Imaging angiogenesis in atherosclerosis in large arteries with 68Ga-NODAGA-RGD PET/CT: relationship with clinical atherosclerotic cardiovascular disease.

Integrin alpha-V-beta-3 (αvβ3) pathway is involved in intraplaque angiogenesis and inflammation and represents a promising target for molecular imaging in cardiovascular diseases such as atherosclerosis. The aim of this study was to assess the clinical correlates of arterial wall accumulation of <sup>68</sup> Ga-NODAGA-RGD, a specific α <sub>v</sub> β <sub>3</sub> integrin ligand for PET. The data of 44 patients who underwent <sup>68</sup> Ga-NODAGA-RGD PET/CT scans were retrospectively analyzed. Tracer accumulation in the vessel wall of major arteries was analyzed semi-quantitatively by blood-pool-corrected target-to-background ratios. Tracer uptake was compared with clinically documented atherosclerotic cardiovascular disease, cardiovascular risk factors and calcified plaque burden. Data were compared using the Mann-Whitney U test, Pearson correlation and Spearman correlation. <sup>68</sup> Ga-NODAGA-RGD arterial uptake was significantly higher in patients with previous clinically documented atherosclerotic cardiovascular disease (mean TBR 2.44 [2.03-2.55] vs. 1.81 [1.56-1.96], p = 0.001) and showed a significant correlation with prior cardiovascular or cerebrovascular event (r = 0.33, p = 0.027), BMI (ρ = 0.38, p = 0.01), plaque burden (ρ = 0.31, p = 0.04) and hypercholesterolemia (r = 0.31, p = 0.04). <sup>68</sup> Ga-NODAGA-RGD holds promise as a non-invasive marker of disease activity in atherosclerosis, providing information about intraplaque angiogenesis

Efficacy of Continuous Interleukin 1 Blockade in Mevalonate Kinase Deficiency: A Multicenter Retrospective Study in 13 Adult Patients and Literature Review

OBJECTIVE: To report efficacy and tolerance of interleukin 1 blockade in adult patients with mevalonate kinase deficiency (MKD). METHODS: We retrospectively collected data on 13 patients with MKD who had received anakinra (n = 10) and canakinumab (n = 7). RESULTS: Anakinra resulted in complete or partial remission in 3/10 and 5/10 patients, respectively, and no efficacy in 2/10, but a switch to canakinumab led to partial remission. Canakinumab resulted in complete or partial remission in 3/7 and 4/7 patients, respectively. CONCLUSION: These data support frequent partial responses, showing a better response with canakinumab. The genotype and therapeutic outcomes correlation should help in the personalization of treatment

Assessing the role of EO in biodiversity monitoring: options for integrating in-situ observations with EO within the context of the EBONE concept

