A Near-Surface Microstructure Sensor System Used During TOGA COARE. Part I: Bow Measurements.

High-resolution probes mounted on the bow of the vessel at a 1.7-m depth in an undisturbed region ahead of the moving vessel were used for microstructure and turbulence measurements in the near-surface layer of the ocean during TOGA COARE. The probes measured temperature, conductivity, pressure, three-component fluctuation velocity, and two components of acceleration. Accumulation of large amounts of high-quality nearsurface data poses a difficult challenge, and deployment from the bow of a ship, such as is done with these sensors, requires rugged, well-calibrated, and low-noise sensors. The heaving motion of the ship that causes the sensors to break through the surface requires data processing algorithms unique to this application. Due to the presence of surface waves and the associated pitching of the vessel, the bow probes ‘‘scanned’’ the near-surface layer of the ocean. Combining the bow sensor’s signals with the ship’s thermosalinograph pumping water from 3-m depth resulted in the near-surface dataset with both fine temporal/spatial resolution and high absolute accuracy. Contour plots calculated using the bow signals reveal the spatial structure of the diurnal thermocline and rain-formed halocline. The localization in narrow frequency bands of the vibrations of the bow sensors allows calculation of dissipation rates. The characteristics of the sensors and the data processing algorithms related to the periodic surface penetration by the sensors are discussed in this paper

Evolution and connectivity in the world-wide migration system of the mallard: Inferences from mitochondrial DNA

<p>Abstract</p> <p>Background</p> <p>Main waterfowl migration systems are well understood through ringing activities. However, in mallards (<it>Anas platyrhynchos</it>) ringing studies suggest deviations from general migratory trends and traditions in waterfowl. Furthermore, surprisingly little is known about the population genetic structure of mallards, and studying it may yield insight into the spread of diseases such as Avian Influenza, and in management and conservation of wetlands. The study of evolution of genetic diversity and subsequent partitioning thereof during the last glaciation adds to ongoing discussions on the general evolution of waterfowl populations and flyway evolution. Hypothesised mallard flyways are tested explicitly by analysing mitochondrial mallard DNA from the whole northern hemisphere.</p> <p>Results</p> <p>Phylogenetic analyses confirm two mitochondrial mallard clades. Genetic differentiation within Eurasia and North-America is low, on a continental scale, but large differences occur between these two land masses (<it>F</it>_ST= 0.51). Half the genetic variance lies within sampling locations, and a negligible portion between currently recognised waterfowl flyways, within Eurasia and North-America. Analysis of molecular variance (AMOVA) at continent scale, incorporating sampling localities as smallest units, also shows the absence of population structure on the flyway level. Finally, demographic modelling by coalescence simulation proposes a split between Eurasia and North-America 43,000 to 74,000 years ago and strong population growth (~100fold) since then and little migration (not statistically different from zero).</p> <p>Conclusions</p> <p>Based on this first complete assessment of the mallard's world-wide population genetic structure we confirm that no more than two mtDNA clades exist. Clade A is characteristic for Eurasia, and clade B for North-America although some representatives of clade A are also found in North-America. We explain this pattern by evaluating competing hypotheses and conclude that a complex mix of historical, recent and anthropogenic factors shaped the current mallard populations. We refute population classification based on flyways proposed by ornithologists and managers, because they seem to have little biological meaning. Our results have implications for wetland management and conservation, with special regard to the release of farmed mallards for hunting, as well as for the possible transmission of Avian Influenza by mallards due to migration.</p

18F-C2Am: a targeted imaging agent for detecting tumor cell death in vivo using positron emission tomography.

INTRODUCTION: Trialing novel cancer therapies in the clinic would benefit from imaging agents that can detect early evidence of treatment response. The timing, extent and distribution of cell death in tumors following treatment can give an indication of outcome. We describe here an 18F-labeled derivative of a phosphatidylserine-binding protein, the C2A domain of Synaptotagmin-I (C2Am), for imaging tumor cell death in vivo using PET. METHODS: A one-pot, two-step automated synthesis of N-(5-[18F]fluoropentyl)maleimide (60 min synthesis time, > 98% radiochemical purity) has been developed, which was used to label the single cysteine residue in C2Am within 30 min at room temperature. Binding of 18F-C2Am to apoptotic and necrotic tumor cells was assessed in vitro, and also in vivo, by dynamic PET and biodistribution measurements in mice bearing human tumor xenografts treated with a TRAILR2 agonist or with conventional chemotherapy. C2Am detection of tumor cell death was validated by correlation of probe binding with histological markers of cell death in tumor sections obtained immediately after imaging. RESULTS: 18F-C2Am showed a favorable biodistribution profile, with predominantly renal clearance and minimal retention in spleen, liver, small intestine, bone and kidney, at 2 h following probe administration. 18F-C2Am generated tumor-to-muscle (T/m) ratios of 6.1 ± 2.1 and 10.7 ± 2.4 within 2 h of probe administration in colorectal and breast tumor models, respectively, following treatment with the TRAILR2 agonist. The levels of cell death (CC3 positivity) following treatment were 12.9-58.8% and 11.3-79.7% in the breast and colorectal xenografts, respectively. Overall, a 20% increase in CC3 positivity generated a one unit increase in the post/pre-treatment tumor contrast. Significant correlations were found between tracer uptake post-treatment, at 2 h post-probe administration, and histological markers of cell death (CC3: Pearson R = 0.733, P = 0.0005; TUNEL: Pearson R = 0.532, P = 0.023). CONCLUSION: The rapid clearance of 18F-C2Am from the blood pool and low kidney retention allowed the spatial distribution of cell death in a tumor to be imaged during the course of therapy, providing a rapid assessment of tumor treatment response. 18F-C2Am has the potential to be used in the clinic to assess early treatment response in tumors

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

Imaging biomarker roadmap for cancer studies.

