The tissue-specific distribution of 3H-seocalcitol (EB 1089) and 3H-calcitriol in rats

Seocalcitol (EB 1089) is under development for the treatment of hepato-cellular carcinoma (HCC). The tissue distribution of 3H-seocalcitol was investigated in comparison to 3H-calcitriol in rats. Quantitative whole-body autoradiography was used to quantify the tissue distribution. The greatest difference in distribution between the two compounds was observed in the bloodstream. For most tissues the ratio seocalcitol/calcitriol varied between 0.2 and 3.1. The concentration of radioactivity in the liver was almost the same for the two compounds. For seocalcitol the concentration in the liver was 10 times higher than in serum. Assuming that the liver/serum concentration ratio is the same in rats and humans, the concentration of seocalcitol in the human liver is expected to be higher than the concentration resulting in more than 50% inhibition of cancer cell proliferation, and thus pharmacologically effective in HCC. It is questionable whether calcitriol would be present in the human liver in sufficient concentrations to be effective for the treatment of HCC, as the antiproliferative activity of calcitriol is generally more than 10-fold lower compared to that of seocalcitol and as calcitriol can only be administered at a dose that is ca. three-fold lower than the dose of seocalcitol.     

Inhibition of Klenow DNA polymerase and poly(A)-specific ribonuclease by aminoglycosides

Aminoglycosides are known to bind and perturb the function of catalytic RNA. Here we show that they also are potent inhibitors of protein-based catalysis using Escherichia coli Klenow polymerase (pol) and mammalian poly(A)-specific ribonuclease (PARN) as model enzymes. The inhibition was pH dependent and released in a competitive manner by Mg2+. Kinetic analysis showed that neomycin B behaved as a mixed noncompetitive inhibitor. Iron-mediated hydroxyl radical cleavage was used to show that neomycin B interfered with metal-ion binding in the active sites of both enzymes. Our analysis suggests a mechanism of inhibition where the aminoglycoside binds in the active site of the enzyme and thereby displaces catalytically important divalent metal ions. The potential causes of aminoglycoside toxicity and the usage of aminoglycosides to probe, characterize, and perturb metalloenzymes are discussed.     

Epizoochorous seed dispersal in relation to seed availability – an experiment with a red fox dummy

Questions: Is the red fox a potential vector for epizoochorous seed dispersal? Can seed attachment and retention be predicted from plant and seed traits? Location: Grasslands in southern Norway. Methods: Epizoochorous seed attachment on the red fox was studied by walking a dummy fox through the vegetation and comparing seeds found on the dummy with the estimated seed availability in the vegetation. Seed retention, i.e. the ability of different seeds to stay on the fox, was estimated in a separate experiment. Seed attachment and retention were related to plant and seed traits using statistical models that account for heteroscedasticity and zero‐inflated data. Results: The majority of seeds attached to the fox originated from a few species, but also species without specific seed traits that are supposed to enhance epizoochory attached at least some seeds to the fox. The probability of seed attachment was positively related to plant height, bristle and hooked seed appendages, and negatively related to winged appendages, seed mass, and seed sphericity. Seed retention was positively related to the seed traits bristles, hooks and pappus. For several species, the results indicate a high potential for dispersal over long distances. Conclusions: In modern agricultural landscapes, large herbivores are often restricted in their mobility or are found at low densities, and other animal vectors may therefore be important for seed dispersal. In our study, a range of plant species were able to disperse by attaching seeds to, and having their seeds retained in, the fox fur some distance. We suggest that the red fox may be an important vector for epizoochorous seed dispersal in the agricultural landscape.     

P2-P1' macrocyclization of P2 phenylglycine based HCV NS3 protease inhibitors using ring-closing metathesis

Macrocyclization is a commonly used strategy to preorganize HCV NS3 protease inhibitors in their bioactive conformation. Moreover, macrocyclization generally leads to greater stability and improved pharmacokinetic properties. In HCV NS3 protease inhibitors, it has been shown to be beneficial to include a vinylated phenylglycine in the P2 position in combination with alkenylic P1' substituents. A series of 14-, 15- and 16-membered macrocyclic HCV NS3 protease inhibitors with the linker connecting the P2 phenylglycine and the alkenylic P1' were synthesized by ring-closing metathesis, using both microwave and conventional heating. Besides formation of the expected macrocycles in cis and trans configuration as major products, both ring-contracted and double-bond migrated isomers were obtained, in particular during formation of the smaller rings (14- and 15-membered rings). All inhibitors had K(i)-values in the nanomolar range, but only one inhibitor type was improved by rigidification. The loss in inhibitory effect can be attributed to a disruption of the beneficial π-π interaction between the P2 fragment and H57, which proved to be especially deleterious for the d-phenylglycine epimers.     

On the hydrographic and ice conditions in the northern North Atlantic during different phases of a glaciation cycle

A theoretical investigation of the hydrographic conditions in the northern North Atlantic (N of the Greenland—Scotland Ridge) for different forcing conditions is undertaken. First a simple dynamical model for the “mediterranean” circulation in the Greenland and Norwegian seas (the Subpolar Sea) is developed. The calculated contemporary rate of deepwater formation (about 2.5 × 10⁶ m³/s) seems to be quite realistic. It is concluded that the mediterranean circulation is possible as long as the cyclonal atmospheric circulation in the Subpolar Sea is strong enough to prevent the fresher water in the coastal currents along the eastern and western boundaries from spreading over the interior.Utilizing the Arctic Ocean model in Stigebrandt (1981) the hydrographic and ice conditions in the Subpolar Sea and the Arctic Ocean during different phases of a glaciation are, finally, investigated. As so many parameters are involved the derivations are, by necessity, rather uncertain. However, it seems possible that the hydrographic state in the Subpolar Sea changes between mediterranean and estuarine circulation several times during a glacial cycle.     

Seventy years of changes in the abundance of Danish charophytes

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Presence of antibodies against Coxiella burnetii and risk of spontaneous abortion: a nested case-control study

Background and Aims

Q fever is a bacterial zoonosis caused by infection with Coxiella burnetii. It is well established that Q fever causes fetal loss in small ruminants. The suspicion has been raised that pregnant women may also experience adverse pregnancy outcome when the infection is acquired or reactivated during pregnancy. The purpose of this study was to assess the potential association between serologic markers of infection with C.burnetii and spontaneous abortion.

Methods

A nested case-control study within the Danish National Birth Cohort, a cohort of 100,418 pregnancies recruited from 1996–2002. Women were recruited in first trimester of pregnancy and followed prospectively. Median gestational age at enrolment was 8 weeks (25 and 75 percentiles: 7 weeks; 10 weeks). During pregnancy, a blood sample was collected at gestational week 6–12 and stored in a bio bank. For this study, a case sample of 218 pregnancies was drawn randomly among the pregnancies in the cohort which ended with a miscarriage before 22 gestational weeks, and a reference group of 482 pregnancies was selected in a random fashion among all pregnancies in the cohort. From these pregnancies, serum samples were screened for antibodies against C. burnetii in a commercial enzyme-linked immunosorbent assay (ELISA). Samples that proved IgG or IgM antibody positive were subsequently confirmatory tested by an immunofluorescence (IFA) test.

Results

Among cases, 11 (5%) were C. burnetii positive in ELISA of which one was confirmed in the IFA assay compared to 29 (6%) ELISA positive and 3 IFA confirmed in the random sample.

Conclusions

We found no evidence of a higher prevalence of C.burnetii antibodies in serum samples from women who later miscarried and the present study does not indicate a major association between Q fever infection and spontaneous abortion in humans. Very early first trimester abortions were, however, not included in the study.