Accumulation of nano-sized particles in a murine model of angiogenesis

Purpose

To evaluate the ability of nm-scaled iron oxide particles conjugated with Azure A, a classic histological dye, to accumulate in areas of angiogenesis in a recently developed murine angiogenesis model.

Materials and methods

We characterised the Azure A particles with regard to their hydrodynamic size, zeta potential, and blood circulation half-life. The particles were then investigated by Magnetic Resonance Imaging (MRI) in a recently developed murine angiogenesis model along with reference particles (Ferumoxtran-10) and saline injections.

Results

The Azure A particles had a mean hydrodynamic diameter of 51.8 ± 43.2 nm, a zeta potential of −17.2 ± 2.8 mV, and a blood circulation half-life of 127.8 ± 74.7 min. Comparison of MR images taken pre- and 24-h post-injection revealed a significant increase in R₂^* relaxation rates for both Azure A and Ferumoxtran-10 particles. No significant difference was found for the saline injections. The relative increase was calculated for the three groups, and showed a significant difference between the saline group and the Azure A group, and between the saline group and the Ferumoxtran-10 group. However, no significant difference was found between the two particle groups.

Conclusion

Ultrahigh-field MRI revealed localisation of both types of iron oxide particles to areas of neovasculature. However, the Azure A particles did not show any enhanced accumulation relative to Ferumoxtran-10, suggesting the accumulation in both cases to be passive.     

Spatial dynamics of Norwegian tetraonid populations

Different species in a given site or population of a given species in different sites may fluctuate in synchrony if they are affected similarly by factors such as spatially autocorrelated climate, predation, or by dispersal between populations of one species. We used county wise time series of hunting bag records of four Norwegian tetraonid species covering 24 years to examine patterns of interspecific and intraspecific synchrony. We estimated synchrony at three spatial scales; national, regional (consisting of counties with similar climate), and county level. Ecologically related species with overlapping distributions exhibited strong synchrony across Norway, but there was much variation between the different regions and counties. Regions with a long coastline to both the North Sea and the Norwegian Ocean exhibited an overall stronger synchrony than those consisting of more continental areas. Intraspecific synchrony was generally low across all counties, but stronger synchrony between counties within regions defined by climatic conditions. Synchrony was negatively related to distance between populations in three of four species. Only the synchrony in willow ptarmigan showed a clear negative relationship with distance, while the other species had both strong positive and negative correlations at short distances. Strong interspecific synchrony between some species pairs within regions and weak intraspecific synchrony across counties within regions suggest a stronger synchronizing effect from environmental factors such as weather or predation and less effect from dispersal. Our results suggest that the complete tetraonid community is structured by environmental factors affecting the different species similarly and causes widespread interspecific synchrony. Local factors affecting the population dynamics nevertheless frequently forces neighbouring populations out of phase.     

Binding inhibition by monoclonal antibodies of ovine placental lactogen to growth hormone receptors in human liver

In the radioreceptor assay for growth hormone (RRA-GH) using [125I]iodo-hGH, hGH and human liver membrane particulate fractions as tracer, hormone standard and receptors, respectively, ovine placental lactogen (oPL) is capable of inhibiting the binding of [125I]iodo-hGH in a parallel manner with hGH and in equipotency. Similarly, in the RRA-GH by employing [125I]iodo-oPL, oPL and human liver membrane particulate fractions as tracer, hormone standard and receptors, respectively, hGH is also equipotent as oPL in inhibiting the binding of [125I]iodo-oPL in a parallel fashion. The addition of monoclonal antibodies against oPL in the assay was effective in inhibiting the binding of [125I] iodo-oPL to human liver, but could not, however, inhibit the binding of [125I]iodo-hGH to human liver. Furthermore, the addition of the monoclonal antibodies in the RRA-GH did not affect the parallelism of the oPL standard but lowered the total binding of oPL. Our studies indicate that the structure of the binding sequence in oPL which binds to the GH receptor of human liver is not identical to the equivalent sequence of hGH and that the monoclonal antibodies compete with GH receptors in human liver for the binding of oPL.     

Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepatocytes

In this study, we present the design and synthesis of an antisense peptide nucleic acid (asPNA) prodrug, which displays an improved biodistribution profile and an equally improved capacity to reduce the levels of target mRNA. The prodrug, K(GalNAc)(2)-asPNA, comprised of a 14-mer sequence complementary to the human microsomal triglyceride transfer protein (huMTP) gene, conjugated to a high-affinity tag for the hepatic asialoglycoprotein receptor (K(GalNAc)(2)). The prodrug was avidly bound and rapidly internalized by HepG2s. After iv injection into mice, K(GalNAc)(2)-asPNA accumulated in the parenchymal liver cells to a much greater extent than nonconjugated PNA (46% +/- 1% vs 3.1% +/- 0.5% of the injected dose, respectively). The prodrug was able to reduce MTP mRNA levels in HepG2 cells by 35-40% (P < 0.02) at 100 nM in an asialoglycoprotein receptor- and sequence-dependent fashion. In conclusion, hepatocyte-targeted PNA prodrugs combine a greatly improved tropism with an enhanced local intracellular availability and activity, making them attractive therapeutics to lower the expression level of hepatic target genes such as MTP.     