Imaging biomarkers (IBs) are integral to the routine management of patients with cancer. IBs used daily in oncology include clinical TNM stage, objective response and left ventricular ejection fraction. Other CT, MRI, PET and ultrasonography biomarkers are used extensively in cancer research and drug development. New IBs need to be established either as useful tools for testing research hypotheses in clinical trials and research studies, or as clinical decision-making tools for use in healthcare, by crossing 'translational gaps' through validation and qualification. Important differences exist between IBs and biospecimen-derived biomarkers and, therefore, the development of IBs requires a tailored 'roadmap'. Recognizing this need, Cancer Research UK (CRUK) and the European Organisation for Research and Treatment of Cancer (EORTC) assembled experts to review, debate and summarize the challenges of IB validation and qualification. This consensus group has produced 14 key recommendations for accelerating the clinical translation of IBs, which highlight the role of parallel (rather than sequential) tracks of technical (assay) validation, biological/clinical validation and assessment of cost-effectiveness; the need for IB standardization and accreditation systems; the need to continually revisit IB precision; an alternative framework for biological/clinical validation of IBs; and the essential requirements for multicentre studies to qualify IBs for clinical use.Development of this roadmap received support from Cancer Research UK and the Engineering and Physical Sciences Research Council (grant references A/15267, A/16463, A/16464, A/16465, A/16466 and A/18097), the EORTC Cancer Research Fund, and the Innovative Medicines Initiative Joint Undertaking (grant agreement number 115151), resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies' in kind contribution

Regulation of Innate Immune Response to Candida albicans Infections by αMβ2-Pra1p Interaction▿

Candida albicans is a common opportunistic fungal pathogen and is the leading cause of invasive fungal diseases in immunocompromised individuals. The induction of cell-mediated immunity to C. albicans is one of the main tasks of cells of the innate immune system, and in vitro evidence suggests that integrin αMβ2 (CR3, Mac-1, and CD11b/CD18) is the principal leukocyte receptor involved in recognition of the fungus. Using αMβ2-KO mice and mutated strains of C. albicans in two models of murine candidiasis, we demonstrate that neutrophils derived from mice deficient in αMβ2 have a reduced ability to kill C. albicans and that the deficient mice themselves exhibit increased susceptibility to fungal infection. Disruption of the PRA1 gene of C. albicans, the primary ligand for αMβ2, protects the fungus against leukocyte killing in vitro and in vivo, impedes the innate immune response to the infection, and increases fungal virulence and organ invasion in vivo. Thus, recognition of pH-regulated antigen 1 protein (Pra1p) by αMβ2 plays a pivotal role in determining fungal virulence and host response and protection against C. albicans infection

αmβ \u3csub\u3e2\u3c/sub\u3e Is Antiatherogenic in Female but Not Male Mice

Atherosclerosis is a complex inflammatory process characterized by monocyte recruitment into the arterial wall, their differentiation into macrophages, and lipid accumulation. Because integrin αMβ 2 (CD11b/CD18) mediates multiple diverse functions of leukocytes, we examined its role in atherogenesis. αM -/- /ApoE -/- and ApoE -/- mice were fed a control or high fat diet for 3 or 16 wk to induce atherogenesis. Unexpectedly, αM deficiency accelerated development of atherosclerosis in female but not in male mice. The size of aortic root lesions was 3-4.5-fold larger in female αM -/- /ApoE -/- than in ApoE -/- mice. Monocyte and macrophage content within the lesions was increased 2.5-fold in female αM -/- /ApoE -/- mice due to enhanced proliferation. αMβ 2 elimination promoted gender-dependent foam cell formation due to enhanced uptake of cholesterol by αM -/- /ApoE -/- macrophages. This difference was attributed to enhanced expression of lipid uptake receptors, CD36 and scavenger receptor A1 (SR-A1), in female mice. Macrophages from female αM -/- /ApoE -/- mice showed dramatically reduced expression of FoxM1 transcription factor and estrogen receptors (ER) a and b. As their antagonists inhibited the effect of 17b-estradiol (E2), E2 decreased CD36, SR-A1, and foam cell formation in ApoE -/- macrophages in an ERa- and ERb-dependent manner. However, female αM -/- /ApoE -/- macrophages failed to respond to E 2 and maintained elevated CD36, SR-A1, and lipid accumulation. FoxM1 inhibition in ApoE -/- macrophages reduced ERs and enhanced CD36 and SR-A1 expression, whereas FoxM1 overexpression in αM -/- /ApoE -/- macrophages reversed their proatherogenic phenotype.We demonstrate a new, surprising atheroprotective role of αMβ 2 in female ApoE -/- mice. αMβ 2 maintains ER expression in macrophages and E 2 -dependent inhibition of foam cell formation