The European Biodiversity Observation Network (EBONE) is a European contribution on terrestrial monitoring to GEO BON, the Group on Earth Observations Biodiversity Observation Network. EBONE’s aims are to develop a system of biodiversity observation at regional, national and European levels by assessing existing approaches in terms of their validity and applicability starting in Europe, then expanding to regions in Africa. The objective of EBONE is to deliver: 1. A sound scientific basis for the production of statistical estimates of stock and change of key indicators; 2. The development of a system for estimating past changes and forecasting and testing policy options and management strategies for threatened ecosystems and species; 3. A proposal for a cost-effective biodiversity monitoring system. There is a consensus that Earth Observation (EO) has a role to play in monitoring biodiversity. With its capacity to observe detailed spatial patterns and variability across large areas at regular intervals, our instinct suggests that EO could deliver the type of spatial and temporal coverage that is beyond reach with in-situ efforts. Furthermore, when considering the emerging networks of in-situ observations, the prospect of enhancing the quality of the information whilst reducing cost through integration is compelling. This report gives a realistic assessment of the role of EO in biodiversity monitoring and the options for integrating in-situ observations with EO within the context of the EBONE concept (cfr. EBONE-ID1.4). The assessment is mainly based on a set of targeted pilot studies. Building on this assessment, the report then presents a series of recommendations on the best options for using EO in an effective, consistent and sustainable biodiversity monitoring scheme. The issues that we faced were many: 1. Integration can be interpreted in different ways. One possible interpretation is: the combined use of independent data sets to deliver a different but improved data set; another is: the use of one data set to complement another dataset. 2. The targeted improvement will vary with stakeholder group: some will seek for more efficiency, others for more reliable estimates (accuracy and/or precision); others for more detail in space and/or time or more of everything. 3. Integration requires a link between the datasets (EO and in-situ). The strength of the link between reflected electromagnetic radiation and the habitats and their biodiversity observed in-situ is function of many variables, for example: the spatial scale of the observations; timing of the observations; the adopted nomenclature for classification; the complexity of the landscape in terms of composition, spatial structure and the physical environment; the habitat and land cover types under consideration. 4. The type of the EO data available varies (function of e.g. budget, size and location of region, cloudiness, national and/or international investment in airborne campaigns or space technology) which determines its capability to deliver the required output. EO and in-situ could be combined in different ways, depending on the type of integration we wanted to achieve and the targeted improvement. We aimed for an improvement in accuracy (i.e. the reduction in error of our indicator estimate calculated for an environmental zone). Furthermore, EO would also provide the spatial patterns for correlated in-situ data. EBONE in its initial development, focused on three main indicators covering: (i) the extent and change of habitats of European interest in the context of a general habitat assessment; (ii) abundance and distribution of selected species (birds, butterflies and plants); and (iii) fragmentation of natural and semi-natural areas. For habitat extent, we decided that it did not matter how in-situ was integrated with EO as long as we could demonstrate that acceptable accuracies could be achieved and the precision could consistently be improved. The nomenclature used to map habitats in-situ was the General Habitat Classification. We considered the following options where the EO and in-situ play different roles: using in-situ samples to re-calibrate a habitat map independently derived from EO; improving the accuracy of in-situ sampled habitat statistics, by post-stratification with correlated EO data; and using in-situ samples to train the classification of EO data into habitat types where the EO data delivers full coverage or a larger number of samples. For some of the above cases we also considered the impact that the sampling strategy employed to deliver the samples would have on the accuracy and precision achieved. Restricted access to European wide species data prevented work on the indicator ‘abundance and distribution of species’. With respect to the indicator ‘fragmentation’, we investigated ways of delivering EO derived measures of habitat patterns that are meaningful to sampled in-situ observations

Tomato protoplast DNA transformation: physical linkage and recombination of exogenous DNA sequences

Tomato protoplasts have been transformed with plasmid DNA's, containing a chimeric kanamycin resistance gene and putative tomato origins of replication. A calcium phosphate-DNA mediated transformation procedure was employed in combination with either polyethylene glycol or polyvinyl alcohol. There were no indications that the tomato DNA inserts conferred autonomous replication on the plasmids. Instead, Southern blot hybridization analysis of seven kanamycin resistant calli revealed the presence of at least one kanamycin resistance locus per transformant integrated in the tomato nuclear DNA. Generally one to three truncated plasmid copies were found integrated into the tomato nuclear DNA, often physically linked to each other. For one transformant we have been able to use the bacterial ampicillin resistance marker of the vector plasmid pUC9 to 'rescue' a recombinant plasmid from the tomato genome. Analysis of the foreign sequences included in the rescued plasmid showed that integration had occurred in a non-repetitive DNA region. Calf-thymus DNA, used as a carrier in transformation procedure, was found to be covalently linked to plasmid DNA sequences in the genomic DNA of one transformant. A model is presented describing the fate of exogenously added DNA during the transformation of a plant cell. The results are discussed in reference to the possibility of isolating DNA sequences responsible for autonomous replication in tomato.