Metal complexes with the quinolone antibacterial agent N-propyl-norfloxacin: synthesis, structure and bioactivity

Nine new metal complexes of the quinolone antibacterial agent N-propyl-norfloxacin, pr-norfloxacin, with VO(2+), Mn(2+), Fe(3+), Co(2+), Ni(2+), Zn(2+), MoO(2)(2+), Cd(2+) and UO(2)(2+) have been prepared and characterized with physicochemical and spectroscopic techniques while molecular mechanics calculations for Fe(3+), VO(2+) and MoO(2)(2+) complexes have been performed. In all complexes, pr-norfloxacin acts as a bidentate deprotonated ligand bound to the metal through the pyridone and one carboxylate oxygen atoms. All complexes are six-coordinate with slightly distorted octahedral geometry. For the complex VO(N-propyl-norfloxacinato)(2)(H(2)O) the axial position, trans to the vanadyl oxygen, is occupied by one pyridone oxygen atom. The investigation of the interaction of the complexes with calf-thymus DNA has been performed with diverse spectroscopic techniques and has shown that the complexes can be bound to calf-thymus DNA resulting to a B-->A DNA transition. The antimicrobial activity of the complexes has been tested on three different microorganisms. The complexes show equal or decreased biological activity in comparison to the free pr-norfloxacin except UO(2)(pr-norf)(2) which shows better inhibition against S. aureus.     

Metabolomic profiling of rapid cold hardening and cold shock in Drosophila melanogaster

A short exposure to a mild cold stress is sufficient to increase cold tolerance in many insects. This phenomenon, termed rapid cold hardening (RCH) expands the thermal interval that can be exploited by the insect. To investigate the possible role of altered metabolite levels during RCH, the present study used untargeted (1)H NMR metabolomic profiling to examine the metabolomic response in Drosophila melanogaster during the 72 h following RCH and cold shock treatment. These findings are discussed in relation to the costs and benefits of RCH that are measured in terms of survival and reproductive output. Cold shock caused a persistent disturbance of the metabolite profile that correlated well with a delayed onset of cold shock mortality. The disruption of metabolite homeostasis was smaller following RCH, where control levels were fully recovered after 72 h. RCH improved both survival and reproductive output after a subsequent cold shock but the RCH treatment alone was associated with costs in terms of reduced survival and reproductive output. The most pronounced changes following the RCH treatment were elevated levels of glucose and trehalose. Although, it is difficult to discern if a change in a specific metabolite is linked to physiological processes of adaptive, neutral or detrimental nature we observed that the onset and magnitude of the increased sugar levels correlated tightly with the improved chill tolerance following RCH. These findings suggest a putative role of cryoprotectants during RCH which are discussed in the light of the existing literature on the mechanistic background of RCH.     

Mononuclear copper(II) complexes with quinolones and nitrogen-donor heterocyclic ligands: Synthesis, characterization, biological activity and interaction with DNA

The neutral mononuclear copper(II) complexes with the quinolone antibacterial drugs, pipemidic acid and N-propyl-norfloxacin, in the presence or absence of nitrogen-donor heterocyclic ligands, 2,2′-bipyridine, 1,10-phenanthroline or 2,2′-dipyridylamine, have been prepared and characterized spectroscopically. The interaction of copper(II) with the deprotonated quinolone ligand leads to the formation of the neutral mononuclear complexes of the type [Cu(quinolone)₂(H₂O)] (1)–(2) while the presence of the N-donor ligand leads to the formation of the neutral mononuclear complexes of the type [Cu(quinolone)(N-donor)Cl] (3)–(8). In all the complexes, copper(II) is pentacoordinate having a distorted square pyramidal geometry. The electron paramagnetic resonance spectra of 1 and 2 are typical of mononuclear Cu(II) complexes, while for the mixed-ligands complexes 3–8 a mixture of dimeric and monomeric species is indicated. The interaction of the complexes with calf-thymus DNA has been investigated with diverse spectroscopic techniques and has shown that the complexes can be bound to calf-thymus DNA by the intercalative mode. The antimicrobial activity of the complexes has been tested on three different microorganisms. All the complexes show an increased biological activity in comparison to the corresponding free quinolone ligand.     

Food web dynamics affect Northeast Arctic cod recruitment

Proper management of ecosystems requires an understanding of both the species interactions as well as the effect of climate variation. However, a common problem is that the available time-series are of different lengths. Here, we present a general approach for studying the dynamic structure of such interactions. Specifically, we analyse the recruitment of the world's largest cod stock, the Northeast Arctic cod. Studies based on data starting in the 1970-1980s indicate that this stock is affected by temperature through a variety of pathways. However, the value of such studies is somewhat limited by the fact that they are based on a quite specific ecological and climatic situation. Recently, this stock has consisted of fairly young fish and the spawning stock has consisted of relatively few age groups. In this study, we develop a model for the effect of capelin (the cod's main prey) and herring on cod recruitment since 1973. Based on this model, we analyse data on cod, herring and temperature going back to 1921 and find that food-web effects explain a significant part of the cod recruitment variation back to around 1950.