Improved Techniques for Acquisition and Analysis of Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Detecting Vascular Permeability in the Central Nervous System

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a noninvasive technique for quantitative assessment of the integrity of blood-brain barrier and blood-spinal cord barrier (BSCB) in the presence of central nervous system pathologies. However, the results of DCE-MRI show substantial variability. The high variability can be caused by a number of factors including inaccurate T1 estimation, insufficient temporal resolution and poor contrast-to-noise ratio. My thesis work is to develop improved methods to reduce the variability of DCE-MRI results. To obtain fast and accurate T1 map, the Look-Locker acquisition technique was implemented with a novel and truly centric k-space segmentation scheme. In addition, an original multi-step curve fitting procedure was developed to increase the accuracy of T1 estimation. A view sharing acquisition method was implemented to increase temporal resolution, and a novel normalization method was introduced to reduce image artifacts. Finally, a new clustering algorithm was developed to reduce apparent noise in the DCE-MRI data. The performance of these proposed methods was verified by simulations and phantom studies. As part of this work, the proposed techniques were applied to an in vivo DCE-MRI study of experimental spinal cord injury (SCI). These methods have shown robust results and allow quantitative assessment of regions with very low vascular permeability. In conclusion, applications of the improved DCE-MRI acquisition and analysis methods developed in this thesis work can improve the accuracy of the DCE-MRI results.

Development of HIF-1α/HIF-1β heterodimerization inhibitors using a novel bioluminescence reporter assay system for in vitro high throughput screening and in vivo imaging

Tumor growth often outpaces its vascularization, leading to development of a hypoxic tumor microenvironment. In response, an intracellular hypoxia survival pathway is initiated by heterodimerization of hypoxia-inducible factor (HIF)-1α and HIF-1β, which subsequently upregulates the expression of several hypoxia-inducible genes, promotes cell survival and stimulates angiogenesis in the oxygen-deprived environment. Hypoxic tumor regions are often associated with resistance to various classes of radio- or chemotherapeutic agents. Therefore, development of HIF-1α/β heterodimerization inhibitors may provide a novel approach to anti-cancer therapy. To this end, a novel approach for imaging HIF-1α/β heterodimerization in vitro and in vivo was developed in this study. Using this screening platform, we identified a promising lead candidate and further chemically derivatized the lead candidate to assess the structure-activity relationship (SAR). The most effective first generation drug inhibitors were selected and their pharmacodynamics and anti-tumor efficacy in vivo were verified by bioluminescence imaging (BLI) of HIF-1α/β heterodimerization in the xenograft tumor model. Furthermore, the first generation drug inhibitors, M-TMCP and D-TMCP, demonstrated efficacy as monotherapies, resulting in tumor growth inhibition via disruption of HIF-1 signaling-mediated tumor stromal neoangiogenesis.

Stable oxygen isotopes of calcite veins in ODP Site 146-892

In situ secondary ionization mass spectrometry (SIMS) analyses of oxygen isotopes in authigenic calcite veins were obtained from an active thrust fault system drilled at Ocean Drilling Program (ODP) Site 892 (44°40.4'N, 125°07.1'W) along the Cascadia subduction margin. The average d18OPDB value of all samples is -9.9 per mil and the values are the lowest of any measured in active accretionary prisms. Ranges in individual veins can be as much as 19.6 per mil. There is an isotopic stratigraphy related to the structural stratigraphy. Mean isotope values in the hanging wall, thrust, and footwall are -14.4 per mil, -9.5 per mil, and -5.2 per mil, respectively. Several veins and crosscutting vein sequences show a general trend from lower to higher d18O values over time. Isotopic and textural data indicate several veins formed by a crack-seal mechanism and growth into open fractures. The best explanation for the strong 18O depletions is periodic rapid flow from 2-3 km deeper in the prism. Relatively narrow isotopic ranges for most veins suggest that fluids were derived from a similar source depth for each episode of fluid pulse and calcite crystallization. Structural and mass balance considerations are consistent with a record preserved in the veins of ten to hundreds of thousands of years. The fluid pulses may relate to periodic large earthquake events such as those recognized in the paleoseismicity records from the Cascadia margin.