Preindustrial control simulations with HadGEM3-GC3.1 for CMIP6

Pre‐industrial control simulations with the HadGEM3‐GC3.1 climate model are presented at two resolutions. These are N216ORCA025, which has a horizontal resolution of 60km in the atmosphere and 0.25° in the ocean, and N96ORCA1, which has a horizontal resolution of 130km in the atmosphere and 1° in the ocean. The aim of this study is to document the climate variability in these simulations, make comparisons against present‐day observations (albeit under different forcing), and discuss differences arising due to resolution. In terms of interannual variability in the leading modes of climate variability the two resolutions behave generally very similarly. Notable differences are in the westward extent of El‐Niño and the pattern of Atlantic multidecadal variability, in which N216ORCA025 compares more favourably to observations, and in the Antarctic Circumpolar Current, which is far too weak in N216ORCA025. In the North Atlantic region, N216ORCA025 has a stronger and deeper AMOC, which compares well against observations, and reduced biases in temperature and salinity in the North Atlantic subpolar gyre (NA SPG). These simulations are being provided to the sixth Coupled Model Intercomparison Project (CMIP6) and provide a baseline against which further forced experiments may be assessed

The role of salinity in the decadal variability of the North Atlantic meridional overturning circulation

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Climate Dynamics 33 (2009): 777-793, doi:10.1007/s00382-008-0523-2.An OGCM hindcast is used to investigate the linkages between North Atlantic Ocean salinity and circulation changes during 1963–2003. The focus is on the eastern subpolar region consisting of the Irminger Sea and the eastern North Atlantic where a careful assessment shows that the simulated interannual to decadal salinity changes in the upper 1500 m reproduce well those derived from the available record of hydrographic measurements. In the model, the variability of the Atlantic meridional overturning circulation (MOC) is primarily driven by changes in deep water formation taking place in the Irminger Sea and, to a lesser extent, the Labrador Sea. Both are strongly influenced by the North Atlantic Oscillation (NAO). The modeled interannual to decadal salinity changes in the subpolar basins are mostly controlled by circulation-driven anomalies of freshwater flux convergence, although surface salinity restoring to climatology and other boundary fluxes each account for approximately 25% of the variance. The NAO plays an important role: a positive NAO phase is associated with increased precipitation, reduced northward salt transport by the wind-driven intergyre gyre, and increased southward flows of freshwater across the Greenland-Scotland ridge. Since the NAO largely controlled deep convection in the subpolar gyre, fresher waters are found near the sinking region during convective events. This markedly differs from the active influence on the MOC that salinity exerts at decadal and longer timescales in most coupled models. The intensification of the MOC that follows a positive NAO phase by about 2 years does not lead to an increase in the northward salt transport into the subpolar domain at low frequencies because it is cancelled by the concomitant intensification of the subpolar gyre which shifts the subpolar front eastward and reduces the northward salt transport by the North Atlantic Current waters. This differs again from most coupled models, where the gyre intensification precedes that of the MOC by several years.Support from NSF Grant 82677800 with the Woods Hole Oceanographic Institution, and (to CF) from the Institut universitaire de France and European FP6 project DYNAMITE (contract 003903-GOCE) and (to JD) from the NOAA Office of Hydrologic Development through a scientific appointment administered by UCAR is gratefully acknowledged

Dynamic Measurements of Membrane Insertion Potential of Synthetic Cell Penetrating Peptides

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Langmuir, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://doi.org/10.1021/la403370p.Cell penetrating peptides (CPPs) have been established as excellent candidates for mediating drug delivery into cells. When designing synthetic CPPs for drug delivery applications, it is important to understand their ability to penetrate the cell membrane. In this paper, anionic or zwitterionic phospholipid monolayers at the air-water interface are used as model cell membranes to monitor the membrane insertion potential of synthetic CPPs. The insertion potential of CPPs having different cationic and hydrophobic amino acids were recorded using a Langmuir monolayer approach that records peptide adsorption to model membranes. Fluorescence microscopy was used to visualize alterations in phospholipid packing due to peptide insertion. All CPPs had the highest penetration potential in the presence of anionic phospholipids. In addition, two of three amphiphilic CPPs inserted into zwitterionic phospholipids, but none of the hydrophilic CPPs did. All the CPPs studied induced disruptions in phospholipid packing and domain morphology, which were most pronounced for amphiphilic CPPs. Overall, small changes to amino acids and peptide sequences resulted in dramatically different insertion potentials and membrane reorganization. Designers of synthetic CPPs for efficient intracellular drug delivery should consider small nuances in CPP electrostatic and hydrophobic properties

