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The purpose of this work was to use various molecular imaging techniques to non-invasively assess GSK2849330 (anti HER3 ADCC and CDC enhanced 'AccretaMab' monoclonal antibody) pharmacokinetics and pharmacodynamics in human xenograft tumor-bearing mice. Immuno-PET biodistribution imaging of radiolabeled 89Zr-GSK2849330 was assessed in mice with HER3 negative (MIA-PaCa-2) and positive (CHL-1) human xenograft tumors. Dose dependency of GSK2849330 disposition was assessed using varying doses of unlabeled GSK2849330 co-injected with 89Zr-GSK2849330. In-vivo NIRF optical imaging and ex-vivo confocal microscopy were used to assess the biodistribution of GSK2849330 and the HER3 receptor occupancy in HER3 positive xenograft tumors (BxPC3, and CHL-1). Ferumoxytol (USPIO) contrast-enhanced MRI was used to investigate the effects of GSK2849330 on tumor macrophage content in CHL-1 xenograft bearing mice. Immuno-PET imaging was used to monitor the whole body drug biodistribution and CHL-1 xenograft tumor uptake up to 144 hours post injection of 89Zr-GSK2849330. Both hepatic and tumor uptake were dose dependent and saturable. The optical imaging data in the BxPC3 xenograft tumor confirmed the tumor dose response finding in the Immuno-PET study. Confocal microscopy showed a distinguished cytoplasmic punctate staining pattern within individual CHL-1 cells. GSK2849330 inhibited tumor growth and this was associated with a significant decrease in MRI signal to noise ratio after USPIO injection and with a significant increase in tumor macrophages as confirmed by a quantitative immunohistochemistry analysis. By providing both dose response and time course data from both 89Zr and fluorescently labeled GSK2849330, complementary imaging studies were used to characterize GSK2849330 biodistribution and tumor uptake in vivo. Ferumoxytol-enhanced MRI was used to monitor aspects of the immune system response to GSK2849330. Together these approaches potentially provide clinically translatable, non-invasive techniques to support dose optimization, and assess immune activation and anti-tumor responses.

There are currently no process‐based approaches that allow detailed spatial information on soil redistribution on hillslopes to be modeled at spatial scales that are appropriate for studying slope processes. In response, we developed a new type of soil‐erosion model, a marker‐in‐cell model, which simulates the redistribution of soil during rainfall events. The model is a hybrid of cell‐ and particle‐based techniques. A cell‐based model is used to determine the hydrology and hydraulics occurring at the cellular scale on the hillslope. Markers, representing sediment, are then moved through the grid according to these properties. The spatial pattern of erosion is determined directly by the properties of the markers. The model allows two‐dimensional spatial patterns of individual particle movement on a hillslope to be simulated within a computationally efficient framework. We have tested the model using data collected from a plot‐scale, rainfall‐simulation experiment. We measured the redistribution of137Cs‐rich tracer soil to resolve the spatial patterns of erosion caused by a single, high‐intensity, rainfall event. The model was able to recreate the key temporal and spatial aspects of the hydrology and hydraulics occurring on the plot, as well as the spatial redistribution of137Cs‐rich tracer soil. The development of the model was used to probe our understanding of how to investigate soil‐erosion processes. The lack of empirical underpinnings of the different model components highlighted the need to understand the spatiotemporal dynamics of soil erosion processes at the grain‐scale so to provide a better process‐based understanding of detachment and transport can be sought. Key Points Developed a new soil‐erosion model for hillslopes, a marker‐in‐cell model Recreates key aspects of hydrology, hydraulics, and spatial distribution of soil Provides a key feedback to our understanding of soil erosion processes

ABSTRACT Purpose This study investigated the effect of different active pharmaceutical ingredients (API) on aerosol electrostatic charges and aerosol performances for pressurized metered dose inhalers (pMDIs), using both insulating and conducting actuators. Methods Five solution-based pMDIs containing different API ingredients including: beclomethasone dipropionate (BDP), budesonide (BUD), flunisolide (FS), salbutamol base (SB) and ipratropium bromide (IPBr) were prepared using pressure filling technique. Actuator blocks made from nylon, polytetrafluoroethylene (PTFE) and aluminium were manufactured with 0.3 mm nominal orifice diameter and cone nozzle shape. Aerosol electrostatics for each pMDI formulation and actuator were evaluated using the electrical low-pressure impactor (ELPI) and drug depositions were analysed using high performance liquid chromatography (HPLC). Results All three actuator materials showed the same net charge trend across the five active drug ingredients, with BDP, BUD and FS showing positive net charges for both nylon and PTFE actuators, respectively. While SB and IPBr had significantly negative net charges across the three different actuators, which correlates to the ionic functional groups present on the drug molecule structures. Conclusions The API present in a pMDI has a dominant effect on the electrostatic properties of the formulation, overcoming the charge effect arising from the actuator materials. Results have shown that the electrostatic charges for a solution-based pMDI could be related to the interactions of the chemical ingredients and change in the work function for the overall formulation.