Trace metals in sediments of the Var Canyon turbidite system at the DYFAMED station in the Ligurian Sea

The magnitude and the chronology of anthropogenic impregnation by Hg and other trace metals of environmental concern (V, Cr, Ni, Cu, Zn, Ag, Cd and Pb, including its stable isotopes) in the sediments are determined at the DYFAMED station, a site in the Ligurian Sea (Northwestern Mediterranean) chosen for its supposed open-sea characteristics. The DYFAMED site (VD) is located on the right levee of the Var Canyon turbidite system, at the end of the Middle Valley. In order to trace the influence of the gravity current coming from the canyon on trace metal distribution in the sediment, we studied an additional sediment core (VA) from a terrace of the Var Canyon, and material collected in sediment traps at the both sites at 20 m above sea bottom. The patterns of Hg and other trace element distribution profiles are interpreted using stable Pb isotope ratios as proxies for its sources, taking into account the sedimentary context (turbidites, redox conditions, and sedimentation rates). Major element distributions, coupled with the stratigraphic examination of the sediment cores point out the high heterogeneity of the deposits at VA, and major turbiditic events at both sites. At the DYFAMED site, we observed direct anthropogenic influence in the upper sediment layer (<2 cm), while on the Var Canyon site (VA), the anthropization concerns the whole sedimentary column sampled (19 cm). Turbiditic events superimpose their specific signature on trace metal distributions. According to the 210Pbxs-derived sedimentation rate at the DYFAMED site (0.4 mm yr-1), the Hg-enriched layer of the top core corresponds to the sediment accumulation of the last 50 years, which is the period of the highest increase in Hg deposition on a global scale. With the hypothesis of the absence of significant post-depositional redistribution of Hg, the Hg/C-org ratio changes between the surface and below are used to estimate the anthropogenic contribution to the Hg flux accumulated in the sediment. The Hg enrichment, from pre-industrial to the present time is calculated to be around 60%, consistent with estimations of global Hg models. However, based on the chemical composition of the trapped material collected in sediment traps, we calculated that epibenthic mobilization of Hg would reach 73%. Conversely, the Cd/C-org ratio decreases in the upper 5 cm, which may reflect the recent decrease of atmospheric Cd inputs or losses due to diagenetic processes.

Bedform measurements from the San Francisco Bay Coastal System

The morphology of ~45,000 bedforms from 13 multibeam bathymetry surveys was used as a proxy for identifying net bedload sediment transport directions and pathways throughout the San Francisco Bay estuary and adjacent outer coast. The spatially-averaged shape asymmetry of the bedforms reveals distinct pathways of ebb and flood transport. Additionally, the region-wide, ebb-oriented asymmetry of 5% suggests net seaward-directed transport within the estuarine-coastal system, with significant seaward asymmetry at the mouth of San Francisco Bay (11%), through the northern reaches of the Bay (7-8%), and among the largest bedforms (21% for lambda > 50 m). This general indication for the net transport of sand to the open coast strongly suggests that anthropogenic removal of sediment from the estuary, particularly along clearly defined seaward transport pathways, will limit the supply of sand to chronically eroding, open-coast beaches. The bedform asymmetry measurements significantly agree (up to ~ 76%) with modeled annual residual transport directions derived from a hydrodynamically-calibrated numerical model, and the orientation of adjacent, flow-sculpted seafloor features such as mega-flute structures, providing a comprehensive validation of the technique. The methods described in this paper to determine well-defined, cross-validated sediment transport pathways can be applied to estuarine-coastal systems globally where bedforms are present. The results can inform and improve regional sediment management practices to more efficiently utilize often limited sediment resources and mitigate current and future sediment supply-related impacts.

A fractional vegetation cover remote sensing product on pan-arctic scale with link to geotiff image

The paper presents first results of a pan-boreal scale land cover harmonization and classification. A methodology is presented that combines global and regional vegetation datasets to extract percentage cover information for different vegetation physiognomy and barren for the pan-arctic region within the ESA Data User Element Permafrost. Based on the legend description of each land cover product the datasets are harmonized into four LCCS (Land Cover Classification System) classifiers which are linked to the MODIS Vegetation Continuous Field (VCF) product. Harmonized land cover and Vegetation Continuous Fields products are combined to derive a best estimate of percentage cover information for trees, shrubs, herbaceous and barren areas for Russia. Future work will concentrate on the expansion of the developed methodology to the pan-arctic scale. Since the vegetation builds an isolation layer, which protects the permafrost from heat and cold temperatures, a degradation of this layer due to fire strongly influences the frozen conditions in the soil. Fire is an important disturbance factor which affects vast processes and dynamics in ecosystems (e.g. biomass, biodiversity, hydrology, etc.). Especially in North Eurasia the fire occupancy has dramatically increased in the last 50 years and has doubled in the 1990s with respect to the last five decades. A comparison of global and regional fire products has shown discrepancies between the amounts of burn scars detected by different algorithms and satellite data.

