Dinucleotide cap analogue affinity resins for purification of proteins that specifically recognize the 5' end of mRNA

Here we present first dinucleotide affinity resins for purification of proteins that specifically recognize the 5' end of mRNA. Constructed resins possess either a naturally occurring mono- or trimethylated cap or their analogues resistant towards enzymatic degradation, bearing a CH(2) bridge between β and γ position of the 5',5'-triphosphate chain. All cap analogues were attached to a polymer support (EAH-Sepharose) through the carboxylic group that had been generated by derivatization of the 2',3'-cis diol of the second nucleotide in the cap structure with levulinic acid.     

Pharmacokinetics of Repeated Sodium Salicylate Administration to Laying Hens: Evidence for Time Dependent Increase in Drug Elimination from Plasma and Eggs

Salicylates were the first non-steroid anti-inflammatory drugs (NSAIDs) to be used in any species and are still widely used in humans and livestock. However, the data on their pharmacokinetics in animals is limited, especially after repeated administration. Evidence exist that in chickens (Gallus gallus) salicylate (SA) may induce its own elimination. The aim of this study was to investigate salicylate pharmacokinetics and egg residues during repeated administration of sodium salicylate (SS) to laying hens. Pharmacokinetics of SA was assessed during 14 d oral administration of SS at daily doses of 50 mg/kg and 200 mg/kg body weight to laying hens. On the 1^st, 7^th and 14^th d a 24 h-long pharmacokinetic study was carried out, whereas eggs were collected daily. Salicylate concentrations in plasma and eggs were determined using high-performance liquid chromatography with ultraviolet detection and pharmacokinetic variables were calculated using a non-compartmental model. Mean residence time (MRT), minimal plasma concentration (C_min, C_16h) and elimination half-life (T_1/2el) of SA showed gradual decrease in layers administered with a lower dose. Total body clearance (Cl_B) increased. Layers administered with the higher dose showed a decrease only in the T_1/2el. In the low dose group, SA was found only in the egg white and was low throughout the experiment. Egg whites from the higher dose group showed initially high SA levels which significantly decreased during the experiment. Yolk SA levels were lower and showed longer periods of accumulation and elimination. Repeated administration of SS induces SA elimination, although this effect may differ depending on the dose and production type of a chicken. Decreased plasma drug concentration may have clinical implications during prolonged SS treatment.     

Dual pro-drugs of 2'-C-methyl guanosine monophosphate as potent and selective inhibitors of hepatitis C virus

We have previously reported the power of combining a 5'-phosphoramidate ProTide, phosphate pro-drug, motif with a 6-methoxy purine pro-drug entity to generate highly potent anti-HCV agents, leading to agents in clinical trial. We herein extend this work with the disclosure that a variety of alternative 6-substituents are tolerated. Several compounds exceed the potency of the prior 6-methoxy leads, and in almost every case the ProTide is several orders of magnitude more potent than the parent nucleoside. We also demonstrate that these agents act as pro-drugs of 2'-C-methyl guanosine monophosphate. We have also reported the novel use of hepatocyte cell lysate as an ex vivo model for ProTide metabolism.     

Lepidopteran species richness of alpine sites in the High Sudetes Mts.: effect of area and isolation

Alpine sites in the High Sudetes Mts. host—due to their history and special climatic conditions—unique assemblages of lepidopteran species. We used data from ten of these sites to study species richness of the lepidopteran fauna and to test the effect of site area, distance to the nearest site and connectivity. For this, we used cluster analyses, species–area relationship and the incidence function model, followed by canonical analysis to test the importance of individual factors. The list of species was compiled from available literature sources with regard to recent findings. Species richness depended significantly on all geographic factors—area, distance and connectivity. Large alpine sites were more species-rich than smaller ones and remote sites differed in species composition from the others. We conclude that any decrease of the area of these sites will drastically affect the unique lepidopteran assemblages living in the High Sudetes Mts.