First published in 1774, Edward Long's \"The History of Jamaica\" covers the island's history from the first occupation by European settlers in 1655 until shortly before its publication. It marked the first occasion that an extended historical narrative had been undertaken by an author with a prolonged association with the island. More than just a social and political history, Long's trilogy offers readers detailed practical advice for life on the island, covering everything from the start-up requirements for a plantation to the tastiest fish. Of particular interest to a contemporary audience is the extensive information about slavery, from the cost of owning a slave to rules governing slaves and slave owners. This new edition makes Long's classic work available once again.

Marine oxygen minimum zones (OMZs) support diverse microbial communities with roles in major elemental cycles. It is unclear how the taxonomic composition and metabolism of OMZ microorganisms vary between particle-associated and free-living size fractions. We used amplicon (16S rRNA gene) and shotgun metagenome sequencing to compare microbial communities from large (>1.6 μm) and small (0.2–1.6 μm) filter size fractions along a depth gradient in the OMZ off Chile. Despite steep vertical redox gradients, size fraction was a significantly stronger predictor of community composition compared to depth. Phylogenetic diversity showed contrasting patterns, decreasing towards the anoxic OMZ core in the small size fraction, but exhibiting maximal values at these depths within the larger size fraction. Fraction-specific distributions were evident for key OMZ taxa, including anammox planctomycetes, whose coding sequences were enriched up to threefold in the 0.2–1.6 μm community. Functional gene composition also differed between fractions, with the >1.6 μm community significantly enriched in genes mediating social interactions, including motility, adhesion, cell-to-cell transfer, antibiotic resistance and mobile element activity. Prokaryotic transposase genes were three to six fold more abundant in this fraction, comprising up to 2% of protein-coding sequences, suggesting that particle surfaces may act as hotbeds for transposition-based genome changes in marine microbes. Genes for nitric and nitrous oxide reduction were also more abundant (three to seven fold) in the larger size fraction, suggesting microniche partitioning of key denitrification steps. These results highlight an important role for surface attachment in shaping community metabolic potential and genome content in OMZ microorganisms.

The spatial distribution of chemical contamination and toxicity of surficial sediments in Sydney Harbour, Australia, was investigated in a 3-tiered, hierarchical approach. An initial chemical investigation throughout the entire estuary (Stage 1) indicated wide ranges and different spatial patterns in sediment chemical concentrations. Sediment quality guidelines (SQGs) were used as a preliminary estimate of possible toxicity in Stage 2 of the investigation. Assessment of chemical mixtures indicated that sediments in a small part (~2%) of the harbour had the highest probability of being toxic (~75%), whereas sediment in almost 25% of the port was estimated to have an intermediate (~50%) probability of being toxic. The SQG assessment in Stage 2 enabled careful stratification of the harbour into areas with different toxicity risks, reducing cost and time commitments in the final tier of assessment. The spatial survey carried out in Stage 3 involved concurrent chemical and ecotoxicological analyses. In this final stage, the degree of response in tests of amphipod survival in whole sediment samples, as well as in tests of microbial metabolism (Microtox©) and sea urchin egg fertilisation and embryo development in pore waters, generally increased with increasing chemical concentrations. However, amphipod response was lower than predicted due to relatively low sensitivity of the indigenous amphipodCorophium colo. Areas initially predicted, using SQGs, to be most at risk were highly toxic in the combined chemistry–toxicity investigation, while sediment from areas with the lowest predicted risk were least toxic, but still toxic in at least one ecotoxicological test. The results demonstrate that the empirical approach used for this study, which was originally developed in North America, produced plausible outcomes elsewhere and that observed toxicity, based on SQGs, matched predictions using different species but similar methodologies.

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Data from toxicity tests of the pore water extracted from Puget Sound sediments were compiled from surveys conducted from 1997 to 2009. Tests were performed on 664 samples collected throughout all of the eight monitoring regions in the Sound, an area encompassing 2,294.1 km 2 . Tests were performed with the gametes of the Pacific purple sea urchin, Strongylocentrotus purpuratus , to measure percent fertilization success as an indicator of relative sediment quality. Data were evaluated to determine the incidence, degree of response, geographic patterns, spatial extent, and temporal changes in toxicity. This is the first survey of this kind and magnitude in Puget Sound. In the initial round of surveys of the eight regions, 40 of 381 samples were toxic for an incidence of 10.5 %. Stations classified as toxic represented an estimated total of 107.1 km 2 , equivalent to 4.7 % of the total area. Percent sea urchin fertilization ranged from >100 % of the nontoxic, negative controls to 0 %. Toxicity was most prevalent and pervasive in the industrialized harbors and lowest in the deep basins. Conditions were intermediate in deep-water passages, urban bays, and rural bays. A second round of testing in four regions and three selected urban bays was completed 5–10 years following the first round. The incidence and spatial extent of toxicity decreased in two of the regions and two of the bays and increased in the other two regions and the third bay; however, only the latter change was statistically significant. Both the incidence and spatial extent of toxicity were lower in the Sound than in most other US estuaries and marine bays.