them with existing paleomagnetic records. We show that the Barmur Group has a latest Miocene to early Pliocene age range (c. 6.0–4.4 Ma; C3r–C3n.2n), older than all previous age models. Thus, the Barmur Group does not record the mid-Piacenzian Warm Period, contra some previous suggestions. Abundant Pacific bivalve molluscs appeared in the Barmur Group during subchrons C3n.4n–C3n.3r at 5.235–4.896 Ma, over 1.3 million years earlier than previously suggested. Appearance of Pacific bivalves in the northern Atlantic occurred shortly after the 5.6–5.4 Ma age previously inferred for first appearance of Arctic bivalves in the Pacific. Thus, our data suggest that first opening of the Bering Strait gateway by the latest Miocene (c. 5.5 Ma) was soon followed by bidirectional trans-Arctic faunal exchange, and argue against a hypothesized two-stage faunal exchange process spanning c. 2 million years. Our results also confirm that first opening of the Bering Strait gateway was not directly associated with the growth of large northern hemisphere icesheets, which occurred several million years later

Petrogenesis of Siletzia: the world’s youngest oceanic plateau

Siletzia is an accreted Palaeocene-Eocene Large Igneous Province, preserved in the northwest United States and southern Vancouver Island. Although previous workers have suggested that components of Siletzia were formed in tectonic settings including back arc basins, island arcs and ocean islands, more recent work has presented evidence for parts of Siletzia to have formed in response to partial melting of a mantle plume. In this paper, we integrate geochemical and geochronological data to investigate the petrogenetic evolution of the province. The major element geochemistry of the Siletzia lava flows is used to determine the compositions of the primary magmas of the province, as well as the conditions of mantle melting. These primary magmas are compositionally similar to modern Ocean Island and Mid-Ocean Ridge lavas. Geochemical modelling of these magmas indicates they predominantly evolved through fractional crystallisation of olivine, pyroxenes, plagioclase, spinel and apatite in shallow magma chambers, and experienced limited interaction with crustal components. Further modelling indicates that Siletzia magmatism was derived from anomalously hot mantle, consistent with an origin in a mantle plume. This plume has been suggested to have been the same as that responsible for magmatism within the Yellowstone Plateau. Trace element compositions of the most primitive Siletzia lavas are similar to suites associated with the Yellowstone Mantle Plume, suggesting that the two provinces were derived from compositionally similar sources. Radiogenic isotope systematics for Siletzia consistently overlap with some of the oldest suites of the Yellowstone Magmatic Province. Therefore, we suggest Siletzia and the Yellowstone Mantle Plume are part of the same, evolving mantle plume system. Our new geochronological data show the province was emplaced during the time when Eocene sea surface temperatures were their highest. The size of Siletzia makes the province a potential contributing factor to the biospheric perturbation observed in the early Eocene

Pulmonary toxicity of synthetic amorphous silica–effects of porosity and copper oxide doping

Materials can be modified for improved functionality. Our aim was to test whether pulmonary toxicity of silica nanomaterials is increased by the introduction of: a) porosity; and b) surface doping with CuO; and whether c) these modifications act synergistically. Mice were exposed by intratracheal instillation and for some doses also oropharyngeal aspiration to: 1) solid silica 100 nm; 2) porous silica 100 nm; 3) porous silica 100 nm with CuO doping; 4) solid silica 300 nm; 5) porous silica 300 nm; 6) solid silica 300 nm with CuO doping; 7) porous silica 300 nm with CuO doping; 8) CuO nanoparticles 9.8 nm; or 9) carbon black Printex 90 as benchmark. Based on a pilot study, dose levels were between 0.5 and 162 µg/mouse (0.2 and 8.1 mg/kg bw). Endpoints included pulmonary inflammation (neutrophil numbers in bronchoalveolar fluid), acute phase response, histopathology, and genotoxicity assessed by the comet assay, micronucleus test, and the gamma-H2AX assay. The porous silica materials induced greater pulmonary inflammation than their solid counterparts. A similar pattern was seen for acute phase response induction and histologic changes. This could be explained by a higher specific surface area per mass unit for the most toxic particles. CuO doping further increased the acute phase response normalized according to the deposited surface area. We identified no consistent evidence of synergism between surface area and CuO doping. In conclusion, porosity and CuO doping each increased the toxicity of silica nanomaterials and there was no indication of synergy when the modifications co-occurred

Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites

The malaria parasite Plasmodium falciparum exports several hundred proteins into the infected erythrocyte that are involved in cellular remodeling and severe virulence. The export mechanism involves the Plasmodium export element (PEXEL), which is a cleavage site for the parasite protease, Plasmepsin V (PMV). The PMV gene is refractory to deletion, suggesting it is essential, but definitive proof is lacking. Here, we generated a PEXEL-mimetic inhibitor that potently blocks the activity of PMV isolated from P. falciparum and Plasmodium vivax. Assessment of PMV activity in P. falciparum revealed PEXEL cleavage occurs cotranslationaly, similar to signal peptidase. Treatment of P. falciparum-infected erythrocytes with the inhibitor caused dose-dependent inhibition of PEXEL processing as well as protein export, including impaired display of the major virulence adhesin, PfEMP1, on the erythrocyte surface, and cytoadherence. The inhibitor killed parasites at the trophozoite stage and knockdown of PMV enhanced sensitivity to the inhibitor, while overexpression of PMV increased resistance. This provides the first direct evidence that PMV activity is essential for protein export in Plasmodium spp. and for parasite survival in human erythrocytes and validates PMV as an antimalarial drug target

Ischemic Heart Disease in Chronic Hepatitis B: A Danish Nationwide Cohort Study

OBJECTIVE: Data on the risk of ischemic heart disease (IHD) in patients with chronic hepatitis B virus (CHB) are conflicting. Our objective was to address the rate of IHD in patients with CHB compared with individuals without CHB (control-persons) from the general population. STUDY DESIGN AND SETTING: We conducted a cohort study of prospectively obtained data from Danish nationwide registries. We produced cumulative incidence curves and calculated the unadjusted incidence rate ratio (IRR) of IHD in persons with and without CHB. The adjusted association between having CHB and developing IHD was examined using a cause-specific Cox regression model. RESULTS: In total, 6472 persons with CHB and 62,251 age- and sex-matched individuals from the general population were followed for 48,840 and 567,456 person-years, respectively, during which 103 (1,59%) with CHB and 1058 (1,70%) control-persons developed IHD. The crude IRR was 1.13 (95% CI: 0.91–1.39). CHB did not have a statistically significant effect on the rate of IHD after adjusting for several confounding factors (adjusted hazard ratio: 0.96, 95% CI: 0.76–1.21). CONCLUSION: In this nationwide cohort study, we did not find any difference between rate of IHD in persons with CHB in comparison with the general population

The kinetics of antibody binding to Plasmodium falciparum VAR2CSA PfEMP1 antigen and modelling of PfEMP1 antigen packing on the membrane knobs

<p>Abstract</p> <p>Background</p> <p>Infected humans make protective antibody responses to the PfEMP1 adhesion antigens exported by <it>Plasmodium falciparum </it>parasites to the erythrocyte membrane, but little is known about the kinetics of this antibody-receptor binding reaction or how the topology of PfEMP1 on the parasitized erythrocyte membrane influences antibody association with, and dissociation from, its antigenic target.</p> <p>Methods</p> <p>A Quartz Crystal Microbalance biosensor was used to measure the association and dissociation kinetics of VAR2CSA PfEMP1 binding to human monoclonal antibodies. Immuno-fluorescence microscopy was used to visualize antibody-mediated adhesion between the surfaces of live infected erythrocytes and atomic force microscopy was used to obtain higher resolution images of the membrane knobs on the infected erythrocyte to estimate knob surface areas and model VAR2CSA packing density on the knob.</p> <p>Results</p> <p>Kinetic analysis indicates that antibody dissociation from the VAR2CSA PfEMP1 antigen is extremely slow when there is a high avidity interaction. High avidity binding to PfEMP1 antigens on the surface of <it>P. falciparum</it>-infected erythrocytes in turn requires bivalent cross-linking of epitopes positioned within the distance that can be bridged by antibody. Calculations of the surface area of the knobs and the possible densities of PfEMP1 packing on the knobs indicate that high-avidity cross-linking antibody reactions are constrained by the architecture of the knobs and the large size of PfEMP1 molecules.</p> <p>Conclusions</p> <p>High avidity is required to achieve the strongest binding to VAR2CSA PfEMP1, but the structures that display PfEMP1 also tend to inhibit cross-linking between PfEMP1 antigens, by holding many binding epitopes at distances beyond the 15-18 nm sweep radius of an antibody. The large size of PfEMP1 will also constrain intra-knob cross-linking interactions. This analysis indicates that effective vaccines targeting the parasite's vulnerable adhesion receptors should primarily induce strongly adhering, high avidity antibodies whose association rate constant is less important than their dissociation rate constant.</p

Estimation of the severity of breathlessness in the emergency department: a dyspnea score