Distribution of organic-walled dinoflagellate cysts in surface sediments of the Benguela upwelling system

To obtain insight in the relationship between the spatial distribution of organic-walled dinoflagellate cysts (dinocysts) and local environmental conditions, fifty-eight surface sediment samples from the coastal shelf off SW Africa were investigated on their dinocyst content with special focus on the two main river systems and the active upwelling that characterise this region. To avoid possible overprint by species-selective preservation, samples have been selected mainly from shelf sites where high sedimentation rates and/or low bottom water oxygen concentrations prevail. Multivariate ordination analyses have been carried out to investigate the relationship between the distribution patterns of individual species to environmental parameters of the upper water column and sediment transport processes. The main oceanographical variables at the surface (temperature, salinity, nutrients chlorophyll-a) in the region show onshore-offshore gradients. This pattern is reflected in the dinocyst associations with high relative abundances of heterotrophic dinocyst species in neritic regions characterised by high chlorophyll-aand low salinity conditions in surface waters. Phototrophic dinocyst species, notably Operculodinium centrocarpum, dominate in the more oceanic area. Differences in the distribution of phototrophic dinocyst species can be related to sea surface salinity and sea surface temperature gradients and to a lesser extent to chlorophyll-a concentrations. Apart from longitudinal gradients the dinocyst distribution clearly reflects regional environmental features. Six groups of species can be distinguished, characteristic for (1) coastal regions (cysts of Polykrikos kofoidii and Selenopemphix quanta), (2) the vicinity of active upwelling (Brigantedinium spp., Echinidinium aculeatum, Echinidinium spp. and Echinidinium transparantum), (3) river mouths (Lejeunecysta oliva, cysts of Protoperidinium americanum, Selenopemphix nephroides and Votadinium calvum), (4) slope and open ocean sediments (Dalella chathamense, Impagidinium patulum and Operculodinium centrocarpum, (5) the southern Benguela region (south of 24°S) (Spiniferites ramosus) and (6) the northern Benguela region (north of 24°S) (Nematosphaeropsis labyrinthus and Pyxidinopsis reticulata). No indication of overprint of the palaeo-ecological signal by lateral transport of allochthonous species could be observed.

Reflectances transect from coast to open sea, Baltic Sea

In this study, retrievals of the medium resolution imaging spectrometer (MERIS) reflectances and water quality products using 4 different coastal processing algorithms freely available are assessed by comparison against sea-truthing data. The study is based on a pair-wise comparison using processor-dependent quality flags for the retrieval of valid common macro-pixels. This assessment is required in order to ensure the reliability of monitoring systems based on MERIS data, such as the Swedish coastal and lake monitoring system (http.vattenkvalitet.se). The results show that the pre-processing with the Improved Contrast between Ocean and Land (ICOL) processor, correcting for adjacency effects, improve the retrieval of spectral reflectance for all processors, Therefore, it is recommended that the ICOL processor should be applied when Baltic coastal waters are investigated. Chlorophyll was retrieved best using the FUB (Free University of Berlin) processing algorithm, although overestimations in the range 18-26.5%, dependent on the compared pairs, were obtained. At low chlorophyll concentrations (< 2.5 mg/m**3), random errors dominated in the retrievals with the MEGS (MERIS ground segment processor) processor. The lowest bias and random errors were obtained with MEGS for suspended particulate matter, for which overestimations in te range of 8-16% were found. Only the FUB retrieved CDOM (Coloured Dissolved Organic Matter) correlate with in situ values. However, a large systematic underestimation appears in the estimates that nevertheless may be corrected for by using a~local correction factor. The MEGS has the potential to be used as an operational processing algorithm for the Himmerfjärden bay and adjacent areas, but it requires further improvement of the atmospheric correction for the blue bands and better definition at relatively low chlorophyll concentrations in presence of high CDOM attenuation.