Localisation of renin-angiotensin system (RAS) components in breast

Angiotensin II has mitogenic and angiogenic effects and its receptors are widespread, particularly in epithelial tissue. Tissue renin angiotensin systems (tRASs) may be a local source of angiotensin II that has specific paracrine functions. To investigate the presence of a tRAS in normal human breast and tumours. Immunocytochemistry, and quantitative RT–PCR was used to establish: (i) the presence and localisation of RAS components, (ii) the possibility of their involvement in cancer. (1) mRNA coding for angiotensinogen, prorenin, angiotensin converting enzyme (ACE), and both AT1 and AT2 receptors was demonstrated in normal and diseased breast tissues. (2) (pro)renin was identified in epithelial cells in both normal and diseased tissue, but in invasive carcinoma, its distribution was mostly confined to fibroblasts or could not be detected at all. (3) Angiotensin converting enzyme was shown in epithelial cells in both normal and malignant tissue. The results are consistent with the hypothesis that a tRAS is present in the breast, and is disrupted in invasive cancer

An abrupt weakening of the subpolar gyre as trigger of Little Ice Age-type episodes

We investigate the mechanism of a decadal-scale weakening shift in the strength of the subpolar gyre (SPG) that is found in one among three last millennium simulations with a state-of-the-art Earth system model. The SPG shift triggers multicentennial anomalies in the North Atlantic climate driven by long-lasting internal feedbacks relating anomalous oceanic and atmospheric circulation, sea ice extent, and upper-ocean salinity in the Labrador Sea. Yet changes throughout or after the shift are not associated with a persistent weakening of the Atlantic Meridional Overturning Circulation or shifts in the North Atlantic Oscillation. The anomalous climate state of the North Atlantic simulated after the shift agrees well with climate reconstructions from within the area, which describe a transition between a stronger and weaker SPG during the relatively warm medieval climate and the cold Little Ice Age respectively. However, model and data differ in the timing of the onset. The simulated SPG shift is caused by a rapid increase in the freshwater export from the Arctic and associated freshening in the upper Labrador Sea. Such freshwater anomaly relates to prominent thickening of the Arctic sea ice, following the cluster of relatively small-magnitude volcanic eruptions by 1600 CE. Sensitivity experiments without volcanic forcing can nonetheless produce similar abrupt events; a necessary causal link between the volcanic cluster and the SPG shift can therefore be excluded. Instead, preconditioning by internal variability explains discrepancies in the timing between the simulated SPG shift and the reconstructed estimates for the Little Ice Age onset

The Use of Phage-Displayed Peptide Libraries to Develop Tumor-Targeting Drugs

Monoclonal antibodies have been successfully utilized as cancer-targeting therapeutics and diagnostics, but the efficacies of these treatments are limited in part by the size of the molecules and non-specific uptake by the reticuloendothelial system. Peptides are much smaller molecules that can specifically target cancer cells and as such may alleviate complications with antibody therapy. Although many endogenous and exogenous peptides have been developed into clinical therapeutics, only a subset of these consists of cancer-targeting peptides. Combinatorial biological libraries such as bacteriophage-displayed peptide libraries are a resource of potential ligands for various cancer-related molecular targets. Target-binding peptides can be affinity selected from complex mixtures of billions of displayed peptides on phage and further enriched through the biopanning process. Various cancer-specific ligands have been isolated by in vitro, in vivo, and ex vivo screening methods. As several peptides derived from phage-displayed peptide library screenings have been developed into therapeutics in current clinical trials, which validates peptide-targeting potential, the use of phage display to identify cancer-targeting therapeutics should be further exploited