BACKGROUND: Dyspnea is a frequent complaint in emergency departments (ED). It has a significant amount of subjective and affective components, therefore the dyspnea scores, based on the patients' rating, can be ambiguous. Our purpose was to develop and validate a simple scoring system to evaluate the severity of dyspnea in emergency care, based on objectively measured parameters. METHODS: We performed a double center, prospective, observational study including 350 patients who were admitted in EDs with dyspnea. We evaluated the patients' subjective feeling about dyspnea and applied our Dyspnea Severity Score (DSS), rating the dyspnea in 7 Dimensions from 0 to 3 points. The DSS was validated using the deterioration of pH, base-excess and lactate levels in the blood gas samples (Objective Classification Scale (OCS) 9 points and 13 points groups). RESULTS: All of the Dimensions correlated closely with the OCS values and with the subjective feeling of the dyspnea. Using multiple linear regression analysis we were able to decrease the numbers of Dimensions from seven to four without causing a significant change in the determination coefficient in any OCS groups. This reduced DSS values (exercise tolerance, cooperation, cyanosis, SpO2 value) showed high sensitivity and specificity to predict the values of OCS groups (the ranges: AUC 0.77-0.99, sensitivity 65-100%, specificity 64-99%). There was a close correlation between the subjective dyspnea scores and the OCS point values (p /=7 points without correction factors) can be useful at the triage or in pre-hospital care

Antibodies to a Full-Length VAR2CSA Immunogen Are Broadly Strain-Transcendent but Do Not Cross-Inhibit Different Placental-Type Parasite Isolates

The high molecular weight, multidomain VAR2CSA protein mediating adhesion of Plasmodium falciparum-infected erythrocytes in the placenta is the leading candidate for a pregnancy malaria vaccine. However, it has been difficult so far to generate strong and consistent adhesion blocking antibody responses against most single-domain VAR2CSA immunogens. Recent advances in expression of the full-length recombinant protein showed it binds with much greater specificity and affinity to chondroitin sulphate A (CSA) than individual VAR2CSA domains. This raises the possibility that a specific CSA binding pocket(s) is formed in the full length antigen and could be an important target for vaccine development. In this study, we compared the immunogenicity of a full-length VAR2CSA recombinant protein containing all six Duffy binding-like (DBL) domains to that of a three-domain construct (DBL4-6) in mice and rabbits. Animals immunized with either immunogen acquired antibodies reacting with several VAR2CSA individual domains by ELISA, but antibody responses against the highly conserved DBL4 domain were weaker in animals immunized with full-length DBL1-6 recombinant protein compared to DBL4-6 recombinant protein. Both immunogens induced cross-reactive antibodies to several heterologous CSA-binding parasite lines expressing different VAR2CSA orthologues. However, antibodies that inhibited adhesion of parasites to CSA were only elicited in rabbits immunized with full-length immunogen and inhibition was restricted to the homologous CSA-binding parasite. These findings demonstrate that partial and full-length VAR2CSA immunogens induce cross-reactive antibodies, but inhibitory antibody responses to full-length immunogen were highly allele-specific and variable between animal species

Multiple var2csa-Type PfEMP1 Genes Located at Different Chromosomal Loci Occur in Many Plasmodium falciparum Isolates

BACKGROUND:The var2csa gene encodes a Plasmodium falciparum adhesion receptor which binds chondroitin sulfate A (CSA). This var gene is more conserved than other PfEMP1/var genes and is found in all P. falciparum isolates. In isolates 3D7, FCR3/It4 and HB3, var2csa is transcribed from a sub-telomeric position on the left arm of chromosome 12, but it is not known if this location is conserved in all parasites. Genome sequencing indicates that the var2csa gene is duplicated in HB3, but whether this is true in natural populations is uncertain. METHODOLOGY/PRINCIPAL FINDINGS:To assess global variation in the VAR2CSA protein, sequence variation in the DBL2X region of var2csa genes in 54 P.falciparum samples was analyzed. Chromosome mapping of var2csa loci was carried out and a quantitative PCR assay was developed to estimate the number of var2csa genes in P.falciparum isolates from the placenta of pregnant women and from the peripheral circulation of other malaria patients. Sequence analysis, gene mapping and copy number quantitation in P.falciparum isolates indicate that there are at least two loci and that both var2csa-like genes can be transcribed. All VAR2CSA DBL2X domains fall into one of two distinct phylogenetic groups possessing one or the other variant of a large (approximately 26 amino acid) dimorphic motif, but whether either motif variant is linked to a specific locus is not known. CONCLUSIONS/SIGNIFICANCE:Two or more related but distinct var2csa-type PfEMP1/var genes exist in many P. falciparum isolates. One gene is on chromosome 12 but additional var2csa-type genes are on different chromosomes in different isolates. Multiplicity of var2csa genes appears more common in infected placentae than in samples from non-pregnant donors indicating a possible advantage of this genotype in pregnancy associated malaria