Discovery of a class of calcium sensing receptor positive allosteric modulators; 1-(benzothiazol-2-yl)-1-phenylethanols

1-(Benzothiazol-2-yl)-1-(4-chlorophenyl)ethanol (1) was identified as a positive allosteric modulator (PAM) of the CaSR in a functional cell-based assay. This compound belongs to a class of compounds that is structurally distinct from other known positive allosteric modulators, for example, the phenylalkylamines cinacalcet, a modified analog (13) potently suppressed parathyroid hormone (PTH) release in rats, consistent with its profile as a PAM of CaSRs.     

Temperature-dependent structural changes in intrinsically disordered proteins: Formation of α-helices or loss of polyproline II?

Structural characterization of intrinsically disordered proteins (IDPs) is mandatory for deciphering their potential unique physical and biological properties. A large number of circular dichroism (CD) studies have demonstrated that a structural change takes place in IDPs with increasing temperature, which most likely reflects formation of transient α-helices or loss of polyproline II (PPII) content. Using three IDPs, ACTR, NHE1, and Spd1, we show that the temperature-induced structural change is common among IDPs and is accompanied by a contraction of the conformational ensemble. This phenomenon was explored at residue resolution by multidimensional NMR spectroscopy. Intrinsic chemical shift referencing allowed us to identify regions of transiently formed helices and their temperature-dependent changes in helicity. All helical regions were found to lose rather than gain helical structures with increasing temperature, and accordingly these were not responsible for the change in the CD spectra. In contrast, the nonhelical regions exhibited a general temperature-dependent structural change that was independent of long-range interactions. The temperature-dependent CD spectroscopic signature of IDPs that has been amply documented can be rationalized to represent redistribution of the statistical coil involving a general loss of PPII conformations.     

Coenzyme Q - Biosynthesis and functions

In addition to its role as a component of the mitochondrial respiratory chain and our only lipid-soluble antioxidant synthesized endogenously, in recent years coenzyme Q (CoQ) has been found to have an increasing number of other important functions required for normal metabolic processes. A number of genetic mutations that reduce CoQ biosynthesis are associated with serious functional disturbances that can be eliminated by dietary administration of this lipid, making CoQ deficiencies the only mitochondrial diseases which can be successfully treated at present. In connection with certain other diseases associated with excessive oxidative stress, the level of CoQ is elevated as a protective response. Aging, certain experimental conditions and several human diseases reduce this level, resulting in serious metabolic disturbances. Since dietary uptake of this lipid is limited, up-regulation of its biosynthetic pathway is of considerable clinical interest. One approach for this purpose is administration of epoxidated all-trans polyisoprenoids, which enhance both CoQ biosynthesis and levels in experimental systems.     

Growing through predation windows: effects on body size development in young fish

The degree to which growth in early life stages of animals is regulated via density‐dependent feedbacks through prey resources is much debated. Here we have studied the influence of size‐ and density‐dependent mechanisms as well as size‐selective predation pressure by cannibalistic perch Perca fluviatilis on growth patterns of young‐of‐the‐year (YOY) perch covering several lakes and years. We found no influence of initial size or temperature on early body size development of perch. In contrast, there was a negative relationship between reproductive output and the length of YOY perch at five weeks of age. However, rather than an effect of density‐dependent growth mediated via depressed resources the relationship was driven by positive size‐selective cannibalism removing large individuals. Hence, given a positive correlation between the density of victims and predation pressure by cannibals, size‐dependent interactions between cannibals and their victims may wrongly be interpreted as patterns of density‐dependent growth in the victim cohort. Overall, our results support the view that density‐dependent resource‐limitation in early life stages is rare. Still, patterns of density‐dependent growth may emerge, but from variation in size‐selective predation pressure rather than density as such. This illustrates the importance of taking overall population demography and predatory interactions into account when studying growth patterns among recruiting individuals.     

Bacterial diversity in faeces from polar bear (<Emphasis Type="Italic">Ursus maritimus</Emphasis>) in Arctic Svalbard

Background  

Polar bears (Ursus maritimus) are major predators in the Arctic marine ecosystem, feeding mainly on seals, and living closely associated with sea ice. Little is known of their gut microbial ecology and the main purpose of this study was to investigate the microbial diversity in faeces of polar bears in Svalbard, Norway (74-81°N, 10-33°E). In addition the level of bla _TEM alleles, encoding ampicillin resistance (amp^r) were determined. In total, ten samples were collected from ten individual bears, rectum swabs from five individuals in 2004 and faeces samples from five individuals in 2006.     

Clinical isolates of Enterococcus faecalis aggregate human platelets

Many endocarditis pathogens activate human platelets and this has been proposed to contribute to virulence. Here we report for the first time that many clinical isolates of Enterococcus faecalis, a common pathogen in infective endocarditis, aggregate human platelets. 84 isolates from human blood and urine were screened for their ability to aggregate platelets from four different donors. Platelet aggregation occurred for between 11 and 65% of isolates depending on the donor. In one donor, a significantly larger proportion of isolates from blood than from urine caused platelet aggregation. Median time to aggregation was 11 min and had a tendency to be shorter for blood isolates as compared to urine isolates. Immunoglobulin G (IgG) was shown to be essential in mediating activation and aggregation. Platelet aggregation could be abolished by an IgG-specific proteinase (IdeS), by an antibody blocking FcRγIIa on platelets, or by preabsorption of plasma with an E. faecalis isolate. Fibrinogen binding to bacteria or platelets does not contribute to platelet activation or aggregation under our experimental conditions. These results indicate that platelet activation and aggregation by E. faecalis is dependent on both host and bacterial factors and that it may be involved in the pathogenesis of invasive disease with this organism.     

Calcium-regulating peptide hormones and blood electrolytic balance in chronic heart failure

Calcium-regulating system is important for the functional activity of myocardium. However, little is known about the role of this system in the pathogenesis of cardiovascular diseases. Blood samples from the patients with chronic heart failure (CHF) caused by ischaemic disease (coronary artery disease) (NYHA class I-IV) were used to analyze the levels of calcium, inorganic phosphate, sodium, potassium, parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). The heart beat rate and arterial blood pressure were chosen as additional tests for the functional status of cardiovascular system. The alteration of electrolytes homeostasis was found dependent on the severity of the pathology being maximally expressed in the NYHA class IV patients. Similar tendency was demonstrated for circulating PTH and PTHrP with the highest blood concentrations observed in patients of the NYHA class III and IV. The extent of these changes was found more pronounced in the female patients. It is suggested that the calcium-regulating hormonal system is involved in the pathogenesis of the ischaemic heart disease; however the sharp increase of PTH and PTHrP at the severe stages of pathology may play a compensatory role in maintaining the heart function.